Journal articles: '73.42 age groups, initiation (ethnology)'

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Brett, Benjamin L., Katherine Breedlove, Thomas W. McAllister, Steven P. Broglio, Michael A. McCrea, April Marie (Reed) Hoy, Joseph B. Hazzard, et al. "Investigating the Range of Symptom Endorsement at Initiation of a Graduated Return-to-Play Protocol After Concussion and Duration of the Protocol: A Study From the National Collegiate Athletic Association–Department of Defense Concussion, Assessment, Research, and Education (CARE) Consortium." American Journal of Sports Medicine 48, no. 6 (April 16, 2020): 1476–84. http://dx.doi.org/10.1177/0363546520913252.

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Background: Organizations recommend that athletes should be asymptomatic or symptom-limited before initiating a graduated return-to-play (GRTP) protocol after sports-related concussion, although asymptomatic or symptom-limited is not well-defined. Hypotheses: (1) There will be a range (ie, beyond zero as indicator of “symptom-free”) in symptom severity endorsement when athletes are deemed ready to initiate a GRTP protocol. (2) Baseline symptom severity scores and demographic/preinjury medical history factors influence symptom severity scores at the commencement of the GRTP protocol. (3) Greater symptom severity scores at GRTP protocol initiation will result in longer protocol duration. (4) Symptom severity scores will not differ between those who did and did not sustain a repeat injury within 90 days of their initial injury. Study Design: Cohort study; Level of evidence, 2. Methods: Across 30 universities, athletes (N = 1531) completed assessments at baseline and before beginning the GRTP protocol, as determined by local medical staff. Symptom severity scores were recorded with the symptom checklist of the Sport Concussion Assessment Tool–3rd Edition. Nonparametric comparisons were used to examine the effect of medical, demographic, and injury factors on symptom endorsement at GRTP protocol initiation, as well as differences in symptom severity scores between those who did and did not sustain a repeat injury within 90 days. A Cox regression was used to examine the association between symptom severity scores at GRTP protocol initiation and protocol duration. Results: Symptom severity scores at the time when the GRTP protocol was initiated were as follows: 0 to 5 (n = 1378; 90.0%), 6 to 10 (n = 76; 5.0%), 11 to 20 (n = 42; 3.0%), and ≥21 (n = 35; 2.0%). Demographic (sex and age), medical (psychiatric disorders, attention-deficit/hyperactivity disorder, learning disorder), and other factors (baseline symptom endorsement and sleep) were significantly associated with higher symptom severity scores at the GRTP initiation ( P < .05). The 4 GRTP initiation time point symptom severity score groups did not significantly differ in total time to unrestricted RTP, χ2(3) = 1.4; P = .73. When days until the initiation of the GRTP protocol was included as a covariate, symptom severity scores between 11 and 20 ( P = .02; hazard ratio = 1.44; 95% CI, 1.06-1.96) and ≥21 ( P < .001; hazard ratio = 1.88; 95% CI, 1.34-2.63) were significantly associated with a longer GRTP protocol duration as compared with symptom severity scores between 0 and 5. Symptom severity scores at GRTP initiation did not significantly differ between those who sustained a repeat injury within 90 days and those who did not ( U = 29,893.5; P = .75). Conclusion: A range of symptom severity endorsement was observed at GRTP protocol initiation, with higher endorsement among those with higher baseline symptom endorsement and select demographic and medical history factors. Findings suggest that initiation of a GRTP protocol before an absolute absence of all symptoms is not associated with longer progression of the GRTP protocol, although symptom severity scores >10 were associated with longer duration of a GRTP protocol. Results can be utilized to guide clinicians toward optimal GRTP initiation (ie, balancing active recovery with avoidance of premature return to activity).

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Alekberova, Z., R. Goloeva, M. Cherkasova, and A. Lila. "AB0477 OVARIAN RESERVE IN PATIENTS WITH RHEUMATIC DISEASES." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1536.2–1537. http://dx.doi.org/10.1136/annrheumdis-2020-eular.3465.

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Background:Access to assays of circulating anti-Mullerian hormone (AMH) levels has opened a new page in the assessment of ovarian function and fertility in various diseases, including rheumatic diseases (RDs). The definition of AMH as a marker of ovarian reserve significantly simplified its interpretation as well as measuring the contribution of the disease itself to the patients’ infertility.Objectives:To evaluate the effects of the disease and it’s treatment on serum AMH levels for Behcet’s disease (BD), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and systemic scleroderma (SSD).Methods:The study included 73 patients with RDs from 18 to 40 years: 42 patients with BD, 12 with SLE, 11 with RA, 8- with SSD, the control group consisted of 15 healthy women. Enzyme-linked immunosorbent assay (ELISA) was used to measure AMH levels. Parametric and nonparametric statistical methods of Statistica 8.0 package were used for statistical processing of data.Results:Mean age in BD patients was 30.0 years, in SLE and RA -33.5 years, in SSD - 35.0 years, and 32.0 years in the control group. The average disease duration was 4.5 years, 11.5 years, 4.0 years and 6.0 years, respectively.BD, n=42SLE, n=12RA, n=11SSD, n=8Control, n=15Mean age, years30,0[26;35]33.5[29;38]33,5[24;36]35,0[28;40]32,0[26;35]Average disease duration, years4,5[2,6;9,0]11,5[2,8;18]4,0[4,0;6,0]6,0[2,0-10,0]-Mean AMH level, ng/ml2,5[1,1;3,7]3,5[0,4-7,1]3,35[2,0;7,6]2,5 [0,3;7,1]3,1[1,9;5,4]There were no significant differences in the mean AMH levels between the groups. No association between AMG levels and clinical manifestations, disease activity or duration of rheumatic disease was found. Baseline AMH – in treatment-naïve patients before initiation of any DMARDs was assessed in 11 BD patients. A significant (p>0.05) decrease of AMH levels was established in patients with high SLE activity treated with CP. Of notice, all examined patients were additionally receiving a GEBD -Rituximab.Conclusion:Decreased ovarian function was found in patients with high SLE activity treated with CP with Rituximab.Disclosure of Interests:None declared

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Moore, Amanda, Zohra Nooruddin, Kelly R. Reveles, Paromita Datta, Lance Brannman, Ion Cotarla, Andrew Frankart, Tiernan Mulrooney, Xavier Jones, and Christopher R. Frei. "Racial disparities in the clinical use of durvalumab for patients with stage III unresectable non–small cell lung cancer treated at Veterans Health Administration facilities." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 8526. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.8526.

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8526 Background: Evidence from the PACIFIC study and real-world data highlight the benefit of durvalumab in patients with stage III unresectable non-small cell lung cancer (UR-NSCLC). However, limited literature exists regarding disparities in durvalumab treatment patterns such as treatment initiation delays (TID), treatment interruptions (TI), number of doses, duration of therapy (DOT), adverse effects (AEs), and treatment discontinuation (TD) in minority populations. Methods: Patients with stage III UR-NSCLC and a self-reported racial identity of Black or White treated with durvalumab following chemoradiotherapy (CRT) at any Veterans Health Administration (VHA) facility from January 1, 2017 to June 30, 2020 were included. Patients were followed from their date of durvalumab initiation through the earliest of their last VHA visit, loss to follow up, death, or end of the study; therefore, all patients had the opportunity to be treated for 12 months. Patients were excluded if durvalumab therapy was ongoing at the end of the study. Patient charts were retrospectively reviewed for baseline characteristics and durvalumab treatment patterns including TID (>42 days from end of CRT to durvalumab start), TI (>28 days between doses), number of doses, DOT, AEs, and TD. Nominal variables were compared using chi-square/Fisher’s exact tests. Continuous variables were compared using Student’s t-tests/Wilcoxon Rank Sum tests. Results: Among 924 patients, Black patients were younger than White patients (median age 67 years [IQR, 63-71] vs. 70 years [IQR, 65-73]; p<0.01), more likely to be current smokers (54% vs. 45%; p=0.03), with more chronic liver disease (22% vs. 9%; p<0.01), but less COPD (63% vs. 72%; p=0.01). Black patients experienced more TI (25% vs. 18%; p=0.03) but TID, number of doses, DOT, and TD were similar between the groups. Black patients were less likely to have an immune-related AE (irAE) (28% vs. 36%; p=0.03) (and less pneumonitis (7% vs. 14%; p<0.01)). Toxicity was the reason for TD in 12% of Black patients vs. 20% of White patients (p=0.01), with no other significant (α < 0.05) differences in reported reasons for TID, TI, or TD between the groups. Conclusions: In this real-world study, Black patients experienced similar TID, number of doses, and DOT as White patients. Black patients were less likely to experience an irAE (including pneumonitis) but experienced more TI; TD were similar but more likely to be from toxicity for White patients. Future research is needed to validate these findings.[Table: see text]

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Cromer, Barbara A., R. David Smith, Jennifer Dwyer, Jamie McArdle Blair, and Robert T. Brown. "A Prospective Study of Adolescents Who Choose Among Levonorgestrel Implant (Norplant), Medroxyprogesterone Acetate (Depo-Provera), or the Combined Oral Contraceptive Pill as Contraception." Pediatrics 94, no. 5 (November 1, 1994): 687–94. http://dx.doi.org/10.1542/peds.94.5.687.

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Objectives. Levonorgestrel implants (Norplant) and medroxyprogesterone acetate injections (Depo-Provera) represent additional contraception options for adolescents. The purpose of this study was to examine prospectively clinical profiles among adolescents who chose one of the two long-term contraceptives compared with profiles among those who chose the combined oral contraceptive pill (OCP). Methods. Girls who needed contraception and did not require confidentiality were presented with a contraceptive menu consisting of Norplant (n = 58), Depo-Provera (n = 66), or OCP (n = 75). At baseline and follow-up visits over 6 months, patients were interviewed regarding gynecologic history, side effect symptoms, and satisfaction. The average age of subjects was 15.5 years (range 11 to 20 years); 66% were African-American and 34% white. Results. Significantly more teens who chose Depo-Provera (73%) reported having used some method of birth control previously than those selecting either Norplant (30%) or OCP (26%). Adolescents who chose either Norplant (34%) or Depo-Provera (43%) were significantly more likely to have been pregnant previously than those choosing OCP (12%). Those selecting Depo-Provera were significantly more likely to report a history of genital infection with Chlamydia trachomatis (42%) than those in the other two contraceptive groups (22%). Prevalences of reported recent depression and fatigue before initiation of treatment were high, exceeding 35% across the three groups. A total of 105 and 40 adolescents were assessed at 3 and 6 months, respectively. At follow-up, more than 80% of OCP users maintained regular menstrual cycles, whereas over 80% of those choosing Norplant or Depo-Provera had disrupted cycles. Complaints of nausea and dizziness among Norplant users and fatigue among Depo-Provera and OCP users increased significantly between the baseline and follow-up visits. Reports of local reactions to the Norplant device were common but not clinically significant. Blood pressure readings, facial acne, and body mass index did not change over time in any treatment group. Subjects in the Norplant and Depo-Provera groups appreciated freedom from daily compliance to maintain contraceptive effectiveness and the "hidden" nature of the method. Appointment compliance at the end of 6 months was 78% for Depo-Provera, 40% for Norplant, and 46% for OCP. Conclusions. The implant and injection forms of contraception appear to be especially popular among girls with previous pregnancies or birth control use. The common occurrences of medical symptoms and sexually transmitted diseases before initiation of therapy underscore the importance of baseline evaluation. Norplant users may be warned about nausea and dizziness as well as minor local symptoms around the insertion site and unpredictable uterine bleeding patterns. Adolescent patients choosing Depo-Provera may expect amenorrhea by the end of 6 months of therapy along with possible fatigue. Early intervention may be needed with adolescents who choose Norplant or OCP to encourage better compliance with follow-up appointments.

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Hegde, Upendra P., Aaron N. Holmes, Christina Elizabeth Stevenson, Sophie Masternak, and Cucka Bethany. "Outcome of metastatic melanoma following immune checkpoint inhibitor treatment by tumor infiltrating lymphocyte of primary cutaneous site." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e22005-e22005. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e22005.

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e22005 Background: TIL include antigen specific clonal T cells responding to tumor antigens (TA) in the tumor microenvironment. Biological relevance of TIL at the PCM following ICI treatment of MM is not clear. Since there is overlap of TA between primary and its metastasis, we hypothesized that TIL at PCM site may serve as a biomarker of response to ICI treatment of MM. Methods: We did a retrospective analysis of MM patients (pts.) receiving ICI treatment between 2012 and 2019 following an IRB approved protocol. Response and survival at 12, 24 and 36 months (mths) was correlated with PCM site TIL. Pts. who received at least one dose of ICI for MM were eligible and those with metastasis from unknown PCM, received anti-BRAF treatment or lacked information on TIL at PCM were excluded. Pts. were stratified as group (gr.) A, B and C representing brisk, non-brisk and absent TIL respectively. Responses defined by RECIST criteria (response, no response, stable disease) as well as overall survival calculated from time of initiation of ICI to death from any cause (OS) at 12, 24 and 36 mths was correlated to TIL at PCM. Results: 42 pts. received ICI for MM between 2012-2019 meeting the eligibility criteria. Median age is 68 years (yrs.) (63, 71 and 73 yr. respectively for group A, B and C), 27 male, 15 women. The median thickness of PCM was 3.5, 3.75 and 4.75 mm in group A, B and C respectively. 11 of 14, 9 of 16 and O of 12 pts. responded to ICI while 2, 5, 14 and 1,2, 0 patients showed no response and stable disease respectively. O.S. at 12, 24, and 36 mths. was 12/14, 11/16 and 1/12 pts.; 10/14, 7/16, 0/12 pts. and 8/14, 6/16 and 0/12 pts. respectively in three groups. Conclusions: Brisk and absent TIL correlated with favorable and unfavorable response to ICI treatment of MM while non-brisk TIL showed intermediate outcomes. Larger data set could help validate our findings.

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Shigematsu, Fumie, Yoshihito Kogure, Hideo Saka, Arisa Yamada, Akane Ishida, Yuko Ise, Kazumi Hori, et al. "Correlation between re-biopsy site and detection of T790M mutation in NSCLC patients treated with EGFR TKI." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e20620-e20620. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e20620.

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e20620 Background: Re-biopsy is important to decide the treatment after EGFR-tyrosine kinase inhibitor (TKI) failure in non-small cell lung cancer (NSCLC) patients. We hypothesized that the T790M mutation in EGFR might show heterogeneity depending on the re-biopsy site. Methods: NSCLC patients who had received initial EGFR-TKI since January 2009 to December 2016, at any stage and recurrence after surgery and at any line of treatment, were included. Results: In total, 128 patients were included. Median age at EGFR-TKI therapy initiation was 73 (range, 38–97) years; 67% patients were female, all were Asian, 56% had never smoked, and 99% had adenocarcinoma. Of total 128 patients, 109 showed progressive disease. Median progression-free survival (PFS) was 10 (0.56–57) months. Median period since EGFR-TKI failure until the first re-biopsy was 197 (0–1322) days. Re-biopsy was performed 50 times in 42 patients; the number of T790M positive, negative, and pathologically negative patients was 20, 17, and 5, respectively, and the number of re-biopsies in these patients was 20, 22, and 8, respectively. Median PFS was longer in T790M positive patients than in negative patients significantly (17 [11–24] vs. 7.6 [4.3–11] months, P = 0.007). Characteristics such as gender, smoking status, proportion of stage IV, time between EGFR-TKI failure and first re-biopsy, and number of biopsies did not affect the T790M status in the biopsies. T790M positive group had more exon 19 deletions than negative group significantly (75% vs. 23%, P = 0.012). Biopsies at primary lesion, distant, and pleural effusion (PE) were 25% vs. 50%, 60% vs. 36%, and 15% vs. 14%, respectively, in the T790M positive vs. negative groups. Compared with the biopsy-site at diagnosis, the site was same as before in 35% vs. 50% cases (primary lesion [20% vs. 45%], distant [10% vs. 4.5%], and PE [5% vs. 0%]) and was new in 55% vs. 41% cases (distant lesions [45% vs. 27%] and PE [10% vs. 14%]) in the T790M positive vs. negative groups, respectively. Conclusions: In NSCLC patients treated with EGFR-TKI, re-biopsy was performed in distant lesions more frequently in the T790M positive cases than in negative cases. However, the T790M status was not correlated with the re-biopsy site.

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Chow, Signy, Rena Buckstein, and David Spaner. "A Link Between Hypercholesterolemia and Chronic Lymphocytic Leukemia." Blood 124, no. 21 (December 6, 2014): 5630. http://dx.doi.org/10.1182/blood.v124.21.5630.5630.

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Abstract Background Dyslipidemia and metabolic syndrome are risk factors for cancer, and clinically aggressive CLL cells are believed to rely on lipid metabolism. Statins promote apoptosis and inhibit CLL cell growth in pre-clinical models, and statin use during salvage therapy for CLL may confer a survival advantage. Methods To investigate the prevalence of hyperlipidemia and the effect of statin therapy, lipid profiling was performed on 238 consecutive patients presenting to a specialized CLL clinic between January 2012 and February 2014. Demographics, timing of diagnosis and initiation of chemoimmunotherapy was ascertained from clinical records. Prognostic information was obtained from pathology or flow cytometeric reports. The first lipid profile following CLL diagnosis was recorded. RAI stage was determined from blood counts and radiology or clinical examination at the time of lipid profiling. Patients were grouped according to statin therapy (yes/no) and hyperlipidemia. Results Of 281 patients reviewed, 238 were evaluable with a lipid profile. 110 patients (46.2%) were either taking statins at the time of their CLL diagnosis (27.3%) or prescribed a statin during the study period (18.5%) and an additional 11 (4.2%) had a diagnosis of dyslipidemia not on therapy. Of the remaining 117 patients, 18 had LDL ³ 3.5mmol/L, giving a total of 139 patients (58.4%) with abnormal lipid profiles. The statin-exposed group was significantly older (median age 69.5 vs 65, p=0.03) and there were a larger proportion of males (68.6% vs. 53.9%, p=0.02). There were no significant differences in RAI staging, cytogenetics, beta-2-microglobulin levels, or CD38 expression between groups. (Table 1) 59.7% of all patients were treatment-free by the end of the study period and there were no differences between statin/no-statin groups. Of those requiring treatment, median time to first treatment (TFT) was 48 (IQR, 24-85.3) months. TFT was significantly longer with statins (57.5 (IQR, 32-77) vs. 36 (IQR, 11-100) months, p<0.02. Initiation of statins following diagnosis of CLL was associated with further prolongation of TFT compared to those on statins at diagnosis (74 (IQR, 62-96) vs. 45 (IQR, 30-64) months, p<0.02). Two cases of spontaneous remission were noted with statin initiation. (Figure 1) Conclusions There is an increased prevalence of hyperlipidemia in CLL patients (58.4%) compared to the general population (35-39%). Statin therapy is associated with a prolonged TFT despite a significantly older population and a higher proportion of male patients in this group. CLL patients should be screened for hyperlipidemia and statin therapy may be an adjunct to CLL treatment. Patient Characteristics by Lipid Abnormalities Abstract 5630. Table 1.Time to First Treatment (TFT) by Statin UseTotal N (%)No statin N (%)Statin Use/Dyslipidemia N (%)p -valueTotal238117121Male146 (61.3)63 (53.9)83 (68.6)0.02Median age (Q1, Q3)67 (60, 74)65 (58, 73)69 (63, 76)0.01RAI Stage0.64N1178 (74.8%)78 (66.7%)99 (81.8%)MBL73407135361341618232102232081241477Lipid profile (Mean ± Std Dev)HDL (mM)1.23 ± 0.471.33 ± 0.491.14 ± 0.420.001LDL (mM)2.55 ± 1.032.69 ± 0.872.42 ± 1.160.05TC/HDL3.92 ± 1.433.80 ± 1.254.03 ± 1.570.21Non HDL-C (mM)3.22 ± 1.143.29 ± 0.993.14 ± 1.270.29B2M (N = 0.6-2.3 m g/ml)0.52Mean ± Std Dev3.20 ± 2.143.19 ± 2.363.21 ± 1.92CD38 status0.86Unknown74 (31.1%)37 (31.6%)37 (30.6%)CD38+331419CD38-1226260Partial945Cytogenetics20.32Unknown125 (52.5%)61 (52.1%)63 (52.1%)13q-62283511q-1367+122081217p-1275normal24159>1 abnormality201010 1stage determined from those untreated at time of lipid profiling 2counted in all pertinent groups if more than one abnormality Abstract 5630. Table 2. Time to First Treatment (TFT) by Statin Initiation Total (N=238) No statin (N=128) Statin Use (N=110) P-value W&W1 (%) 142 (59.7) 74 (58.8) 68 (61.8) 0.53 Available TFT data/Total Treated2 89/96 51/54 38/42 Median TFT (IQR) (mo) 48 (24, 83) 36 (11, 100) 57.5 (32, 77) 0.02 1watch & wait 2could not determine TFT for some patients. Abstract 5630. Table 3. No statin (N=128) Statin Started (N=43) Statin Previous (N=67) P-value W&W1 (%) 74 (58.8) 29 (67.4) 39 (58.2) 0.55 Available TFT data/Total Treated2 51/54 13/14 25/28 Median TFT (IQR) (mo) 36 (11, 100) 74 (62, 96) 45 (30, 64) 0.04 1watch & wait 2could not determine TFT for some Figure 1 Figure 1. [1]Spaner DE, Lee E, Shi Y, Wen F, Li Y et al. Leukemia 2013; 27:1090-1099. [2]Chae YK, Trinh L, Jain P, Wang X, Rozovski U et al. Blood 2014; 123: 1424-1426. Disclosures No relevant conflicts of interest to declare.

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Okoroji, Grace-Julia, Leandro de Padua Silva, Rima M. Saliba, Martin Korbling, McLaughlin Peter, Chitra Hosing, Paolo Anderlini, et al. "Outcome In Follicular Lymphoma (FL) Patients (pts) Relapsing After Autologous Stem Cell Transplantation (ASCT): Allografting Vs. Conventional Therapy." Blood 116, no. 21 (November 19, 2010): 3510. http://dx.doi.org/10.1182/blood.v116.21.3510.3510.

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Abstract Abstract 3510 Background: The outcome in FL pts relapsing after ASCT has not been well studied. While the use of nonmyeloablative allogeneic stem cell transplantation (NST) has been promising in this setting, one could not underestimate the results of selective inclusion criteria. Methods: All patients with FL who experienced a relapse after ASCT at The University of Texas M. D. Anderson Cancer Center between 1997 (the initiation of the rituximab and NST era) and 2007, were analyzed. Results: Fifty pts were identified. Fifteen (30%) pts underwent NST after ASCT relapse (Group A); 25 (50%) pts (Group B) met the eligibility criteria for NST but were not allotransplanted due to either physician/pt preference (n=14), lack of suitable donors (n=5), insurance requirements (n= 3), other causes (n=3). Ten (20%) pts (Group C) were not eligible for NST due to refractory disease or co-morbidities. At the time of progression after ASCT, the comparison of pts who were considered for NST showed that Group A pts and Group B pts had a comparable age [median 57 years(range, 45–64) vs 58 years (range, 40–70), p=0.7, respectively], serum LDH level (p=0.1), # of extranodal sites of disease (p=0.4), marrow involvement (p=0.1), and stage III/IV (p=0.2). The histology subtypes were also equally distributed in both groups (FL grades 1, 2, and 3 were found in 27%, 40% and 30% of Group A pts, respectively, and in 16%, 44% and 40% of Group B pts, respectively). The majority of pts in Groups A and B had a good ECOG PS of 0–1 (100% vs 96%, respectively). The median time from ASCT to progression was 16 months (range, 4–42) in Group A, and 19 months (range, 3–99) in Group B. Group A pts underwent their NST at a median of 8 months after their ASCT relapse. At their progression post ASCT, pts in Group B were treated with either rituximab as a single agent (n=12, 48%), or combination chemo-antibodies (n=7, 28%); the therapy received in the remaining 6 (24%) pts was unknown. With a median follow-up time of 49 months (range 23–113 months) for Group A, and 37 months (range, 17–130 months) for Group B, the actuarial survival rates at 4-year were 73%(%95 CI, 42–89) and 71% (%95 CI, 46–86), respectively, (Figure, p = 0.9). The causes of death in Group A were related to infection (1), organ failure (1), progression (2), and unknown (1). Five pts in Group B died of progression and one died of secondary leukemia. Pts in Group C had a median survival time of 7 months; only 2 pts of this group were still alive at the time of this analysis was made. Conclusions: Single institution results show that 30% of pts with FL relapsing after ASCT undertook an allotransplant. While allogeneic NST is an effective therapy for these pts, a significant proportion of pts can be observed for several years before an allotransplant should be considered. Disclosures: No relevant conflicts of interest to declare.

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Michallet, Mauricette, Mohamad Sobh, Quoc Hung Le, Fiorenza Barraco, Charles Dumontet, Youcef Chelghoum, Emmanuelle Nicolas-Virelizier, et al. "Long-Term Follow-up of Multiple Myeloma Patients Treated by Bortezomib (Velcade®): A Study on Efficacy, Tolerance, Survival and Time to Progression." Blood 112, no. 11 (November 16, 2008): 5197. http://dx.doi.org/10.1182/blood.v112.11.5197.5197.

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Abstract We conducted a retrospective single institution analysis to evaluate the immediate and long-term efficacy, tolerance, survival and time to progression of MM patients (pts) who received VELCADE (Vel.) as induction and in those who relapsed or were refractory after standard therapies. A total of 92 pts were included, 62 (67%) males and 30 (33%) females. Median age at treatment was 60 years [35–79]. At diagnosis, there were 48 (52%) IgG, 24 (26%) IgA, 2 (2%) IgD, 15 (16%) light chains and 3 (4%) plasma cell leukaemias, 11pts (12%) were in stage I A, 12 (13%) stage IIA and 69 (75%) stage III (51 A and 18B). The median level of β2 microglobulin was 3.28 mg/l (1.12–24). Among 42 evaluated del(13), 19 (45%) were + in which there was two t(4;14)+. We defined 3 groups: group1:16 (17%) pts who received Vel. as induction, group2:58 (63%) pts who received Vel. as 2nd line n=41 or 3rd line n=17, group 3:18 (12%) pts who received Vel. as ≥ 4th line. Prior to Vel.(groups 2 and 3), 53 (70%) pts had received an autologous hematopoietic stem cell transplantation (HSCT), 13 (14%) allogeneic HSCT and 35 (46%) thalidomide (Thal.) (median dose of 200mg/day, median duration of 4 months). The median interval between diagnosis and Vel. initiation was 28.3 months (0.2–125); 28 pts had an interval less than 12 months (16 in 1st line), 27 pts between 12 and 36 months and 37 pts with more than 36 months. The median number of Vel. cycles in group 1, 2 and 3 were 4[2–9], 5[2–12] and 5[3–12] respectively with a standard dose of 1.3 mg/m2 decreased to 1.0 mg/m2 in case of toxicity (<3 cycles: n=18, 4–6: n=52; 7–8: n=14; >8: n=8). Fifty-two (57%) pts received an association of dexamethasone (40mg/day). There were 6 Vel. discontinuation (<3 Vel.cycles) and 25 (27%) dose reduction due to neuropathy [3cycles n=2 (17%), 4–6 cycles n=12 (23%), 7–8 cycles, n=7 (50%) and ≥9 n=4 (50%)]. Peripheral neuropathy occurred in 61 pts (66%) [32 (52%)gr1, 18 (30%)gr2, 9 (15%)gr3 and 4 (3%)gr4], in which, 25 (41%) had previously received Thal. [12 (48%)gr1, 8 (32%)gr2, 5 (20%)gr3]. The most other common toxicities were, fatigue n=35 (38%), constipation n=18(20%), diarrhea n= 11(12%), nausea n=14(15%) and vomiting n=7(8%). The overall response rate was observed in 67 (73%) pts [13 (14%)CR, 22 (24%)VGPR and 32 (35%)PR]. With a median follow-up of 23.4 months, the median overall survival (OS) for the whole population and for group 1 and 2 was not reached, and was 17 months for group 3. The probability of OS at 3 years for the whole population was 61%[50–73.5] (Figure 1) and were: 80%[62–100], 66%[54–81] and 45%[25–82.5] for groups 1, 2 and 3 respectively (Figure 2). The probability of OS at 5 years for the whole population from MM diagnosis was 72.5%[63–84]. The median time to progression (TTP) was 25.5 months for the whole population; it was not reached for group 1, were 25.5 and 13 months for group 2 and 3 respectively. The probability of progression-free survival (PFS) at 2 years was 51%[40–64,5] for the whole population and 66%[45–96], 52%[39–70] and 29%[12–71] for group 1, 2 and 3 respectively. We showed no significant difference in term of OS (p=0,166) and PFS (p=0.495) between the patients with del(13) [51% (31–83) and 42(23–78)] and without del(13) [83%(68,5–99,6) and 58%(40–85,5)]. Finally we observed a better PFS at 2 years for pts receiving lenalidomide after Vel. versus those who did not, 64%[42–96] and 48%[36–63] respectively. The multivariate analysis (studying: age, sex, stage, beta2M, del(13), previous lines, allogeneic HSCT, Thal., and interval diag-Vel.) showed only a significant impact of thalidomide HR=3.06 (1.37–6.85) (p=0,006), and a trend for interval diag-Vel. In conclusion, this analysis showed a very good percentage of long-term OS with a median not reached for Vel. naïve or 2nd, 3rd Vel line MM pts. Moreover, we showed a significant negative impact of previous Thal. treatment and no impact of del(13). Figure 1. Probability of OS for the whole population Figure 1. Probability of OS for the whole population Figure 2. Probability of OS for groups 1, 2 and 3 Figure 2. Probability of OS for groups 1, 2 and 3

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Uhm, Jieun, Sung-Hyun Kim, Sukjoong Oh, Dae Young Zang, Young Rok Do, Won Sik Lee, Myung Hee Chang, Sung-Eun Lee, and Dong-Wook Kim. "High Incidence of Hepatitis B Viral Reactivation in Chronic Myeloid Leukemia Patients Treated with Tyrosine Kinase Inhibitors." Blood 132, Supplement 1 (November 29, 2018): 3010. http://dx.doi.org/10.1182/blood-2018-99-117543.

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Abstract Background: Reactivation of hepatitis B virus (HBV) is a well-recognized complication in patients with chronic HBV infection undergoing cytotoxic or immunosuppressive therapy. Currently, BCR-ABL1 tyrosine kinase inhibitors (TKIs) have been a standard of first-line treatment for chronic myeloid leukemia (CML) about last two decades. As there have been several case reports of HBV reactivation in CML patients treated with TKIs, the test for hepatitis B infection before initiating TKIs is recommended. Therefore, this study aimed to evaluate the risk of HBV reactivation in a large cohort of CML patients on TKIs treatment. Methods: We retrospectively reviewed the medical records of 1817 patients, who were diagnosed with CML and had available HBV serology between 2001 and 2017 from St. Mary's Hospital, Seoul, Korea. Results: Among 1817 patients, 76 patients (4.2%) were HBs-antigen (HBs-Ag) positive and 1741 (95.2%) were HBs-Ag negative. 302 patients (17.3%) of 1741 HBs-Ag negative patients were HBc-antibody positive indicating past infection of HBV. After exclusion of 7 patients who did not receive TKIs treatment, 69 patients were analyzed for HBV reactivation. The median age at diagnosis of CML was 42 (range 21-73) years and 44 (64%) were males. Median duration of follow-up from the recognition of HBs-Ag was 66.7 months (range, 2.4 - 192.7 months). Of 69 patients, a patient had been on antiviral therapy for chronic HBV infection before the diagnosis of CML. Eighteen patients (26% of 68) received antiviral prophylaxis prior to or concomitantly with the initiation of TKIs. Additional 4 patients were simultaneously initiated antiviral treatment with TKIs due to the evidence of active HBV infection such as the high titer of HBV DNA or elevated level of Alanine aminotransferase. Among 46 patients who did not receive antiviral prophylaxis, 12 patients (26%; 95% CI, 12-36%) eventually required antiviral treatment due to the development of active HBV hepatitis while on TKI therapy. HBV reactivation according to each TKI treatment was developed in 7 patients with imatinib, 2 patients in dasatinib, 1 patient in nilotinib, and 1 patient in radotinib therapy. One patient developed HBV reactivation permanently discontinued TKI therapy. Median time to HBV reactivation from CML diagnosis was 22.1 (range, 6.3-124.6 months) months. Median duration of antiviral therapy of 35 patients who received antiviral therapy was 38.2 months (95% CI, 25.7 ~ 50.7 months). 9 patients were off antiviral therapy at the last follow-up, 5 patients from prophylaxis group and 4 patients from treatment group. There was no difference in the duration of antiviral treatment between prophylactic and treatment groups. The initial choice of antiviral therapy as prophylaxis or treatment were entecavir for 14 (41% of 34), lamivudine for 8 (24%), tenofovir for 8 (24%), telbivudine for 3 (9%), and adefovir for 1 (3%). Conclusion: We evaluated HBV reactivation in a large cohort of HBs-Ag positive patients with CML from a single center, who received TKIs treatment. The reactivation rate of HBV was high at 26% without antiviral prophylaxis, which strongly support the routine screening of HBV serology prior to initiation of TKI therapy to identify HBs-Ag positive patients and the close monitoring of hepatic functions and HBV serology during TKI therapy. Given the high incidence of HBV reactivation with TKI treatment, concomitant antiviral prophylaxis with TKIs should be considered in HBs-Ag positive patients receiving TKI treatment. Figure. Figure. Disclosures Kim: Ilyang: Research Funding; Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding.

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Cunningham, Julia M., Jimmy Wang, and Catherine Broome. "Presentation and Time to Treatment of Atypical Hemolytic Uremic Syndrome Is Influenced By Complement Amplifying Conditions: A Single Center Experience." Blood 128, no. 22 (December 2, 2016): 2543. http://dx.doi.org/10.1182/blood.v128.22.2543.2543.

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Abstract Introduction: Atypical hemolytic uremic syndrome (aHUS) is a complement-mediated disorder classically defined as microangiopathic hemolytic anemia, thrombocytopenia, and renal dysfunction. Defects in complement regulation may be inherited or acquired, resulting in chronic activation of complement - the pathophysiologic basis of aHUS. aHUS is classified as a rare disorder; however available epidemiologic data is based on pediatric or post-transplant populations. The incidence and prevalence of aHUS remains unknown in the general adult population. Clinical recognition of aHUS may be obscured or delayed due to the absence of a diagnostic test and unfamiliarity with the diverse presentations of these patients. Complement-amplifying conditions (CACs) often unmask aHUS in patients with defects in complement regulation (Kavanagh et al. Br Med Bull 2006). The co-existence of aHUS and CACs frequently presents additional diagnostic challenges. Data demonstrates that earlier recognition and treatment of aHUS with eculizumab, a humanized monoclonal antibody that binds to C5 inhibiting terminal complement activation, leads to better overall outcome for patients. (Legendre et al. NEJM 2013) Methods: We performed a retrospective chart review of all patients treated with eculizumab for clinically diagnosed aHUS at Medstar Georgetown University Hospital (MGUH) between December 2011 and January 2016. Results: 48 patients received at least one dose of eculizumab for the clinical diagnosis of aHUS at our center between 2011 and 2015. Median age at diagnosis was 46 years (range: 19 to 71 years) with a slight female-to-male predominance (27 to 22, respectively). Seventy three percent (35/48) of patients had identifiable complement-amplifying conditions (CACs) at diagnosis. Identified CAC categories include 11% (5/48) autoimmune/mixed connective tissue disease, 6% (3/48) infections, 4% (2/48) HIV, 4% (2/48) chemotherapy exposure, 40% (19/48) non-renal solid-organ transplant, 10% (5/48) renal transplant, 4% (2/48) surgery, and 8% (4/48) inflammatory bowel disease. Ninety four percent (45/48) of patients had evidence of 1 or more extra-renal manifestations of aHUS at the time of diagnosis. Six percent (3/48) of patients presented with renal involvement only, compared with 23% (11/48) who had 1 extra renal manifestation, 18% (9/48) with 2 extra renal manifestations, 35% (17/48) with 3 extra renal manifestations, and 17% (8/48) with 4 or more extra renal manifestations. Extra renal systems involved include cardiovascular (67%), pulmonary (65%), gastrointestinal (58%), and CNS (42%). Patients with CACs presented with a similar distribution of extra-renal manifestations compared with patients who had no identified CACs. No significant difference was observed in presenting hematologic and renal labs, but we observed a trend towards more severe renal involvement at presentation in those without CACs (see Table). Regardless of CAC status, similar proportions of patients were on dialysis prior to or at the time of eculizumab initiation. Time to recognition and initiation of eculizumab in hospitalized patients with CACs took an average of 37 days (median 15 days) compared with an average of 17 days (median 7 days) in those without CACs. Conclusions: aHUS was diagnosed in patients in all age-groups and affected both sexes with similar frequency. We confirm other reports of a significant association between CAC and aHUS with 73% of our patients presenting with a CAC at the time of diagnosis of aHUS. While the majority of patients with and without CACs (91% and 100%, respectively) presented with extra-renal manifestations, those with CACs experienced less-severe renal involvement compared to those with no CACs. Patients with comorbid CACs were diagnosed and initiated on eculizumab later than those without CACs. Our experience emphasizes the importance of recognizing early non-renal systemic manifestations of thrombotic microangiopathy to make the diagnosis of aHUS, especially in patients with comorbid CACs. Disclosures Wang: Alexion Pharmaceuticals: Employment. Broome:Alexion Pharmaceuricals: Honoraria; True North Therapeutics: Honoraria.

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Benton, Christopher B., Peng Qiu, Farhad Ravandi, Hagop M. Kantarjian, Guillermo Garcia-Manero, Sherry A. Pierce, Anisha Borthakur, et al. "Dynamics and Prognostic Impact of Peripheral Blood Blast Clearance in Patients with Acute Myeloid Leukemia (AML) Receiving FLT3 Inhibitor Therapy in Combination with Induction Chemotherapy." Blood 120, no. 21 (November 16, 2012): 1417. http://dx.doi.org/10.1182/blood.v120.21.1417.1417.

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Abstract Abstract 1417 Background: We have previously shown that for patients with acute myeloid leukemia (AML) treated with induction chemotherapy with cytarabine (ara-C) plus an anthracycline, the day of blast clearance from peripheral blood (PB) is a powerful prognostic marker. Earlier PB blast (but not white blood cell [WBC]) clearance portends improved overall survival (OS). We expanded our investigation to include patients with AML undergoing induction chemotherapy with ara-C (1.5g/m2 ×3 days) plus idarubicin (12mg/m2×3 days) that is, the AI regimen, plus sorafenib (400mg orally twice daily). Patients and Methods: We reviewed the clearance of PB blast and WBC (PB blasts = 0%, WBC≤0.1×109/dL), for patients with AML (except APL) undergoing AI alone (n=168) or AI+sorafenib (n=75). Patient characteristics for the AI alone group (n=168) were as follows: median age 55 years (range, 19–72), diploid cytogenetics (n=57, 34%), poor cytogenetics (n=61, 36%), FLT3-ITD positive (n=15, 9%), FLT3-negative (n=122, 73%), median WBC 5.0×109/dL (range, 0.3–132.3), median platelets 37×109/dL (range, 1–581), median hemoglobin 9.1g/dL (range, 4.0–13.2), median PB blasts 15% (range, 1–96), median BM blasts 42% (range, 1–96). Patient characteristics for the AI+sorafenib group (n=75) were as follows: median age 52 years (range, 18–66), diploid cytogenetics (n=38, 51%), poor cytogenetics (n=10, 13%), FLT3-ITD (n=25, 33%), FLT3-negative (n=48, 64%) median WBC 5.9×109/dL (range, 0.6–228.5), median platelets 51×109/dL (range 7–306), median hemoglobin 9.2g/dL (range, 7.4–12.6), median PB blasts 21% (range 0–98), median BM blasts 56% (range 6–98). Results: The overall response rate (ORR=CR+CRp) in the AI group was 63% (58%+5%) and 50 patients (30%) were resistant to therapy. The ORR in the AI+sorafenib group was 79% (72%+7%) and 11 patients (15%) were resistant. We analyzed OS by dividing patients based on the day of PB blast clearance: group 1 (0–1 days), 2 (2–3 days), 3 (4–5 days), 4 (6–8 days), and 5 (>8 days). For the patients receiving AI induction therapy, a total of 32, 59, 38, 18, and 2 patients were included in groups 1–5, and median OS for groups 1–4 were 167, 48, 67, and 25 weeks respectively. A logrank test comparison revealed these four OS curves were significantly different (p-value=0.0015). For the AI treatment group, earlier blast disappearance corresponded with better OS. In contrast, for patients in the AI+sorafenib group, the correlation between day of PB blast clearance and OS was less clear. A total of 10, 23, 25, 6, and 3 patients were included in groups 1–5. The median OS for groups 1, 3, and 4 were 101, 74, and 66 weeks respectively, and the median survival for group 2 could not be estimated because the curve did not fall below 0.5. The difference between these four survival curves was not significantly different (p-value=0.35). Survival differences for the AI group were more clearly demarcated when patients were divided based on blast disappearance within 0–5 days or >5 days (p-value=0.0004). A similar analysis in the AI+sorafenib group revealed no significantly different OS (p-value=0.13). Among patients in the AI+sorafenib treatment group, the mean day of blast disappearance for FLT3-ITD versus FLT3-negative patients was 5.2 vs. 4.5 days, and this difference was not statistically significant (p-value=0.33). While FLT3-ITD patients who cleared their blasts within 0–3 days (n=10) tended to have better OS survival than FLT3-ITD patients who cleared their blasts after 3 days (n=13), the difference in OS curves did not reach significance (p-value=0.18). Conclusion: The day of PB blast clearance is prognostic among patients receiving classic induction chemotherapy, where early clearance predicts better long-term outcomes. The addition of a targeted agent to a standard induction regimen limits the prognostic power of early PB blast clearance. We are currently investigating a novel mathematical approach to evaluate the prognostic value of clearance of peripheral blasts compared to WBC after initiation of therapy in patients receiving targeted agents during induction therapy; the approach aims to integrate the prognostic impact of FLT3 and NPM1 in combination with cytoreduction kinetics to better identify prognostically distinct groups. Disclosures: Off Label Use: Plerixafor plus G-CSF as a part of conditioning in allogenic transplant for AML/MDS.

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Cassaday, Ryan D., Philip A. Stevenson, Brent L. Wood, Pamela S. Becker, Paul C. Hendrie, Brenda M. Sandmaier, Jerald P. Radich, and Andrei R. Shustov. "Time to Minimal Residual Disease (MRD) Negativity Is Independently Predictive of Outcome in Adults with Acute Lymphoblastic Leukemia (ALL) Receiving Hyper-CVAD." Blood 126, no. 23 (December 3, 2015): 2498. http://dx.doi.org/10.1182/blood.v126.23.2498.2498.

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Abstract Background: MRD is an established prognostic/predictive factor in ALL. Achieving MRD negativity (MRDNeg) early during treatment is associated with superior outcomes with pediatric regimens. However, little is known about how to use MRD assessments with hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with methotrexate and cytarabine), one of the most commonly used regimens in adults with ALL. MRDNeg at 3 months has been shown to be predictive of outcome with hyperCVAD + tyrosine kinase inhibitor (TKI) in Philadelphia chromosome (Ph)+ ALL (Ravandi, Blood, 2013, p. 1214), but this is relatively late in the treatment course. We hypothesized that achieving MRDNeg earlyduring treatment would be associated withbetter outcomes with hyperCVAD. Methods: We performed a retrospective analysis of our center's experience since 2005 under an IRB-approved protocol. We included pts with ALL (excluding Burkitt and mixed-phenotype) age >18 years (yrs) who received hyperCVAD as initial therapy. MRD was assessed primarily by either multiparameter flow cytometry or BCR-ABL quantitative PCR on bone marrow, though other techniques (e.g., cytogenetics [CG]) were considered if obtained. Timing and nature of assessments were left to treating physicians. Pts were not defined as MRDNeg until all assays performed were unable to detect any disease. Clinical risk at diagnosis was defined by age (> 35 yrs), white blood cells (WBC; > 30 for B-ALL, > 100 for T-ALL), and CG (Ph+, MLL rearranged, -7, +8, complex, low hypodiploid, and near triploid). Events included morphologic or MRD recurrence, change in treatment due to inadequate response, death from any cause, or secondary malignancy. Frequencies of characteristics between groups were compared using a Fisher exact test. Cox proportional hazards (PH) models were used to investigate associations between variables. A test of PH was used to assess the impact of time on the association between MRD and outcome, in which MRD was modeled as a time-dependent covariate with left-truncation. Clinical follow-up was updated as of June 2015. Results: We identified 142 pts for this analysis: 18% T-ALL, 73% > 35 yrs, 24% had high WBC (6 unknown), and 48% had high-risk CG, 71% of which (34% of total) were Ph+ (11 unknown). Sixty-five pts (46%) underwent hematopoietic cell transplantation (HCT) in first remission (CR1): 32% with reduced-intensity and 68% with myeloablative conditioning. All Ph+ pts received TKI with hyperCVAD: 23 (48%) received imatinib and 25 (52%) received dasatinib. Median time of 1st MRD assessment (relative to start of treatment) was 37 days, with 27% occurring by 21 days and 85% by 90 days; 42% were MRDNeg at 1stassessment, 26% became MRDNeg later, and 32% did not become MRDNeg during treatment with hyperCVAD. Incidences of age > 35 yrs (P = 1), high-risk CG (P = 0.08), Ph+ (P = 0.72), and high WBC (P = 0.38) were not significantly different in MRDNeg pts. HCT in CR1 was more common in MRDNeg pts (P = 0.05). In Cox PH models adjusted for HCT in CR1, CG, and WBC, MRDNeg pts had significantly better overall survival (OS; hazard ratio [HR] 0.43, 95% confidence interval [CI] 0.23-0.81; P = 0.01; 48 events) and event-free survival (EFS; HR 0.27, 95% CI 0.16-0.46; P < 0.01; 84 events). Through an exploratory landmark analysis, the benefit of MRDNeg on EFS became more pronounced after 8 weeks: pts who were MRDNeg by 8 weeks had significantly better EFS (HR 0.53, 95% CI 0.32-0.89; P = 0.02) than those who were not. Further, achieving MRDNeg earlier during treatment was associated with better EFS. In a test of PH on the time-dependent Cox PH model, time to MRDNeg had a significant impact on the association between MRD status and EFS (P = 0.02) but not OS (P = 0.19). This is depicted in Fig 1, where being MRDNeg earlier after treatment initiation is associated with a smaller beta (i.e., significantly less hazard for an event). Conclusions: MRDNeg is an independent predictor of superior OS and EFS in adults receiving hyperCVAD for ALL. Further, achieving MRDNeg earlier during treatment was associated with better EFS. When considering the time-dependent nature of MRD status relative to EFS, 8 weeks after initiation of hyperCVAD may represent an important prognostic time point. If confirmed in an independent dataset, this may prove to be a useful surrogate in both routine clinical practice and future clinical trials with this regimen. Disclosures Cassaday: Pfizer: Research Funding; Seattle Genetics: Research Funding.

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Al Sabty, Firas, Martin Mistrik, Mikulá Hrubiko, Eva Bojtárová, Ján Martinka, and Angelika Batorova. "Optimal Use of Granulocyte Colony Stimulating Factor (G-CSF) after Autologous Hematopoietic Stem Cell Transplantation." Blood 124, no. 21 (December 6, 2014): 2519. http://dx.doi.org/10.1182/blood.v124.21.2519.2519.

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Abstract Introduction:high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (autoHSCT) is widely used in the treatment of patients with haematological and non-haematological malignancies. One of the most common causes of mortality after HSCT is infection during the time of prolonged neutropenia. Prolonged neutropenia more than 7 days increase the risk of fungal infections and it is an indication for the use of antifungal prophylaxis. After hematopoietic SCT, G-CSF is commonly used to enhance stem cell engraftment to minimize the morbidity and mortality associated with prolonged neutropenia. However, there is no consensus on the optimal use of G-CSF after autoHSCT, most studies have been conducted on small numbers of patients and have varied significantly in patient’s demographics, G-CSF dosage regimen and other factors affecting outcomes. Objective:restrospective study to evaluate the efficacy of early vs. delayed initiation of G-CSF after autoHSCT in patients with lymphoid malignancies. Methods: between January 2009 and July 2014, 117 patients with lymphoid malignancies who underwent autoHSCT in the Department of Hematology and Transfusion medicine in Bratislava were included. The patients were divided into two groups; in the first group (43 patients), G-CSF (filgrastim, 5μg/kg s.c.) was applied late (on day 6.-8.) after autoHSCT. In the second group (74 patients), G-CSF (filgrastim, 5μg/kg s.c.) was applied early (on day 3.-4.) after autoHSCT. All patients received standard conditioning regimen for the underlying disease, and standard supportive treatment, including treatment of febrile neutropenia. Patient’s demographics are shown in table 1. Statistical analysis was performed using SPSS statistical software v. 20, with significant Pvalue of 0.05 (two-tailed). Results: sever neutropenia (ANC < 0.5 x 109) and very severe neutropenia (ANC < 0.1 x 109) for more than 7 days were recorded as following: in the first group (delayed G-CSF), 34/42 (81%) and 25/41 (61%) patients respectively. In the second group (early G-CSF), 11/66 (17%) and 2/52 (4%) patients respectively (RR = 4.8, 95% CI = 2.7 to 8.4 and RR = 15, 95% CI = 3.9 to 63). Median time to engraftment of leukocytes above 1, granulocytes above 0.5, and 0.1 x 109/l was 6, 5, and 4 days for patients who received G-CSF early and 7, 7 and 5 days for patients who received G-CSF late (P <0001). The median duration of hospitalization was 19 (15-28) days in the first group and 16 (11-23) days in the second group (P = 0.001, 95% CI =2.02-4.17). There was no significant difference in the rate of febrile neutropenia in both groups (P = 0.53), but the rate of fungal infection and the use of HRCT scan of the lung was higher in the group of patients who received delayed G-CSF than early G-CSF (19% vs. 3%, P=0.005) and (23% vs. 6%, P=0.007) respectively. Conclusion:early application of G-CSF (3rd-4th day) after autologous HSCT accelerates engraftment, shorten the duration of neutropenia, reduce the risk of infectious complications (especially fungal infections), reduce the use of antimicrobial drugs, shorten the hospital stay and overall costs. Table.1 Delayed application of G-CSF Early application of G-CSF Patient N. 43 74 Age, m edian(range) 60 (39-67) years 59 (33-68) years P = 0.694 Sex P = 0.079 Male, N (%) 16 (37%) 40 (54%) Female, N (%) 27 (63%) 34 (46%) CD34+cells x106/kg, m edian(range) 2.5 (1.3-5.6) 2.3 (1.3-4.5) P = 0.138 Diagnosis P = 0.855 Multiple myeloma, N (%) 41 (95%) 72 (97%) NHL, N (%) 2 (5%) 2 (3%) ECOG performance status P = 0.221 0 35 (82%) 53 (72%) 1 7 (16%) 18 (24%) 2 1 (2%) 2 (3%) 3 0 0 4 0 1 (1%) Engraftment , median(range) Leu. > 1 x 109/l 7 (4-12) days 6 (3-9) days P ≤ 0,0001 Neut.> 0.5 x 109/l 7 (5-9) days 5 (3-7) days P ≤ 0,0001 Neut. > 0.1 x 109/l 5 (3-6) days 4 (2-6) days P ≤ 0,0001 Hospitalization, median(range) 19 (15-28) days 16 (11-23) days P= 0,001 Sever neutropenia ≥ 7 days, N (%) 34/42 (81%) 11/66 (17%) RR = 4.8, 95% CI = 2.7 to 8.4 Very sever neutropenia ≥ 7 days, N (%) 25/41 (61%) 2/52(4%) RR = 15, 95% CI = 3.9 to 63 Febrile neutropenia, N (%) 40 (93%) 64 (88%) P = 0.531 Invasive fungal infection, N (%) 8/43 (19%) 2/73 (3%) P = 0,005 HRCT scan use, N (%) 10 (23%) 4 (6%) P = 0.007 Cost 3582 (787-18187) Eur. 1408 (263-2143) Eur. P=0,041 Disclosures No relevant conflicts of interest to declare.

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Dulery, Remy, Anny Dewilde, Julie Gay, Julien Rossignol, Louis Terriou, Valerie Coiteux, Jean-Pierre Jouet, and Ibrahim Yakoub-Agha. "Early Human Herpes Virus Type 6 Reactivation in Patients Undergoing Allogeneic Stem Cell Transplantation (allo-SCT)." Blood 114, no. 22 (November 20, 2009): 794. http://dx.doi.org/10.1182/blood.v114.22.794.794.

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Abstract Abstract 794 Introduction: Human herpes virus 6 (HHV6) is known to reactivate after allo-SCT. It has been suggested that HHV6 may be associated with severe clinical manifestations, but little is known about its exact role in patients' outcomes following allo-CST. Patients and methods: Here we report our findings in 225 consecutive patients who underwent allo-SCT in our unit between January 2004 and March 2009. The median age was 42 years (3-62). Donors were HLA-identical sibling (n=110), and unrelated (n=115). Source of stem cells was bone marrow (BM; n=124), peripheral blood stem cell (PBCS; n=69) and cord blood (CB; n=32). Conditioning regimen was myeloablative (n=151), or reduced intensity (RIC; n=74). HHV6 plasma loads were measured almost weekly by quantitative PCR. We treated symptomatic patients when no other cause than HHV6 reactivation could explain the symptoms. However, patients with associated CMV reactivation were also treated with anti-viral therapy. At the time of analysis on July 31st 2009, the median follow-up was 33 months (4-68). A total of 105 (46%) patients had early positive HHV6-PCR within the first 100 days following transplantation (group I). In this retrospective study we compared the outcome of patients in group I to those who did not reactivate HHV6 or those who had positive HHV6-PCR after day 100 (group II; n=120). Results: Patients with PBSC and those who received RIC showed evidence of HHV6 reactivation less often than the others (p=0.049 and p=0.076, respectively). When HHV6-PCR was positive, only 10 patients in group I were asymptomatic while 95 patients experienced either fever (n=55), skin rash (n=51), diarrhea (n=41), pulmonary complications (n=16), neurological disorders (n=12), liver dysfunction (n=8) and/or others (n=7). Of note, 73 patients (70%) experienced more than one symptom concomitant to HHV6 reactivation. Thirty-seven patients received anti-viral therapy for HHV6-reactivation alone (n=18) or associated with CMV reactivation (n=19) resulting in negative HHV6-PCR in 31 of them. Out of the 6 patients who failed to have negative HHV6-PCR, 2 died 25 and 90 days after anti-viral therapy initiation, respectively. Although, there was no significant difference in overall survival or relapse-free survival between the two groups, patients in group II had earlier platelet engraftment (> 50 G/L) than those in group I with a median of 22 versus 28 days (p=0.003). In addition, patients in group I developed more often acute grade III-IV graft-versus-host disease (GvHD) than those in group II (34/105 versus 15/120, p=0.008). Of note, for 53% patients in group I with acute grade III-IV GvHD, HHV6 reactivation was observed before the development of acute GvHD. In multivariable analysis, the most important factors influencing acute grade III-IV GvHD were early HHV6 reactivation, [HR: 2.10; 95%CI, 1.20-3.66] (p=0.011) and unrelated donor, [HR: 1.17; 95%CI 1.04-1.32] (p=0.007). Conclusions: HHV6 reactivation is common after allo-SCT and is responsible for platelet engraftment delay and high-grade acute GvHD. Careful monitoring of HHV6-PCR is warranted during the early period of transplantation, as symptomatic patients require treatment. Disclosures: No relevant conflicts of interest to declare.

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Michaud, K., and S. Pedro. "POS0238 SIDE EFFECT PROFILE OF HYDROXYCHLOROQUINE USE IN PATIENTS WITH RA, SLE, AND OTHER RMDs OVER 20 YEARS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 357–58. http://dx.doi.org/10.1136/annrheumdis-2022-eular.2400.

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BackgroundDuring the pandemic, hydroxychloroquine (HCQ) became a household name, yet despite more than 70 years as a csDMARD treatment, relatively little is known about its overall side effect (SE) profile.ObjectivesTo understand the types, severity, and rates of patient-reported side effects of HCQ in adults with RA, SLE, and other RMDs alone and in comparison with methotrexate (MTX).MethodsAdult participants in the Forward Databank observational registry reported all medication use and medication side effects through biannual questionnaires from 1999 through 2021. Incident use of HCQ and MTX were measured at enrollment and longitudinally with additional reporting of severity of side effects, certainty of medication as cause of side effect, and affected body systems. We analyzed incident rates of side effects overall and by HCQ or MTX categorical use, respectively: monotherapy, with concomitant use of another csDMARD, or with concomitant use of a bDMARD or tsDMARD. Finally, the likelihood of having any side effects was analyzed in Cox regression models by comparing HCQ initiators to MTX initiation, and within each, combination MTX or HCQ with csDMARD or bDMARD to monotherapy; these models were adjusted for age, sex, RD Comorbidity Index, patient global, pain, disease duration, and number of bDMARDs used.ResultsOverall, 5874 patients initiated HCQ and 10420 initiated MTX, with RA as the predominant diagnosis. Mean baseline characteristics were similar for RA: 59 years old, 80% female and 12 years of RA duration. HCQ was mostly used with other csDMARDs, while MTX was mostly used with bDMARDs. In the other RMD and SLE groups, most were on HCQ monotherapy. For all RMDs, SE incidence for HCQ (16 – 17%) was lower than MTX (26 – 39%). The Table 1 provides incidence rates by HCQ/MTX for any SE, a SE that forces medication discontinuation, and SE leading to hospitalization. Reported SE rates were always higher for MTX vs. HCQ for all SE severity and diagnoses.Table 1.Incidence rates (IR) per 1000 patient-years of SEs by diagnoses for HCQ and MTX initiatorsRASLEOtherPt-yrsIR (95% CI)Pt-yrsIR (95% CI)Pt-yrsIR (95% CI)Any HCQ SE1271126 (23, 29)130525 (18, 36)56741 (27, 61)Mono HCQ339728 (24, 33)79728 (18, 42)34752 (32, 82)HCQ + csDMARDs547328 (24, 33)41624 (13, 45)12732 (12, 84)HCQ + bDMARDs384122 (17, 27)9311 (2, 77)9311 (2, 76)SE stopping HCQ1271113 (11, 15)130512 (7, 19)56714 (6, 35)Mono HCQ339712 (9, 16)79711 (6, 22)34714 (6, 35)HCQ + csDMARDs547315 (12, 18)41613 (5, 31)12724 (8, 73)HCQ + bDMARDs384112 (9, 16)930930HCQ SE hospitalization127110.31 (0.12, 0.84)13050.77 (0.1, 5.4)5670Any MTX SE8123451 (49, 52)151659 (48, 72)214572 (61, 84)Mono HCQ2298049 (46,52)36941 (25, 67)80262 (47, 82)MTX + csDMARDs1544772 (68, 77)87269 (53, 89)229131 (91, 187)MTX + bDMARDs4274843 (41, 45)26549 (29, 85)110667 (53, 84)SE stopping MTX9147726 (25, 27)163841 (32, 52)233544 (36, 53)Mono MTX2606019 (17, 20)39033 (19, 57)88527 (17, 39)MTX + csDMARDs1743038 (36, 42)93348 (36, 65)25590 (60, 136)MTX + bDMARDs4783225 (23, 26)30526 (13, 53)118847 (36, 61)MTX SE hospitalization964362.4 (2.1, 2.8)16745.4 (2.8, 10.3)25023.2 (1.6, 6.4)By body system, the patterns of any SE were similar between HCQ or MTX initiators. Gastrointestinal SEs were the most common for both. Only ocular SEs were higher for HCQ vs. MTX. Multivariable Cox regression models of HCQ vs MTX SEs had a HR 0.46 (0.41 - 0.51) for RA, HR 0.47 [0.27 – 0.82] for SLE, and HR 0.51 [0.25 – 1.02] for other RMDs. While there was no difference in HCQ SEs by concomitant category or diagnoses, there was consistently higher SE rates in MTX for those on concomitant csDMARD vs monotherapy: RA HR 1.27 (1.16 - 1.38), SLE HR 1.97 (1.03 - 3.52), and other RMDs HR 2.04 (1.28 - 3.24).ConclusionThis is the largest study yet to review patient-reported SEs from HCQ and MTX in RA and other RMDs over a 20-year period. While validating SEs was beyond the scope of the current study, we found an overall low incidence of SEs from HCQ use, with an adjusted rate half of those reported for MTX, and that this low rate did not differ by diagnosis or concomitant DMARD use.Disclosure of InterestsNone declared

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Zhan, Huichun, Michael B. Streiff, Karen E. King, and Jodi B. Segal. "Thrombotic Thrombocytopenic Purpura at Johns Hopkins from 1993 to 2008: Clinical Outcomes and Risk Factors for Relapse in 75 Patients." Blood 112, no. 11 (November 16, 2008): 2288. http://dx.doi.org/10.1182/blood.v112.11.2288.2288.

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Abstract Background: Since the introduction of plasmapheresis, TTP-associated mortality has declined from 90% to 10–20%. However, 20–50% of patients experience recurrent disease. The goal of this study was to describe the clinical spectrum of TTP, determine the clinical outcome of patients with TTP and identify risk factors for disease relapse or recurrence. Methods: We retrospectively reviewed consecutive TTP patients treated between January 1992 and April 2008 at the Johns Hopkins Hospital. Complete demographic, clinical, laboratory, treatment, and response data were collected. A standard treatment protocol of corticosteroids (Methylprednisolone 100 mg IV q12h) and daily plasmapheresis (1.5 plasma volumes) was used during the study period. Rituximab, azathioprine and vincristine were employed in refractory or relapsing patients at physician’s discretion. Logistic regression was used to examine the association of clinical and laboratory parameters with four ordered outcome categories in TTP survivors: relapse (<30days), early recurrence (1–6 mo), late recurrence (≥ 6mo), and remission. Results: A total of 75 patients and 138 episodes of TTP were treated during the study period. Microangiopathic hemolytic anemia was noted in all cases. The median follow-up was 31.5 months (IQR 6 – 76 months). The median age was 42 years (range 13–82). Of the 75 patients, 73% were females and 56% were African American. 68% of the TTP episodes presented acutely (< 1 week), while 25% were subacute (1–4 weeks) and 7% had a chronic presentation (≥ 1 month). Neurologic abnormalities were present in 67% episodes while 35% had abnormal renal function on admission; 95% and 90% resolved on discharge or during follow-up, respectively. The median platelet count on admission was 15×103/μL (range 1 – 144) and the median lactate dehydrogenase (LDH) value was 927U/L (range 152 – 5950). The mean time for platelet recovery was 10 days (range 2 – 48) while the mean time for LDH recovery was 20 days (range 2 – 100) (p < 0.0001). The mean length of hospital stay for each episode was 21 days (range 1 – 84). ADAMTS13 results were available in 45 episodes (39 patients) — 69% had severe ADAMTS13 deficiency (<10%), 11% had moderate deficiency (10–25%), and 20% had minimal deficiency or normal ADAMTS13 activity (>25%). Inhibitors were present in 74% of episodes with severe ADAMTS13 deficiency and 60% of episodes with moderate deficiency. All patients received plasmapheresis and most (95%) received corticosteroid treatment. The mean time from admission to plasmapheresis initiation was 1.9 days (range 1– 14). The mean number of pheresis sessions required to achieve a complete remission was 17 (range 3 – 66) over a total of 22 days (range 3 – 89). The mortality rate was 4% in both first-episode patients and all TTP episodes. The relapse/recurrence rate was 44% in first-episode patients and 50% in all TTP episodes. The average time-to-relapse/recurrence was 14 months (range 0.07–93 months) and 83% of relapses or recurrences occurred during the first two years. When categorized into four different outcome groups (i.e. relapse vs. early recurrence vs. late recurrence vs. remission), patients who relapsed were more likely to be African American (p = 0.002), had a higher platelet count (p = 0.02) and white blood cell count (p = 0.009) on admission and a higher LDH value on discharge (p = 0.031). There was no significant difference in ADAMTS13 results among the four groups. In a secondary analysis when we pooled all suboptimal outcomes, we found that African American patients had an odds of remission that was just 0.42 (p=0.042) that of Caucasians. Episodes with an admission platelet count in the upper quartile (mean of 82 x103/μL) were 2.9 times (95% confidence interval 1.2 to 6.8) more likely to have a suboptimal outcome than episodes with platelet count in the lowest quartile (mean of 8 x103/μL). Analysis restricted to the first-episode patients yielded similar outcomes. Conclusion: Using a standardized protocol of daily plasmapheresis and high-dose corticosteroids we have achieved a low mortality rate (4%) in patients with TTP. Risk factors for recurrence include African American ethnicity and high platelet counts on admission. If these risk factors remain valid in prospective studies, they may prove useful in identifying TTP patient in whom more aggressive initial treatment (e.g., Rituximab, etc.) may be warranted.

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Lin, Tasha, Hassan B. Alkhateeb, Aref Al-Kali, Michelle Ann Elliott, Naseema Gangat, William J. Hogan, Grzegorz S. Nowakowski, et al. "Prognostic Correlates and Outcomes of Relapsed T-Cell Acute Lymphoblastic Leukemia/Lymphoma: An Analysis of 41 Consecutive Patients." Blood 126, no. 23 (December 3, 2015): 3730. http://dx.doi.org/10.1182/blood.v126.23.3730.3730.

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Abstract Background: Acute T-cell lymphoblastic leukemia (T-ALL)/ lymphoma (T-LBL) are immature T-cell malignancies with very poor outcomes. In patients with relapsed disease, survival is often < 12 months (Marks et al, Blood, 2009). Prognostic correlates and treatment outcomes after relapse remain largely unknown. Aims: To evaluate prognostic correlates and treatment outcomes in patients with relapsed T-ALL/LBL. Methods: After IRB approval, 92 consecutive patients with T-cell ALL/LBL were identified. 41 patients with relapsed disease after achieving a first complete remission (CR1) were included in the study group. Features at the time of relapse were retrospectively abstracted and analyzed. Survival time after relapse was calculated from the time of relapse until death or last follow-up. Conventional methods were used for statistical analysis. Results: A. Baseline characteristics of all patients 92 patients were identified [41 LBL, 51 ALL]. Median age was 33 years (range; 18-88) and 66 (72%) were males. Median follow-up was 25 months (range 0.9-260). 13(14%) received palliative care or were lost to follow-up before treatment initiation. At last follow-up, there were 41 (52%, n = 79) relapses and 42 (46%, n = 92) deaths. Of 79 patients, 71 (90%) achieved a CR1 and 8 (10%) had primary refractory disease. Comparisons between ALL and LBL revealed expected differences in presenting features such as frequency of primary mediastinal mass at presentation in LBL and high leukocyte count in ALL. Significant differences in treatment were seen. Asparaginase-based and ALL-directed therapy were more common in the ALL group (71% vs. 45%, p = 0.009; 88% vs. 71%, p = 0.04). 13 (81%) LBL and 14 (27%) ALL underwent allogeneic SCT. The remaining three in each group underwent autologous SCT in CR1. B. Characteristics of relapsed patients 41 relapsed after achieving CR1 [23 LBL, 18 ALL]. Median time to relapse was 8.0 months (range 2.3-130), with no difference between ALL and LBL groups. Median age was 34 years (range 19-71) and 29 (71%) were males. Median follow-up after relapse was 7.2 months (range 0.3-207). At time of last follow-up, there were 30 (73%) deaths, 25 (61%) achieved a second complete remission (CR2) and 14 (34%) had persistent disease. 12 (48%) had relapse following CR2. 34 (83%) relapsed following CR1 after induction chemotherapy alone. 6 (15%) and 1 (2%) relapsed following allogeneic and autologous SCT respectively. 27 (66%) had BM involvement, 5 (12%) had CNS involvement, 13 (32%) had mediastinal involvement, and 3 (7%) had isolated extramedullary relapse. Ten (43%) patients with LBL relapsed with ALL. Of 27 patients with available data, 9 (33%) had high-risk cytogenetics at relapse, defined as ≥ 5 chromosomal abnormalities and/or markers known to confer an unfavorable prognosis. 16 of these 27 patients had follow-up cytogenetic studies performed, of which 8 (50%) had evidence of clonal evolution. Patients were treated with up to five regimens. 12 (31%) received asparaginase-based therapy and 13 (33%) received nelarabine with CR2 rates of 75% and 25% respectively. Median number of regimens needed to achieve CR2 was one. 18 (46%) went onto SCT following CR2: 14 (allogeneic), 3 (autologous), and 1 (donor lymphocyte infusion). The majority received myeloablative conditioning (92%). C. Outcomes and prognostic correlates for survival after relapse Median survival following relapse was 8.2 months (IQR 4.1-21.3) and did not differ between LBL and ALL. Nine (36%) who achieved CR2 are alive at time of last follow-up. 25 (61%) achieved CR2, but 12 (48%) relapsed following CR2, with median time to second relapse of 7.6 months (IQR 4.7-14). Nine of 18 who underwent SCT following CR2 had disease relapse (8 allogeneic, 1 autologous). Only BM involvement at relapse significantly correlated with post-relapse survival (HR 2.4 [1.1, 5.1], p = 0.03). Clonal evolution, high-risk cytogenetics, nelarabine therapy, achieving CR2, and SCT were not independent predictors of survival in our small subset of patients. Conclusion: Patients with relapsed T-ALL/LBL have dismal outcomes, in spite of advances in therapy with newer agents such as nelarabine and the use of allogeneic SCT. Regardless of T-ALL/LBL subtype, BM involvement at relapse appears to be a significant factor negatively impacting post-relapse survival. Further studies are needed to validate these findings. Disclosures Al-Kali: Celgene: Research Funding. Thompson:Kite Pharma: Research Funding.

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Roy, Lydia, Jean Christophe Ianotto, Joelle Guilhot, Christian Récher, Laurence Legros, Dana Ranta, Emmanuel Raffoux, et al. "Long Term Efficacy and Tolerance of Pegylated Interferon Alpha Therapy for Patients with High Risk Essential Thrombocythemia: An Observational Study of the French Intergroup of Myeloproliferative Disorders (FIM)." Blood 124, no. 21 (December 6, 2014): 1845. http://dx.doi.org/10.1182/blood.v124.21.1845.1845.

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Abstract Background: Therapeutic guidelines in essential thrombocytemia (ET) are based on established criteria, ie. age more than 60 years, history of thrombosis, platelets more than 1000-1500 ×109/L and to lesser degree cardio-vascular risk factors. Hydroxyurea and anagrelide are the most commonly used cytoreductive therapy for high risk ET. Despite a proven activity in Ph negative myeloproliferative disorders, generalized use and efficacy of Interferon-alpha (IFN-α) have been hampered by frequent side effects. Nonetheless it is a non leukemogenic therapeutic option for younger patients (pts) and during pregnancy. Two phase II trials using Pegylated (Peg) forms of IFN-α in pts with polycythemia vera (PV) or high risk ET have provided interesting results: i) an improved toxicity profile generally associated with a rapid hematolologic response, ii) a molecular response described in a subset of JAK2V617F positive PV or ET pts treated with PegIFN-α. Aim: To estimate the rationale of PegIFN-α therapy selection in high risk ET patients, efficacy and tolerance. Methods:Cases of high risk ET patients, who started PegIFN-α therapy between 2006 and 2011, were reported by centres of the French Intergroup of Myeloproliferative disorders and included in an observational study. We collected information regarding history of MPN, treatment, hematologic response at different timepoints, toxicities related to PegIFN-α, thrombo-hemorrhagic events and hematologic progression. The current analysis was performed on 103 consecutive pts. Results: Median follow-up from ET diagnosis was 9 years (3-27). 74% of pts were female, median age was 37 years (range 16-67). Previous vascular event was observed in 36% of cases and JAK2V617F mutation was detected in 52% of pts. . Median time from diagnosis to PegIFN-α was 40 months (1-255). PegIFN-α was administered after hydroxyurea and anagrelide in second or third line (56% and 27% respectively). No prior therapy has been used for 16% of pts. Reasons for starting PegIFN-α were lack of hematologic response (21%), toxicity to prior therapies (17%), pregnancy (15%), or medical decision for younger pts (47%). Pts received either PegIFNα-2a (n=91) or PegIFNα-2b (n=12), based on physician decision. According to the 2009 European LeukemiaNet criteria and with a median exposure to PegIFN-α of 29 months (1-92), 81% of pts achieved a complete hematologic response (CHR). Cumulative incidence of CHR were 58 % (95% CI: 49-68), 73% (95% CI: 65-81) and 80% (95% CI: 71-87) at 6, 12 and 24 months respectively. By analysing the response according to JAK2 status, cumulative incidence of CHR was better for the JAK2V617F positive subgroup (p=0.0183, overall). At 36 months estimated CHR rates were 89% (95% CI: 79-95) and 70% (95% CI: 57-82) for JAK2VF positive vs negative subgroup respectively. Median exposure to PegIFN-α was 29 months in both groups. At last follow-up, with a median of 42 months since PegIFN-α initiation, 53% of the pts were still treated with PegIFN-α. Among them, 76% have maintained a CHR. Reasons for discontinuation of PegIFN-α (47% of pts) were consecutive to PegIFN-α toxicity (59%), -mainly chronic moderate non hematologic toxicity-, or hematologic responses were considered insufficient in16%. In addition, PegIFN-α has been stopped in a subset of pts who achieved a durable stable CHR. In Conclusion, This study provides results of PegIFN-α therapy in a cohort of high risk ET pts not included in clinical trials. In this selected population of young pts, a durable efficacy of therapy was observed in half of patients. Characteristics of hematologic response according to molecular status will be presented. These results support the PegIFN-α as an alternative therapy to hydroxyurea and anagrelide in high risk ET, and warrant its investigation in further prospective randomized studies. Disclosures Roy: Merck: Peg-Interferon provided for academic clinical trial in CML Other. Off Label Use: Peg-Interferon in essential thrombocythemia. Gyan:Roche: Research Funding. Nicolini:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kiladjian:Roche: Peg-Interferon provided for academic clinical trial in PV Other.

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Nikitina, O. V., I. P. Mikhailov, N. Y. Kudryashova, E. V. Migunova, O. A. Alekseyechkina, E. V. Kungurtsev, N. M. Udalova, S. Z. Khusainov, and I. B. Kostyuchenko. "THROMBOLYTIC AND ANTICOAGULANT THERAPY FOR PULMONARY EMBOLISM: AN EFFECT ON PULMONARY PERFUSION (PART 2)." Russian Sklifosovsky Journal "Emergency Medical Care" 7, no. 2 (July 25, 2018): 134–43. http://dx.doi.org/10.23934/2223-9022-2018-7-2-134-143.

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Background.Perfusion scintigraphy reveals perfusion defects in the occlusion of pulmonary vessels of any caliber and makes it possible to quantify pulmonary blood flow disorders, which allows the method to be used for the comparison of the thrombolytic and anticoagulant therapy efficacy in patients with acute pulmonary embolism.Aim of study .To compare the efficacy of thrombolytic and anticoagulant therapy in the treatment of acute pulmonary embolism in the dynamics of pulmonary perfusion disorders.Study Design.A prospective non-randomized study. The quantitative result of pulmonary perfusion deficiency obtained during perfusion scintigraphy was compared in patients with pulmonary embolism treated with thrombolytics or anticoagulants before treatment and in dynamics. The dynamics was evaluated the next day after administration of thrombolytics and on day 4–5 after initiating anticoagulant therapy. Preliminary analysis of these parameters in the group with anticoagulant therapy a day after the start of administration (by analogy with TLT) revealed no statistically significant differences.Description of the method.Radionuclide and CT studies were performed on a hybrid system SPECT/CT “Discovery NM/CT 670” (GE, USA): perfusion was evaluated with 80–120 MBq of Macrotech 99mTc radiopharmaceutical (RP), CT angiography was performed with 70-100 ml of radiopaque substance “Visipaque.” To determine the total perfusion deficiency, each defect of accumulation with an area equal to the segment was taken as a perfusion deficiency of 5% (subsegmental — 2.5%), equal to the lower lobe — 25%, an area equal to the right lung — 55%, the left lung — 45%. Characteristics of the sample.The perfusion scintigraphy was performed in 381 cases out of 503 patients with a diagnosis of pulmonary embolism of high/intermediate risk of early death, treated in the Intensive Care Unit for Surgical Patients from 2011 to 2016. In 166 cases out of 381, thrombolysis was performed; in 215 cases, an anticoagulant was prescribed. The groups did not differ in age and gender composition: 60±16 years; Me 61 (50; 71) and 62±15 years; Me 63 (53; 74); p=0.22, Mann-Whitney test; men/women: 73/93 and 89/126; p=0.68, the Fisher test.Results of the study.In 96.1% (366/381), perfusion disorders were observed in both lungs; in 3.9% (15/381) there was a unilateral lesion. The comparison of the treatment efficacy was conducted in 169 patients: in 127 cases the next day after introduction of a thrombolytic and in 42 cases on day 4–5 of anticoagulant therapy. In the group with thrombolysis, the initial perfusion deficiency was statistically significantly higher than in the anticoagulant group: 50±10%; Me 50 (40; 60) vs. 39±10; Me 40 (30; 45); p<0.00001, the Mann–Whitney test. The level of pulmonary hypertension was also higher: the systolic pressure in the pulmonary artery was 56±17 Me 54 (45, 68) versus 40±24 Me 40 (22; 56); p<0.00001, the Mann–Whitney test. As a result of treatment, the perfusion deficiency statistically significantly decreased in both groups: in the group with TLT from 50±10%, Me 50 (40; 60) to 26±14%; Me 25 (15; 35); p<0.00000.1, Wilcoxon test; and in the treatment with anticoagulant it decreased from 39±10%, Me 40 (30; 45) to 23±15%; Me 15 (15; 30); p<0.0001, Wilcoxon test. In the TLT group, the perfusion disorders regression was stronger compared to ACT and was registered the next day after administration of a thrombolytic: the standardized effect Es=2.0 and Es=1.2. In the treatment with anticoagulants, statistically significant differences were detected only on day 4–5 from the beginning of its administration. The study power for both groups was 1.00. After thrombolysis the systolic pressure in the pulmonary artery decreased statistically significantly within the next 24 hours: from 56±17 mmHg, Me 54 (45, 68) to 36±14 mmHg, Me 35 (25; 43); p=0.0002, Wilcoxon test; Es=1.3; P=1.00. With anticoagulant treatment, no statistically significant changes in pulmonary arterial pressure occurred 4-5 days after the initiation of treatment: 40±24 mmHg, Me 40 (22; 56) and 50±31 mm Hg, Me 48 (30; 58) ); p=0.72, Wilcoxon test.Conclusion.The advantage of thrombolysis over anticoagulant therapy was the ability to improve pulmonary blood flow, reduce pulmonary hypertension, and stabilize the patients’ condition quickly. Anticoagulant therapy did not allow this effect to be achieved in a short time: the statistically significant reduction in pulmonary perfusion deficiency occurred only on day 4–5 of treatment and was less significant; the statistically significant regression of pulmonary hypertension did not occur at that time.

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Binotto, Gianni, Fausto Castagnetti, Gabriele Gugliotta, Elisabetta Abruzzese, Massimo Breccia, Alessandra Iurlo, Fabio Stagno, et al. "One Size Does Not Fit to All: Intolerant or Resistant CML Patients Could Benefit from Different Ponatinib Starting Dose Strategies. Multicenter Italian Experience." Blood 132, Supplement 1 (November 29, 2018): 1732. http://dx.doi.org/10.1182/blood-2018-99-116825.

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Abstract Background: Ponatinib is effective as salvage treatment for chronic phase (CP) Ph+ chronic myeloid leukemia (CML) patients resistant or intolerant to prior TKIs. Based on the concern for an unfavourable cardiovascular toxicity profile, a dose reduction to 15 mg daily is currently recommended in CP patients after the achievement of treatment milestones. As more flexible approaches with TKIs dosage are increasingly adopted in clinical practice, identifying specific profiles of patients eligible for different treatment strategies, in order to improve the benefit/risk ratio, would be of particular interest. Aims: To update previous observations in an extended cohort of CML patients, resistant or intolerant to prior TKIs, describing the efficacy and toxicity of two different ponatinib schedules (de-escalated vs 15 mg starting dose). Secondly, to investigate whether specific subsets of CML patients were managed more successfully with one strategy. Methods: A retrospective analysis of CML-CP patients treated with ponatinib 15 mg, as starting or de-escalated dose has been performed. No pre-specified criteria to switch to ponatinib, to reduce or to start therapy with a lower dose were indicated. Cytogenetic and molecular responses were evaluated according to the ELN2013 recommendations. Toxicities under ponatinib treatment leading to transient or definitive discontinuation were recorded. Results: 68 patients were included in this analysis. Median age at ponatinib start was 57 years (range: 28-87). The median time from CML diagnosis to ponatinib treatment was 4.6 years (range: 0.4-19). Most patients (70.6%) were treated with imatinib as frontline treatment. 30/68 patients (44%) received ponatinib as 4th or subsequent line of therapy. ABL1 mutations were detected in 18 (26.5%) patients (being 44% of them positive for the T315I mutation). 50/68 (73.5%) of cases had less than MR2 at the time of ponatinib initiation, with one third exhibiting primary refractoriness to all prior treatments. Resistance to prior TKIs was the reason for switch in 85% of patients treated with higher doses of ponatinib, while 13/26 patients starting with 15 mg were purely intolerant or intolerant and resistant (p= 0.001). No other significant differences between the two groups were identified. MR2, MR3 and MR4/MR4.5 rates were 78.6%, 59.6% and 28.6% in 42 patients treated with the "de-escalated" approach, respectively. First step of dose reduction was decided after a median time of 3.1 months, with a subsequent decrease to 15 mg after a median of 10 months. Dose modifications were guided mostly by adverse events (73%) and, less frequently, to prevent toxicity and/or following response attainment (27%). Median duration of treatment was 27 months (range: 2-81), with 5/42 patients discontinuing ponatinib (1 cerebrovascular accident, 2 severe hematologic toxicities, two cases of resistance/progression). 4 deaths were registered, three after blast crisis and one for a fatal cardiovascular event. 26 patients started ponatinib 15 mg daily, with a median duration of treatment was 15 months (range: 2-58). MR2 was obtained in 77%, MR3 in 69.3% and MR4 in 46.2% of cases, respectively. MR3 or deeper responses were maintained in 80% of patients; 7/26 lost their best acquired response, with subsequent dose escalation to higher than 15 mg in 5/26 patients. Treatment discontinuation was necessary in 3 cases (1 coronary vasospasm-induced acute coronary syndrome, 2 muscle skeletal pain). Of note, patients with ABL mutations gained benefit only from the "de-escalated" approach, with response improvements in 10/14 of cases vs 0/4 in the "low dose" group. Similarly, a higher rate of at least a MR2 was obtained in primary refractory patients treated ab initio with higher doses of ponatinib (57.1 % vs 14.3 %). However, focusing only on pure intolerant patients, 15 mg starting dose was very effective, with all patients achieving at least a MR3 or deeper response. Summary/Conclusion: With the limits of the retrospective nature and small sample size, these data suggest that different dose strategies could be applied to specific subsets of CP-CML patients. While mutations or refractoriness to previous treatments should address towards a "debulking approach" with 45 or 30 mg ponatinib dose, intolerant or "low level resistance" cases could benefit from lower starting dose. Further investigation in larger prospective trials is warranted. Disclosures Castagnetti: Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gugliotta:Bristol-Myers Squibb: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Abruzzese:Ariad: Consultancy; BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Breccia:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria; Incyte: Honoraria. Levato:Novartis: Other: Advisory board. Pane:AMGEN: Speakers Bureau; BMS: Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

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Alp, Suzan, Ayse Salihoglu, Ahmet Emre Eskazan, Emine Gulturk, M. Cem Ar, Seniz Ongoren Aydin, Zafer Baslar, et al. "Imatinib for Chronic Myeloid Leukemia Patients: A Single Institution Experience." Blood 118, no. 21 (November 18, 2011): 4429. http://dx.doi.org/10.1182/blood.v118.21.4429.4429.

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Abstract Abstract 4429 Background Imatinib mesylate (IM) is considered the mainstay of chronic myeloid leukemia (CML) treatment for almost a decade. The primary goal of the study is to share data of a substantial number of CML patients followed at one center. Methods We analyzed data from 177 CML patients who were treated in our institution and received IM for at least 24 months. They were stratified into low, intermediate and high risk groups based on Sokal score. Early chronic phase (ECP) (within one year from diagnosis to IM start), late chronic phase (LCP) (≥ 12 months from diagnosis), and accelerated phase (AP) CML patients were included in the study. Patients were evaluated for hematologic, cytogenetic and molecular responses, event-free survival (EFS) and overall survival (OS), frequency of adverse events. Results The median age was 51.2 years (range, 22–86 years), with 77 females and 100 males. Patients were followed for a median of 60 months (range, 24–116 months). IM was started at a dose of 400 mg daily. 97.7% were in chronic phase, and 2.3% were in accelerated phase.75.1% of chronic phase CML patients were in early and 24.9% in late chronic phase. 42% of patients were low Sokal risk, 44% intermediate and 14% were high risk patients. 12% of the patients did not receive any prior therapy, 1% had received prior therapy with interferon (IFN), 73% were treated with hydroxyurea (HU) (mostly short course) and 14% with both HU and IFN. Complete hematologic response (CHR) was achieved in 90% of patients at 3 months (median time, 2.02 months). Cumulative rates of cytogenetic and molecular responses at 6, 12, 18 and 24 months are summarized in Table 1. Complete cytogenetic response (CCyR) was achieved in a significantly higher proportion of patients within the low and intermediate Sokal risk group (79.4%, 85.2%) compared with the high risk patients (14.3%, p=0.001). There was a significant difference in the complete molecular response (CMR) ratio achieved by low, intermediate and high Sokal risk patients (70.4%, 63.8% and 33.3%, p<0.05). 5-year OS rates were 100% and 84% among low-intermediate and high Sokal risk patients (p=0.0001) (Figure 1). The EFS at 5 years was 77%, 81%, and 63% in low, intermediate and high Sokal risk patients (p=0.001) (Figure 2). ECP CML patients achieved higher CCyR rates (87%) compared with LCP CML patients (48.6%, p=0.001). CMR rates were 67.7% and 46.9% in ECP and LCP CML patients (p<0.05). 62.2% of the patients remained on 400 mg/day IM treatment and in 3.4% the dose was increased to 600 mg/day. Second-generation tyrosine kinase inhibitors (TKIs) were initiated in 21% of the study population. Hematological and non-hematological toxicities were experienced in 23.7% and 56.7% of our patients. In 6.2% a dose reduction and in 3.4% a switch to a second generation TKI was necessary due to toxicity. 5-year OS and EFS rates of the entire cohort were calculated as 97% and 77%. EFS rates at 5 years were significantly higher among patients achieving CCyR compared with those without a CCyR (92%, 64%, p=0.0001) (Figure 3A). 5-year EFS rates were significantly higher in patients achieving CMR compared with those who did not (95%, 58%, p=0.0001) (Figure 3B). Conclusion In the current report, we described the outcome of unselected CML patients, treated outside of clinical trials. Grouping patients according to their Sokal prognostic score predicted IM response in this cohort. A longer interval from diagnosis to the start of IM and high Sokal risk score were adverse prognostic factors. 'Real life' data of our study are in accordance with the previous data reflecting the prognostic impact of cytogenetic and molecular responses on survival. Close follow-up of the responses and timely initiation of second-generation tyrosine kinase inhibitors were associated with high survival rates. Disclosures: No relevant conflicts of interest to declare.

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Lazareva, Olga V., Ekaterina Yu Chelysheva, Olga Vinogradova, Anton Kulikovsky, Varvara I. Bakhtina, Eva Burnasheva, Tatiana Chagorova, et al. "The 15 Year Long-Term Survival of Patients with Chronic Myeloid Leukaemia from 35 Regions of Russian Federation: A Follow up of a Multicenter Observation Study Eutos Osp Initiated By European Leukemia NET." Blood 138, Supplement 1 (November 5, 2021): 5035. http://dx.doi.org/10.1182/blood-2021-151371.

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Abstract The results of long-term follow-up of patients (pts) with chronic myeloid leukemia (CML) do not lose their importance. Data from routine clinical practice are of particular interest. The use of 1 st (imatinib, IM) and 2nd generation TKI (2G TKI) led to a significant increase in survival, so the probability of death associated with CML could be significantly lower than the probability of death due to common causes of death other than CML. To analyze the overall survival (OS) and causes of mortality in CML pts treated in routine clinical practice in Russian Federation for a long period (>15 years) of time. The long-term follow-up data of the Russian part of the European LeukemiaNet (ELN) OSP EUTOS multicenter observational study were evaluated. The analyzed cohort consisted of 678 Ph/BCR-ABL-positive CML pts from 35 regions of Russia diagnosed in 2002-2006 with IM therapy initiation ≤6 months (mo) after diagnosis. Median (Me) age was 47(range 18-81) years (y), 47% males. Chronic phase, accelerated phase and blast crisis at diagnosis was in 631 (93%), 41(6%) and 6(1%) pts, respectively. The annual number of newly diagnosed pts was as follows: 2002 - 15 pts, 2003 - 38 pts, 2004 - 46 pts, 2005 - 206 pts, 2006 - 302 pts. The last update for 209 pts was done in Jun. 2021; last contact for 100 pts - in 2020, for 39pts - in 2019, for the other - before 2018. The date of the last contact/death could not be established for 14 pts. Statistical analysis included 661 pts, the OS was evaluated by Kaplan-Mayer method using the SAS 9.4 package. In total, 331 (50%) pts of the analyzed cohort were alive with the Me follow-up of 180 (range 2-232) mo or 15 y (range 2 mo-19,3 y). All pts started therapy with IM with 25% switched to 2G TKI in subsequent therapy lines. In total, 218 (66%) pts achieved MR4, 183 (55%) pts got MMR; 46 (21%) of these pts with deep molecular response (DMR) were observed in hematology centers of Moscow. The 15-y OS in the total cohort was 63% (CI 59-70%)(fig.1). The OS by age groups was as follows: 18-40yy-75% (CI 73-82%), 40-60yy- 63% (CI 59-70%), 60-80yy- 37% (CI 30-45%). The most complete information was provided by Moscow centers (2 centers, 113 pts). The 15-y OS of pts receiving treatment in Moscow was significantly higher vs pts from other regions (32 centers, 548 pts): 75% vs 60%, p=0,0030 (fig.2). The mortality in the whole cohort of 661 pts was 35% (233 pts). Of these 233 pts, 112(48%) pts deaths were due to CML progression to AP or BP (including non-compliant cases); 3pts (1,5%) died after allogenic stem cell transplantation (infection complications); the cause of death was unknown in 50 (21,5%) pts. The highest death rate from CML progression was at 4-9 y of follow-up. Deaths caused by concomitant diseases were in 68 (29%) pts: coronary artery disease/myocardial infarction/heart failure in 42 (62%) of 68 pts, acute ischemic stroke in 10 (15%) pts, second malignancies (Cr- cancer) in 10 (15%) pts (lung tumor, metastatic esophageal Cr, stomach Cr, brain tumor, sigmoid colon Cr, rectal colon Cr, melanoma, renal Cr, breast tumor, other hematological malignancies), accidents - 1 pt, liver cirrhosis - 2 pts, in 2 cases - respiratory virus infections complicated with pneumonia, 1 pt died due to Covid-19. Conclusions. The long-term follow-up of the multicenter study EUTOS OSP in 35 regions of Russian Federation allows not only to characterize the 15-y OS in CML pts but also provides the long-term outlook of the routine clinical practice. Probably, better OS of CML patients receiving treatment in Moscow (2 centers) may be related to organizational issues of interaction with the federal center, better monitoring and timely switching to 2G TKI therapy. The organization and support of multicenter studies may improve the situation with the treatment of diseases of the blood system. Figure 1 Figure 1. Disclosures Chelysheva: Novartis Pharma: Speakers Bureau; Pfizer: Speakers Bureau; Pharmstandart: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Vinogradova: Pharmstandart: Speakers Bureau; Novartis Pharma: Speakers Bureau; Pfizer: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Lomaia: Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Pharmstandard: Honoraria. Voloshin: Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Astra Zeneca: Consultancy, Speakers Bureau; Pfizer: Consultancy; Biacad: Consultancy, Speakers Bureau. Turkina: Pharmstandart: Speakers Bureau; Pfizer: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Novartis Pharma: Speakers Bureau.

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Verstovsek, Srdan, Jean-Jacques Kiladjian, Alessandro M. Vannucchi, Ruben A. Mesa, Robyn Scherber, J. E. Hamer-Maansson, and Claire N. Harrison. "Does Early Intervention in Myelofibrosis Impact Outcomes? a Pooled Analysis of the Comfort I and II Studies." Blood 138, Supplement 1 (November 5, 2021): 1505. http://dx.doi.org/10.1182/blood-2021-150894.

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Abstract Introduction Myelofibrosis (MF) is characterized by cytopenias, splenomegaly, burdensome symptoms, and poor overall survival (OS). To date, few studies have investigated if earlier intervention with targeted MF therapies affects response and OS. In a pooled analysis of the COMFORT I and II trials of ruxolitinib (RUX), the first approved treatment for MF, patients (pts) who received RUX at randomization or after crossover from placebo (PBO) or best available therapy (BAT) had improved OS. The survival advantage in the crossover group was less than that among pts initially randomized to RUX, suggesting that earlier intervention may provide greater clinical benefit. Additionally, previous reports have shown that pts earlier in their disease course (lower- vs higher-risk category or grade of bone marrow fibrosis) and those who initiated RUX earlier (≤2 y vs >2 y from diagnosis) had improved responses to RUX. The objective of this analysis was to assess the association of MF disease duration before treatment with disease outcomes using pooled COMFORT data. Methods COMFORT I (NCT00952289) and COMFORT II (NCT00934544) were phase 3 trials of RUX vs PBO or BAT, respectively, in pts with intermediate-2 or high-risk MF. In this post hoc analysis, data from RUX-treated pts in both studies were combined (RUX treatment group), and data from the PBO/BAT arms were pooled (control group). Pt subgroups were defined based on disease duration before RUX initiation (≤12 mo or >12 mo from diagnosis). Assessments included frequency of thrombocytopenia (platelets [PLT] <100 Gi/L or PLT transfusion) and anemia (hemoglobin <100 g/L or red blood cell transfusion) events, spleen volume response (SVR; spleen volume reduction ≥35% from baseline [SVR35]), symptom response (MF-Symptom Assessment Form total symptom score [TSS] reduction ≥50% from baseline [TSS50]; available in COMFORT I only), and OS. OS was assessed using the Kaplan-Meier method; pts randomized to PBO/BAT were included in the PBO/BAT group regardless of crossover. Results A total of 525 pts were included in the analysis (RUX: ≤12 mo, n=84; >12 mo, n=216; PBO/BAT: ≤12 mo, n=66; >12 mo, n=159). Median age across groups ranged from 65.0 to 70.0 y. Baseline clinical characteristics were generally similar across subgroups, although pts with shorter vs longer disease duration were slightly younger and tended to have higher blood counts. Among pts who received RUX, fewer thrombocytopenia events were observed among those who initiated treatment earlier (≤12 mo vs >12 mo), with differences observed as early as Wk 4-8 on treatment (18% vs 33%) and sustained over time; a similar trend was observed for anemia events (Wk 4-8, 59% vs 72%). Mean (SD) reduction from baseline in spleen volume was greater for pts who initiated RUX at ≤12 mo vs >12 mo at Wk 24 (-35% [21] vs -29% [18]) and Wk 48 (-36% [24] vs -28% [22]). Likewise, the proportion of pts with SVR35 was greater among those who initiated RUX earlier (≤12 mo vs >12 mo) at Wk 24 (48% vs 33%) and 48 (44% vs 27%). Spleen responses were more durable among those with shorter vs longer disease course (median duration of response, not reached vs 230 wk, respectively). A greater proportion of pts who initiated RUX at ≤12 mo vs >12 mo achieved TSS50 at Wk 24 (56% vs 40%); mean (SD) change from baseline in TSS at Wk 24 was -52% (42) vs -44% (51), respectively. OS at Wk 240 was improved among pts who initiated RUX at ≤12 mo vs >12 mo (63% [95% CI, 51%-73%] vs 57% [95% CI, 49%-64%]; P=0.0430; Figure). Comparatively, OS was longer with RUX vs PBO/BAT regardless of disease duration. A sensitivity analysis using a 24-mo cutoff was also conducted but yielded weaker associations between disease duration and SVR, TSS, and OS. Discussion These findings suggest that earlier RUX initiation in MF may improve clinical outcomes, including fewer cytopenia events, durable spleen volume response, symptom burden, and OS. Although younger age and higher baseline blood counts may have been confounders for improved clinical outcomes in this study, these factors likely reflect an earlier disease stage, and the observed outcomes support the rationale for early intervention in a real-world setting. While "watch and wait" remains a common treatment approach for newly diagnosed patients, these data suggest that patients with MF may benefit from earlier intervention. Additional studies to further evaluate the impact of early intervention are warranted. Figure 1 Figure 1. Disclosures Verstovsek: Incyte Corporation: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; CTI BioPharma: Research Funding; Genentech: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Ital Pharma: Research Funding; Protagonist Therapeutics: Research Funding; PharmaEssentia: Research Funding; Blueprint Medicines Corp: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Kiladjian: Taiho Oncology, Inc.: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Other: Personal fees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Vannucchi: Incyte Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mesa: Genentech: Research Funding; Gilead: Research Funding; La Jolla Pharma: Consultancy; AOP: Consultancy; Novartis: Consultancy; Samus: Research Funding; Promedior: Research Funding; CTI: Research Funding; CTI: Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Pharma: Consultancy; Constellation Pharmaceuticals: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding. Scherber: Incyte Corporation: Current Employment, Current holder of stock options in a privately-held company. Hamer-Maansson: Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Harrison: Incyte Corporation: Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sierra Oncology: Honoraria; Constellation Pharmaceuticals: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Schou, M., B. Claggett, A. Fernandez, G. Filippatos, C. Granger, K. Jering, A. Maggioni, et al. "Sacubitril/valsartan compared to ramipril in high risk post myocardial infarction patients stratified according use of mineralocorticoid receptor antagonists: insight from PARADISE MI trial." European Heart Journal 43, Supplement_2 (October 1, 2022). http://dx.doi.org/10.1093/eurheartj/ehac544.977.

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Abstract Background Mineralocorticoid receptor antagonists (MRAs) reduce the risk of cardiovascular death or heart failure admission in patients with myocardial infarction (MI) and left ventricular systolic dysfunction (LVSD) combined with either heart failure (HF) or diabetes. Whether use of MRA and initiation of sacubitril/valsartan are safe and whether MRAs modify the effect of sacubitril/valsartan initiation in high-risk MI patients is unknown. Purpose This analysis examined whether background treatment with a MRA modifies the treatment effect and safety of sacubitril/valsartan in patients with a MI and LVSD and/or pulmonary congestion. Methods In the PARADISE MI Trial (Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction) N=5661 patients were randomized to either sacubitril/valsartan (97/103 mg twice daily) or ramipril (5 mg twice daily) within 7 days of their MI. The primary outcome in this analysis was the composite of worsening HF (HF hospitalization or outpatient worsening) or cardiovascular death evaluated by the clinical endpoint committee (CEC-adjudicated) or the investigators. Safety was defined as symptomatic hypotension, hyperkalemia >5.5 mmol/L or permanent drug discontinuation. Results A total of 2338 patients (41%) were treated with an MRA and they were more often Caucasian (79% vs. 73%), had worse left ventricular ejection fraction (34±8 vs. 38±10%), a higher KILLIP Class (63% vs. 55% in class II or more) and a lower estimated Glomerular filtration rate (71 vs. 73 ml/min/1.73 m2), than patients not taking an MRA. Age (63 years), sex (24% females), and frequency of diabetes (42%) did not differ. The treatment effect of sacubitril/valsartan compared with ramipril was similar in patients taking or not taking an MRA: hazard ratio (MRA): (95% confidence interval [CI]): 0.96 (0.77, 1.19) versus (95% CI: 0.87 (0.71, 1.05), respectively, for the primary endpoint (p value for interaction = 0.51) (CEC adjudicated) (Figure 1); similar findings were observed if investigator reported endpoints were evaluated (P=0.61 for interaction). Safety of sacubitril/valsartan compared to ramipril initiation was not changed by +/−MRA use, but an increase in symptomatic hypotension was observed (HR(MRA): 1.37 and HR: 1.39, P<0.001) in both groups (P=0.968 for interaction), whereas an increased risk of hyperkalemia or permanent drug discontinuation was not observed in the sacubitril/valsartan group (P>0.05 for all comparisons). Conclusions As expected, patients taking MRAs had a higher risk. Use of a MRA did not modify the treatment effect and safety of initiation of sacubitril/valsartan compared to ramipril in the post MI setting in patients with LVSD and/or congestion. Our analyses support that sacubitril/valsartan and MRAs can be used simultaneously. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Novartis sponsored Randomized clinical trial

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Hussien, Hani, Mugurel Apetrii, Mihai Onofriescu, Andra Nastasa, Gabriel Mircea, Iuliana Teodor, Irina Apascaritei, and Adrian Covic. "P0253FRAILTY SCREENING TOOLS, FUNCTIONAL STATUS AND LIFE EXPECTANCY IN ELDERLY PATIENTS WITH PRE-DIALYSIS ADVANCED CHRONIC KIDNEY DISEASE." Nephrology Dialysis Transplantation 35, Supplement_3 (June 1, 2020). http://dx.doi.org/10.1093/ndt/gfaa142.p0253.

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Abstract Background and Aims Patients with chronic kidney disease (CKD) are at high risk of being frail, which is associated with poor outcomes including falls, low functional status, decreased quality of life, hospitalization, and mortality. Furthermore, the presence of frailty might decrease the potential benefits of renal replacement therapy initiation or even leads to worse outcomes. Currently, there are over 51 known tools for screening of frailty in the general population. The aim of this study was to describe the prevalence of frailty in elderly patients with pre-dialysis advanced CKD (G4 and G5) according to different frailty assessment tools from the 4 main categories of frailty screening: self-reporting questionnaires, subjective scores, simple single physical tools and complex scores. Also, we compared the functional status and the 10-year survival expectancy in frail Vs non-frail patients. Method In this cross-sectional study, we included patients from the Outpatient Department from Nephrology unit in a tertiary health facility “Dr C. I. Parhon Clinical Hospital’’ who were ≥65 years old with CKD G4–5 (eGFR < 30 ml/min/1.73 m2 using the CKD-EPI formula) on at least two occasions in the previous 3 months prior to the time of inclusion. The frailty was assessed using one method from each frailty screening category: self-reporting score as PRISMA-7, subjective score as Clinical Frailty Scale (CFS), a complex score as Frailty Phenotype (FP) and two simple single physical tools as gait speed in 4.5 meters (GS) and handgrip strength using a dynamometer (HGS). All participants had the Charlson Comorbidity Index (CCI) score calculated and the Karnofsky Performance Status Scale (KPS) performed. Results We included a total number of 201 patients, of which 53.23 % were males with a mean age of 73.9 ± 6.8 years. Mean eGFR was 19 ± 6.21 ml/min/1.73 m2. Using the three proposed scores, 69.15% of patients were at risk of frailty using PRISMA-7, compared to 45.77% and 40.3% who were frail according to CFS and FP respectively. HGS was weak in 51.74% of the patients while only 35.82% had slow GS. Half of the patients (50.25 %) had a Karnofsky score of ≤ 60, which corresponds to different degrees of losing autonomy. Comparing functional status in frail Vs. non-frail patients, we found that the mean KPS points for non-frail patients was similar regardless of the used tool: 73 according to FP, 75 according to CFS and 76 points according to PRISMA 7. Same results were obtained in patients with normal GS or with a normal HGS with mean KPS of 71 points. The 10-year survival expectancy was significantly lower in frail patients with similar mean values: 20% for both CFS and FP and 26 % for PRISMA-7, compared to non-frail patients with a predicted survival of 43% for CFS, 41% for FP and 47% for PRISMA-7. Similarly, in patients with slow GS and weak HGS, the mean CCI was 24 % for both groups, in comparison with 42% and 37 % in patients with normal HGS and normal GS respectively. Conclusion To the best of our knowledge, this is the first study to compare five frailty assessment tools in terms of functional status and life expectancy in elderly patients with pre-dialysis advanced CKD, but taking into consideration that those tools must be from different frailty assessment categories. Our study has shown that non-frail elderly patients with pre-dialysis advanced CKD have enjoyed a significantly higher degree of autonomy as well as higher 10-year survival expectancy in comparison with frail patients. The proposed frailty assessment tools have shown very close results in terms of functional status and life expectancy regardless of the complexity of the tool being used. Therefore, we suggest that using a simple self-reporting tool as PRISMA-7 or a simple single physical tool like handgrip strength or gait speed would be appropriate for screening of frailty in elderly patients with pre-dialysis advanced CKD who are at a high risk of losing autonomy and lower life expectancy.

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Journal articles on the topic '73.42 age groups, initiation (ethnology)'

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