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1
Kornakov, V. "Problems of legislative regulation of the crime recurrence and measures of its warning." Bulletin of Science and Practice 4, no. 6 (2018): 296–303. https://doi.org/10.5281/zenodo.1289986.
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Some issues concerning the problems of legislative regulation of recidivism in Russian criminal law are considered. The author comes to the conclusion that the construction of the article of the Criminal Code of the Russian Federation is not perfect and requires some additions. The need to legislatively fix the provision that conditional conviction and delay should be taken into account in the recognition of a relapse if they were abolished, but the person shied away from serving a prison sentence. In addition, the article addresses the issue of preventing recidivism and conviction as an indispensable feature of professional crime. In addition, measures to prevent recidivism are proposed, as well as suggestions for improving existing criminal legislation.
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Шляпникова, Ольга, Olga Shlyapnikova, Николай Паршин, and Nikolay Parshin. "Specially-criminological prevention of the sexual crimes made against minors." Vestnik of the St. Petersburg University of the Ministry of Internal Affairs of Russia 2019, no. 3 (2019): 111–17. http://dx.doi.org/10.35750/2071-8284-2019-3-111-117.
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Sexual encroachments on sexual inviolability and sexual freedom of the persons who have not reached their majority age are one of the most topical and acute problems of the Russian society as for as the deformation of physical and mental development of the minors and juveniles threatens to the nation’s health. For the last few years it is observed a considerable growth of crimes concerning the minors made on sexual ground. The considerable share of crimes against the sexual inviolability and sexual freedom of the minors is characterized by the criminological relapse emphasizing the imperfection of the criminal legal legislation, and also an inefficiency of the preventive measures from law enforcement bodies. The questions of crimes prevention in any democratic state are one of priority nation-wide directions, that represents multi-level and aspect activity of the various state structures and civil institutions, directed on hindrance of committing crimes. In the article the authors offer some measures on enhancement of specially-criminological prevention of the sexual crimes made against the minors. The special attention is given to revealing of the facts of sexual violence over the minors by means of psycho diagnostics, to the officers’ training to methods of work with the minors taking into account the social-demographic features of children paying attention to age groups and difference of posttraumatic experiences from age features. The authors also pay a special attention that the results in decreasing the level of sexual criminality can be reached only after the considerable period of time at the regular and complex approach in the decision of problems not only the sexual violence, but also the violence as that.
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Derish, Melinda T., and Kathleen Vanden Heuvel. "Mature Minors Should Have the Right to Refuse Life-Sustaining Medical Treatment." Journal of Law, Medicine & Ethics 28, no. 2 (2000): 109–24. http://dx.doi.org/10.1111/j.1748-720x.2000.tb00001.x.
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Imagine that you are a teenager and have cancer. You undergo a year of chemotherapy and after a brief return to normal life, you have a relapse. Your physician says that chemotherapy and radiation therapy could be tried, but a bone marrow transplant (BMT) is your only chance of a real cure. He tells you and your parents that you could die as a result of complications from the transplant, but without it you would only be expected to live one year. You and your family discuss the alternatives and decide to have the transplant. You ask what will happen if the BMT fails, but both your physician and your family tell you that right now you must fight to get better and not think negative thoughts. You do not ask any more questions.
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Milyukov, Sergey, and Nina Skripchenko. "Strengthening Criminal Repressions for Sexual Assaults: Regulatory Vision and Prospective Law Enforcement." Russian Journal of Criminology 16, no. 5 (2022): 580–89. http://dx.doi.org/10.17150/2500-4255.2022.16(5).580-589.
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In view of the permanent reforms of criminal law norms protecting sexual inviolability that are aimed at the penalization and differentiation of criminal liability for sexual assaults against minors, the authors conduct a comprehensive analysis of amendments to the Criminal Code of the Russian Federation by laws of January 28, 2022 № 3-FZ and of March 6, 2022 № 38-FZ. They note a new round of strengthening penal prosecution for pedophilic assaults and point out technical and legal drawbacks in the new norms, expressing doubts regarding their criminological validity. By widening the special qualifying features of such crimes as rape and sexual assault, the legislators set stricter punishments for assaults against sexual inviolability than for aggravated types of homicide. The authors analyze the contents of Part 5, Art. 131 and 132 of the Criminal Code of the Russian Federation in its new edition and point out difficulties that could arise during the qualification of sexual assaults committed against two or more minors or associated with committing another grave or very grave crime against a person, as well as in cases of special relapse. They present a critical assessment of Part 3, Art. 133 of the Criminal Code of the Russian Federation and raise the questions of the validity of strengthening criminal liability for group coercion to sexual actions only against minors (clause «a»), and the feasibility of including «the use of mass media» in the characteristics that increase the public danger of harassment. It is noted that the criminalization of the concealment of grave crimes against minors makes the law enforcers face the problem of the admissibility of incriminating a set of crimes included in Parts 1 and 2, Art. 316 of the Criminal Code in cases when the concealed crimes against minors belong to different categories but have a common intent.
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Gartvik, E. V., and V. S. Krasnik. "Experience in combining rehabilitation and rehabilitation approaches in the work on the prevention of recidivism among minors in the work of the court." Psychology and Law 8, no. 4 (2018): 4–19. http://dx.doi.org/10.17759/psylaw.2018080402.
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The article deals with the experience of the Kalininsky District Court of Chelyabinsk on the prevention of juvenile delinquency. It is noted that for effective prevention of relapse among juvenile offenders it is not enough only to confess guilt, to apologize to the victim, to compensate for the damage caused. Prevention of juvenile delinquency should be a complex system of interacting services and departments, as well as forms and methods of work aimed at: identifying and neutralizing adverse social conditions that adversely affect the adolescent's psyche; identification of adolescents falling into "risk groups", carrying out preventive and corrective work with them. A complex of preventive measures implemented in the practice of the court is of a combined nature. Restorative procedures are applied in the form of mediation, which is aimed at restoring the situation, admission of guilt by the person guilty of forming a readiness to make amends for the harm done and "cure" the victim. For the psychological rehabilitation of the offender, we use a rehabilitation approach. More than 90% of the examined minors whose criminal records were referred to the court had a mental trauma caused by the loss of one of the parents (divorce or death of one of them). Procedures for rehabilitation are in the work with child psychic trauma, which, violating the integrity of the "personality-subject" system, is a predictor of criminal behavior. As a result, for the period from 2015 to 2017. among minors who have gone through the mediation and therapy of child psychiatric trauma, to date, there has not been a single case of relapse.
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Yerlikaya Oral, E., and M. Tekden. "Involuntary Psychiatric Hospitalization of Minors Due to Court Orders: Effectiveness Assessing Through a Case Series." European Psychiatry 67, S1 (2024): S92—S93. http://dx.doi.org/10.1192/j.eurpsy.2024.232.
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IntroductionInvoluntary treatments in forensic psychiatry represents a complex intersection of mental health, legal systems and ethics. Judicial authorities may compulsorily refer children to inpatient clinics for receiving necessarily treatment. Despite its importance, there is limited research on the reasons behind and effectiveness of such interventions in minors.ObjectivesThe objectives of this study were to describe the clinical characteristics of minors who have risks of harming themselves and/or others so receiving involuntary treatment due to a court order. It is aimed to assess the effectiveness of involuntary treatment.MethodsA follow-up case series was conducted on 9 minors who hospitalized by court orders in a secure inpatient child and adolescent psychiatry clinic, in the year of 2023. Data collected from medical records, including demographic information, clinical presentation, diagnosis and discharge treatment. After one, three and six month of the discharge, interviews made with the patients and their families. Current data collected on treatment regimen, compliance, behavioral outcomes and reoffending rates. All data were anonymized to maintain patient confidentiality.ResultsThe case series consisted of 3 males and 6 females, with a mean age of 16.5 years at the time of admission. The most common reason to hospitalization was homicide risk 88%, followed by substance use 66%. Conduct Disorder was the most common diagnosis with the rate of 88%, followed by Substance Use Disorder(66%) and Attention Deficit and Hiperactivity Disorder(50%). 44% of minors had a history of juvenile delinquency. School dropout rates were 100%. Treatment consisted of a combination of individual and group therapy and medication. Treatment refusal rates were 88% so in terms of treatment, 88% of the minors in this sample treated with depot form antipsychotic medications, with the most common medication being risperidone. Overall all of the sample showed a significant reduction in disruptive behaviors during their hospital stay. Follow-up data collecting is still continue and preliminary statistics show us that relapse rates are low and treatment compliance is relatively high of the sample.ConclusionsThe findings suggest that involuntary hospitalization can be effective in reducing disruptive behaviors and increasing treatment compliance in minors with conduct disorders, substance abuse disorders and a history of juvenile delinquency. These results underscore the need for comprehensive, multidisciplinary approaches that integrate psychiatric treatment, psychoeducation and social support. Given the relatively small sample size and short-term follow-up, further research is needed to determine the long-term effects of involuntary treatment and to identify factors that predict treatment response.Disclosure of InterestNone Declared
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Qu, Min, Jing Zhou, Song-Jun Yang, and Ze-Ping Zhou. "Efficacy and safety of rituximab for minors with immune thrombocytopenia: a systematic review and meta-analysis." Journal of International Medical Research 48, no. 10 (2020): 030006052096234. http://dx.doi.org/10.1177/0300060520962348.
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Objective We reviewed relevant research on rituximab (RTX) treatment for pediatric immune thrombocytopenia (ITP) to elucidate the efficacy and safety of RTX. Methods Prospective clinical trials of RTX for the treatment of pediatric ITP were collected by searching the PubMed, Cochrane Library, Web of Science, and OVID: EMBASE databases and ClinicalTrials.gov. We examined rates of overall response (OR), complete response (CR), partial response (PR), sustained response (SR), relapse (R), and adverse drug reaction (ADR). The Methodological Index for Nonrandomized Studies scale was used, and sensitivity analyses were performed. Results For five studies, including 100 patients, the pooled OR, CR, PR, SR, R, and ADR rates were 52% (95% CI: 0.36–0.77, I2 = 78%), 52% (95% CI: 0.41–0.67, I2 = 45%), 18% (95% CI: 0.10–0.33, I2 = 33%), 43% (95% CI: 0.29–0.63, I2 = 0%), 25% (95% CI: 0.06–0.96, I2 = 52%), and 30% (95% CI: 0.15–0.58, I2 = 64%), respectively. Conclusion There is evidence, albeit low quality, that RTX may be a better second-line therapy than splenectomy for children with ITP; however, its efficacy and safety need to be validated by further high-quality clinical trials, such as randomized controlled trials.
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Skripchenko, N. Yu. "Strengthening Criminal Repression for Criminal Assaults on Minors: Is It One More Step in Implementation of the Strategy or Irrational Regulatory Activity?" Lex Russica 75, no. 10 (2022): 105–12. http://dx.doi.org/10.17803/1729-5920.2022.191.10.105-112.
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The paper contains a comprehensive analysis of the amendments made to the Criminal Code of the Russian Federation by Federal Laws No. 3-FZ dated January 28, 2022 and No. 38-FZ dated March 06, 2022. Noting the next round of strengthening criminal repression for pedophile assaults, the author draws attention to the legislative bias in assessing the public danger of acts, since rape or violent sexual acts committed against two or more minors are punished more severely than the murder of these victims. Having identified technical and legal flaws in the content of Part 5 of Articles 131 and 132 of the Criminal Code of the Russian Federation, the author identifies issues that may arise when qualifying violent sexual crimes committed against two or more minors; involving the commission of another grave or especially grave crime against the person; with a special relapse. Critically assessing the content of Part 3 of Article 133 of the Criminal Code of the Russian Federation, the author raises the question of the validity of strengthening criminal liability for group coercion to sexual acts only against minors (paragraph «a«); attribution of «use of mass media» to the number of signs that increase the public danger of harassment. The author pays special attention to one of the obvious defects of the norms of Chapter 18 of the Criminal Code of the Russian Federation, which violate the principles of equality and justice, namely, the normative separation according to the degree of public danger of sexual intercourse and sodomy or lesbianism with a person under the age of 16, which does not correspond to the principle of gender equality. The conducted legal analysis testifies not to the consistent normative implementation of the strategic course, but to the spontaneity of decisions aimed at solving particular problems.
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Pantyuhina, Inga V. "Critical assessment of new particularly qualifying signs of crimes against sexual inviolability of minors (Part 5 of Articles 131, 132 and Part 3 of Article 133 of the Criminal Code of the Russian Federation)." Yugra State University Bulletin 18, no. 4 (2023): 25–32. http://dx.doi.org/10.18822/byusu20220425-32.
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Subject of research: the particularly qualifying signs of violent sexual crimes included in Articles 131, 132 and 133 of the Criminal Code of the Russian Federation in 2022, which are aimed at protecting the sexual integrity of minors.
 Purpose of research: to analyze the content of new particularly qualifying signs of sexual crimes, their consistency with each other, validity and necessity of inclusion in the Criminal Code of the Russian Federation.
 Methods and objects of research: the work uses the general scientific dialectical method of cognition and private scientific methods, such as analysis, linguistic, comparative legal, statistical, formal and logical. The method of analysis was used in the study of the content of particularly qualifying signs of sexual crimes. Linguistic when interpreting the wording of the norm provided for in Part 5 of Articles 131 and 132 of the Criminal Code of the Russian Federation. Comparative legal when comparing the content of the sign of a special relapse contained in Articles 131 and 132 of the Criminal Code of the Russian Federation and in Articles 134 and 135 of the Criminal Code of the Russian Federation. Statistical when processing indicators about the number of convicts for forcing minors to sexual acts. Formal-logical in the disclosure of concepts and categories used in the formulations of the investigated signs of crimes and the presentation of proposals to change the design of Part 5 of Articles 131 and 132 of the Criminal Code of the Russian Federation.
 Main results of research: based on the analysis of the content of the signs regulated in Part 5 of Articles 131 and 132 and Part 3 of Article 133 of the Criminal Code of the Russian Federation, the author identified technical and substantive flaws in their designs, inconsistency of some of the new signs with similar signs of other sexual crimes against minors. To eliminate the identified shortcomings of the studied norms, it is necessary to replace the wording of Part 5 of Articles 131 and 132 of the Criminal Code of the Russian Federation with an indication in it of an act committed against a minor, without references to other parts of these articles, from paragraph "b" " the same part of these articles should exclude an indication of a minor victim, from paragraph "c" remove the indication of the type of crimes against the person. In Part 3 of Article 133 of the Criminal Code of the Russian Federation, it is necessary to exclude the signs provided for in paragraphs "a" and "b", and in Part 6 of Article 134 and Part 5 of Article 135 of the Criminal Code of the Russian Federation, increased responsibility for the special recidivism of crimes established in them should be extended to all victims of these crimes.
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Yaya Castañeda, Elena Esther, Victor Hugo Ucedo Silva, and Carlos Lopez Villavicencio. "Habilidades sociales asociados a los procesos de cambio en niños y adolescentes consumidores de sustancias psicoactivas de una comunidad terapéutica de Lima." PsiqueMag 14, no. 1 (2025): 163–79. https://doi.org/10.18050/psiquemag.v14i1.3384.
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The consumption of psychoactive substances in children and adolescents has increased in recent years, with a worrying age of onset between 11 and 14 years in Peru. Therapeutic communities have played a fundamental role in the intervention of these cases, providing treatment and social support to minors in vulnerable situations. In this context, the development of social skills has been identified as a crucial factor for rehabilitation and relapse prevention. Social skills, such as communication, empathy and conflict resolution, play a key role in the processes of change related to substance use. Previous research has shown that strengthening these skills significantly reduces the risk of consumption and facilitates social integration. The present research, based on data from 113 children and adolescents in treatment in a therapeutic community in Lima, analyzes the relationship between social skills and the phases of change according to the Prochaska and DiClemente model. The results showed a significant association between social skills and the process of change (p < 0.05). It was identified that 62% of the participants were in the precontemplation phase, presenting high levels of social anxiety and withdrawal. In adolescents, the correlation between social skills and change was more marked (χ² = 4.87, p < 0.01) than in children, suggesting that psychosocial maturation plays a key role in the transition to abstinence. These findings reinforce the need for interventions aimed at strengthening social skills as a strategy for rehabilitation and prevention of drug use in minors.
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Marinescu, Elena-Cristina, Horia Bumbea, Iuliana Iordan, et al. "The Philadelphia Chromosome, from Negative to Positive: A Case Report of Relapsed Acute Lymphoblastic Leukemia following Allogeneic Stem Cell Transplantation." Medicina 59, no. 4 (2023): 671. http://dx.doi.org/10.3390/medicina59040671.
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Relapsed acute lymphoblastic leukemia (ALL) represents a continuous challenge for the clinician. Despite recent advances in treatment, the risk of relapse remains significant. The clinical, biological, cytogenetic, and molecular characteristics may be different at the time of relapse. Current comprehensive genome sequencing studies suggest that most relapsed patients, especially those with late relapses, acquire new genetic abnormalities, usually within a minor clone that emerges after ALL diagnosis. We report the case of a 23-year-old young woman diagnosed with Philadelphia chromosome-negative B cell acute lymphoblastic leukemia. The patient underwent allogeneic stem cell transplantation (allo-HSCT) after complete remission. Despite having favorable prognostic factors at diagnosis, the disease relapsed early after allo-HSCT. The cytogenetic and molecular exams at relapse were positive for the Philadelphia chromosome, respectively for the Bcr-Abl transcript. What exactly led to the recurrence of this disease in a more aggressive cytogenetic and molecular form, although there were no predictive elements at diagnosis?
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Mensch, Noemi, Andrea Katharina Hemmig, Markus Aschwanden, et al. "Rapid glucocorticoid tapering regimen in patients with giant cell arteritis: a single centre cohort study." RMD Open 9, no. 3 (2023): e003301. http://dx.doi.org/10.1136/rmdopen-2023-003301.
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ObjectivesWe evaluated the feasibility of a rapid glucocorticoid tapering regimen to reduce glucocorticoid exposure in patients with giant cell arteritis (GCA) treated with glucocorticoids only.MethodsNewly diagnosed patients with GCA treated with a planned 26-week glucocorticoid tapering regimen at the University Hospital Basel were included. Data on relapses, cumulative steroid doses (CSD) and therapy-related adverse effects were collected from patients’ records.ResultsOf 47 patients (64% women, median age 72 years), 32 patients (68%) had relapsed. Most relapses were minor (28/32) and 2/3 of those were isolated increased inflammatory markers (19/32). Among major relapses, one resulted in permanent vision loss. The median time until relapse was 99 days (IQR 71–127) and median glucocorticoid dose at relapse was 8 mg (IQR 5–16). Nine of 47 patients stopped glucocorticoids after a median duration of 35 weeks and did not relapse within 1 year. Median CSD at 12 months was 4164 mg which is lower compared with published data. Glucocorticoid-associated adverse effects occurred in 40% of patients, most frequently were new onset or worsening hypertension (19%), diabetes (11%) and severe infections (11%).ConclusionWe could demonstrate that 32% of patients remained relapse-free and 19% off glucocorticoids at 1 year after treatment with a rapid glucocorticoid tapering regimen. Most relapses were minor and could be handled with temporarily increased glucocorticoid doses. Consequently, the CSD at 12 months was much lower than reported in published cohorts. Thus, further reducing treatment-associated damage in patients with GCA by decreasing CSD seems to be possible.
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KÄLSCH, ANNA-ISABELLE, ELENA CSERNOK, DOMINIK MÜNCH, et al. "Use of Highly Sensitive C-Reactive Protein for Followup of Wegener’s Granulomatosis." Journal of Rheumatology 37, no. 11 (2010): 2319–25. http://dx.doi.org/10.3899/jrheum.100302.
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Objective.Since Wegener’s granulomatosis (WG) represents a relapsing disease, efforts have been made to reliably predict relapses using blood tests. Followup measures such as conventionally determined C-reactive protein (CRP), antineutrophil cytoplasmic antibody (C-ANCA) titer, and proteinase-3 (PR3) ELISA are applied. We evaluated whether during remission elevated highly sensitive CRP (hsCRP) precedes relapse as a marker of subclinical inflammation and thus might improve clinical assessment.Methods.We investigated 227 sera of 57 patients with WG: 74 sera collected from patients in remission who subsequently relapsed (before relapse), 30 sera collected during relapse, and 123 sera from patients in remission without relapse. We also distinguished between major and minor relapse. hsCRP, conventionally determined CRP (CRP), C-ANCA, PR3-ELISA, and erythrocyte sedimentation rate (ESR) were measured using commercial kits, and levels were correlated to clinical status.Results.Only hsCRP and ANCA titer, but not CRP levels, were higher in sera from patients who subsequently relapsed versus those who did not, indicating patients at risk. Levels of hsCRP, CRP, and ESR were higher in sera collected during relapse than in the sera before relapse. hsCRP, conventional CRP, and ESR were also higher in samples collected during major relapse than before major relapse. Looking at the levels just before relapse compared to previous levels during remission, none of these measures rose directly before the clinical manifestation of the relapse.Conclusion.Our study provides evidence for an additional value of hsCRP in the clinical assessment of patients with WG.
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Demidova, L. Y. "The Role of Cognitive Distortions in Maintaining the Pattern of Sexual Violence." Современная зарубежная психология 12, no. 1 (2023): 89–99. http://dx.doi.org/10.17759/jmfp.2023120110.
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<p style="text-align: justify;">Distorted judgments supporting commitment of criminal sexual acts are widely used in persons with abnormal sexual behavior and considered by foreign researchers as one of the dynamic risk factors of relapse of sexual crimes against minors. The submitted article is an analytical review of the main foreign research papers on the problem of cognitive distortions in sexual offenders. Various attempts to conceptualize and categorize cognitive distortions are presented with their theoretical and empirical verification, structural characteristics and some features of the development of such distorted judgements. The self-report questionnaires are mainly used in foreign studies of cognitive distortions, also samples of sexual offenders are studied include both persons with sexual disorders and situational offenders. The article shows the necessity of distinguishing between prior and posterior cognitive distortions, as well as self-justification inherent in human nature and distorted judgements that contribute to the commission of criminal acts. It has been suggested that the assessment of cognitive distortions should be carried out not only by unified questionnaires, but using a phenomenological analysis of situational behavior and a retrospective analysis of criminal&rsquo;s beliefs before the latter committed the incriminated act.</p>
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Jan, Max, Matthew J. Leventhal, Elizabeth A. Morgan, et al. "Recurrent genetic HLA loss in AML relapsed after matched unrelated allogeneic hematopoietic cell transplantation." Blood Advances 3, no. 14 (2019): 2199–204. http://dx.doi.org/10.1182/bloodadvances.2019000445.
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Abstract Immune evasion is a hallmark of cancer and a central mechanism underlying acquired resistance to immune therapy. In allogeneic hematopoietic cell transplantation (alloHCT), late relapses can arise after prolonged alloreactive T-cell control, but the molecular mechanisms of immune escape remain unclear. To identify mechanisms of immune evasion, we performed a genetic analysis of serial samples from 25 patients with myeloid malignancies who relapsed ≥1 year after alloHCT. Using targeted sequencing and microarray analysis to determine HLA allele-specific copy number, we identified copy-neutral loss of heterozygosity events and focal deletions spanning class 1 HLA genes in 2 of 12 recipients of matched unrelated-donor HCT and in 1 of 4 recipients of mismatched unrelated-donor HCT. Relapsed clones, although highly related to their antecedent pretransplantation malignancies, frequently acquired additional mutations in transcription factors and mitogenic signaling genes. Previously, the study of relapse after haploidentical HCT established the paradigm of immune evasion via loss of mismatched HLA. Here, in the context of matched unrelated-donor HCT, HLA loss provides genetic evidence that allogeneic immune recognition may be mediated by minor histocompatibility antigens and suggests opportunities for novel immunologic approaches for relapse prevention.
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Antic, Zeljko, Jiangyan Yu, Simon V. van Reijmersdal, et al. "Genomic Architecture and Clonal Dynamics of Early Relapsed BCP-ALL." Blood 128, no. 22 (2016): 4072. http://dx.doi.org/10.1182/blood.v128.22.4072.4072.
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Abstract Relapse represents the most common cause of therapy failure in B-cell precursor ALL acute lymphoblastic leukemia (BCP-ALL), and is caused by selective outgrowth of therapy-resistant leukemic cells. Two-third of BCP-ALL relapses present after treatment, i.e. after two years. These relapses may originate from leukemic (sub)clones that remained in a quiescent state during treatment or that could not be reached by the chemotherapeutics. Relapses that occur during treatment are different in that they display clonal outgrowth in the presence of chemotherapeutics, and these patients have poorer outcomes. The aim of this study is to explore the genomic abnormalities in leukemia with early relapse, and investigate the clonal dynamics of relapses that arise during treatment. We included 17 BCP-ALL cases which relapse during treatment (<2yrs) according to DCOG protocols ALL9, ALL10 or ALL11. Median remission time was 1.08 yrs (range 0.48-1.95). Whole exome sequencing was performed on DNA isolated at time of first diagnosis, complete remission and relapse from bone marrow or peripheral blood, with an average read depth on target of 108x. After mapping of the reads, variants were called using HaplotypeCaller. In total, we identified 1771 somatic mutations in 1562 genes. Per case, a median of 21 mutations were detected at diagnosis (range 10-630) and 31 at relapse (range 10-652). A hypermutation profile was observed in one diagnosis-relapse pair, and two additional relapses. All cases harbored mutations shared between diagnosis and relapse, which were mostly part of the major clone at both time points. However, the fraction of shared mutations varied considerably between cases, ranging from <10% in 3 cases to >80% in 4 cases. Based on the clonal dynamics, 3 distinct groups were recognized. Group I includes two cases, with relapses within 6 months, in which the (sub)clonal mutation spectrum between diagnosis and relapse was identical. Group II (n=10) presented with a relapse closely resembling the major clone at diagnosis. Mostly, these relapses acquired new mutations and they often branched off from the major clone already before the time of diagnosis. Finally, Group III (n=5) consists of cases in which the relapse originates from a minor subclone at diagnosis that hardly resembled the major clone, suggesting a clonal switch during treatment. Next, we analyzed the genes with mutations that were predicted to be damaging (truncating and non-synonymous conserved missense variants). We performed pathway analysis for these genes and identified RAS pathway genes to be frequently mutated among shared mutations, while mutations in genes involved in epigenetic regulation, chromatin condensation and regulation of transcription were acquired. In total, 7 of the genes with (predicted) pathogenic mutations in relapse were affected in at least two cases, including known genes like KRAS, CREBBP, and WHSC1 (NSD2). CREBBP mutations were never part of the major clone at diagnosis and were present in cases with numerical chromosomal aberrations. Both cases with hotspot E1099K mutation in WHSC1 were t(1;19) translocation-positive. Recent studies showed that somatic mutational signatures, composed of the six substitution subtypes in a 3-nucleotide context, expose specific biological processes underlying tumor development, including defects in genomic maintenance and repair. Currently 30 mutational signatures have been described [http://cancer.sanger.ac.uk/cosmic/signatures]. Despite the low number of mutations in most samples, we identified at least 5 of these signatures, including the most common signature 1, a signature associated with aberrant AID/APOBEC activity (signature 2), and three signatures associated with mismatch repair deficiency (6, 15, 26). Most cases carried multiple signatures, but signature 2 was very prominent is one relapse and one diagnosis-relapse pair. Most signatures were preserved from diagnosis to relapse suggesting that the same mutational processes remained active. Taken together, our results show considerable heterogeneity in the group of children with early relapse of BCP-ALL. Two cases with the shortest remission times relapsed without notifiable somatic changes, whereas most other early relapses appeared to arise from minor or newly appearing subclones. These findings demonstrate the strong clonal selection that occurs during treatment in cases with very early relapse. Disclosures No relevant conflicts of interest to declare.
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Fitch, K., C. Bazell, S. Metz, and I. Von Hennigs. "POS0835 RELAPSE RATES IN NEWLY DIAGNOSED AND ESTABLISHED PATIENTS WITH ANTI-NEUTROPHIL CYTOPLASMIC AUTOANTIBODY (ANCA)-ASSOCIATED VASCULITIS." Annals of the Rheumatic Diseases 81, Suppl 1 (2022): 708.2–709. http://dx.doi.org/10.1136/annrheumdis-2022-eular.4243.
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BackgroundAnti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis is a life- or organ-threatening condition in which patients experience severe inflammation of small- to medium-sized blood vessels. Clinical relapses are common in ANCA-associated vasculitis and previously reported rates vary between 21-89% at 5 years depending on the regimens used for induction and maintenance (1). Relapses require repeated treatment with immunosuppressive therapy and increase the risks of adverse events.ObjectivesIdentify the incidence of relapse in newly diagnosed and established granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) patients in commercially insured and Medicare fee-for-service (FFS) populations.MethodsUsing the 2016-2019 Milliman proprietary commercial claims data and Medicare 100% FFS Innovator Research data, newly diagnosed and established GPA and MPA patients were identified in index years 2017 and 2018. Newly diagnosed patients were identified as those with at least two qualifying claims on different dates of service, coded with a GPA or MPA ICD-10-CM code, and no claim coded with GPA or MPA in the 12 months prior to their first claim. Established patients required 12-months continuous enrollment in the year of their established status and 12-months continuous enrollment in the year prior to their established status. Relapses for incident patients were identified during the 7 to 12 months after the index date for newly diagnosed patients to avoid mischaracterizing claims around the time of the initial diagnosis as relapses and over a 12-month period for the established patients.Relapse was defined based on specific inpatient and outpatient claims with a GPA or MPA diagnosis code or claims coded with one major or at least three minor vasculitis signs or symptoms followed by a claim within 30 days for plasmapheresis or cyclophosphamide or glucocorticoids (> 20 mg prednisolone equivalent) or 2+ rituximab claims within 30 days of each other. Relapse had to occur 30 days after the previous event and 6 months after index date for incident patients.Results542 (GPA) and 83 (MPA) commercially insured newly diagnosed patients with 12 months eligibility following their index date and 1,748 (GPA) and 184 (MPA) commercially insured established patients were identified. 15.5% (GPA) and 15.7% (MPA) newly diagnosed patients relapsed during months 7-12 after diagnosis and 27.9% (GPA) and 29.3% (MPA) established patients relapsed over a 12-month period.2,397 (GPA) and 655 (MPA) Medicare FFS newly diagnosed patients with 12 months of eligibility following their index date and 5,955 (GPA) and 833 (MPA) Medicare FFS established patients were identified. 19.3% (GPA) and 27.2% (MPA) newly diagnosed patients relapsed during months 7-12 after diagnosis and 33.5% (GPA) and 40.2% (MPA) established patients relapsed over a 12-month period.ConclusionUsing administrative healthcare claims, we observed relapse rates after GPA and MPA diagnosis ranging between 15.5-27.2% in months 7-12 after diagnosis for newly diagnosed patients and between 27.9-40.2% over a 12-month period for established patients. There is an unmet need for new therapies that sustain remission and decrease relapse rates in patients with ANCA-associated vasculitis. This is an important clinical strategy to reduce the risks of adverse events from long-term immunosuppression therapy and decrease end-organ damage.References[1]Salama AD. Relapse in Anti-Neutrophil Cytoplasm Antibody (ANCA)-Associated Vasculitis. Kidney Int Rep. 2019;5(1):7-12.Disclosure of InterestsKate Fitch Consultant of: ChemoCentryx, Carol Bazell Consultant of: ChemoCentryx, Steven Metz Consultant of: ChemoCentryx, Irene von Hennigs Shareholder of: ChemoCentryx, Consultant of: ChemoCentryx, Employee of: ChemoCentryx
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Fagius, J., J. Lundgren, and G. Öberg. "Early highly aggressive MS successfully treated by hematopoietic stem cell transplantation." Multiple Sclerosis Journal 15, no. 2 (2008): 229–37. http://dx.doi.org/10.1177/1352458508096875.
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Background During the last 15 years, high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HSCT) has globally been performed for severe multiple sclerosis (MS). Most patients have been in progressive phase with long disease duration. As a rule, treatment effect has been minor or moderate. Patients Since 2004, we have performed HSCT in nine young patients with “malignant” relapsing–remitting MS. Criteria for treatment were short duration of disease; very frequent, severe relapses; recent improvement periods indicating potential for recovery after strong immunosuppression. Findings Median age at treatment was 27 (range 9–34) years, MS duration 26 (4–100) months, and annualized relapse rate 10 (4–12). Median Disability Status Scale (extended disability status scale, EDSS) at HSCT was 7.0 (3.5–8.0). Median follow-up time April 2008 is 29 (23–47) months. Median EDSS improvement is 3.5 (1.0–7.0), clearly surpassing most previous reports. One patient relapsed mildly with rapid recovery 7 months after HSCT. All patients are otherwise stable, median EDSS being 2.0 (0–6.0). Before HSCT, 61 relapses occurred in 82 patient months; during follow-up, one relapse in 289 patient months. Conclusion This small series of patients with “malignant” relapsing–remitting MS suggests HSCT to be an effective treatment option for this relatively rare disease course. It further suggests that future criteria for HSCT in MS should be close to the present ones.
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Hernandez, Kevin, Tauseef Ahmed, Delong Liu, Karen Seiter, and Amir Steinberg. "Equity and Resource Allocation: The Case for Allogeneic Transplant in Emergency Medicaid Patients." Blood 142, Supplement 1 (2023): 7349. http://dx.doi.org/10.1182/blood-2023-178225.
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Background:When an uninsured, undocumented immigrant presents with an emergency medical condition, they may qualify for Emergency Medicaid. Notably, the care and services related to HSCT are not covered, except in California and Washington state. Therefore, many patients with MRD-positive or relapsed ALL who may otherwise be good candidates for HSCT are unable to receive it. This may lead to months of resource-intensive treatment without the chance of cure. Here we present 3 such patients and their course of treatments and outcomes. Patient 1:A28-year-old male from Mexico was diagnosed with Ph+ B-ALL and treated with three cycles of hyper-CVAD + dasatinib. BCR-ABL PCR remained elevated at 27.9% and the patient was switched to nilotinib for 5 more cycles of hyper-CVAD; nilotinib was continued until later relapse. He began maintenance BCNU/cytoxan, then several cycles 6-MP/MTX/vincristine. On day +554 after diagnosis, he relapsed and started decitabine/venetoclax, then decadron + dasatinib, then MVP, followed by 3 cycles of inotuzumab. Later, he started blinatumomab on day +648, which was discontinued after 22 days due to increasing peripheral blasts. He then started SMILE, then CCE. As his condition worsened he was put on ponatinib, then asciminib before expiring on day +940. Patient 2: A37-year-old male from Mexico was diagnosed with CML and started on nilotinib. On day +212 he progressed to lymphoid blast phase CML with CNS involvement and received hyper-CVAD/dasatinib; was switched to nilotinib on cycle 4 due to concerns about pleural effusion while hospitalized for PNA. On day +447 he started blinatumomab + IT MTX + nilotinib. A brain MRI on day +544 suggested carcinomatous meningitis and he got 4 cycles RMVP. He then switched to ponatinib and HiDAC for 8 cycles despite continued ALL in CSF. He was admitted for worsening ALL-induced headache on day +1016 and imaging discovered multifocal pneumonia. He then had seizure-like activity consistent with metabolic encephalopathy and expired on day +1055. Patient 3: A28-year-old male from Ecuador was diagnosed with Ph+ mixed phenotype (B/myeloid) acute leukemia. The patient underwent leukapheresis and started HiDAC + mitoxantrone + etoposide + dasatinib. Subsequent bone marrow biopsy showed 1% blasts, with BCR-ABL PCR at 1.4%. He was admitted on day +170 with Ph+ B-ALL relapse and underwent leukapheresis + 2 cycles hyper-CVAD. On day +255 he began blinatumomab for 3 cycles. He continues to receive treatment for his B-ALL at this time. See table 1 below. Discussion: There is an increasing population of undocumented immigrants entering the United States and receiving treatment for ALL while on emergency Medicaid. It is important to understand the special considerations in this population, including the inability to have HSCT authorized as a treatment option. Studies comparing the costs of HSCT to chemotherapy have found that chemotherapy is cheaper at the expense of patient mortality. Therefore, HSCT's incremental cost-effectiveness ratio, measured as cost per quality-adjusted life years, may still be favorable. As our case series demonstrates, extensive resources including traditional chemotherapies, immunotherapies like blinatumumab, and targeted oral drugs, can further increase the costs relative to HSCT. Moreover, the National Bureau of Economic research has calculated that undocumented workers add about $45,000 per worker to the US GDP annually. Therefore, offering HSCT and allowing them to continue to work may be a reasonable financial option. Likewise, many undocumented adults are the parents of US citizen minors who would benefit economically from their survival. For consideration we will explore cost analysis to further elucidate the potential benefit of allowing coverage of HSCT.
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Тіточка, Тетяна. "Віктимолого-психологічна модель реабілітації неповнолітніх жертв сексуального насильства". Copernicus Political and Legal Studies 1, № 4 (2022): 55–62. http://dx.doi.org/10.15804/cpls.20224.06.
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The article examines the peculiarities of victimological and psychological rehabilitation of adolescents who suffered from sexual violence. Attention is drawn to the fact that statistical data and judicial practice show that the consequences of sexual violence against minors are often irreparable, especially if the child was not provided with timely help. It is indicated that sexual violence, in any case, is the so-called «trigger point» for counting the formation of psychological injuries, which in most cases lead to the emergence of a person, especially a minor, in a retrospective phenomenon, which consists in an episodic return to the event , which caused an injury. In this regard, the rehabilitation of such children should begin with establishing not only psychological and physiological determination, but also criminological and victimological conditions and background phenomena, which in symbiosis contributed to or facilitated the commission of sexual violence. As in the case of working with criminal offenders, as well as with victims, the creation of specific models of actual or potentially deviant behavior with the allocation of correlations with psychological and moral features of a person’s personality becomes especially relevant. Victimological prevention should always include identifying the basic conditions for the creation of deviant instructions that contributed to the adolescent getting into an unfavorable situation and working out possible ways to avoid it in retrospect. Any rehabilitation should begin with a balanced dialogue, which will give the child the opportunity in a favorable environment to work with a specialist on all aspects of a socially dangerous event and build a behavioral algorithm that will allow him to avoid victim relapse in the future. It was concluded that the main rehabilitation measures and means are: 1) creating a sense of security in the minor victim of sexual violence; 2) building a dialogue taking into account the characteristics of the child’s personality and the event of a criminal offense committed against him; 3) working out, if possible, the maximum number of trigger zones associated with a socially dangerous event; 4) adjusting the child to positive reframing; 5) prevention of repeated and secondary victimization; 6) closure of gestalts associated with episodes of sexual violence. Rehabilitation of such children should take place due to the consolidation of efforts of medical workers, teachers, psychologists, criminologists and victimologists.
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Yamashita, Yuka, Masashi Sanada, Kenichi Yoshida, et al. "Clonal Evolution in Relapsed Pediatric Acute Lymphoblastic Leukemia." Blood 126, no. 23 (2015): 1425. http://dx.doi.org/10.1182/blood.v126.23.1425.1425.
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Abstract Introduction Clinical outcome of relapsed pediatric B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) remains poor, although survival rate for children with BCP-ALL has greatly increased over time and is now reached 90%. To clarify the molecular pathogenesis of relapsed ALL may provide novel prognostic markers and therapeutic targets. Some genome-wide analyses for specific patients group with poor prognosis, such as early-relapsed patients and Ph- or BCR-ABL-like patients, were reported. They described important insights to understand genetic background of poor prognosis. However, the majority of relapsed cases did not have any poor prognostic marker, and the molecular mechanisms of relapse in these cases still remained unclear. Therefore we performed whole exome sequencing (WES) to describe clonal evolution in 21 relapsed pediatric BCP-ALL patients. Our cohort included various cases whose time to relapse from diagnosis were between 6 months to over 10 years. We also analyzed the clonality of leukemia cells using immunoglobulin (Ig) and T-cell receptor (TCR) rearrangements. Patients and Methods Genomic DNA was isolated from 21 cases whose median time to relapse was 33 months. Somatic mutations including SNVs (single nucleotide variants), insertions / deletions and CNVs (copy number variants) were detected by WES using Agilent SureSelect and illumine HiSeq systems. To evaluate accurate VAF (valiant allele frequency), targeted deep sequencing was performed in candidate somatic mutations. The clonality analysis of leukemia cells was performed by standard PCR methods using Ig and TCR rearrangements. Results WES was performed in samples obtained at diagnosis, remission and relapse from 21 pediatric BCP-ALL patients. Tumor specific mutations had been identified by WES. Three of 21 were hypermutated with over 150 somatic mutations at relapse. Mutation of DNA mismatch repair gene, MSH3, was detected in 2 of them. Except for these hypermutated cases, the median number of somatic mutations detected at relapsed phase was 22 (range 8 to 53), which was higher than that at diagnosis (median 16, range 6 to 31). Sixteen recurrently mutated genes were identified in 21 cases by WES. Some known leukemia associated genes were detected, including KRAS and WHSC1 observed only at diagnosis and IKZF1 and CREBBP observed at relapse. Then we compared VAFs of these mutations between at diagnosis and relapse to solve the clonal architectures over time. Three patterns of clonal evolution were estimated from VAFs using targeted deep sequencing; (i) In 7 cases, all mutations described at diagnosis were shared at relapse, suggesting that relapse clone derived from predominant clone at diagnosis with additional mutations in these cases. (ii) In other 13 cases, most of mutations in predominant clone at diagnosis were not detected at relapse except for some shared mutations at diagnosis and relapse, indicating that relapsed clone occurred from founder clone existing as subclone at diagnosis. (iii) In one very late-relapsed case, there were no shared mutations at diagnosis and relapse. According to clonality analysis of Ig and TCR, none of rearrangements identified at diagnosis were conserved at relapse in this case. On the other hand, most rearrangement at diagnosis were conserved at relapse in other 20 cases except one patient who relapsed in 10 years after diagnosis. Relapse from predominant clone at diagnosis were observed in only one out of 8 late-relapsed cases (> 36 months), whereas a half of the early-relapsed showed this clonal evolution pattern. The number of shared mutations between diagnosis and relapse was very limited in very late-relapsed cases over 10 years. Discussion Our study suggests that the clonal evolution pattern differs according to the time to relapse. In a half of early-relapsed cases, relapsed clone derived from major clone at diagnosis with additional mutations, and clonal selection of resistant clones occurred during treatment. Meanwhile, in late-relapsed cases, relapse was frequently associated with clonal evolution from minor subclone with some conserved mutations and same Ig/TCR rearrangements. The founder clone should be remained dormant for a long period until additional mutations lead to relapse. Towards a better understanding of clonal evolution in ALL, our study will shed light on the early prediction of relapse risk and new treatment strategies for relapsed ALL. Disclosures No relevant conflicts of interest to declare.
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van Delft, Frederik W., Sharon Horsley, Sue Colman, et al. "Clonal origins of relapse in ETV6-RUNX1 acute lymphoblastic leukemia." Blood 117, no. 23 (2011): 6247–54. http://dx.doi.org/10.1182/blood-2010-10-314674.
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Abstract B-cell precursor childhood acute lymphoblastic leukemia with ETV6-RUNX1 (TEL-AML1) fusion has an overall good prognosis, but relapses occur, usually after cessation of treatment and occasionally many years later. We have investigated the clonal origins of relapse by comparing the profiles of genomewide copy number alterations at presentation in 21 patients with those in matched relapse (12-119 months). We identified, in total, 159 copy number alterations at presentation and 231 at relapse (excluding Ig/TCR). Deletions of CDKN2A/B or CCNC (6q16.2-3) or both increased from 38% at presentation to 76% in relapse, suggesting that cell-cycle deregulation contributed to emergence of relapse. A novel observation was recurrent gain of chromosome 16 (2 patients at presentation, 4 at relapse) and deletion of plasmocytoma variant translocation 1 in 3 patients. The data indicate that, irrespective of time to relapse, the relapse clone was derived from either a major or minor clone at presentation. Backtracking analysis by FISH identified a minor subclone at diagnosis whose genotype matched that observed in relapse ∼ 10 years later. These data indicate subclonal diversity at diagnosis, providing a variable basis for intraclonal origins of relapse and extended periods (years) of dormancy, possibly by quiescence, for stem cells in ETV6-RUNX1+ acute lymphoblastic leukemia.
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Wu, Kai, Qianyi Ma, Darren King, Jun Li, and Sami Malek. "Paired Analyses of AML at Diagnosis and Relapse By Single-Cell RNA Sequencing Identifies Two Distinct Relapse Patterns." Blood 134, Supplement_1 (2019): 183. http://dx.doi.org/10.1182/blood-2019-124170.
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Introduction: Despite achievement of complete remission (CR) following chemotherapy, Acute Myelogenous Leukemia (AML) relapses in the majority of adult patients. While relapsed AML is almost always clonally related to the disease at diagnosis, the actual molecular and cellular contributors to chemotherapy resistance and to AML relapse remain incompletely understood. Some molecular determinants of relapse have been identified in genomic, epigenetic and proteomic aberrations, while cellular relapse reservoirs have been identified in leukemia stem cells as well as in more mature leukemic cell compartments. Here, we set out to determine the cellular composition, gene mutation status and gene expression of paired AML specimens procured at diagnosis and at relapse aiming at a better understanding of the AML relapse process. Methods: We employed the drop-seq 3' single cell RNA sequencing (scRNA-seq) method (Macosko 2015) with minor modifications to analyze the mRNA expression in single cells derived from 12 paired AML specimens procured at diagnosis and at relapse from prior CR. We obtained scRNA-seq data on 1000-2000 single cells per sample detecting approximately 2000-3000 unique molecular identifiers (UMIs) and 800-1500 genes per cell. Using WES or panel-based sequencing we determined mutations in known driver genes. Subsequently, we optimized novel methods for detection and mapping of mutated driver genes to individual cells using mutation specific PCR conditions and novel bioinformatics approaches. We annotated scRNA-seq expression profiles of the diagnosis and relapsed AML specimens individually using publicly available data for cell type-specific RNA markers derived from sorted normal cell populations and further compared the scRNA-seq data to scRNA-seq data of 5 pooled normal human bone marrows generated for this study. Results: Through analyses of scRNA-seq data of paired diagnosis and relapse AML specimens via principle components analyses (PCA) or t-distributed stochastic neighbor embedding (t-SNE) we detected varying degrees of separation of cell clusters in all cases analyzed indicative of substantial changes in single cell gene expression between AML diagnosis and relapse. A few of these observed cluster shifts were paralleled by gain or loss of mutated genes (e.g. FLT3-ITD) at relapse while most others lacked obvious clonal genomic markers. Through subsequent comparison of the expression similarities of single AML cells to sorted normal human bone marrow cells we detected two distinct AML relapse patterns: i) a pattern of relapse suggesting simple leukemia regrowth as evidenced by similar proportions of leukemia cells mapping onto discrete normal bone marrow cells (e.g. monocyte-like or GMPs or CMPs), and, ii) a pattern of relapse whereby the gene expression of relapsed cells (but not diagnosis cells) had similarity to normal hematopoietic cells that are conventionally placed more apical in the classical hematopoiesis differentiation cascade (HSCs, MPPs, CMPs; a phenotypic shift to immaturity). In addition, no leukemia sample mapped to just one classically defined bone marrow cell type but instead to multiple cell types, suggesting that most AML leukemia cells harbor aberrant hybrid cell gene expression patterns. Finally, we detected quantitative shifts in T cells and NK cells in some samples at relapse, which will be analyzed in greater detail. Conclusions: The comparative analysis of scRNA-seq data of paired AML specimens procured at diagnosis and relapse, identifies frequent and previously unrecognized changes in gene expression in leukemia cells at relapse. Through a comparison of gene mutation and gene expression at single cell resolution we identify two distinct AML relapse patterns in adult AML. Disclosures No relevant conflicts of interest to declare.
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Thakur, Rozy, Prateek Bhatia, Minu Singh, et al. "Therapy-Acquired Clonal Mutations in Thiopurine Drug-Response Genes Drive Majority of Early Relapses in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia." Diagnostics 13, no. 5 (2023): 884. http://dx.doi.org/10.3390/diagnostics13050884.
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Methods: Forty pediatric (0–12 years) B-ALL DNA samples (20 paired Diagnosis-Relapse) and an additional six B-ALL DNA samples (without relapse at 3 years post treatment), as the non-relapse arm, were retrieved from the biobank for advanced genomic analysis. Deep sequencing (1050–5000X; mean 1600X) was performed using a custom NGS panel of 74 genes incorporating unique molecular barcodes. Results: A total 47 major clones (>25% VAF) and 188 minor clones were noted in 40 cases after bioinformatic data filtering. Of the forty-seven major clones, eight (17%) were diagnosis-specific, seventeen (36%) were relapse-specific and 11 (23%) were shared. In the control arm, no pathogenic major clone was noted in any of the six samples. The most common clonal evolution pattern observed was therapy-acquired (TA), with 9/20 (45%), followed by M-M, with 5/20 (25%), m-M, with 4/20 (20%) and unclassified (UNC) 2/20 (10%). The TA clonal pattern was predominant in early relapses 7/12 (58%), with 71% (5/7) having major clonal mutations in the NT5C2 or PMS2 gene related to thiopurine-dose response. In addition, 60% (3/5) of these cases were preceded by an initial hit in the epigenetic regulator, KMT2D. Mutations in common relapse-enriched genes comprised 33% of the very early relapses, 50% of the early and 40% of the late relapses. Overall, 14/46 (30%) of the samples showed the hypermutation phenotype, of which the majority (50%) had a TA pattern of relapse. Conclusions: Our study highlights the high frequency of early relapses driven by TA clones, demonstrating the need to identify their early rise during chemotherapy by digital PCR.
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Celkan, Tiraje, Serap Karaman, Alp Ozkan, Hilmi Apak, Aylin Canpolat, and Inci Yildiz. "Outcome after Relapse in Childhood Acute Lymphoblastic Leukaemia - Results of a Single Center for a Period of 15 Years." Blood 106, no. 11 (2005): 4582. http://dx.doi.org/10.1182/blood.v106.11.4582.4582.
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Abstract Approximately 25–30 % of children newly diagnosed with acute lymphoblastic leukemia (ALL) will eventually experience leukemic relapse. Bone marrow is the most common site of recurrence. Usually achieving a durable second remission is complicated by toxicity and resistance of the disease. Here we documented our patients in order to see the prognosis of relapsed pediatric ALL cases. RESULTS. From August 1990 to August 2005 children diagnosed with ALL and treated with BFM based protocols in Cerrahpasa Medical Faculty Pediatric Hematology-Oncology Department were enrolled to this study. There were 225 children aged median 6 years( 3 months–18 years) (136 boys/89 girls), 28 % SR, 50 % MR, 22 % HR. The whole group EFS is 72,6 % and RFI 81,8 %. Twenty-nine (12,8 %) patients were relapsed. Bone marrow recurrences were isolated in 19 patients, and combined with an extramedullary site in 8 patients (4 CNS, 2 testis, 1 retinal,1 dermal). Only two patients had isolated extramedullary site (testis) relapse. The median time to recurrence was 23 months (range 4–128 months). Five patients refused a secondary treatment. Of 24 chemotherapy given patients, 6 patients were lost just after induction therapy due to toxicity before a reliable remission evaluation was done. In three early relapses a second remission could not be attained. Twenty-one patients (72.4 %) achieved a second remission (median length, 4 months; range, 1–114 months)( mean16 ± 80 months). The 5-year survival probability among all patients was 27.2 % ± 8.2 %. Of 8 surviving patients, 3 are in remission more than 5 years, 3 are in remission 2–5 years of period and only 2 less than 1 year. One patient who relapsed for second time is in 3th remission for 65 months period. Bone marrow transplantation was the done for only 3 patients, one is very newly done, the other two relapsed after engrafmant and were lost. CONCLUSIONS. Despite acceptable long-term second EFS rates for a minor group of patients, childhood ALL recurrences signal a poor outcome being the problem of childhood ALL therapy.
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Béldi, T. G., M. Nagy-Vincze, K. Szabó, et al. "POS1219 INCIDENCE, FEATURES AND OUTCOME OF DISEASE RELAPSE AFTER COVID-19 VACCINATION IN PATIENTS WITH IDIOPATHIC INFLAMMATORY MYOPATHIES." Annals of the Rheumatic Diseases 82, Suppl 1 (2023): 944.1–944. http://dx.doi.org/10.1136/annrheumdis-2023-eular.4867.
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BackgroundThe approved COVID-19 vaccines showed clear safety and efficacy in reduction of severe SARS-CoV-2 disease. Patients with idiopathic inflammatory myopathies (IIM) were not well represented in these vaccine trials and there are limited data in the literature about development of confirmed disease flare after COVID-19 vaccination.ObjectivesTo evaluate frequency, features and outcome of disease relapses in patients with IIM following SARS–CoV-2 vaccination.MethodsA cohort of 176 IIM patients (mean age:57.6 years, 117 females, 59 males, 106 PM, 70 DM) were interviewed after the 3rd wave of COVID-19 pandemic and prospectively followed. Relapses were determined using the IMACS disease state criteria, outcome of the flares with myositis response criteria, calculating the total improvement score (TIS).ResultsA total of 146 (82.9%) patients received vaccination and 17/146 (11.6%) patients had relapse within 3 months and 13/146 (8.9%) patients within one month. The relapse rate of unvaccinated patients (1/30; 3.3%) was not significantly different (p>0.1). No fatal flare has been observed. Three months after the post-vaccination relapses, 70.6% of the patients (12/17) achieved improvement of disease activity (average TIS score:30±15.81; 7 minor, 5 moderate and 0 major improvement). Six months after flares improvement was detected in 14/16 (87.5%) of relapsed patients (average TIS score: 43±20.17; 3 minimal, 7 moderate and 4 major). Forward stepwise logistic regression analysis revealed that the active state of myositis at time of injection (p<0.0001; OR: 31.2 CI: 9.0 – 108) and the application of BNT162b2 vaccination (p=0.026; OR: 4.06 CI: 1.1 – 14.7) were significantly associated with the occurrence of relapse.ConclusionMinority of the vaccinated IIM patients had confirmed disease flare after COVID-19 vaccination and majority of the relapses improved after individualized treatment. Active disease state at the time of vaccination probably contributes to the increased risk of post vaccination myositis flare.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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Yu, Jiangyan, Esmé Waanders, Simon V. van Reijmersdal, et al. "The Majority of RAS Pathway Mutations Detected in Relapsed B-Cell Precursor Acute Lymphoblastic Leukemia Are Present in Major or Minor Subclones at Diagnosis." Blood 124, no. 21 (2014): 2397. http://dx.doi.org/10.1182/blood.v124.21.2397.2397.
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Abstract B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is one of the most common cancers in children. The relapse incidence varies between 15% and 25%, dependent on the treatment protocol. It has been demonstrated that the presence of mutations in the RAS pathway genes, which regulate signal transduction upon binding of ligand to a variety of membrane receptors, are frequently associated with high-risk ALL and may be relapse drivers (Zhang et al., Blood 2011 118:3080-7; Irving et al., ASH 2013). Relapses in ALL are thought to result from the outgrowth of therapy-resistant residual leukemia cells and recent studies have shown a complex, dynamic architecture of clonal diversity in ALL (Anderson et al., Nature 2011 469:356-61; Notta et al. Nature 2011 496:362-7). In this study, we have investigated the clonal origin of RAS pathway mutations in relapsed BCP-ALL. We screened 146 relapse samples from children with relapsed BCP-ALL for mutations in five RAS pathway genes using IonTorrent sequencing with a read-depth of approximately 150x. A total of 30% of relapse samples carried RAS pathway mutations, including mutations in KRAS (n=22), NRAS (n=13), PTPN11 (n=8), and FLT3 (n=2). No RAS mutations were found in 103 patients, whereas one patient had both a PTPN11 and a KRAS mutation, and another patient had two KRAS mutations. For 28 mutations we collected matched diagnosis samples and determined mutation presence using Sanger sequencing. We found that 12 of the RAS mutations were also present at diagnosis (43%) and 16 were initially not detected at diagnosis (57%). In order to gain more insight into the clonal evolution of relapse development, we performed amplicon based ultra-deep sequencing on the diagnosis samples, with an average read-depth of 50,000x for each mutation. The ultra-deep sequencing allows for sensitive and accurate detection of relapse-prone clones at diagnosis. A total of 22 mutations were identified at diagnosis samples (79%), of which 10 mutations had a low mutant allele frequency (average 3.8%), and were initially missed by Sanger sequencing (Fig.1). The 12 mutations determined using Sanger sequencing were detected at an average mutant allele frequency of 30.8%. We were unable to detect 6 mutations in the matched diagnosis samples, indicating that these mutations were newly acquired in the relapse clone at a time point after relapse. Our results indicate that cells harboring RAS pathway mutations are recurrently present in subclones at diagnosis. These cells may survive initial therapy and subsequently emerge at relapse. Patients with (minor clones with) RAS pathway mutations identified by ultra-deep sequencing, may benefit from treatment with MEK inhibitors added to the frontline therapy strategy. Figure 1. Backtracking of RAS pathway mutations by ultra-deep sequencing. A total of 22 mutations (out of 28) were detected in matched diagnosis samples. The 12 mutations (solid grey) determined by Sanger sequencing were detected at high mutant allele frequency ranging from 22% to 42%. Ten mutations (diagonally striped) were missed by Sanger sequencing but detected by ultra-deep sequencing. These mutations showed a low mutant allele frequency varying from 0.3% to 8%. Figure 1. Backtracking of RAS pathway mutations by ultra-deep sequencing. A total of 22 mutations (out of 28) were detected in matched diagnosis samples. The 12 mutations (solid grey) determined by Sanger sequencing were detected at high mutant allele frequency ranging from 22% to 42%. Ten mutations (diagonally striped) were missed by Sanger sequencing but detected by ultra-deep sequencing. These mutations showed a low mutant allele frequency varying from 0.3% to 8%. Disclosures No relevant conflicts of interest to declare.
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Konrad, Marianne, Markus Metzler, Simon Panzer, et al. "Late relapses evolve from slow-responding subclones in t(12;21)-positive acute lymphoblastic leukemia: evidence for the persistence of a preleukemic clone." Blood 101, no. 9 (2003): 3635–40. http://dx.doi.org/10.1182/blood-2002-10-3252.
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TEL/AML1-positive childhood acute lymphoblastic leukemias (ALLs) generally have low-risk features, but still about 20% of patients relapse. Our initial molecular genetic analyses in 2 off-treatment relapses suggested that the initial and relapse clones represent different subclones that evolved from a common TEL/AML1-positive, treatment-resistant precursor. In order to further elaborate on this hypothesis, we studied 2 patients with late systemic relapses of their TEL/AML1-positive ALL (41 months and 49 months after initial diagnosis, respectively) who had distinct clonal antigen receptor gene rearrangements at diagnosis and relapse. These clone-specific markers enabled us to determine the responsiveness of the individual clones to treatment. The matching genomic TEL/AML1 breakpoints of the initial and the relapse clones in these patients confirmed their origin from a common progenitor cell. This proof was especially important in one of these 2 leukemias without a common antigen receptor gene rearrangement. Our retrospective analysis revealed that in both cases the relapse clone was already present at diagnosis. Despite their small sizes (5 × 10−3 and 1 × 10−4, respectively), we were able to detect their much slower responses to therapy compared with the dominant leukemic clone. Moreover, in all instances, these initially slow-responding clones, after they had developed into the relapse leukemia, were rapidly eradicated by the relapse treatment, underlining their different biology at the 2 time points of leukemia manifestation. We thus hypothesize that the minor clone was not fully malignant at initial diagnosis but acquired further mutations that may be necessary for the manifestation of relapse.
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Dvorakova, Dana, Zdenek Racil, Ivo Palasek, et al. "Monitoring of Minimal Residual Disease in NPM1 Mutated Acute Myeloid Leukemia (AML) – a Single Center Experience in 27 Patients." Blood 114, no. 22 (2009): 4672. http://dx.doi.org/10.1182/blood.v114.22.4672.4672.
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Abstract Abstract 4672 Background Mutations within NPM1 gene occurs in about 60% of adult cytogenetic normal AML (CN-AML) and represent the single most frequent molecular aberration in this subgroups of patients. These mutations usually occur at exon 12 and induce most frequently a net insertion of four base pairs. Aims To examine the applicability and sensitivity of DNA-based real-time quantitative polymerase chain reaction (RQ-PCR) with mutation-specific reverse primers and common minor groove binding (MGB) probe and to evaluate whether minimal residual disease levels are of prognostic relevance in CN-AML patients with NPM1 mutations. Methods Patients were treated within different AML trials and follow-up samples of peripheral blood or bone marrow were referred to perform an RQ-PCR. Samples were analysed at diagnosis, during, and after therapy. The NPM1 mutations were A (17 pts), B (1 pt), D (2 pts) and 7 patients with individual rare types. For all cases, levels of minimal residual disease were determined by DNA-based RQ-PCR with mutation-specific reverse primer, one common forward primer and one common MGB probe. The NPM1 mutation value was normalized on the number of albumin gene copies and expressed as the number of NPM1 mutations every 106 genomic equivalents. This assay is highly specific as no wildtype NPM1 could be detected. Maximal reproducible sensitivity was 10 plasmide molecules per reaction. Results A total of 950 samples of bone marrow and/or peripheral blood from 27 patients have been analyzed. Twenty of 27 patients (74%) achieved molecular remission (MR), twenty-six of 27 patients (96%) achieved hematological remission (HR). 6 of 27 (22%) patients achieved HR without MR and one patient failed therapy. 8 of 20 patients (40%) with MR after treatment relapsed at molecular level and except one in all these patients hematological relaps occured (one patient is still in HR with bone marrow blast present, but < 5%). Considering relapsed patients, time from molecular to hematological relapse was 1 to 5 months (median: 3 months). Considering all 14 patients with HR without MR (6 pts) or with molecular relapse (8 pts), in 11 of them hematological relaps occured (79%) and molecular positivity anticipating hematological relaps with median of 3,5 month (1-7 months). 3 of these 14 patients are still in HR. Conclusions Mutations within NPM1 gene are a sensitive marker for monitoring minimal residual disease in CN-AML patients. RQ-PCR using a MGB probe is an efficient approach to long-term follow-up of residual leukemia cells and frequent quantitative monitoring is useful for reliably predicting hematological relapse. Achievement of negativity appears to predict favorable clinical outcome. This work was partially supported by research grant No. MSM0021622430 Disclosures: No relevant conflicts of interest to declare.
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Cazzaniga, Valeria, Paola De Lorenzo, Federica Mottadelli, et al. "Clonal Evolution and Lack of BCR-ABL1 Mutations in Pediatric Ph+ ALL Patients Resistant/Refractory to Imatinib Treatment." Blood 126, no. 23 (2015): 2622. http://dx.doi.org/10.1182/blood.v126.23.2622.2622.
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Abstract Philadelphia positive acute lymphoblastic leukemia (Ph+ ALL) is characterized by the translocation t(9;22), resulting in the BCR-ABL1 fusion gene. It occurs in 2-3% of pediatric ALL and is associated with poor prognosis. Despite the introduction of tyrosine kinase inhibitors (TKIs), such as Imatinib, resulting in a significant increase in the cure rate, a consistent number of patients show resistance to treatment and subsequently relapse. In an adult cohort, more than 70% of relapses during TKI treatment involve selection of tyrosine kinase domain (TKD) mutations. In order to better understand the mechanism of Imatinib resistance in pediatric Ph+ ALL, we selected as our cohort a subgroup of patients treated with Imatinib on top of chemotherapy, according to the EsPhALL clinical trial and enrolled in Italy from January 2004 to December 2014 by the AIEOP study group. Patients (n=10) either didn't achieve remission or experienced early relapse by the end of 2014. Patients' samples have been screened for mutations in the ABL1 tyrosine kinase domain (TKD). Nine out of ten BM samples collected at relapse showed wild type TKD. Accordingly, no subsequent relapses showed the appearance of an ABL1 mutated clone. Only one patient carried the tyrosine 243 to phenylalanine substitution (Y253F) at the first and second relapses, but not at diagnosis, demonstrating the expansion of a resistant minor clone at diagnosis, following TKI treatment. In addition, we monitored the BCR-ABL1 transcript level by RQ-PCR at diagnosis, relapse and multiple follow up points. In nine out of ten patients the expression of BCR-ABL1 was highly positive at the time of the relapse, and in five out of six cases the increase of the transcript level was predictive of a subsequent clinical relapse. Moreover, we investigated the cooperative copy number alterations by MLPA analysis in 6 matched diagnosis and relapse(s) samples. MLPA data showed a heterogeneous scenario of clonal evolution. In three patients, the relapse clone shared only a minor genetic identity with the predominant clone at diagnosis and wasn't the product of its direct evolution. In one case, the clone at relapse was identical to that at diagnosis, while in two cases the predominant clone at relapse was the product of the direct clonal evolution of the main clone at diagnosis. In 4 cases, the dynamics of clonal evolution were confirmed by the analyses of the IG/TCR rearrangements. In conclusion, our data depict a very different scenario of resistance in childhood Ph+ ALL compared to the adult cohort. Indeed, Imatinib resistance doesn't seem to be dependent on ABL1 mutations in pediatric Ph+ ALL. Moreover, the MLPA results contribute to the description of clonal heterogeneity in Ph+ ALL, and may partially explain the different response to treatment. Disclosures No relevant conflicts of interest to declare.
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De Miguel, E., R. Karalilova, P. Macchioni, et al. "POS0712 WHAT IS THE OUTCOME OF PATIENTS WITH OR WITHOUT SUBCLINICAL GIANT CELL ARTERITIS IN POLYMYALGIA RHEUMATICA? PRELIMINARY DATA OF AN OBSERVATION STUDY." Annals of the Rheumatic Diseases 82, Suppl 1 (2023): 642.1–642. http://dx.doi.org/10.1136/annrheumdis-2023-eular.1286.
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BackgroundSubclinical giant cell arteritis (GCA) in polymyalgia rheumatica (PMR) is found in the 22.8% of patients on ultrasound examinations. The outcome and the optimal management of subclinical giant cell arteritis (GCA) in patients with polymyalgia rheumatica (PMR) have not been defined yet.ObjectivesThe aim of this study was to investigate the short-term outcome of PMR patients with concurrent subclinical GCA that were included in our multicenter project on the prevalence, characteristics and outcome of subclinical GCA (diagnosed by vascular ultrasound) in PMR[1].MethodsWe analyzed follow up data at 3, 6, 12 and 18 months of consecutive PMR patients from 7 European rheumatology centers. All patients fulfilled 2012 EULAR/ACR Provisional Classification Criteria for Polymyalgia Rheumatica and they had not symptom of clinical GCA. Patients were stratified into two groups: pure PMR and PMR with subclinical GCA, and the outcome between these two groups were compared. A relapse was defined as clinical and/or laboratory worsening of the disease after the initial remission and minor and major relapse EULAR definition was used[2].ResultsWe included 116 PMR patients (47 with concurrent subclinical GCA and 69 with pure PMR) followed for a median (IQR) of 21 (17; 23) months. We observed relapses in 35/116 patients (30.2%), 27/47 (57.4%) in PMR with subclinical GCA and 8/69 (11.6%) in pure PMR group (p<0.001). All relapses in the pure PMR group were minor relapses, whereas we observed 2 major relapses in the subclinical GCA group. The dose of corticosteroids used at the baseline visit was significantly higher in the GCA subclinical group, but tapering of steroids occurred faster than recommended by clinical guidelines[2]. Prednisone dose was significantly higher in patients with PMR and subclinical GCA than in patients with pure PMR both at baseline and at month 6 (Table 1). In patients with PMR with subclinical GCA mean starting dose of prednisone was 32.2±16.1 mg in those who relapsed and 36.2±12.8 in those who maintained remission (p=0.166); at 3 months, it was 13.2±7.1 and 18.2±7.9, respectively (p<0.05). Three patients in the PMR with subclinical GCA group received biological therapy at diagnosis; one of them had a minor relapse.Table 1.Patients characteristicsPure PMR(n=69)Subclinical GCA/PMR(n=47)pAge years (mean ± SD)71.2±8.074.8±7.60.079Sex (females %)59%52%0.526Relapses n (%)8/69 (11.6%)27/47 (57.4%)0.001Minor Relapses n (%)8/69 (11.6%)25/47 (53.2%)0.001Major Relapses n (%)02/47 (4.2%)Steroids basal (mean ± SD))18.3±9.134±14.80.001Steroids month 3 (mean ± SD)9.9±5.114.6±8.30.001Steroids month 6 (mean ± SD)5.6±2.18.8±6.80.037Steroids month 12 (mean ± SD)1.7±2.18.0±14.20.062Steroids month 18 (mean ± SD)1.1±1.83.6±5.60.09Steroids = mg prednisone; SD = standard deviation; n= number of patientsConclusionPMR patients with subclinical GCA had a significantly higher number of relapses during the follow-up than pure PMR group. These results suggest that subclinical GCA in PMR should be treated in the same manner as clinically overt GCA.References[1]De Miguel et al. Prevalence of subclinical giant cell arteritis in patients with polymyalgia rheumatica. Ann Rheum Dis 2022; volume 81, supplement 1, page 122.[2]Hellmich B et al. 2018 Update of the EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis. 2020 Jan;79:19-30.AcknowledgementsWe would like to thank to the GCA/PMR study group for her contributions to the development of collaborative studies.Disclosure of InterestsNone Declared.
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Nasrollahi, Elham, Hafsa M. Gundroo, Becky Alford, et al. "Systemic Review and Meta-Analysis of Safety and Efficacy of Bispecific Antibodies Among Older Adults with Multiple Myeloma." Blood 144, Supplement 1 (2024): 6921. https://doi.org/10.1182/blood-2024-204029.
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Introduction: T-cell redirecting bispecific antibodies (BsAb) are transforming the care of patients with relapsed/refractory (RR) multiple myeloma (MM). However, despite being a disease of older adults (OA), these patients remain under-represented in pivotal clinical trials and there are limited data to inform the management of this subgroup. To address this knowledge gap, we performed a systematic review and meta-analysis of clinical trials and real-world studies to describe the safety and efficacy of BsAb in OA (age ≥65 years) with RRMM. Methods: A comprehensive literature search was conducted across multiple databases, including Medline, Web of Science (WOS), Scopus, CINAHL, Cochrane Library, Open Dissertations, and ProQuest Dissertations for studies involving BsAb in MM independent of target (data cut-off May 14, 2024). Abstracts from major meetings were included. Additionally, Global Index Medicus and Scielo searches were performed to encompass grey literature. Studies were included if one or more primary outcomes measures were reported for OA. The primary outcome measures included overall response rate (ORR), complete response rate (CRR), the incidence of cytokine release syndrome (CRS), immune cell-effector-associated neurotoxicity syndrome (ICANS) and infections (any grade/grade ≥3). Other outcomes assessed included progression-free survival (PFS), non-relapse mortality (NRM) and overall survival (OS). The quality of the included studies was assessed using the methodological index for non-randomized studies (MINORS) scoring system. Subgroup analyses were performed to explore sources of potential heterogeneity and were based on proportion of patients in the study with revised international staging system (R-ISS) stage 3 disease and Eastern Oncology Cooperative Group (ECOG) performance status (PS) ≥2. A proportional meta-analysis was performed when outcomes from ≥2 studies were available. This study was registered with PROSPERO (# CRD42024541711). Results: We identified a cohort of 449 patients, of which 48.9% (n=220) were older adults (OA). After identifying 544 records, 116 studies were selected for full-text review, and four studies were included in the meta-analysis (phase 2 clinical trials, n=2; phase 1 clinical trial, n=1; real-world study, n=1). Notably, one study (Dima et al, 2024) used a cut-off of ≥70 years to define older patients but was kept in the analysis. All studies included B-cell maturation agent targetting BsAb. Three out of 4 studies had a MINORS score of ≥15 (indicating high methodological quality) and one study had a MINORS score of 7. The pooled ORR among OAs was 64% [95% confidence interval (CI), 57%, 70%), which was comparable to the ORR of 63% (95% CI, 56%, 69%) among younger patients. Data on CRR by age group was not reported in any of the included studies. Subgroup analyses revealed no significant heterogeneity in response based on proportion of patients with R-ISS stage 3 disease. Three studies had ≤20% of patients with R-ISS stage 3 disease with a pooled ORR among OA of 62% (95% CI, 55%, 69%) and in one study, 25% of patients had R-ISS stage 3 disease with an estimated ORR of 71% (95% CI, 53%, 85%), p=0.371. There was no significant heterogeneity in response among studies stratified by proportion of patients with an ECOG PS ≥2. In two studies, &lt;10% of patients had a reported ECOG PS ≥2, with a pooled ORR among OA of 64% (95% CI, 54%, 73%). In one study, &gt;10% of patients had an ECOG PS ≥2 and another study reported patients by ECOG PS ≥1 with &gt;10% of patients in this category. The pooled ORR among OA in these two studies was 64% (95% CI, 55%, 73%) which was comparable to the former subgroup, p=0.973. Only one study (MagnetisMM-3) reported incidence of toxicities by age group precluding a meta-analysis. The rate of CRS in this study was 57.5% in OA compared to 58.3% in patients &lt;65 years. Similarly, the rate of ICANS was 6.3% versus 2.3% respectively. No patients had grade ≥3 CRS or ICANS. The rate of infections (any grade/grade ≥3) among OA was 72.1%/37.3% which was comparable to patients &lt;65 years (68.8%/46.3%). No studies reported NRM, PFS or OS by age group. Conclusion: OA receiving BsAb experience comparable response rates to younger patients. Reporting on toxicities in this age group is very limited but suggests comparable rates of CRS, ICANS and infections. Studies with longer follow up are needed to assess durability of response and risk for NRM in OA.
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Ghesquieres, Herv, Cecile Dalban, Emmanuelle Nicolas-Virelizier, et al. "BeEAM (Bendamustine, Etoposide, Cytarabine, Melphalan) Prior to Autologous Stem Cell Transplant for Chemosensitive Relapses in Patients with Follicular Lymphoma: A Prospective Multicenter Phase II Study from Lymphoma Study Association (LYSA) Centers." Blood 132, Supplement 1 (2018): 4612. http://dx.doi.org/10.1182/blood-2018-99-116301.
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Abstract Introduction: high dose chemotherapy (HDT) and autologous stem cell transplantation (ASCT) is an effective treatment in relapsed follicular lymphoma (FL). Alternative regimens including bendamustine based conditioning (BeEAM) had been developed to improve lymphoma outcome. Visani et al. showed in a phase I/II for relapsed aggressive lymphomas and relapsed Hodgkin lymphomas that bendamustine used at a dose of 200mg/m2, 2 days in combination with cytarabine (400 mg/m2, day-5 to day-2), etoposide (200 mg/m2, day-5 to day-2) and melphalan (140 mg/m2, day-1) was well tolerated with promising efficacy results. We designed a single arm, multicenter, phase II study for first and second chemosensitive relapses in FL patients (pts) evaluating this conditioning regimen. Methods: The primary endpoint is the efficacy of BeEAM by measuring the 2-year event-free survival (2-year EFS) rate defines by relapse, progression, death from any cause and initiation of a new therapy. The hypothesis was the improvement of 2-year EFS rate from 70% (H0) to 85% (H1). Based on a Fleming-A'Hern single-stage design, 50 pts are needed. Secondary endpoints are: overall response rate (ORR) at day 100 according to 2007 Cheson criteria; progression-free survival (PFS); overall survival (OS) and safety profile of BeEAM. Main eligible criteria are: histologically confirmed FL relapsed (WHO grade 1, 2, 3a); aged 18-65 years; first or second chemosensitive relapses after salvage immunochemotherapy based on 2007 Cheson criteria with a complete (CR) or a partial response (PR) before the BeEAM; eligibility for ASCT; signed informed consent. This trial was funded by the French government PHRC program 2012. Results: Twenty-one pts were included between July 2014 and November 2016 in 7 LYSA centers. One patient did not receive the treatment. The final analysis was based on 20 pts. Inclusion were performed for 16 (80%) and 3 (15%) pts at 1st and 2nd relapses, respectively. One patient (5%) was included at 3rd relapse and is considered as protocol minor deviation. The median time between the initial diagnostic and the 1st relapse was 3.6 years (0.7-12.9). In first-line therapy, 17/20 pts (85%) were treated with immunochemotherapy. At the relapse allowing inclusion, the FLIPI score were 0-1, 2, ≥3 for 6 (32%), 7 (36%), 6 (32%) pts, respectively. Salvage treatments were rituximab (R) associated with, dexamethasone, cytarabine, and platin in 19 pts and R-CHOP in one patient. The median age at inclusion was 57 years (range, 39-63); 16 (80%) and 4 (20%) pts were in CR and PR before BeEAM. After 18 included pts, the protocol was amended due to unexpected toxicities especially two hepatic veino-occlusive diseases (VOD), leading to the reduction of bendamustine dosage. Finally, 17 and 3 pts were respectively treated at 200mg/m2, 2 days and 160mg/m2, 2 days. The median time for neutrophil>0.5 G/L and platelet recoveries>20 G/L were 7.5 (0-11) and 7 (2-18) days. Patients received a median of 4 (0-12) packed red blood cell units and 6 (3-21) platelet units until J100. The median duration of hospital stay duration was 27 days (20-50). Response evaluation at J100 showed 19 CR pts and one patient in progressive disease. The ORR was 95.0% (95%CI, 75.1-99.9). Six pts progressed with two deaths of the FL (Figure 1A). With a median follow-up of 31 months (16-42), the 2-year EFS rate was 59.6% (95%CI, 35.1-77.4) but two events correspond to unplanned rituximab maintenance in two CR pts (Figure 1B). The PFS and OS rates were 69.6% (95%CI, 44.5-85.1) and 90% (95%CI, 65.6-97.4), respectively (Figure 1C). Fifteen pts (75%) had infectious complications until J100 that needed treatments for more than 7 days. Grade ≥3 toxicities were infections (N=18, 90%), gastrointestinal disorders (N=14, 70%), mucositis (N=12, 60%); atrial flutter (N=1, 5%); acute renal failure (N=2, 10%); HHV6 reactivation (N=3, 15%). In total, 29 serious adverse events (SAE) were declared for 16 pts. Two pts experienced VOD classified as unexpected SAE; one of them needed a hepatic transplantation. No patient presented toxic death. Conclusions: the prospective evaluation of BeEAM conditioning in FL pts with a chemosensitive relapses showed excessive toxicities especially infectious complications, cases of VOD leading to premature termination of the trial. Based on the 20 treated pts, the outcome seems not improve with the use of BeEAM. Our study does not encourage the use of BeEAM conditioning in relapsed FL pts. Disclosures Ghesquieres: Sanofi: Consultancy; Gilead: Consultancy; Celgene: Consultancy. Le Bras:Amgen: Consultancy. Le Gouill:Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria. Cartron:Celgene: Consultancy, Honoraria; Gilead Sciences: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Roche: Consultancy, Honoraria.
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Jan, Max, Matt J. Leventhal, Elizabeth A. Morgan, et al. "Recurrent Genetic HLA Loss in Acute Myeloid Leukemia Relapsed after Matched Unrelated Allogeneic Hematopoietic Cell Transplant." Blood 132, Supplement 1 (2018): 817. http://dx.doi.org/10.1182/blood-2018-99-113911.
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Abstract Introduction: Leukemic escape from the graft versus leukemia (GVL) effect of allogeneic hematopoietic cell transplantation (HCT) is poorly understood. During prolonged periods of post-transplant remission, immunologic selection pressure can favor relapse mediated by acquired resistance to GVL-mediated clearance, such as loss of mismatched HLA in haploidentical transplants. We hypothesized that genetic mechanisms of immune evasion can cause late relapses after matched unrelated donor transplants for myeloid malignancies. Methods: We evaluated 580 adult patients with myeloid malignancies who underwent allogeneic HCT at our institution between 2001 and 2014 and experienced subsequent disease relapse. In 19% of these patients (n=112) relapse occurred at least one year after transplantation. The 25 patients included in the study had specimens banked at each of three timepoints: 1) prior to transplantation, with AML or MDS involvement, 2) approximately 100 days after transplantation, during the period of remission 3) at the time of disease relapse. The indications for transplantation were AML (n = 20) and MDS (n = 5). Transplants were from matched unrelated (n=14), matched related (n=9), and mismatched unrelated (n=2) donors. 12 patients received myeloablative conditioning and 13 received reduced-intensity conditioning regimens. Targeted sequencing of 187 genes, selected based on pathogenic involvement in myeloid malignancies or suspected involvement in immune evasion, was performed on all three timepoints from each patient. Genome-wide microarray-based copy number assessment was performed onthe pre-transplant specimen and post-transplant relapse specimens. Results: We identified three recipients with relapse-specific HLA loss via 1-8 Mb deletions or chromosome 6p arm-level copy neutral uniparental disomy (UPD). One of the HLA alterations was a deletion spanning HLA-B and HLA-C in a donor/recipient pair mismatched at HLA-C. However, in two other cases, relapse-specific HLA losses were identified in donor/recipient pairs that were fully matched at A, B, C, and DRB1. These findings suggest that HLA loss may allow leukemic cells to escape allogeneic immune recognition of minor HLA discrepancies and/or the presentation of minor histocompatibility antigens in the context of matched MHC presentation. These three HLA losses were identified among 14 recipients of matched unrelated donor HCT. HLA losses were not identified among recipients of matched related (n = 9) or mismatched unrelated (n = 2) allogeneic HCT. To evaluate potential interactions between canonical myeloid driver mutations and immunologic alterations, we defined the genetic characteristics of paired pre-transplant MDS/AML samples and post-transplant relapsed samples. In 22 out of 25 cases, at least one driver mutation that was present in the pre-transplant sample was also detected in the relapse sample. Clonal genetic evolution was common at the time of relapse and predominantly involved the acquisition of new subclonal mutations affecting mitogenic signaling (n = 9) and myeloid transcription factors (n = 11). TP53 alterations, including point mutations and 17p deletions were identified in 6 out of 25 patients, including two that remained stable before and after transplantation, and four that were newly detected at the time of relapse. Conclusions: We identified recurrent HLA loss via 6p UPD and segmental deletions in 3 out of 14 patients with late relapse after matched unrelated HCT. Although HLA loss has been observed at relapse after haploidentical HCT, the role of HLA loss as a mechanism of relapse after non-haploidentical HCT has remained unclear. HLA loss in cases with late relapse indicates a prolonged period of immunologic equilibrium, where effective GVL serves as a selective pressure for clonal genetic mechanisms of alloimmune evasion. In the context of MURD HCT, HLA loss provides genetic evidence that allogeneic immune recognition may be mediated by minor histocompatibility antigens and suggests opportunities for novel immunologic approaches for relapse prevention. Disclosures Ho: Jazz Pharmaceuticals: Consultancy. Nikiforow:Kite Pharma: Consultancy. Antin:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Soiffer:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.
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Gray, O. M., G. V. McDonnell, and R. B. Forbes. "A systematic review of oral methotrexate for multiple sclerosis." Multiple Sclerosis Journal 12, no. 4 (2006): 507–10. http://dx.doi.org/10.1191/1352458506ms1299oa.
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Oral methotrexate is a potent immunosuppressant, which could have a beneficial effect on relapse rates and delay disease progression in multiple sclerosis (MS). We performed a systematic review of all randomized controlled trials of oral methotrexate for MS. Of the two randomized controlled trials identified, one was excluded due to its allocation concealment and definition of a relapse and time to sustained disease progression. The other trial studied 60 participants with progressive MS only. This trial reported a non-significant reduction in sustained Expanded Disability Status Scale (EDSS) progression and number of relapses in favour of methotrexate therapy. There were no data on relapse rate and no difference in time to first relapse. Minor side-effects were reported in both methotrexate (87.1%) and placebo groups (89.7%), but there were no major side-effects. Further trials are required in both relapsing-remitting and progressive groups to establish the role of oral methotrexate in MS.
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Kuiper, Roland P., Simon V. van Reijmersdal, Marc M. Hahn, Edwin Sonneveld, Peter M. Hoogerbrugge, and Ad Geurts van Kessel. "Exome Sequencing and Ultra-Deep Sequencing of Paired Diagnosis, Remission and Relapse Samples Reveals the Clonal Diversity and Treatment-Induced Evolution of Childhood Acute Lymphoblastic Leukemia." Blood 120, no. 21 (2012): 126. http://dx.doi.org/10.1182/blood.v120.21.126.126.
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Abstract Abstract 126 Relapse is the major cause of treatment failure in pediatric acute lymphoblastic leukemia (ALL). Recent studies have shown a complex, dynamic architecture of clonal diversity in ALL and other leukemia subtypes, both at diagnosis and relapse. This multiclonal diversity follows a Darwinian model of evolution, and likely contributes to the selective outgrowth of therapy-resistant leukemic cells during or after chemotherapy treatment, resulting in relapse. In order to gain more insight into the multiclonal architecture of ALL, we selected two cytogenetically normal B-cell precursor ALL patients treated according to the DCOG-ALL9 protocol who, based on a previous study (Kuiper et al, Leukemia 2010, 24:1258–64), developed relapses with only minor genomic alterations as compared to diagnosis. Patient 1 had an IKZF1 deletion (exons 4 to 8) and a 23-nt insertion in IKZF1 exon 4 at diagnosis and developed a relapse after 12 months, whereas patient 2 was IKZF1 wild-type, and developed two relapses at 32 months and 4.5 years after diagnosis, respectively. Comparison of clonal rearrangements in the Ig and TCR genes between diagnosis and relapse(s) revealed that both leukemias were genomically stable. Copy number analysis revealed an acquired intragenic PAX5 deletion at relapse in patient 1 and two acquired copy number changes in the second relapse of patient 2 (Kuiper et al., 2010). In the current study, we performed whole exome sequencing on diagnosis, remission and relapse samples of both patients, and identified and confirmed 21 and 7 somatic missense, frameshift or splicesite mutations in the diagnosis and/or relapse samples, respectively. These variants were subsequently selected for amplicon-based ultra-deep sequencing (IonTorrent PGM with 318 chip, Applied Biosystems), using 15 ng of genomic DNA (corresponding to 2,200 haploid genome copies), reaching an average read-depth of 15,000x. All amplicons were mixed at equimolar levels and barcoded per patient sample. In patient 1, 19 mutations, including the 23-nt insertion in IKZF1 exon 4, were detected in 44–52% of the reads at both diagnosis and relapse, thus confirming that this leukemia was genomically stable. Two mutations were present at subclonal levels both at diagnosis and relapse, of which one (FMN1) was detected at 4-fold higher levels in relapse (Table 1). The second patient showed substantially more subclonal variability, revealing a mutation in GHR at diagnosis that was lost at relapse, and three mutations that appeared as novel mutations in the second relapse. These latter mutations thus may have been induced during treatment of the first relapse. Three mutations were detected at subclonal levels already at diagnosis, albeit in very low amounts for RANBP17 (Table 1). Based on these findings, we conclude that i) using paired whole-exome sequencing of diagnosis, remission and relapse samples we have identified novel somatic mutations in childhood ALL, ii) amplicon-based ultra-deep sequencing allows the sensitive detection of relapse-prone subclones at diagnosis, iii) this sequencing effort provides insight into the complex dynamic architecture of clonal diversity in childhood ALL. Table 1. Subclonal mutations in relapsed childhood ALL patients patient gene mutation status at relapse mean read depth per sample % variant reads diagnosis (1st) relapse 2nd relapse 1 FMN1 subclonal outgrowth 20,292 8% 34% - 1 NAT8 preserved subclone 4,249 24% 27% - 2 GHR lost 14,530 38% 0% 0% 2 ARHGEF1 acquired 14,370 0% 0% 44% 2 PNPLA8 acquired 19,301 0% 0% 44% 2 IQGAP1 acquired 19,811 0% 0% 46% 2 RANBP17 subclonal outgrowth 30,260 <0.1% <0.1% 43% 2 RAG3A subclonal outgrowth 10,935 0.7% 1.0% 49% 2 PTPN5 subclonal outgrowth 4,228 9% 49% 44% Disclosures: No relevant conflicts of interest to declare.
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Soverini, Simona, Alessandra Gnani, Sabrina Colarossi, et al. "Long-Term Mutation Follow-up of Philadelphia-Chromosome Positive Leukemia Patients Treated with Second-Generation Tyrosine Kinase Inhibitors after Imatinib Failure Shows That Newly Acquired Bcr-Abl Kinase Domain Mutations Leading to Relapse Are Mainly Detected during the First Year." Blood 112, no. 11 (2008): 2118. http://dx.doi.org/10.1182/blood.v112.11.2118.2118.
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Abstract Resistance to imatinib in Philadelphia-positive (Ph+) leukemia patients is often associated with selection of point mutations in the Bcr-Abl kinase domain (KD). Dasatinib and nilotinib are second-generation tyrosine kinase inhibitors (TKIs) with different binding modes with respect to imatinib, that have been shown to confer in vitro and in vivo activity against many Bcr-Abl mutated forms. However, both dasatinib and nilotinib have been shown to retain some ‘Achilles heels’, and they include both imatinib-resistant mutations (e.g., T315I) and some novel, inhibitor-specific ones. Selection of either type of KD mutations has frequently been observed in patients (pts) who relapse after an initial response to dasatinib or nilotinib and represents one of the major hurdles on the road to successful treatment of imatinib-resistant pts. We have monitored Abl KD mutation status in a total of 121 pts who received dasatinib (n= 78) or nilotinib (n=43) as 2nd TKI after imatinib failure since February 2005. Fifty-eight (48%) pts had chronic phase (CP) chronic myelogenous leukemia (CML), 63 pts (52%) had accelerated phase (AP) or blast crisis (BC) CML or Ph+ acute lymphoblastic leukemia (ALL). Median age was 55 years (range, 18–76); median time from diagnosis was 49 months (range, 4–181); median time on imatinib was 32 months (range, 4–66). Median follow-up of all pts who received a 2nd TKI is 7 months (range, 1–38). Median follow-up of pts who are still on 2nd TKI treatment is 32 months (range, 28–38). Relapses after an initial response have so far been observed in 46/121 pts. Thirty-eight out of these 46 pts had AP/BC CML or Ph+ ALL at the time 2nd TKI was started. Forty-one out of 121 (34%) pts have experienced relapse after an initial response during the first 12 months of 2nd TKI treatment (median time to relapse, 6,5 months; range 4–12 months), while only five of the 45 (11%) pts who were still on 2nd TKI treatment after &gt;12 months have relapsed (at 13, 15, 18, 20 and 33 months, respectively). Interestingly, none of these 5 pts had never achieved more than a minor cytogenetic response (CgR), and 4/5 pts were receiving a reduced TKI dose because of toxicity. In 36/46 (78%) cases, relapse was associated with newly acquired Abl KD mutations. In particular 26/30 (87%) pts who relapsed on dasatinib and 10/16 (63%) pts who relapsed on nilotinib had evidence of a newly acquired KD mutation presumably responsible for treatment failure. Newly acquired mutations in pts who relapsed on dasatinib as 2nd TKI were T315I (n= 12 pts) F317L (n= 8 pts) T315A (n=3 pts); V299L (n=3 pts); F317I (n=2 pts); 2 pts had multiple mutations. Newly acquired mutations in pts who relapsed on nilotinib as 2nd TKI were E255K (n=3); E255V (n=2); Y253H (n=2); T315I (n=1); F359V (n=1); F359C (n=1). Sixteen pts (but none of those harboring the T315I) switched to dasatinib or nilotinib or high-dose imatinib as 3rd TKI and this rescued hematologic or even cytogenetic responses in a proportion of cases. Our observations suggest that: newly acquired mutations leading to relapse in Ph+ leukemia pts receiving dasatinib or nilotinib as 2nd TKI usually arise rapidly; the likelihood of mutation selection consistently decreases over time, and seems mainly confined to advanced phase pts and to pts with no or minor CgR; almost all (87%) cases who developed resistance to dasatinib had newly acquired KD mutations - suggesting that the higher potency with respect to imatinib can overcome Bcr-Abl gene amplification and that Src kinase inhibition may turn off Bcr- Abl-independent resistance mechanisms; a lower incidence (63%) of newly acquired KD mutations was observed in pts who developed resistance to nilotinib; with the exception of T315I, there is little if no overlap between dasatinib and nilotinib-resistant mutants, which may allow to regain responses by switching TKIs.
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Leblay, Noemie, Sungwoo Ahn, Sheri Skerget, et al. "A High-Risk Subgroup Multiple Myeloma Classification Based on the Detection of PR Minor Subclones." Blood 142, Supplement 1 (2023): 1941. http://dx.doi.org/10.1182/blood-2023-189567.
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In the last two decades several classifications of Multiple Myeloma (MM) have been proposed based on gene expression signatures. These include the supervised translocation and cyclin D (TC) molecular subgroup approach or unsupervised methods to elucidate the molecular heterogeneity of MM and identify high risk subgroups. In particular, two RNA based gene expression studies have identified 8 to 10 unique subtypes, including the MS, MAF, CD1, CD2, and PR subtypes. The PR subgroup represents a highly proliferative gene signature that is associated with very poor survival outcomes. However, assigning this PR subgroup based on bulk transcriptome signatures can be challenging giving the mixture of genetic backgrounds that can be observed within this subtype. Furthermore, the presence of a minor PR subclone can often be missed with bulk genomic studies leading to the misclassification of a patient as standard risk. We here postulated that minor PR subclones expand under selective therapeutic pressures to become the predominant clones at subsequent relapses and the presence of PR subclones can impact any of the molecular subgroups pertaining poor survival outcomes. Bulk RNA or single cell RNA (scRNAseq) analysis were performed in bone marrow sorted primary MM cells obtained from 718 patients from the CoMMpass trialand 32 relapse/refractory MM patients, respectively. For scRNAseq, serial samples with paired baseline and relapse samples were available in 18 cases. Bone marrow plasma cells samples were separated from bone marrow aspirates using positive sorting selection of CD138 + cells. For bulk RNA-seq we used the mRNA HyperPrep kit (Kapa Biosystems) with RNA from 50,000 cells.For scRNA studiesunbiased mRNA profiling was conducted using the GemCode system (10x Genomics). Cell Ranger and Seurat were used for sample de-multiplexing, barcode processing, single-cell 3' gene and data analysis. Sequencing was performed on Illumina. By performing GSEA at the single cell level using the Zhan gene data set we have classified patients in the appropriate TC groups. FISH data was used to insure accurate calls. For the survival analysis OS was analyzed by the Kaplan-Meier method. In the CoMMpass dataset, with bulk RNA sequencing, the PR subtype contained 7.1% of patients with an admixture of classic genetic subtypes and very poor clinical outcome, with a median OS of 21.3 months. High proliferation index scores were concentrated in this subtype. There was also a strong tendency for patients to transition to the PR subtype at progression, with 25.5% of patients in a non-PR subtype at diagnosis transitioning to PR. Regardless of original subtype, patients that transitioned to the PR subtype rapidly succumbed to their disease with a median OS after the detected progression of 88 days. Using subtype prediction weight we could identify non-PR patients with PR subtype weights above 5% and these patients have a significantly shorter OS of 50 months compared to patients with &lt;5% PR. At the single cell level, investigating the relapsed patients cohort, we have analyzed 92,139 cells and identified 59 clusters. A PR signature (defined as present in ≥15% of cells) was identified in 38% of cases despite baseline favorable prognostic group by FISH cytogenetics (7% HP, 28% t(11;14), and 57% normal FISH). A good concordance with FISH data was observed. In serially relapsed paired samples, all the PR patients maintain their signature overtime and 44% of patients transitioned to PR at subsequent relapse (Fig1A). Survival analyses were performed to evaluate how the presence of minor PR clones at the single cell level relate to clinical outcomes. Notably, the overall survival of patients classified as PR was dramatically reduced with a median OS of 6 months compared to 34 months for non-PR patients (Fig1B). In conclusion, we here show that minor PR clones defined by transcriptional signature through bulk or scRNA may be detectable in patients with variable MM molecular subgroups, including those classified as standard risk by the currently adopted classifications. We also show that the presence of these PR minor clones pertains adverse outcomes with very poor survivals. At relapse, most acquired PR cases originated from standard-risk presentations consistent with a Darwinian clonal evolution. Future classifications should account for the presence of these PR subclones for a better disease prognostication and developments of novel therapeutics.
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Shlush, Liran I., Amanda Mitchell, Lawrence Heisler, et al. "On the Origins of AML Relapse." Blood 126, no. 23 (2015): 223. http://dx.doi.org/10.1182/blood.v126.23.223.223.
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Abstract While induction into remission is effective in the majority of acute myeloid leukemia (AML) patients, disease recurrence is common, especially among the elderly. Understanding the origins of AML relapse would permit better treatments targeting the specific cells that survive chemotherapy. While some evidence suggests that AML relapse can originate either from a minor or a major clone that is already present at diagnosis, the exact origins of AML relapse are still obscure. In the current study we aimed at identifying the origins of AML by identifying genetic variants that appear at relapse, and to then track these variants back into specific cell populations present at diagnosis. We hypothesized that relapse might have multiple origins: from the major blast population, from rare leukemia imitating cells (LIC) as detected using xenografting, or from preleukemic stem cells (preL-HSCs). Methods: The bulk diagnosis and relapse samples of peripheral blood from eleven AML patients were analyzed, first by whole genome sequencing (50X coverage) to identify somatic mutations and genetic variants which were specifically present at relapse (relapse variants-RVs). The presence RVs was then reassessed in phenotypically defined sub-fractions sorted from the diagnosis samples, at a sensitivity of 1 in 1000 by digital PCR. The following sub-populations were genotyped: 1) isolated CD33+ blasts (the major population) 2) phenotypically defined leukemic and preleukemic stem cells 3) functionally defined leukemia initiating cells (LICs) harvested from xenografts (an average of 30 xenografts were generated from each diagnosis and relapse sample). Results: LICs, but not the dominant blast population from diagnosis carried the RVs in 3 of 11 cases. In these patients CD33-CD34+CD45RA+ immature cells from diagnosis also carried the RVs. In a second subset of 3 of 11 AML samples, relapse originated from a minor clone present within the CD33+ leukemic blasts; these samples did not produce exnografts. Other samples (2/11) exhibited relapse samples that arose from a combined origin (both LICs, and CD33+ blasts, or from the major clone (1/11). In two cases we could not identify the origins of relapse. As our initial results suggested that the cells responsible for AML relapse can come from distinct origins within the diagnosis sample, we next asked whether other functional and phenotypic differences might be present between the patients that have different relapse origins. RNA sequencing analysis of bulk cells from diagnosis demonstrated a remarkable clustering of the global gene expression that correlated with the origin of relapse. Unsupervised hierarchical clustering grouped together the AML samples who relapsed from the LICs, while all other samples were in a very distinct second cluster. The gene expression signature of the samples that relapsed from LICs was consistent with a monocytic phenotypic signature, while the other samples were more progenitor-like. To further expand and validate our findings we used the same unsupervised clustering on the RNA sequencing data of AML samples who relapsed in the TCGA dataset (n=86). Remarkably, the similar two main clusters were generated; comparison by GSEA provided evidence that the gene expression clusters in our study were generated by the same genes as in the TCGA clusters. Conclusion: Our results provide for the first time evidence that AML can relapse from distinct, predictable and pre-existing origins: AMLs with a monocytic phenotype relapse from chemo-resistant LICs; and AMLs with a progenitor gene expression pattern (yet lacking xenografting capacity) that relapse from CD33+ cells. These results pose a series of predictions as to the success of different therapies. For example, in the former group the major monocytic clone is sensitive to chemotherapy, yet relapse originates from CD33-CD34+CD45RA+ cells and would therefore be predicted to be resistant to Anti-CD33 therapeutics. On the other hand, relapse in the latter group originates from CD33+ cells and these are predicted to be sensitive to Anti-CD33 therapeutics. The results of this study document the complexity in origins of AML relapse and have important implications for the design of future more effective and personalized strategies for preventing AML relapse. Disclosures No relevant conflicts of interest to declare.
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Amin, Nisar A., Erlene Kuizon Seymour, Peter Ulintz, et al. "A Quantitative Analysis of Subclonal and Clonal Gene Mutations Occurring Pre- and Post-Therapy in 53 Cases of Chronic Lymphocytic Leukemia." Blood 126, no. 23 (2015): 2909. http://dx.doi.org/10.1182/blood.v126.23.2909.2909.
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Abstract Introduction: The landscape of gene mutations in CLL prior to therapy is well-characterized. Comparatively less is known about gene mutations and their frequency in CLL patients that have relapsed after potent chemo-immunotherapy. Further, despite knowledge of subclonal TP53 mutations that enrich and likely drive CLL relapse in a fraction of cases, a comprehensive profile of gene mutations and their variant allele frequencies (VAFs) and clonal dynamics before and after chemo-immunotherapy in CLL is lacking. Methods: We have procured paired pre-treatment and post-treatment samples from 53 CLL cases that had relapsed after chemo-immunotherapy and purified CLL CD19+ cells and CD3+ T-cells to purity with FACS. DNA from relapsed CLL was subjected to exome capture and whole exome sequencing (WES) at a mean coverage of 72-fold (range 52-102) and sequence data analyzed using three variant callers: MuTect v.1.1.4, Strelka v.1.0.13, and VarScan2 v.2.3.7. Somatically acquired gene mutations occurring in 2 or more rCLL cases were confirmed by Sanger sequencing in relapsed CLL samples and also re-sequenced in pre-treatment samples. Genes with mutation frequencies ≥5% in rCLL underwent custom gene panel-based deep coverage re-sequencing in paired pre-treatment and post-treatment samples. Analysis of deep re-sequencing data was done using the Broad GATK HaplotypeCaller v3.3.0 in parallel with VarScan2. Selected low-level variants were measured using droplet digital PCR (ddPCR) that was adapted to detection of VAFs as low as 1/10,000. Results: In CLL relapsed from potent chemo-immunotherapy, we detected mutated TP53, NOTCH1, SF3B1, XPO1, BIRC3, MYD88, NXF1, POT1, CACNA1E, CHD2, EGR2, FAM50A, FAT3, FBXW7, MGA, SAMHD1 and ZMYM3 with frequencies ≥5%. An additional 64 genes were mutated in 2/53 rCLL cases each. We performed ultra-deep panel-based re-sequencing of the 17 genes with frequencies ≥5% in 53 paired diagnosis and relapse samples, complementing selected variants with ddPCR validation to determine VAFs. TP53 mutations constituted the most frequently enriched gene at relapse (7/53=13%) and the VAFs of all TP53 mutations substantially increased at relapse often from very minor subclones at diagnosis. Importantly, none of the clonal TP53 mutations in rCLL appeared directly induced by chemotherapy, but instead all were selected from pre-existing subclones. Similarly, subclonal mutations in SAMHD1 substantially enriched in four cases at relapse (4/53=8%) suggesting a role in resistance to chemotherapy. The majority of NOTCH1 mutations (8/13) were already fully clonal at diagnosis without further enrichment at relapse. Three (3/13) subclonal NOTCH1 mutations substantially enriched at relapse, while two (2/13) clonal NOTCH1 mutations substantially decreased. The VAFs for SF3B1 mutations similarly demonstrated three patterns: i) clonal that remained clonal (4/10), ii) clonal that substantial declined and became subclonal at relapse (4/10), and, iii) subclonal that enriched but remained subclonal (2/10) at relapse. Of the 13 remaining genes, most demonstrated no consistent enrichment or depletion or remained subclonal at relapse. Of biological interest, the genes FBXW7, MYD88, NOTCH1, NXF1, ZMYM3, XPO1, SF3B1 and POT1, were often already fully clonal in the pre-treatment samples, suggesting an early role in CLL pathogenesis rather than a later role in the development of CLL relapse. Conclusion: In this large WES study focused on gene mutations in relapsed CLL paired with analysis of subclone dynamics using deep panel re-sequencing and ddPCR, we identify the genes TP53 and likely SAMHD1 as drivers of CLL relapse in 20% of cases. Multiple other genes previously implicated as CLL drivers did not consistently enrich at relapse. Further, a subset of the mutated genes was often already fully clonal pre-treatment; these genes likely serve an important role early in CLL pathogenesis that is independent of therapy. The majority of relapsed CLL in this cohort were not associated with the recurrent clonal emergence of known CLL driver mutations and based on the gene mutations frequencies reported here, much larger rCLL cohorts would need analysis to confirm possible additional low frequency gene drivers of rCLL. Disclosures Malek: Gilead Sciences: Equity Ownership; Abbvie: Equity Ownership; Janssen Pharmaceuticals: Research Funding.
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Zhang, Jinghui, Mignon L. Loh, Xiaotu Ma, et al. "Comparison Of Mutational Profiles Of Diagnosis and Relapsed Pediatric B-Acute Lymphoblastic Leukemia: A Report From The COG ALL Target Project." Blood 122, no. 21 (2013): 824. http://dx.doi.org/10.1182/blood.v122.21.824.824.
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Abstract Characterization of the genetic landscape of relapsed pediatric acute lymphoblastic leukemia (ALL) and changes that occur with disease progression provides insight into the molecular basis of relapse and may identify new therapeutic targets. We analyzed 20 diagnosis-remission (germline)-relapse trio samples of pediatric B-ALL by high-coverage (>200x) whole-exome sequencing. Included patients were originally NCI high risk (HR) by either age (≥10 years) or white blood count (≥50,000/microliter), enrolled on a Children’s Oncology Group B-ALL trial, and experienced bone marrow relapse. Samples were selected based upon availability of sufficient high quality material from all three time points. We identified recurrent relapse-specific somatic mutations in 5 genes with significant frequency found in genes encoding the purine 5’ nucleotidase NT5C2 (n=7, 35%) and the histone acetyltransferase CREBBP (n=2, 10%). Furthermore, we discovered novel recurrent somatic mutations that were highly enriched in relapsed ALL (20%) compared with diagnosis (5%) in WHSC1, USH2A and NT5C1B, another enzyme involved in purine metabolism. Three of the four WHSC1 mutations cause the same amino acid change E1099K in the highly conserved SET domain in which structural modeling predicts perturbed WHSC1-substrate interactions resulting in increased WHSC1 activity. The WHSC1 and NT5C2 mutations are mutually exclusive with a combined prevalence of 55% in relapsed tumors. Analysis of a validation cohort of 63 independent trios from both NCI standard risk and HR cohorts replicated the findings in NT5C2 (n=8, 13%) and WHSC1 E1099K (n=6, 10%). Five pathways were significantly mutated at relapse with high-frequency somatic mutations present at diagnosis and/or relapse of the 20 ALL trio samples: the Ras signaling pathway (NRAS, KRAS, PTPN11, FLT3; 65%), genes involved in histone modification (MLL2, WHSC1, SETD2, CREBBP; 50%), purine metabolism (NT5C2 and NT5C1B; 45%), tyrosine kinase signaling (JAK2, CRLF2; 25%) and genes regulating B-cell development (PAX5, IKZF1; 15%). The median number of non-silent coding region sequence mutations in diagnostic samples was 10 (range 4-25) while that of the relapse samples was 25 (range 7-506) including 3 hypermutated samples with >100 non-silent mutations accompanied by a dominance of C(G)>T(A) substitution in relapse-specific mutations, suggesting a possibility that these mutations may be induced by a specific mutagen. Most of the diagnostic and relapse tumors were polyclonal based on diagnosis-relapse comparison of mutant allele fraction (MAF). Inter-tumor MAF of a recurrently mutated gene was highly heterogeneous despite an estimated >70% leukemia involvement for most specimens, suggesting presence of subclonal mutations. For example, NT5C2 MAF in the relapsed specimens ranges from a low of 0.08 to a high of 0.93. Ten relapsed specimens demonstrated evolution from a minor subclone (<10%) in the diagnostic specimen; 8 of the subclones have oncogenic mutations in NRAS, KRAS, JAK2, WHSC1 or CRLF2. A notable finding was the lack of preservation of specific clonal RAS pathway mutations from diagnosis to relapse as subclonal mutations in KRAS, PTPN11 and FLT3 present in diagnosis were replaced by a dominant NRAS mutation in relapse. We were also able to identify structural alterations present in both relapse and diagnosis tumors from exome sequencing data, including IGH@-CRLF2 fusion (n=2), BTG1 deletion (n=2), ETV6-RUNX1 fusion (n=1), intragenic deletion of RUNX1 (n=1) and MAP3K2 (n=1), focal amplification in the last exon of MYC (n=1) and a t(1;14)(p36;q32) translocation resulting in truncation of SLC2A5 and BTBD7. These results provide new insights into the genetic events contributing to the relapse of pediatric B-ALL, and suggest new potential therapeutic targets. Disclosures: No relevant conflicts of interest to declare.
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van Delft, Frederik W., Sharon W. Horsley, Kristina Anderson, et al. "Clonal Origins of 'late' Relapses in ETV6-RUNX1 Acute Lymphoblastic Leukemia.." Blood 114, no. 22 (2009): 1583. http://dx.doi.org/10.1182/blood.v114.22.1583.1583.
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Abstract Abstract 1583 Poster Board I-609 Approximately a quarter of B cell precursor childhood acute lymphoblastic leukemia (ALL) is characterized by an ETV6-RUNX1 (TEL-AML1) fusion gene and has an overall good prognosis. The majority of these children will be treated on the standard risk arm of the United Kingdom ALL treatment protocols. Relapse usually occurs after cessation of treatment but remarkably can present many years later. The incidence of ETV6-RUNX1 at relapse has been reported to be less than or similar to de novo ALL. Molecular studies on neonatal bloodspots and on twins with concordant ALL have demonstrated the prenatal origin of major subtypes of childhood ALL, including most ETV6-RUNX1 fusion gene positive cases. In addition these investigations have suggested the existence of a preleukaemic stem cell requiring additional mutations or ‘hits’ in order to develop frank leukemia. To understand the genetic basis and clonal origin of late relapses we have compared the profiles of genome-wide copy number alterations (CNA) at relapse versus presentation in samples matched with remission DNA from 24 patients. The selected samples had tumor cell purity >75% before DNA extraction. DNA copy number alteration data was generated using the Affymetrix 500K SNP arrays. LOH analysis was performed using CNAG 3.0 and dCHIP 2008. Overall we identified 168 CNA at presentation and 252 at relapse (excluding deletions at IgH and TCR loci), equating to 6.96 and 10.3 CNA at presentation and relapse respectively. Although the number of CNA increased at relapse, no single gene or pathway was uniquely targeted in relapse. The most frequent alterations involved loss of 12p3.2 (ETV6), 9p21.3 (CDKN2A/B), 6q16.2-3 and gain of 21q22.1-22.12. A novel observation was gain of part or whole of chromosome 16 (2 patients at presentation, 5 at relapse) and deletion of the oncogene Plasmocytoma Variant Translocation 1 (PVT1) in 3 patients. Pathway analysis demonstrated frequent involvement at presentation and relapse of genes implicated in both B cell development (44 versus 46%) and cell cycle control (46 versus 71%). In order to study the clonal origin of relapse, we devised a classification describing the change in CNA between presentation and relapse in each individual patient. The clonal relationship between the presentation and relapse clone was established by the persistence of both the ETV6-RUNX1 fusion and at least 1 Ig and/or TCR rearrangement. We used a classification focussed on ‘driver’ CNA, defined as CNA that target genes functionally involved in leukemogenesis or CNA that are recurrently targeted as described in the literature. The four categories of relapse were type 1 (the dominant clone at presentation presented unchanged at relapse), type 2 (the relapse clone was derived from the major subclone at presentation with additional CNA), type 3 (the relapse clone was derived from a minor clone at presentation with gains and losses of CNA) and type 4 (the relapse clone is derived from an ancestral or preleukemic clone at initial presentation with all CNA gained). Twenty-one of the 24 patients were classifiable in this way (Figure 1). Although comparative relapse / presentation CNA profiles cannot identify precise clonal origins of relapse, the data indicate that irrespective of time to relapse (<2 to 9.9 years), the relapse clone appeared to be derived from either a major or minor clone at diagnosis with none (0/6) of the very late relapses (>5 years) derived from pre-leukemic cells lacking CNA. This data indicate diverse clonal origins of relapse and extended periods of dormancy, possibly via quiescence, for stem cells in ETV6-RUNX1+ ALL. Relapse type Remission duration (years) < 2 2 - 5 > 5 1 • • 2 • ••••••• •• 3 •• •• ••• 4 •• Figure 1. Each patient is represented by a black dot. Each patient is classified on the basis of the relapse type and remission duration. Disclosures No relevant conflicts of interest to declare.
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Liu, C., and L. D. Blumhardt. "Assessing relapses in treatment trials of relapsing and remitting multiple sclerosis: can we do better?" Multiple Sclerosis Journal 5, no. 1 (1999): 022–27. http://dx.doi.org/10.1177/135245859900500105.
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Published Phase III immunomodulatory treatment trials in relapsing and remitting multiple sclerosis have demonstrated a modest decline in attack rates, but only a minor effect on disability. As genuine disability progression is difficult to ascertain in relatively short studies with the conventional rating scales available, the acquisition and analysis of relapse data are critical. However, there are as yet unresolved questions related to the latter. We will first discuss the problems associated with relapse definitions by trial investigators, the paucity of the data collected (especially on the magnitude and duration of exacerbations) and statistical issues in their analysis. We will then suggest practical points for obtaining more accurate information on relapses and evaluating them meaningfully. While there is still general consensus among neurologists that primary endpoints for therapeutic trials should be clinical, improvements for future protocols are essential.
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Pulsoni, Alessandro, Irene Della Starza, Maria Elena Tosti, et al. "Early Stage Follicular Lymphoma. Predictive Role of Minimal Residual Disease (MRD) and Impact of MRD-Driven Treatment with Radiotherapy and Rituximab on Clinical Outcome." Blood 128, no. 22 (2016): 2959. http://dx.doi.org/10.1182/blood.v128.22.2959.2959.
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Abstract Background. In localized follicular lymphoma (FL, stage I-II), BCL2/IGH+ cells can be detected in the peripheral blood (PB) and/or bone marrow (BM) in 66.7% of cases (Pulsoni et al, BJH 2007). We hereby analyzed the prognostic impact of MRD in localized FL and explored the possibility of a MRD-guided therapeutic approach on a series of patients with a long follow-up. Methods. Between April 2000 and February 2015, 67 consecutive patients with a confirmed histologic diagnosis of stage I/II FL followed at our Center were enrolled in the study. PB and BM samples were collected at enrollment in all patients and investigated by qualitative PCR to identify the presence of a BCL2/IGH rearrangement. Paraffin-embedded lymph nodes (LN) were studied when available. Patients who proved positive at baseline were studied for MRD every 6 months. Real-Time Quantitative PCR (RQ-PCR) was retrospectively performed according to material availability. All patients were treated with involved field radiotherapy (RT) (24-30 Gy); from 2005, patients who were MRD+ after RT received rituximab (R) (375 mg/m2, 4 weekly administration). The median follow-up is 67 months (17-183); 21 patients (31%) have relapsed after a median of 37 months (17-165) from diagnosis. Results. At baseline, a clonal marker was found by qualitative PCR in 48/67 cases (72%): 36 were MBR+ (54%), 6 mcr+ (9%), 6 showed a minor BCL2 rearrangement (9%), while 19 (28%) were negative. Fifteen of the latter 19 were analyzed by RQ-PCR and 4 proved MBR+. Of the 13 available LNs, 11 showed the same molecular marker identified in the PB/BM; 2 cases, negative in the PB/BM, showed a rearrangement in the LN only. After RT, 40/42 MBR+/mcr+ patients were analyzed: 20 resulted MRD-, while 20 persisted MRD+. Regardless of the post-RT MRD status, an equal number of relapses was recorded in both groups (7 each). R treatment was administered to the 20 MRD+ patients after RT. Sixteen (80%) achieved a MRD- status after R: over time, 7/16 patients converted to MRD+ and 4 relapsed, whilst 9/16 patients (56.2%) remain persistently MRD- and none has relapsed so far. To evaluate the impact of R, we considered a series of 27 patients MRD+ after RT or who were MRD- and became MRD+ during the follow-up. Of the 19 patients who received R (1 could not be studied), 15 (79%) did not relapse, while of the 8 untreated patients (pre-2005), 6 (75%) relapsed (p=0.025). Progression-free survival (PFS) was significantly longer for R-treated patients (p=0.0412) (Fig. 1). To define the predictive role of MRD in the entire cohort regardless of post-RT treatment, we considered the 39 patients with molecular follow-up. Thirteen have relapsed: 10/13 (77%) were MRD+ in the follow-up, including the pre-relapse time point, while 3 resulted persistently MRD-. Contrariwise, of the 26/39 patients in continuous remission, 18 (69%) were persistently MRD- while 8 were MRD+ (p=0.015). PFS was significantly better for MRD- patients (p=0.0163) (Fig. 2). RQ-PCR was performed in 30 MBR+ patients: 17 (57%) showed a tumor burden ≥10-5 and 13 <10-5. Tumor burden at diagnosis predicted the MRD clearance following RT: 9/13 (69%) cases with low tumor burden resulted MRD- after RT compared to 2/17 (12%) cases with high tumor burden (p=0.0027). Contrariwise, tumor burden did not predict the occurrence of relapse. Conclusions. Early stage FL at diagnosis can have a heterogenous disease extension: 2 of our cases were truly localized, showing a molecular marker only in the LN. However, in most cases the use of combined qualitative approaches, including canonical MBR/mcr and minor rearrangements, together with RQ-PCR has allowed to identify circulating BCL2/IGH+ cells (52/67 cases: 77.6%), despite a negative BM biopsy. RT induced a MRD negativity in 50% of BCL2/IGH+ patients, but this did not impact on clinical outcome. The administration of R in MRD+ patients decreased significantly the risk of a subsequent relapse and improved PFS. Regardless of treatment, MRD positivity during the follow-up is a predictor of relapse and PFS. Tumor burden at diagnosis is associated with MRD clearance after RT. We support the use of a MRD-driven treatment with anti-CD20 monoclonal antibodies in patients with localized FL after RT. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Kuba, Nahoko, Shintaro Shiobara, Tatsuo Hurukawa, Jyunichi Tsukada, Sinji Nakao, and Mine Harada. "Incompatibilities of HA-1 and 3 Polymorphic Adhesion Molecules Including CD62L, CD31 codon563 and CD31 codon125 Induce Graft-Versus-Leukemia Effect Rather Than GVHD Resulting in Long-Term Survival in HLA Identical SCT." Blood 106, no. 11 (2005): 3095. http://dx.doi.org/10.1182/blood.v106.11.3095.3095.
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Abstract Mismatches of minor histocompatibility antigen (mHag) between HLA identical stem cell donor and host are known as a major risk factor for graft-versus-host disease (GVHD). We determined the alleles of 4 polymorphic molecules including HA-1 and 3 adhesion molecules; CD62L, CD31 codon563 and CD31 codon125 in 114 patients transplanted HLA identical stem cell grafts and investigated the association of mismatches as rates of relapse and GVHD. All 114 recipients underwent stem cell transplantation after myeloablative conditioning between 1985 and 2004. Risk ststus of the disease at SCT was standard (n=71) and high (n=43). After SCT, 36, 57 and 35 developed acute GVHD (≥2), chronic GVHD and relapsed, respectively. Our patients relapsed at rates of 14.3% and 38.0% with one or more and without incompatibilities (P=0.011). In standard risk group, the relapse rates of 20 and 51 patients with and without mHag incompatibilities were 5.0% and 39.2%, respectively (P=0.011). The relapse rates of patients with CD62L, CD31 codon563, HA-1, CD31 codon125 incompatibilities were 5.3%, 11.8%, 16.7%, 23.1% respectively. The frequency of acute GVHD (≥2) did not differ regardless of incompatibilities. The probability of 10 year survival rates were 84.0% with incompatibility and 54.3% without incompatibility patients (P=0.009). Our data suggests that incompatibilities of at least one of 4 polymorphic molecules contribute to GVL effect rather than to GVHD, resulting in prolonged survival after HLA identical SCT. Figure Figure
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Charbonnier, Amandine, Berengere Gruson, Delphine Lebon, et al. "Sequential Allogeneic Transplantation for Multiple Myeloma Patient in Early Relapse Post-Autograft." Blood 128, no. 22 (2016): 5768. http://dx.doi.org/10.1182/blood.v128.22.5768.5768.
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Abstract Multiple myeloma (MM) remains mostly incurable despite novel therapeutic approaches. Allogeneic stem cell transplantation (ASCT) in MM could be the only curative treatment but is associated with a high morbidity and mortality, and relapses remain, mainly in high risk (17p deletion, (4;14) translocation, plasma cell leukemia, extramedullary disease or early relapse post-autograft). In refractory or poor risk cytogenetic acute myeloid leukemia (AML), sequential conditioning, followed by prophylactic immunomodulation with donor lymphocyte infusion (DLI), seems improve the outcome, compared to conventional ASCT regimens. Based on this sequential approach ASCT, we developed a sequential conditioning for MM, with a systematic immunomodulation strategy. The conditioning included melphalan 100mg/m² at day-10, followed by FB2 conditioning (fludarabine 30mg/m²/d day-6, -5,-4, -3, -2, busulphan 3.2mg/kg/d day-5, -4 and horse antithymoglobulin 2.5mg/kg/d day-3, -2). Prophylaxis of GVHD included cyclosporine and methotrexate according to ABO compatibility. This schema was proposed for young patients with early relapse after autograft (<1 year). The aim of the study was to evaluate feasibility and safety. In the absence of GVHD, 2 cycles of bortezomib (1,3mg/m² day 1, 4, 8, 11) without steroids followed by 3 escalated doses of DLI. Four patients received this sequential conditioning. All were low risk cytogenetic but were in early relapse post-autograft. Patients' characteristics are shown in table1. One patient received 2 autologous transplantation (patient 3). They received 2 or 3 lines of combination chemotherapy before allograft including: bortezomib (n=4), lenalidomide (n=4), pomalidomide (n=1). All of them were in partial response at time of ASCT. All patients were grafted with peripheral blood stem cells (median dose = 8 CD34+/kg [5.44-8.15]). Only one patient received methotrexate in addition to cyclosporine for GVH prophylaxis for ABO minor incompatibility. Two patients presented grade 3-4 acute GVHD: 1 was steroid-resistant and responded secondary to ruxolitinib, but unfortunately he died of septic shock. Patient 4 was in sCR with MRD negative 6 months post ASCT but currently presents signs of disease evolution without treatment criteria at 10 month. Two patients didn't presented GVHD and received prophylactic schedule with bortezomib followed by escalated doses of DLI. Three doses of DLI were planned: first dose=5x106 CD3+/kg, second dose=1x107CD3+/kg and third dose=5x107CD3+/kg. Only 2 doses were administrated because patients relapsed before the third dose. Patient 3 presented limited chronic GVHD (oral lichen) after DLI2 but relapsed 11 months post ASCT. Patient 1 relapsed at 10 months: they were retreated with pomalidomide and are now alive. In conclusion, sequential conditioning for young patients with MM in early relapse post-autograft is feasible. The addition of melphalan to the classical FB2 is safe without early toxicity (no mortality related to transplantation at day +100). 2 patients however presented severe acute GVHD. Despite the post ASCT immunomodulation, this procedure was not capable to control the disease. The optimization of conditioning procedure, the post-allograft immunomodulation and a maintenance therapy may provide a benefit to patients and, thus, requires further study. Table 1 Table 1. Disclosures No relevant conflicts of interest to declare.
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Rutherford, P., and D. Götte. "SAT0248 PATTERNS OF DRUG TREATMENT FOR MAINTENANCE PHASE OF ANCA-ASSOCIATED VASCULITIS (AAV) IN REAL WORLD PRACTICE IN EUROPE – PROLONGED GLUCOCORTICOID USE IS COMMON AND VARIOUS TREATMENT REGIMES ARE USED." Annals of the Rheumatic Diseases 79, Suppl 1 (2020): 1066.3–1067. http://dx.doi.org/10.1136/annrheumdis-2020-eular.848.
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Background:Maintenance therapy following remission induction in ANCA associated vasculitis (AAV) is required to prevent relapse but patients are also still at risk from long term organ damage. This can be due to disease activity and also adverse events from therapy in particular high dose and prolonged use of glucocorticoids (GC).Objectives:This retrospective study aimed to examine clinical outcomes and in particular the drug treatment used for maintenance in AAV patients managed in routine clinical practice in Europe.Methods:1478 AAV patients (France, Germany, Italy, Spain and UK) managed by 493 physicians (37% Rheumatologists) who completed induction therapy for organ or life threatening AAV and initiated maintenance therapy between 2014-16 were studied. Data were collected at the time maintenance was determined to begin by the physician and then at 6, 12, 18 and 36 months. 49% had granulomatosis with polyangiitis,; mean age 54.2 years with 56% male. 49% had incident AAV and 51% were studied from a relapse. 70% received cyclophosphamide and GC and 30% received rituximab (RTX) and GC for remission induction therapy.Results:Definition of maintenance start from the time of incidence/relapse and initial maintenance therapy varied between incident patients (mean time 4.7 months, GCs 66%, Azathioprine 38%, RTX 19%, Cyclophosphamide 11%) and relapsed patients (mean time 6.5 months *, GCs 63%, Azathioprine 30% *, RTX 24% *, Cyclophosphamide 20% *, p<0.05 vs incident). RTX use was notably higher in relapsing patients in Italy, Spain and UK compared to incident patients. Control of AAV activity varied over follow up and prolonged GC use was common even after 36 months including in RTX treated patients.Maintenance start6 months12 months18 months36 monthsRemission full/partial %43 / 5059 / 3867 / 3072 / 2574 / 22Receiving GC %65615346395mg or less19405868725-10mg344135272310-20 mg2516644More than 20mg223211Receiving RTX %2121191714RTX alone101010118RTX + GC1010855RTX + other + no GC11111RTX maintenance schedules varied - 375mg/6 monthly 22%, 500mg/6 monthly 36%, 1000mg/6 monthly 31%, 375mg/12 monthly 1%, 500mg/12 monthly 4% and 100mg/12 monthly 3%. 32% had RTX initial regime adjustments on basis of B cell counts (44%), age (34%) or immunoglobulin levels (22%). Over 36 months 28% patients relapsed, 18% minor and 10% major (who then left follow up in this study). This led to greater GC use in the minor relapse patients at 36 months compared to those maintaining remission without relapse (48% vs 38%).Conclusion:Maintenance therapy regimes used in clinical practice in Europe are variable including on basis of incident vs relapsing disease yet full remission is often not maintained. Many patients remain on GCs for long periods placing the patients at higher risk of GC related adverse events and organ damage. Even minor relapse increases the prolonged use of GCs. The high burden of prolonged GC use in AAV should be more clearly recognized and new therapeutic approaches explored.Disclosure of Interests:Peter Rutherford Shareholder of: Vifor Pharma, Employee of: Vifor Pharma, Baxter Healthcare, Dieter Götte Shareholder of: Vifor Pharma, Employee of: Vifor Pharma
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Merkel, P. A., H. Yue, E. deGoma, P. Bekker, and D. Jayne. "OP0180 EFFECT OF AVACOPAN ON RELAPSE RATES AND RELAPSE-FREE TIME IN PATIENTS WITH ANCA-ASSOCIATED VASCULITIS, RESULTS OF THE PHASE 3 ADVOCATE STUDY." Annals of the Rheumatic Diseases 81, Suppl 1 (2022): 120. http://dx.doi.org/10.1136/annrheumdis-2022-eular.4283.
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BackgroundFor patients with ANCA-associated vasculitis, both failure to achieve remission and relapse after achieving remission are associated with worse long-term outcomes. Avacopan, an oral selective inhibitor of the C5a receptor, is approved for the treatment of ANCA-associated vasculitis. The phase 3 ADVOCATE study tested daily avacopan as a substitute for a standard oral glucocorticoid taper regimen. At week 26, the avacopan group achieved a remission rate (72.3%) comparable to the prednisone group (70.1%) and superior sustained remission at Week 52 (65.7% avacopan vs. 54.9% prednisone groups, respectively [1]). The median (mean) total glucocorticoid dose from all sources was 400 mg (1349 mg) in the avacopan group versus 2939 mg (3655 mg) in the prednisone group, representing 86% (63%) lower glucocorticoid exposure in the avacopan group. Compared with the prednisone group, the avacopan group showed a reduction in the proportion of patients who relapsed after achieving remission and, among patients who achieved remission, a longer time to relapse (1).ObjectivesTo further characterize efficacy, additional post-hoc analyses compared the avacopan and prednisone groups regarding i) failure to achieve remission and ii) relapse after achieving remission.MethodsADVOCATE, a phase 3, randomized, double-blind, controlled trial in 330 patients, evaluated the efficacy and safety of avacopan. Patients with ANCA-associated vasculitis (new-onset or relapsing disease) were randomized to receive avacopan 30 mg twice daily, or a standard 20-week oral prednisone taper, plus matching placebos, in addition to background immunosuppressant therapy. For the purpose of these analyses, remission was defined as the first timepoint when a BVAS of 0 was achieved. Relapse was defined as worsening of disease, after having previously achieved remission, that involved one or more major or three or more minor items in the BVAS, or one or two minor items in the BVAS recorded at two consecutive study visits.Two post-hoc sensitivity analyses of patients in the intent-to-treat population examined: i) the proportion of patients who failed to achieve remission, or achieved remission and subsequently relapsed after achieving that remission, and ii) relapse-free time. For patients who achieved remission, relapse-free time was calculated as the number of days from the initial remission achieved to relapse. For patients who failed to achieve remission, relapse-free time was imputed as one day (remission and relapse on the same day). Patients who did not relapse were censored at the time of the last BVAS assessment.ResultsBaseline characteristics and time to achieve initial remission were similar between groups, and the incidence of BVAS 0 at any point in the study occurred approximately equally in both groups (158 avacopan vs. 157 prednisone). In the first sensitivity analysis, the avacopan group showed a reduction in the proportion of patients who failed to achieve remission, or relapsed after remission, compared with the prednisone group (24 [14.5% vs 40 [24.4%], p=0.011). In the second sensitivity analysis that included all patients in the trial, the hazard ratio of relapse-free time for avacopan vs prednisone was 0.57, 95% CI (0.35, 0.96), p=0.029 (log-rank test) (Figure 1).Figure 1.Relapse-free time among patients with ANCA-associated vasculitis in ADVOCATE (intention-to-treat population).ConclusionIn the phase 3 ADVOCATE study of ANCA-associated vasculitis, more patients in the avacopan group compared to the prednisone group achieved remission, and fewer in the avacopan group relapsed after achieving remission. Patients receiving avacopan had a longer relapse-free time compared to the prednisone group. These post-hoc sensitivity analyses provide additional evidence of the efficacy of avacopan for the treatment of ANCA-associated vasculitis.References[1]Jayne D et al., Avacopan for the Treatment of ANCA-Associated Vasculitis. N Engl J Med 2021 384(7):599-609.Disclosure of InterestsPeter A. Merkel Consultant of: AbbVie, AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, ChemoCentryx, CSL Behring, Dynacure, EMDSerono, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, Immagene, InflaRx, Jannsen, Kiniksa, Kyverna, Magenta, MiroBio, Neutrolis, Novartis, Pfizer, Regeneron, Sparrow, Takeda, Talaris.Royalties: UpToDate., Grant/research support from: AbbVie, AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, ChemoCentryx, Eicos, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Sanofi, Takeda, Huibin Yue Shareholder of: ChemoCentryx, Employee of: ChemoCentryx, Emil deGoma Shareholder of: ChemoCentryx, Employee of: ChemoCentryx, Pirow Bekker Shareholder of: ChemoCentryx, Consultant of: ChemoCentryx, David Jayne Paid instructor for: Lecture Fees: Amgen, Vifor, Consultant of: Astra-Zeneca, BMS, Boehringer-Ingelheim, Chemocentryx, GSK, NICE, Novartis, Otsuka, Roche/Genentech, Takeda, UCB & Vifor. Board Member: Aurinia., Grant/research support from: Commercial: GSK, Roche/Genentech; Non-commercial: EU, MRC, NIHR, Versus Arthritis
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Parekh, Jay, Soniya Abraham, Karthik Chamarti, Yaw Adjepong, and Adolfo Enrique Diaz Duque. "Venetoclax for Mantle Cell Lymphoma: A Systematic Review and Meta-Analysis of Clinical Outcomes." Blood 142, Supplement 1 (2023): 6142. http://dx.doi.org/10.1182/blood-2023-187878.
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Background: No standard of care first line therapy has been established for treatment naive patients with mantle cell lymphoma (MCL). Limited options exist in the treatment armamentarium for patients who cannot tolerate induction therapy. Venetoclax (V) based regimens have been studied recently in retrospective studies and in early phase clinical trials. We aim to systematically review the evidence of efficacy and safety of V based regimens in mantle cell lymphoma. Methods: We carried out a systematic search on MEDLINE, Cochrane, ASH and ASCO meetings library. Screening was done to include studies with MCL patients who were treated with V monotherapy or any combination. Retrospective studies, case series, reports and reviews were excluded. Quality assessment was performed using methodological index for non-randomized studies (MINORS) tool. The primary efficacy outcomes evaluated included complete response (CR) by Lugano criteria, minimal residual disease (MRD) by flow cytometry, PCR or next generation sequencing (NGS). Safety outcomes evaluated included grade 3 or more adverse events including neutropenia and any tumor lysis syndrome (TLS) as assessed by common terminology criteria for adverse events (CTCAE) version 4. Predefined subgroup analysis was performed based on studies with first line vs RR disease and concurrent bruton tyrosine kinase inhibitor (BTKi) use vs not. Random effects model was used. Data was analyzed using R version 4.2.1. Results: 11 clinical trials with 300 patients were included. 5 out of 11 trials had V based regimen evaluated in treatment naïve population only while 3 trials evaluated only relapse refractory population. MRD assessment data was reported in 7 studies. V based combination regimens used in the trials are listed in table 1 below. Meta-analysis of 300 evaluable patients from 11 trials showed a pooled CR rate of 71% (95% CI: 61- 79%) with high heterogeneity (I 2 = 62%, p value 0.001)(figure 1). Pooled CR rate among studies with only treatment naïve patients was 82% (95% CI: 74 - 88%) with low heterogeneity (I 2 = 0%, p = 0.45) compared to other studies with pooled CR rate 62% (95% CI: 51 - 72%, I 2 = 41%, p 0.13) with significant difference between the two subsets by testing of moderator coefficient (p 0.009). However, there was no difference in CR outcomes noted based on studies conducted with concurrent (BTKi) use (p 0.7). Pooled analysis from 7 studies reporting MRD data revealed an overall MRD rate of 67%(95% CI: 56 - 78%) with high heterogeneity(I 2 = 57%, p 0.02). Pooled grade 3 or more neutropenia rate was 35%(95% CI: 14 - 58%, I 2 = 88%, p&lt; 0.01). The overall TLS rate among 9 reporting studies was 3.1%(95% CI: 0.2- 7.9%, I 2 = 46.7%, p 0.06). Conclusions: V is a viable option as part of treatment regimen for MCL patients with high response rates among treatment naïve patients as well and modest response rates among patients with relapse refractory disease. There is considerable heterogeneity of MRD rates accross studies, due in part to differences in study populations and to methodology of MRD testing. Pooled neutropenia and TLS rates appear to be low and make V a safe option as part of regimen.
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Richardson, Paul, Constantine Mitsiades, Robert Schlossman, et al. "The Treatment of Relapsed and Refractory Multiple Myeloma." Hematology 2007, no. 1 (2007): 317–23. http://dx.doi.org/10.1182/asheducation-2007.1.317.
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AbstractRelapsed and refractory multiple myeloma (MM) constitutes a specific and unmet medical need. Median survival ranges from as little as 6 to 9 months, and responses to treatment are characteristically short. Patients with relapsed/refractory disease are defined as those who, having achieved minor response or better, relapse and then progress while on salvage therapy, or experience progression within 60 days of their last therapy. In the era prior to the development of novel biologically based therapies for MM, relapse from successive treatment regimens resulted in progressively shorter response durations, which typically reflected emerging drug resistance, as well as changes in disease biology within each patient, with tumor cells expressing a more aggressive phenotype, higher proliferative fraction and lower apoptotic rates.Both bortezomid- and lenalidomide-based therapies are expecially active, with bortezomib in particular being shown to provide a platform for combinations able to overcome resistance in this setting. The addition of novel and conventional agents to the treatment backbone of lenalidomide, thalidomide, and bortezomib are areas of active study, with participation in clincial trials a clear priority for such patients. Clinical challenges in the relapsed/refractory population include light chain and IgA isotype, renal failure, extramedullary disease, hyposecretory myeloma, and advanced bone disease.