Academic literature on the topic 'D 3.5 UL 2006 D463'

Abstract Background Treatment related toxicity complicates outcome in elderly patients with AML (Estey et al. Blood. 2006). Conventionally, 7+3 induction (anthracycline plus cytarabine) results in Complete Remission rate of about 30%. Regimens with less toxicity, such as 10-days (d) schedule of DAC, seem promising with CR rate of 47% (Blum et al. PNAS. 2010). In secondary MDS derived AML, response prediction could be derived from mutation status in epigenetic modifiers (IDH1, IDH2, DNMT3 A, TET2), transcriptional regulators (RUNX1, CBL), and genes in spliceosome machinery, such as SF3B1 and SRSF2 (Husseinzadeh et al. American Society of Hem Meeting. Abstract # 1698. 2012). IDH-1 mutation is known to induce hypermethylator phenotype (fig 1) (Figueroa et al. Cancer Cell. 2010) and might be present in conjunction with SRSF2 mutations, an unique unreported molecular subset, feasible for exploring azanucleoside response prediction. Herein, we report a case of trisomy 8 MDS derived IDH1 and SRSF2 mutated AML who underwent rapid morphological blast differentiation in the context of acute differentiation syndrome while treated with 10 days (d) of hypomethylating dose of DAC. Methods A 61-year-old male with performance status (PS) = 3 presented with leukocytosis of 18.9 K/uL (peripheral blast 90%). He had a history of low-grade MDS diagnosed 2 years before AML transformation. After morphological confirmation of M5 AML, fluorescent in situ hybridation (FISH) revealed 81% nuclei with trisomy 8. Extracted DNA was tested with a custom-designed Leukemia Cancer Gene Mutation Panel using AmpliSeq™ technology and showed IDH1 c.394C>T(p.R132C) mutation (Fig. 2B) and c.284C>T(p.P95L) mutation of SRSF2 gene (Fig. 2C). DAC was initiated at 15 mg/m2 for a total of 10 days every 28 d cycle. Results By day 5 of cycle (C)1 of DAC treatment, brisk and significant rebound leukocytosis of 60 K/uL (Fig. 3) was observed, along with shortness of breath, hypoxemia and radiological evidence of floppy bilateral pulmonary infiltrates suggestive of acute-like differentiation syndrome. In addition to broad-spectrum antimicrobial and antifungal, dexamethasone at 4 mg intravenously (IV) every 8-hour (h) and hydroxyurea at 1 g orally every 8 h resulted in progressive normalization of peripheral blood count and hypoxemia after 48 h. Patient (pt) recovered from C1 and proceeded with C2 of treatment. A similar episode of brisk/robust leukocytosis was observed by day 5 of C2 requiring dexamethasone and hydroxyurea. Progressive morphological differentiation was observed to full mature and morphologically normal monocytes and neutrophil (Fig. 4). Pt expired as result of severe clostridium difficile colitis during C3 of DAC. Conclusions In our case, we observed robust acute differentiation syndrome characterized by rapid increase of WBC, shortness of breath and hypoxemia associated with azanucleoside treatment. Beside a novel association of IDH-1 and SRSF2 mutations, acute differentiation might suggest potential feature for azanucleoside response phenotype. Our case adds body of evidence of connection between epigenetic regulator and spliceosome mutations. Further studies on the impact of dual mutations in epigenetic reprogramming, leukemia transformation, and azanucleoside response will allow improved decision algorithm and therapeutic design. Disclosures: No relevant conflicts of interest to declare.

7545 Background: Lenalidomide (Revlamid [R]) is the leading clinical compound in a new group of drugs called IMiDs. Our group demonstrated that clarithromycin (Biaxin [Bi]) augments tumor mass reduction and improves responses in patients (pts) receiving low-dose thalidomide and/or dexamethasone (D). We report the results of the combination of Bi plus R plus D (BiRD) in newly diagnosed MM. Methods: A phase II trial designed to accrue 50 pts. A 2-stage design rejects a CR rate of < 10% (alt >30%). Between Nov. 2004 and Jan. 2006, 46 pts have been accrued of which 40 pts are eligible for evaluation. R is given po at 25 mg daily on days 1–21 of a 28-day cycle. D is given po at 40 mg once weekly. Bi is given po at 500 mg bid. Pts receive low dose aspirin (ASA)(81mg) qd as thrombosis (TE) prophylaxis. Responses are defined according to modified EBMTR criteria. Analysis is by intent-to-treat. Patient Selection: Median age: 62.5 years (36–80), Male/Female 25/15, Hgb: 10.6 g/dL (7.2–15.1), Plt 234 k/uL (51–526), β2m: 3 mg/L (0.8–12.8), CRP: 0.6 mg/dL (0.12–14.2), creat: 1.1 mg/dL (0.6–3.1), albumin 3.5 g/dL (2.3–4.9). SD stage IIIa: 48%, stage IIIb: 10% and IIa: 42%. ISS stage I: 50%, stage II: 25% and stage III: 25%. Cytogenetics and FISH: trisomy 11 (10 pts), tetrasomy 11 (3 pts), del13q14 (14 pts), t (4,14) (1pt), t (11,14) (3 pts). Results: Of the 40 evaluable pts, 38 (95%) have achieved an objective response (>PR) within 3–4 months of Rx with the remaining pts continuing to respond. Seventeen pts (43%) had a >90% reduction of the initial paraprotein. Nearly one third of pts have achieved either a CR (10/40) or a nCR (2/40-continuing on Rx). CR has been confirmed in all pts by normalization of free light chain levels and ratio. The remaining 26 pts (65%) achieved a PR. Of those pts who achieved a PR, 5/26 pts (19%) had >90% reduction in the initial paraprotein. Nineteen pts have experienced grade ≥3 adverse events. Heme toxicities: anemia (11%), neutropenia (9%) and thrombocytopenia (9%). Non-heme toxicities (NHT) include TE in 7 patients (15%) 2 of them fatal. Four of the TE events were while off ASA. Other NHT include myopathy (6%), GI (4%), and mood (4%). Conclusions: BiRD therapy is a safe and highly effective primary therapy for symptomatic, treatment-naïve MM. [Table: see text]

Abstract Introduction: Haploidentical (HI) HSCT offers a curative option to patients (pts) who lack an HLA matched donor. In the 2-step approach, pts receive a relatively large, fixed T-cell dose (2 x 108/kg) followed 2 days later by cyclophosphamide (CY). CY eradicates only the alloreactive T-cells, thus inducing bidirectional tolerance. CD34-selected stem cells are then infused and are not exposed to CY. Unlike T-cell depleted approaches, the 2 step regimen allows for rapid immune recovery and lower infectious complications. Coupled with acceptable GVHD rates, this approach has been associated with low non-relapse mortality. Given the consistent T-cell dose utilized in all pts, we investigated the effects of the variable CD34 stem cells on clinical outcomes and immune recovery. Methods: We retrospectively analyzed data from 148 pts who underwent a 2-step approach to haploidentical peripheral blood HSCT at Thomas Jefferson University between February 2006 and February 2014. The myeloablative (MA) conditioning regimen consisted of 12 Gy of TBI administered over 4 days, while the reduced intensity conditioning (RIC) regimen consisted of fludarabine (30 mg/m2 D1-4) + cytarabine (2 gm/m2 D1-4)/or thiotepa (5 mg/kg D1-3) and a fraction of 2 Gy TBI (D6). Conditioning was followed by an infusion of 2 x 108 CD3+ cells/kg donor T cells (step 1). CY 60 mg/kg/d x 2 was given starting 2-3 days after the T cell infusion. A CD34 selected product was then infused (step 2). Tacrolimus and MMF were utilized for immune suppression. In a prior multivariate analysis in patients older than 60, we identified CD34 dose as affecting survival. Using recursive partitioning, a dose of 5.2 x106 was identified as the cutoff point demarcating differences in survival. This analysis compares differences in outcome in all patients who underwent the 2-step haploidentical HSCT regardless of age, using a cutoff CD34 dose of 5.2x106 to demarcate both groups. Results: Eighty-five pts received a CD34 dose &lt; 5.2 x 106(low dose- LD) and 61 received a dose &gt; 5.2 x 108 (high dose- HD). Pts characteristics are shown in the table. Median follow up was 19 months. HD group had a faster platelet recovery (p=0.007) and more rapid CD3/4 and CD3/8 recovery by day 30 (p=0.001). The incidence of grades II-IV GVHD was not statistically different between both groups (p= 0.76). Probability of overall survival (OS) at 5 years was 50% and 62% in the LD and HD groups, respectively (log-rank= 0.14) with relapsed disease being the major cause of death in both groups. OS was significantly better in the HD in a subset of patients above the age of 60 (n=57, log-rank= 0.032). The 5-year cumulative incidence of relapse related mortality and non-relapse related mortality were not statistically significant between both groups; RRM: LD= 27%, HD= 20% (p=0.45); NRM: LD= 24%, HD=17% (p=0.32). Conclusion: Based on a platform of identical T cell dosing, the higher CD34 stem cell dose group had more rapid platelet engraftment, earlier immune recovery and better overall survival in a subset of patients above the age of 60. There were no differences in GVHD rates between both groups, which favors the use of a higher CD34 stem cell dose in this approach. Table Lower Dose (&lt;5.2 x 106) Higher Dose (&gt;5.2 x 106) Number 85 61 Age (range) 58 (19-74) 52 (19-78) Sex (M/F) 49/36 36/25 Median CD3/4 day 30 (cells/ uL) 34 71 Median CD3/8 day 30 (cells/ uL) 30 57 Median CD34 cells [x 106/kg] (range) 3.52 (1.4-5.18) 7.31 (5.3-10.6) Disease status at time of HSCT Remission (%) 38 (45) 24 (39) Active disease (%) 47 (55) 37 (61) Disease Myeloid Malignancy (%) 58 (68) 31 (51) ALL (%) 11 (13) 11 (18) NHL (%) 11 (13) 13 (21) Others (%) 5 (6) 6 (10) Conditioning MA (%) 52 (61) 34 (56) RIC (%) 33 (39) 27 (44) Outcomes: Median ANC recovery [days] 12 11 Median Platelet recovery [days] 19 17 aGVHD II-IV (%) 33 (39) 26 (43) aGVHD III-IV (%) 8 (9.4) 4 (6.5) cGVHD (%) 14 (16) 2 (3) Relapse (%) 25 (29.4) 14 (23) Deaths (%) 41 (48) 20 (33) Relapse 21 10 Infection 6 3 Toxicity 10 7 GVHD 4 0 CMV Reactivation 41 (48) 25 (41) Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 2555 High hyperdiploidy is present in 30% of children with acute lymphocytic leukemia (ALL), and is associated with a favorable prognosis. We evaluated pts with newly diagnosed ALL treated on SWOG trials S9400 (1995–2000) and S0333 (2005–2010) to determine the prevalence and prognostic impact of hyperdiploidy in adults with ALL. Additionally, we examined the prognostic impact of hypodiploidy, a feature typically associated with a poor prognosis in children. Methods: One-hundred and eighty-five pts treated on S9400 and S0333 with successful cytogenetic (CG) analysis were included. The treatment regimens were: S9400 [Induction: Daunorubicin (D), vincristine (V), prednisone (P), PEG-asparaginase (PEG); Consolidation: Cytoxan (Cy), cytarabine (AraC), 6-mercaptopurine (6MP), intrathecal methotrexate (IT Mtx). Consolidation was followed by allogeneic stem cell transplant or maintenance chemotherapy] and S0333: Double Induction Chemotherapy [Induction 1: D, V, P, PEG; Induction 2: high dose AraC, mitoxantrone, decadron. Consolidation: Cy, AraC, 6MP, Mtx; consolidation was followed by maintenance therapy]. Karyotypes were centrally reviewed and clonal abnormalities described according to ISCN (2009). Hyperdiploidy was defined as: low hyperdiploidy [47–49 chromosomes (cs)], high hyperdiploidy (51–65 cs), near triploidy (66–79 cs), and near tetraploidy (84–100 cs). Hypodiploidy was defined as: near haploidy (25–29 cs), low hypodiploidy (31–39 cs), and high hypodiploidy (42–45 cs). When more than one cell line was present, ploidy was assigned by the most complex clonal karyotype. Hypodiploidy and hyperdiploidy were analyzed as prognostic factors for complete response (CR) rate and residual disease (RD) by logistic regression and chi-square tests; and for overall survival (OS) and relapse-free survival (RFS) by proportional hazards. Multivariable analyses were stratified by study and using the baseline variables: age, WBC, lineage, and CG risk. Results: The median age was 32 yrs (range 17–64), and median WBC at diagnosis 17.2 K/uL (range 0.6–396.6). CG risk was ascribed by (Pullarket V et al. Blood 2008; 111: 2563). Forty-five pts (24%) had normal CG, and 73 (39%) had poor risk CG. Fourteen pts (8%) had hypodiploidy (2: low hypodiploidy; 12: high hypodiploidy). Fifty-three pts (29%) had hyperdiploidy [40: low hyperdiploidy, 10: high hyperdiploidy (5%), 3: near tetraploidy or tetraploidy (2%)]. The CR rate for all pts was 72%; with a median RFS of 15 mos (95% CI: 12–29 mos) and median OS of 28 mos (95% CI: 21–36 mos). There was no significant association with ploidy status and age, WBC, or lineage. However, there was an increased prevalence of the t(9;22) in the high hypodiploidy group compared to the normal/pseudo diploidy group (p=0.049). Neither hypodiploidy nor hyperdiploidy were predictive of CR or RD; although pts with hypodiploidy had a higher rate of RD (p=0.062). The 2 pts with low hypodiploidy had very poor outcomes (1 had RD and died after 11 mos; the other relapsed after 3 mos from CR and died 4 mos after study registration). There were no statistically significant differences in OS, CR rate, or RFS between the ploidy groups even after adjusting for baseline characteristics in multivariate analysis. Surprisingly, when excluding pts with poor risk CG there was still a trend towards a worse RFS (29 vs. 32 months, p=0.20) and OS (40 vs. 68 mos, p=0.29) in pts with hyperdiploidy compared to normal/pseudodiploidy. In addition, the 3 pts in the high hyperdiploidy group without poor risk CG had poor OS (median 23 mos). Conclusions: The prevalence of high hyperdiploidy is much lower in adults with ALL, compared to children. The prevalence of hypodiploidy and near tetraploidy/tetraploidy is comparable to that seen in children with ALL. Hypodiploidy and high hyperdiploidy were not prognostic factors for outcome in this group of patients. Given the low prevalence of these abnormalities, it is possible that larger numbers of pts may be needed to detect such a difference. The poor outcomes of pts with low hypodiploidy are consistent with findings by Moorman et al. (Blood 2006; 109: 3189). However, in contrast to Moorman's results, there was no evidence of an association of hyperdiploidy with age/WBC, and there was a trend towards a worse prognosis in this subset of patients. This suggests that the biology and prognosis of high hyperdiploidy may be affected more by WBC and age in the adult population. Disclosures: No relevant conflicts of interest to declare.

Abstract Backgrounds and Aims The classic hallmarks of Upshaw Schulman syndrome (USS) are severe newborn jaundice with a negative Coombs test that requires an exchange transfusion and repeated childhood episodes of thrombocytopenia and microangiopathic hemolytic anemia that are reversed by infusions of fresh frozen plasma. But now, it is well established that USS is a hereditary deficiency in the activity of von Willebrand factor (VWF)-cleaving protease, termed ADAMTS13. The inheritance mode is autosomal recessive, and their parents are usually asymptomatic carriers having one disease-causing mutation (DCM) of the gene. In the absence of ADAMTS13, unusually large VWF multimers (UL-VWFMs) released from vascular endothelial cells are inappropriately cleaved, leading to platelet hyperagglutination under high shear stress. Thus, USS is alternatively called congenital thrombotic thrombocytopenic purpura (TTP). But, unlike acquired TTP, clinical signs of USS patients are usually mild during childhood and often an isolated thrombocytopenia is found. Further, now it is known that TTP-bouts are aggravated or initiated by the following factors: 1) severe infections such as influenza, 2) pregnancy, 3) 1-deamino-8-D-arginine vasopressin (DDAVP) administration, 4) interferon therapy, 5) heavily drinking alcohol, and 6) aging. So far, in worldwide approximately 150 patients with USS have been found, of which we identified 51 patients in Japan. Among them, 48 patients were received ADAMTS13 gene analysis, and a pair of DCMs, either homozygotes or compound heterozygotes, was identified in all patients except for one. Interestingly, these DCMs are quite different from those found in patients of Western countries and United States, but several DCMs in Japanese patients are also found in Korean and Chinese patients. Thus, it appears that Caucasians and Asians have two different DCM routs for ADAMTS13. Further, since USS is an extremely rare disease, no one can predict the life-long clinical outcome in these patients. Thus, in this study using our cohort of 51 Japanese USS patients, we have extensively analyzed a long-term phenotype, with special references to pregnancy and renal failure that requires hemodialysis. Methods and Patients ADAMTS13 activity and its neutralizing antibodies (inhibitors) were determined by chromogenic ADAMTS13-act-ELISA [Kato et al. Transfusion, 2006], and the IgG type binding antibodies were assayed as described [Ferrari et al, JTH 2009]. Fifty-one patients with USS (19 males and 32 females, born in 1931-2013) were enrolled in this study. None of the patients had the neutralizing antibodies, but 6 patients (6/51, 12%) developed the IgG type non-neutralizing antibodies. Results and Discussion Pregnancy: We identified 26 episodes of pregnancy in 15 patients with USS (Table 1). Briefly, 22 pregnancies were identified before a diagnosis of USS, and as consequence 3 episodes are related to abortion, 10 episodes to stillbirth, and 9 episodes to live birth, in which 6 babies were premature. In contrast, 4 pregnancies were after a diagnosis of USS, and they all had the planned FFP infusions from the early phase of pregnancy, resulting in all successful deliveries, but with 2 premature babies. Renal failure: We identified that 6 male patients finally fell into the end-stage severe renal diseases that required hemodialysis, of which 4 patients were deceased (Table 2). Median time from a diagnosis of USS to dialysis initiation was 15 years (range 1-25). Curiously, all these patients except for one had received FFP infusions biweekly after a diagnosis of USS. Causes of death in these 4 patients were the followings: heart failure (n=1), renal failure (n=1), and sudden death (n=2). The reason why all the patients, who fell into severe renal dysfunction, are male left unaddressed. Disclosures: Fujimura: Alexion Pharma: Membership on an entity’s Board of Directors or advisory committees; Baxter BioScience: Membership on an entity’s Board of Directors or advisory committees. Matsumoto:Alexion Pharma: Membership on an entity’s Board of Directors or advisory committees.

This study develops procedures for cloning ITS and matK genes on six specimens in order to exploit and conserve the genetic resources of H. nepalensis and evaluate its genetic diversity based on molecular markers. The study methods include DNA extraction from dried leaf samples, amplification of ITS and matK regions using PCR, sequencing and comparing with the sequences on Genbank. The study results include a successfully-established process of cloning ITS and matK genes; successful amplification and sequencing of the ITS and matK regions. The results also show that four samples (N1-N4) were 100% homologous to H. nepalensis and H1and H2 samples were 100% homologous to H. helix. The results provide data and tools for further studies of exploitation and development of the H. nepalensis K. Koch genetic resources in Vietnam. Keywords ITS, matK, Hedera nepalensis K. Koch, PCR References [1] V.V. Chi. Dictionary of Vietnamese Medicinal Plants, Publ. 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