Allogeneic hematopoietic stem cell transplant (alloHCT) remains the only potentially curative treatment for patients with myelodysplastic syndrome (MDS). However, this treatment is associated with ...significant risk of transplant-related mortality/morbidity such as graft-versus-host disease, infections, and regimen-related toxicities. Since there has been no “randomized” trial comparing between patients undergoing or not undergoing transplantation, the relative benefit of this treatment, particularly in elderly patients, is largely unknown. Retrospective comparative studies are significantly limited by the inherent selection bias of healthier/well-supported patients in the alloHCT group. Therefore, a critical knowledge gap exists regarding the survival outcome of MDS patients who are transplant eligible yet did not undergo alloHCT due to lack of suitable donors or other reasons.
Herein, we retrospectively identified a consecutive case-series of 73 patients with MDS (excluding CMML), who were considered alloHCT candidates, based on initiation of an official donor search from 2005 to 2015, yet did not proceed with alloHCT. Median age at time of donor search was 60 years (range: 20-79) with the majority (63%) being male. Classifications of MDS were single or multi-lineage dysplasia (n=20), excess blast (n=39), MDS unclassified (n=6) or other/unknown classification (n=8). The cohort included 51 de novo MDS and 14 therapy-related MDS (t-MDS). Per International Prognostic Scoring System (IPSS) 29 patients (39.7%) were Intermediate (Int)-1, 14 (19.2%) were Int-2, and 23 (31.5%) were high risk at the time of donor search (Table 1). Reasons for no alloHCT were lack of donor (n=29), persistent/progressive disease (n=9), patient choice (n=13), or infections/complications after initiating the donor search (n=18). Treatments of these patients included chemotherapy (n=14), hypomethylating agents (n=61) and supportive care (n=23). Of the 73 patients, 15 (20.5%) had disease progression to acute leukemia at 1 year. There were 38 deaths with the median OS of 26.2 months (95%CI: 17.3-48.3 months). The 2-year probability of OS was 51% (95%CI: 36.7-62.9%).
We next compared outcomes of these MDS patients who had a donor search without subsequent HCT to a consecutive case-series of MDS patients who underwent alloHCT from matched related and unrelated donors (cord blood and haploidentical transplants were excluded) during the same time period (n=276) at our center (Aldoss et al. Haematologica 2017). Patient demographics and MDS disease characteristics were similar between the two groups (Table 1). Median number of days from HLA typing to HCT were 168. By Kaplan-Meier method, OS (from the time of donor search) was significantly better for the alloHCT group (74% at 2-years) compared with non-HCT group (51% at 2-years), log-rank P<0.001 (Figure 1a). This survival benefit was primarily driven by the subgroup of patients with int-2/high risk IPSS. While the difference in the OS did not reach statistical significance in low/int-1 patients between HCT and non-HCT groups (OS probability at 2-years: 80% vs 68%, respectively, p= 0.182), the 2-year OS was significantly better (p<0.001) in the alloHCT group (67%, n=133) compared with non-HCT group (34%, n=37), when analysis was done in int-2 or high-risk patients. (Figure 1b) In an attempt to further assess the inherent selection bias, we analyzed and compared patients with no available donor (n=29, biologic assignment) with patients who did not receive HCT for other reasons (n=44). No statistically significant difference (p=0.13) was seen in the 2 year-OS (58% vs. 45%).
In conclusion, using a unique cohort of patients who were referred for a donor search, our study in real-world practice demonstrates that transplant eligible MDS patients (at the time of donor search) who do not undergo alloHCT have worse survival outcomes compared to those undergoing transplantation. A prospective biologic assignment study is currently underway by the BMT CTN (#1102) to more definitively determine the impact and relative benefits of alloHCT in patients (≥50 years old) with Int2/high-risk de novo MDS.
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Khaled:Alexion: Consultancy, Speakers Bureau; Daiichi: Consultancy; Juno: Other: Travel Funding. Salhotra:Kadmon Corporation, LLC: Consultancy. Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding. Stein:Celgene: Speakers Bureau; Amgen Inc.: Speakers Bureau.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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The combination of venetoclax and hypomethylating agents (HMA) has demonstrated potent activity in acute myeloid leukemia (AML), both in newly diagnosed patients (pts) and those with ...relapsed/refractory (r/r) disease. We analyzed the association between response to therapy and leukemic somatic mutations, cytogenetics, and other pertinent patient- and leukemia-related features in a large series of newly diagnosed and r/r AML in adults treated with venetoclax in combination with HMA at City of Hope between October 2016 and May 2018.
We identified 107 evaluable adults with AML treated with the combination of venetoclax and HMA. Sixty-one (57%) pts had r/r AML at the time of initiating treatment (median prior lines of therapy: 2; range: 1-10), while 46 (43%) were treated in the frontline setting. The median age of pts was 68 years (range: 19-86). AML was de novo in 57 (53%), therapy-related in 23 (21%) and secondary in 27 (25%) pts. Thirty-six (34%) pts had prior exposure to HMA, and 21 (20%) pts had relapsed following prior allogeneic hematopoietic cell transplantation (HCT). The majority of treated pts had unfavorable (52%) or intermediate-risk (39%) AML based on combined cytogenetics and molecular profiles. The most common detected somatic mutations (majority by next generation sequencing) were FLT3 (17%), followed by DNMT3A (15%), RAS and TET2 (each 14%), RUNX1 (13%), TP53 (12%), and IDH1/2 (11%). Most pts received decitabine in combination with venetoclax (N=97, 91%); only 10 (9%) pts received 5-azacitidine together with venetoclax.
Complete remission (CR)/CR with incomplete hematologic recovery (CRi) was achieved in 57 (53%) pts after a median of 2 (range 1-4) cycles. For 36 pts who achieved CR/CRi and had available minimal residual disease (MRD) assessment by multicolor flow cytometry (MFC), 23 (64%) became MRD-. CR/CRi was higher in pts carrying favorable- or intermediate-risk AML compared to poor-risk AML (100% vs. 60% vs. 45%, P=0.029). CR/CRi was 48% in those with complex cytogenetics (N = 31), 45% in monosomal karyotype (N = 22), 36% in KMT2A gene rearrangement (N = 11), 74% in normal karyotype (N = 19), and 25% in inversion 3 (N =4). The CR/CRi rate was not significantly different between newly diagnosed or r/r AML (61% vs. 48%, P = 0.17), nor was there a difference associated with AML type (de novo vs. therapy-related vs. secondary, P= 0.26), patient age (> or ≤ 65 years) at time of therapy (P = 0.13), prior allogeneic HCT (P = 0.29), prior administration of HMA (P = 0.37) and the type or schedule (5- or 10-day decitabine) of HMA (P = 0.52). In multivariate analysis, only favorable- or intermediate-risk cytogenetics was associated with better CR/CRi (P = 0.036). CR/CRi was also comparable regardless of the presence or absence of various analyzed somatic AML mutations. However, in recursive partitioning analysis of detectable somatic mutations and response to therapy, the combined lack of RAS, TP53 and RUNX1 mutations was linked to an improved rate of CR/CRi. When AML cases were stratified into functional gene alteration subgroups (according to the TCGA data set), there was no significant difference in CR/CRi according to the presence or absence of certain functional genes/fusions.
Median overall survival (OS) for all pts was 12.5 months and was 14.6 months for pts who achieved CR/CRi, in contrast to 4.6 months for non-responders (P <0.001). Only AML subtype (de novo vs. therapy-related vs. secondary) (P <0.001) and AML genetic risk (favorable/intermediate vs. high) (P = 0.042) independently impacted OS in multivariate analysis. None of the AML individual somatic mutations influenced OS for this cohort, however, in recursive partitioning analysis of detectable mutations, the presence of any of SRSF2, IDH1/2 or RUNX1 were associated with improved OS. Furthermore, the presence of myeloid transcription factor (P = 0.033) and spliceosome complex mutations (P = 0.004) predicted superior OS, whereas the presence of a chromatin modifying mutation predicted inferior OS (P = 0.004). Thirteen (23%) responders subsequently underwent allogeneic HCT.
We report remarkable activity with venetoclax and HMA across various high-risk genetics and clinical features in AML patients. Prospective studies are warranted to compare this combination directly with chemotherapy in all AML subsets. This is particularly true for high risk AML where response to conventional chemotherapy is poor.
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Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Salhotra:Kadmon Corporation, LLC: Consultancy. Khaled:Alexion: Consultancy, Speakers Bureau; Juno: Other: Travel Funding; Daiichi: Consultancy. Stein:Celgene: Speakers Bureau; Amgen Inc.: Speakers Bureau. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: AZA is first line therapy for pts with HR-MDS with an overall response rate (ORR) between 35 and 60% in various publications; with CR/PR rates ranging between 23 and 29% in 3 randomized ...phase II/III studies (Silverman et al., JCO 2002; Fenaux et al., Lancet Oncol 2009; Sekeres, JCO 2017). AZA also has demonstrated efficacy in older pts with AML (Dombret et al., Blood 2015; Fenaux et al., JCO 2010). Rigosertib interferes with the RAS-binding domains of RAF kinases and inhibits the RAS-RAF-MEK and the PI3Ks pathways (Athuluri-Divakar, Cell 2016). RAS and other genes in this pathway are frequently mutated in HR MDS and putatively drive the malignant clone (Sperling et al., Nat Rev CA 2017). In vitro, the combination of rigosertib with AZA synergistically inhibits growth and induces apoptosis of leukemic cells in a sequence-dependent fashion (Skidan et al; AACR 2006 Abstract 1310).
In a trial in lower-risk MDS, oral rigosertib was studied as a single agent at various doses including 560 mg BID for 14-21 days in 28 day cycles and yielded a transfusion independence (TI) rate of 44% - the highest reported TI rate (Raza, ASH Abstract #108660 2017). Based on this observation we expanded the ongoing Phase I/II trial and tested rigosertib at a total of 1120 mg per day with standard dose parenteral AZA (75mg/m2 x 7 days q28 days) in two different schemes as described in methods (NCT01926587). At a dose of 560 mg AM, 280 mg evening the ORR was 77%; 88% for the HMA naïve group and importantly 60% for the HMA Rel/Ref group. Of note, adverse events of interest have been genitourinary (GU) toxicities, particularly hematuria and dysuria. Thus, risk-mitigation strategies (Table 1) were employed to minimize hematuria with higher dose rigosertib at 1120 mg; including the rationale for the lower afternoon (280 mg) dose. We report here the initial results of efficacy and safety.
Methods: In the Phase II Expansion cohort, up to 45 pts with HR MDS/RAEB-t/non-proliferative AML were randomized 1:1 into 2 cohorts both to receive 1120 mg of rigosertib over 24 hours: either 560 mg in the morning and 560 mg in the afternoon, or 840 mg in the morning and 280 mg in the afternoon (part of hematuria/dysuria risk mitigation; moving second dose from evening to afternoon to minimize overnight bladder dwell time as permitted by PK analysis (Maniar, ASH Abstract 2018). Each cohort is stratified among HMA naïve and HMA Rel/Ref pts. Hematologic response is determined per IWG 2006.
Results: As of July 2018 in the rigosertib 1120 mg cohort in combination with AZA, 45 pts were enrolled; 43 treated, 31 evaluable for response; 14 pts continue on treatment, and 31 pts discontinued (includes 2 enrolled but not treated). To be evaluable for response, a minimum of 12 weeks of the doublet was required.
Of the 31 pts evaluable for response, 17 pts are prior Rel/Ref, 14 pts are HMA naïve. The # of prior HMA cycles is 2-15; 13 failed AZA; 1 failed DAC; 2 failed both; and 1 failed other (experimental). The median duration of treatment at this time point for the overall population is 5 months (1-14+). The ORR (Table 2) for the all patients is 68%; 59% for the prior Rel/Ref cohort and 79% for the HMA naïve cohort. For responding patients, responses are seen in both 1120 mg cohorts as shown.
Safety: In 43 patients treated with oral rigosertib at 1120 mg and AZA, with risk-mitigating strategies to minimize hematuria, Grade 1 & 2 hematuria = 16%; ≥3 Grade Hematuria = 5% have been seen to date (Table 3). This compares to an incidence of 12 % Gr 3 hematuria at a lower dose of rigosertib (840 mg); and prior to risk mitigation strategies. Incidence of hematuria of any grade with single agent AZA is 6.3 % & Grade ≥3 2.3% (VIDAZA, package insert 2004).
Conclusion: The combination of oral rigosertib and AZA in HMA naïve patients with HR-MDS is encouraging compared to single agent AZA. The combination also has activity and reverses the HMA clinical resistance in a substantial number of patients after Rel/Ref, a finding with potentially significant clinical implications. Dose exploration with a higher dose of oral rigosertib (1120mg) administered in different dosing schemes in combination with standard dose AZA continues to be studied to optimize safety and efficacy. By employing risk mitigation strategies, the incidence of GU AEs, including hematuria, has been substantially reduced. We will update the safety and efficacy data at the time of presentation. Based on this data a pivotal trial is planned.
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Navada:Onconova: Research Funding. Atallah:Pfizer: Consultancy; Abbvie: Consultancy; Jazz: Consultancy; BMS: Consultancy; Novartis: Consultancy. Shammo:Incyte: Consultancy, Honoraria, Research Funding; Onconova: Other: research support; Alexion: Honoraria, Other: research support; Novartis: Consultancy, Honoraria; Celgene: Other: research support. Griffiths:Novartis, Inc.: Research Funding; Celgene, Inc: Honoraria, Research Funding; Astex/Otsuka Pharmaceuticals: Honoraria, Research Funding; Pfizer, Inc.: Research Funding; Alexion Inc.: Honoraria, Research Funding. Khaled:Juno: Other: Travel Funding; Alexion: Consultancy, Speakers Bureau; Daiichi: Consultancy. Pemmaraju:abbvie: Research Funding; stemline: Consultancy, Honoraria, Research Funding; celgene: Consultancy, Honoraria; Affymetrix: Research Funding; samus: Research Funding; SagerStrong Foundation: Research Funding; cellectis: Research Funding; daiichi sankyo: Research Funding; novartis: Research Funding; plexxikon: Research Funding. Zbyszewski:Onconova Therapeutics, Inc: Employment, Equity Ownership. Maniar:Onconova Therapeutics, Inc: Employment, Equity Ownership. Petrone:Onconova Terapeutics Inc.: Employment, Equity Ownership. Fruchtman:Onconova Therapeutic Inc: Employment, Equity Ownership. Silverman:Johnson and Johnson: Research Funding; Onconova Therapeutics Inc.: Patents & Royalties, Research Funding; Bayer: Research Funding; Celgene: Research Funding; Medimmune: Research Funding; Mount Sinai School of Medicine: Employment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Several prognostic models have been developed to predict survival outcomes and response in patients with myelofibrosis (MF). MIPSS70 prognostic system, developed by incorporation of all the key ...clinical characteristics, cytogenetics, and mutational factors into one system, has recently been revised to MIPSS70+ v2.0 with refinements in degrees of anemia, cytogenetics, and HMR. While allogeneic hematopoietic cell transplantation (alloHCT) is the only curative treatment for patients with MF, limited data exists on the impact of molecular markers on transplant outcomes. Here, we evaluated the transplant outcome in MF patients who uniformly received fludarabine/melphalan (FluMel) conditioning at City of Hope and assessed the impact of cytogenetics, somatic mutations on transplant outcomes based on a 72 gene next-generation sequencing (NGS) panel and MIPSS 70+ v2.0.
A total of 110 consecutive MF patients (primary: n=58, secondary: n=52) without prior acute leukemic transformation, underwent alloHCT between 2004 and 2017. Median age at the time of transplant was 58.5 years (range: 38-72 years) with median interval from diagnosis of primary or secondary MF to HCT of 15.2 months (range: 1.6-332.5 months). AlloHCT donors were matched related (n=51), matched unrelated (n=44), and mismatched unrelated (n=15). Intermediate-2 and High risk by DIPSS accounted for 83 (76%) of patients at the time of transplant. Tacrolimus/Sirolimus-based GVHD prophylaxis was used in 100 (91%) patients, and 16 had splenectomy prior to alloHCT.
Pre-transplant DNA sample were available for 93 patients and cytogenetics information was available for 106 patients; among which 60 had abnormal cytogenetics. Based on recently developed revised cytogenetic risk stratification on transplant outcomes, we identified 67 patients (61%) in favorable, 24 (22%) in unfavorable, and 15 (14%) in very high risk groups. Median number of 2 mutations were detected with at least one mutation in 95% (n=88) of patients. JAK2 V617F was the most common alteration noted in 54 (58.1%) patients. Other common mutations were ASXL1 (n=41, 44%), CALR type 1 (n=15, 16.1%), TET2 (n=12, 13%) SRSF2 and DNMT3A (each n=10, 11%). No detectable mutations were found in 5 (5.4%) patients. HMR genes (ASLX1, EZH2, IDH1/2, SRSF2, and U2AF1) were identified in 48 patients (52%), with 30 patients (32%) carrying one and 18 patients (19%) carrying more than 1 HMRs.
With a median follow-up of 63.7 months (range: 11.9-158.5), 5 year overall survival (OS) and non-relapse mortality (NRM) were 65% (95% CI: 54-73) and 17% (95%CI: 10%-24%), respectively. Detailed transplant outcomes were previously reported (Ali et al. American Society of Hematology. Vol. 130. Atlanta, GA: Blood; 2017:199) (Figure 1a). On multivariable analysis, unfavorable and VHR cytogenetic changes had significantly shorter OS and PFS (p=0.001 and 0.008), and relapse risk (p=0.035) (Figure1b). Triple negative status (p=0.063), HMR (p=0.73), and more than 1 HMR (p=0.59) did not significantly impact survival post-HCT. (Figure1c) Similarly, CALR type 1 (p=0.42), and ASXL1 (p=0.29) mutations also did not impact survival after HCT. Only CBL mutation was significantly associated with lower OS (HR=2.64, 95% CI: 1.09-6.38, p=0.032) and lower DFS (HR=4.35, 95% CI: 1.83-10.36, p<0.001), largely attributable to increased NRM (HR=3.68, 95% CI: 1.45-9.35, p=0.004). In addition U2AF1 mutations were significantly associated with NRM (HR=3.42, 95%CI: 1.50-7.80, p=0.009). Per MIPSS70+ 2.0, patients were classified into intermediate (n=11), high (n=47), or very high-risk (VHR) (n=35). MIPSS70+ 2.0 predicted OS, DFS, and NRM. Compared to high risk group, intermediate risk patients had better OS (HR=0.291, 95% CI: 0.04-2.26) and DFS (HR=0.24, 95% CI: .03-1.91), whereas VHR group had much lower OS (HR=5.05, 95% CI: 2.39-10.74, p=<0.001) and DFS (HR=3.87, 95% CI: 1.9.0-7.88 p<0.001). (Figure 1d) Compared to high risk, intermediate risk group had lower and VHR had higher NRM (HR=0.51, 95% CI: 0.06-4.23), and (HR=3.24, 95% CI: 1.47 - 7.13, p=0.004), respectively.
In summary, we are presenting one of the largest single center experiences of FluMel-based alloHCT for MF patients, demonstrating revised cytogenetic changes and MIPSS70+ v2.0 accurately predicts transplant outcomes, thus would better inform physicians and patients in discussing and decision making about alloHCT.
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Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Khaled:Juno: Other: Travel Funding; Alexion: Consultancy, Speakers Bureau; Daiichi: Consultancy. Salhotra:Kadmon Corporation, LLC: Consultancy. Stein:Amgen Inc.: Speakers Bureau; Celgene: Speakers Bureau. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: Patients (pts) with MDS or AML who relapse after allogeneic transplantation (allo-HCT) have a very poor prognosis. Hypomethylating agents (HMA) and checkpoint blockade with the anti-CTLA4 ...blocking antibody ipilimumab (IPI) have each induced responses with acceptable toxicity in AML pts who relapse after allo-HCT. We hypothesized that adding decitabine (DAC) would improve response compared with IPI alone by activating and promoting T cell-mediated anti-leukemic immune reactivity. We are conducting a multicenter phase I study (CTEP 10026) of DAC plus IPI in pts with R/R MDS/AML in both post allo-HCT and transplant-naïve settings to assess safety and estimate efficacy.
Methods: The primary objective is to determine the maximum tolerated dose (MTD) or RP2D of combination DAC + IPI in pts with R/R MDS/AML who are post allo-HCT (Arm A) or transplant-naïve (Arm B). Cohorts of 3-6 are sequentially enrolled in 3 dose levels (DL) of IPI using a 3+3 design with expansion in each arm; DLs 0-2 are 3, 5 and 10 mg/kg, respectively. Eligibility for both arms: relapsed AML (extramedullary or ≥ 5% blasts) or R/R MDS (≥ 5% blasts) or unfit elderly AML; Arm A only: ≥ 2 wks off systemic immunosuppressive (IS) therapy, T cell chimerism ≥ 20%, and no prior acute GVHD ≥ gr III. DLT is defined as ≥ gr 3 non-heme, ≥ gr 3 acute GVHD or ≥ gr 3 steroid-refractory immune-related adverse events (AEs) occurring within 8 weeks from first IPI dose. Epigenetic priming with DAC lead-in cycle 0 was followed by combination cycles of DAC + IPI. DAC is given at 20 mg/m2 days 1-5 q 28 days. IPI is given on day 1 of cycles 1-4 and every other cycle in cycles 5-12. Pts who discontinued study either in cycle 0 or DLT period without IPI-toxicity were replaced. Arm A opened after safety was confirmed at DL0 in Arm B.
Results: As of June 9, 2019, 26 pts (15M, 11 F) have enrolled in this on-going trial.
Of the 12 pts (11 AML and 1 MDS) enrolled in Arm A (post allo-HCT), median age was 66.5 (range 29-74) and 9 had previously received HMA. 7 of 8 pts in DL0 (1 progressed in cycle 0) and 3 of 4 pts in DL1 (1 died from pneumonia in cycle 0) received DAC + IPI. DL0 was expanded to 6 to confirm safety without DLT. Median treatment duration after first IPI dose was 5 cycles (range 1-7); 4 pts continue on trial. Common AEs were gr 1-2 dyspnea (n=4), gr 1-3 fatigue (n=4), and gr 1-2 fever (n=4). Gr 3 AEs were febrile neutropenia (n=2), pneumonia (n=1), and candidemia (n=1). Gr 1 immune-related dermatitis (n=1) reversed with steroids. Acute GVHD was not observed. Moderate-severe chronic GVHD was noted in 2 pts mainly involving skin, which was responsive to photopheresis and oral IS. Though 1 CR and 1 marrow CR have been observed at DL0, dose-escalation up to DL2 is on-going to determine MTD.
Of the 14 pts (11 AML and 3 MDS) enrolled in Arm B (transplant naïve), median age was 75.5 (range 34-82) and 9 had previously received HMA. 4 of 6 pts in DL0 (1 progressed and 1 withdrew in cycle 0), 3 of 5 pts in DL1 (2 withdrew in cycle 0) and 3 of 3 pts in DL2 received DAC + IPI. Median treatment duration after first IPI dose was 4 cycles (range 1-8); 3 pts remain on study. Common AEs were gr 1-3 fatigue (n=9), gr 1-2 anorexia (n=5), and gr 3 febrile neutropenia (n=8). Immune-related gr 2 colitis (n=1) and gr 2/3 (n=4) dermatitis were all steroid-responsive. Of the 10 pts who received at least one IPI dose, 5 (50%) achieved an objective response including 3 CR, 1 CRi and 1 PR. All responses were observed in AML pts, including 1 with only skin involved. Expansion to confirm MTD is underway.
No treatment-related deaths or DLTs were observed in either Arm. Reasons for discontinuation after IPI: progression (n=9), proceeding to allo-HCT or DLI (n=2), withdrawal (n=1), stroke due to underlying atrial fibrillation (n=1) and disseminated nocardiosis (n=1).
In both Arms, multiplex immunofluorescence (MIF) staining of BM biopsies revealed a higher density of CD3+CD4+ cells after 4 cycles of DAC + IPI in 4 responders (R) compared to 4 non-responders (NR) (p=0.0433). Longitudinal MIF IHC in an Arm B responder identified the increasing presence of a tumor immune infiltrate composed of CD3+CD8+GZMB+ T cells prior to achieving CR (Fig 1).
Conclusions: Combination DAC + IPI is tolerable and has encouraging clinical activity in post allo-HCT and transplant naïve pts with R/R MDS/AML. Ongoing studies focus on comparing the immunologic and genetic characteristics of the tumor immune infiltrate in each cohort to understand the contribution of alloimmunity to treatment response.
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Garcia:Abbvie: Research Funding; Genentech: Research Funding. Keng:agios: Membership on an entity's Board of Directors or advisory committees. Brunner:Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Research Funding. Khaled:Omeros: Consultancy; Alexion: Consultancy, Speakers Bureau; Daiichi Sankyo: Other: Travel support. Steensma:H3 Biosciences: Other: Research funding to institution, not investigator.; Arrowhead: Equity Ownership; Onconova: Consultancy; Stemline: Consultancy; Aprea: Research Funding; Pfizer: Consultancy; Summer Road: Consultancy; Astex: Consultancy. Winer:Jazz Pharmaceuticals, Pfizer: Consultancy. Cutler:Omeros: Consultancy; Kadmon: Consultancy; BiolineRx: Other: DSMB; Cellect: Other: DSMB; Kalytera: Other: DSMB; ElsaLys: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Fate Therapeutics: Consultancy; Incyte: Consultancy; Jazz: Consultancy; BMS: Consultancy. Ho:Omeros Corporation: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Consultancy. Neuberg:Madrigal Pharmaceuticals: Equity Ownership; Pharmacyclics: Research Funding; Celgene: Research Funding. Lindsley:Takeda Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Research Funding; Medlmmune: Research Funding. Galinsky:ABIM: Other: Member of specialty oncology board; Merus Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; AbbVie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Ritz:TScan Therapeutics: Consultancy; LifeVault Bio: Consultancy; Kite Pharma: Research Funding; Talaris Therapeutics: Consultancy; Draper Labs: Consultancy; Avrobio: Consultancy; Celgene: Consultancy; Merck: Research Funding; Equillium: Research Funding; Aleta Biotherapeutics: Consultancy. Davids:AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding; Research to Practice: Honoraria. Wu:Pharmacyclics: Research Funding; Neon Therapeutics: Other: Member, Advisory Board. Stone:AbbVie, Actinium, Agios, Argenx, Arog, Astellas, AstraZeneca, Biolinerx, Celgene, Cornerstone Biopharma, Fujifilm, Jazz Pharmaceuticals, Amgen, Ono, Orsenix, Otsuka, Merck, Novartis, Pfizer, Sumitomo, Trovagene: Consultancy; Argenx, Celgene, Takeda Oncology: Other: Data and Safety Monitoring Board/Committee: ; Novartis, Agios, Arog: Research Funding. DeAngelo:Blueprint: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Abbvie: Research Funding; Glycomimetics: Research Funding; Amgen, Autolus, Celgene, Forty-seven, Incyte, Jazzs, Pfizer, Shire, Takeda: Consultancy. Soiffer:Jazz: Consultancy; Gilead, Mana therapeutic, Cugene, Jazz: Consultancy; Juno, kiadis: Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Kiadis: Other: supervisory board; Mana therapeutic: Consultancy; Cugene: Consultancy.
Combination of ipilimumab and decitabine for MDS/AML treatment for patients who are post-transplant or transplant naive
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: Pracinostat is a potent oral inhibitor of histone deacetylases (HDAC’s), selective for class I, II and IV isoforms. In-vitro cytotoxicity assays in AML cell lines revealed an IC50 of ...<0.1µM, and the combination with azacitidine was synergistic (CI=0.44). A Phase I study of single agent pracinostat showed activity in AML and a pilot Phase II study of pracinostat in combination with azacitidine in higher risk MDS demonstrated a complete response (CR)/CR with incomplete blood count recovery (CRi) rate of 89% (Proc ASH:3821, 2012). We report initial results from a Phase II study of pracinostat with azacitidine in previously untreated, elderly AML.
Methods: Eligibility includes previously untreated AML (≥ 20% bone marrow blasts), age ≥65 years, deemed inappropriate for intensive induction therapy, with intermediate or high risk cytogenetics based on SWOG criteria. De-novo, treatment-related, or AML evolved from an antecedent hematologic disorder (AHD) are allowed. Pracinostat is administered orally (60 mg) 3 days a week (e.g., Monday, Wednesday, Friday) for 3 weeks followed by a 1 week break. Azacitidine is administered subcutaneously or intravenously (75 mg/m2) day 1-7 or day 1-5 and 8-9 of each 28-day cycle. The primary endpoint is CR+CRi+ morphologic leukemia free state (MLFS) according to IWG criteria. Response assessments occur at the end of cycle 1 or 2 followed by every other cycle or when clinically indicated. A Simon 2-stage statistical design is utilized with the following assumptions: null=0.10, alternate=0.25, α=0.10, power=0.90. Transition from stage 1 to 2 requires ≥ 3/27 response events; the null hypothesis will be rejected if ≥ 7 response events are observed in the total planned sample of 40 patients.
Results: As of August 01, 2014, 21 patients have been enrolled from 12 study sites and are evaluable for safety; 14 are evaluable for efficacy (Table 1), and 7 are 'too early’ for response assessment. Baseline disease characteristics include: median age 77 (range 69-84); 16 de novo AML, 4 evolved from AHD, 1 treatment related; 11 intermediate-risk, 8 high-risk cytogenetics, and 2 are pending; baseline bone marrow blast counts ranged from 22% to 89%. The primary endpoint of CR +CRi+MLFS was observed in 8 of 14 evaluable patients (57%), the majority after 1 or 2 cycles. No responders have progressed. The most common treatment emergent adverse events (TEAE) were neutropenia/neutropenic fever (n=15), thrombocytopenia (n=12), nausea (n=10), fatigue (n=8), and anemia (n=7). Serious adverse events include febrile neutropenia (n=6) and pulmonary infiltrate/pneumonia (n=2). Three patients discontinued study therapy due to a TEAE, including one each with cellulitis, bacteremia, and subdural hematoma after a fall. There have been 3 deaths on study: 1 bacteremia, 1 subdural hematoma, and 1 progressive disease.
Abstract 947. Table 1Patient NumberDays on StudyBaseline BM Blast %1st On-Study BM Blast %Subsequent On-Study BM Blast %Best Response on Study2172+221 (C2)—CR3165+244 (C1)0 (C4)CRi5162+279 (C1)1 (C4)CRi6156+819 (C1)0 (C4)CRi7148+7844 (C1)17 (C3), 0 (C5)CR8114+894 (C1)—CR1086+453 (C1)—CRi1281+412 (C2)—CRi4902243 (C2)Off due to SAESD11563760 (C2)—PD152870—Patient Withdrew172860—PD12670—Off due to AE92638—Off due to AE+=Patients continue on study; C=cycle; SD=Stable Disease; PD=Progressive Disease
Conclusions: The study has achieved the primary goal of rejecting the null hypothesis. The CR+CRi +MLFS response rate estimate of 57% is high compared to historical results with hypomethylating agents alone in this population, and the responses occur rapidly, most within the first 2 cycles. The combination appears tolerable with no unexpected toxicities. Recruitment continues to the final planned sample size of 40 to further define the tolerability and efficacy of the regimen, including remission duration. Updated data will be presented at the meeting.
Garcia-Manero:MEI Pharma, Inc.: Consultancy. Off Label Use: Azacitidine is not approved for use in acute myelogenous leukemia.. Odenike:Sanofi-Aventis: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Algeta Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Spectrum Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Suneisis Pharmaceuticals : Honoraria, Membership on an entity’s Board of Directors or advisory committees. Medeiros:MEI Pharma, Inc: Research Funding. Cortes:Celgene: Research Funding. Esquibel:MEI Pharma, Inc.: Employment. Cha:MEI Pharma, Inc.: Employment. Khaled:Sequenom: Research Funding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: Combination studies with histone deacetylase (HDAC) inhibitors plus hypomethylating agents (HMA) have suggested beneficial clinical activity in higher risk MDS and AML, though exceptions ...have also been reported. Pracinostat is a potent oral HDAC inhibitor selective for class I, II and IV isoforms. A pilot phase Ib study of pracinostat in combination with azacitidine (AZA) in higher risk MDS demonstrated a complete response (CR)/CR with incomplete blood count recovery (CRi) rate of 89% (Proc ASH:3821, 2012). Preliminary data on 33 patients from a multi-center, open-label, single-arm Phase II study of Pracinostat in combination with AZA in elderly AML also reported a high CR/CRi rate (ASH 2014). Herein we report the latest survival and response results for this study.
Methods: Eligibility includes previously untreated AML (≥20% bone marrow blasts), age ≥65 years, unsuitable for intensive therapy due to co-morbidities and/or AML related features, and intermediate or high-risk cytogenetics. Study therapy includes pracinostat, 60 mg p.o. 3 alternate days/week for 3 weeks plus AZA, 75 mg/m2) days 1-7 or days 1-5 and 8-9 either s.c. or i.v. with cycles repeated every 28 days until progressive disease, lack of response or intolerance. The primary endpoint is CR+CRi+ morphologic leukemia free state (MLFS) per IWG criteria. Response assessments occur at the end of cycle 1 or 2 then every other cycle or when clinically indicated. A Simon 2-stage statistical design is utilized with the following assumptions: null=0.10, alternate=0.25, a=0.10, power=0.90. Stage 1 n=27 and total stage 2 n=40. Secondary endpoints include overall response rate (ORR; CR+CRi+MLFS+partial response PR+PRi), duration of response and overall survival.
Results: Between Dec 2013 and Dec 2014, 50 patients from 15 study sites were enrolled. At this time, 50 are evaluable for efficacy. Baseline disease characteristics for all patients include: median age 75 (range 66-84); 32 de novo AML, 13 evolved from AHD, 5 were treatment-related; 28 intermediate-risk and 20 high-risk cytogenetics and 2 unknown; baseline bone marrow blast counts ranged from 20% to 89% with a median of 40%. Thirty-one patients (62%) continue to be followed for survival (range: 8.5 to 18.5 months). Median overall survival has not been reached in the overall study population and neither in patients with high-risk cytogenics or those with AML secondary to MDS or prior anti-cancer therapy. The 1-year overall survival estimate is 60%. The primary endpoint of CR +CRi +MLFS has been observed in 27/50 evaluable patients (54%) to date, including 21/50 (42%) CR. The 60-day all-cause mortality rate is 10% (5/50). Treatment emergent adverse events (TEAEs) Grade ≥3 seen in >5% of patients: febrile neutropenia 30%; thrombocytopenia 22%; neutropenia 10%; cellulitis 10%; anemia 8%; fatigue 8%; sepsis 6%, and pancytopenia 6%. TEAE's leading to study therapy discontinuation: peripheral motor neuropathy (1), parainfluenza (1), atrial fibrillation/prolonged QTc (1), subdural hematoma after a fall (1), and sepsis (3).
Conclusions: Pracinostat plus AZA produces a high rate of durable responses in this AML population. Median overall survival has not been reached; 1-year overall survival is estimated at 60%. Final response data and overall survival estimates will be presented at the meeting.
Off Label Use: Azacitidine is not approved for use in acute myelogenous leukemia.. Khaled:Sequenom: Research Funding. Arellano:Cephalon Oncology: Research Funding. Butler:MEI Pharma, Inc.: Employment. Ashby:MEI Pharma, Inc.: Employment. Medeiros:Celgene: Honoraria, Research Funding; Agios Pharmaceuticals: Honoraria.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Allelic variants implicated in drug absorption, distribution, metabolism, and excretion (ADME) affect drug pharmacokinetic variability and have been increasingly recognized as important factors in ...medical therapy. In solid organ transplantation, certain ADME genes affect the blood level of immunosuppressants as well as clinical outcomes despite rigorous traditional therapeutic drug monitoring (TDM). The influence of ADME pharmacogenetics in Hematopoietic Stem Cell Transplantation (HSCT) has not been well studied, with few publications and none reporting the effects in the setting of the tacrolimus (TAC)/ sirolimus (SIR) GVHD-preventive combination. In this exploratory pilot study, the objective was to evaluate possible associations between ADME variants with TAC/SIR blood levels and clinical outcomes in the allogeneic HSCT setting. The primary focus was on 3 ADME genes ABCB1 (MDR1), CYP3A4, and CYP3A5 known to influence TAC/SIR outcomes in solid organ transplant. Secondarily we explored associations with other gene variants on the ADME panel. We analyzed archived DNA samples from 179 HSCT recipients on the Sequenom MassARRAY® platform. This panel is based on the PharmADME Working Group core list and interrogates 184 allelic variants and 12 copy number variants and 4 gene conversions (in 36 pharmacogenetically relevant genes). Blood levels of TAC and SIR were collected for all patients at least once weekly for the first 100 days post-transplant. For this analysis, median blood levels of TAC and SIR were obtained for the first 7 and 14 days post-transplant. Conditioning regimens consisted of fludarabine/melphalan (n=106), total body irradiation (TBI)/cyclophosphamide (n=11), TBI/etoposide (n=46) and busulfan/cyclophosphamide (n=14). All patients received TAC/SIR-based GVHD prophylaxis according to Shayani et al. (Biol Blood Marrow Transplant 2013). No azoles were used as fungal prophylaxis. Of 179 samples genotyped, 178 showed high quality data. The average call rate for these samples was 98.85% over 200 assays, with a median call rate of 100%. Of these assays, 66 variants were identified that could be evaluated for association with TAC/SIR levels and clinical outcomes; other assays were excluded due to homozygosity or >10% missing data. In the setting of the TAC/SIR combination, the median SIR blood level over the first 14 days post-HSCT was higher in rs2032582 (ABCB1) T carriers vs other groups (p=0.01), as was the median concentration/dose (C/D) ratio (p=0.05) (Table). We also found that the median TAC blood level over the first 7 days post-HSCT was lower in the rs776746 ( CYP3A5) AA group compared to GG or GA groups (p<0.002), as well as for TAC C/D ratio (p=0.01). To evaluate effects of gene variants on drug levels over time, the generalized estimating equation (GEE) approach were used to facilitate the analysis; results showed a significant difference in SIR levels between rs2032582 (ABCB1) T-carriers vs other groups. This is consistent with our observation that initial genetic influences on drug levels lessen over time due to TDM dose adjustments (Fig 1). Despite TDM dose adjustment, the presence of the CYP3A5 AA polymorphism (fast drug metabolizers) was associated with increased incidence of acute and chronic GVHD (Fig 2). None of the SNPs for the 3 primary genes tested were significantly associated with renal dysfunction or thrombotic microangiopathy. Our exploratory analysis identified multiple other genetic variants potentially associated with TAC / SIR levels and clinical outcomes, but none reached statistical significance after adjustment for multiple testing. These variants will be included in a focused panel for future validation. Our study is the first to demonstrate the influence of ADME genetic variants on drug levels and clinical outcomes after HSCT using TAC/SIR as GVHD prophylaxis. Our results may lead to individualized dosing of immunosuppressive medications post-HSCT based on ADME genetic polymorphisms. Abstract 2492. TableSIR Drug Level First 14 DaysSIR C/D Ratio First 14 DaysGeneSNPGroupNMedianRangep-valueNMedianRangep-valueABCB1rs2032582AA/GG/GA606.92.1-13.10.01601.90.6-12.30.05TT/TA/GT1128.32.8-18.71122.20.8-5.4TAC Drug Level First 7 DaysTAC C/D Ratio First 7 DaysGeneSNPGroupNMedianRangep-valueNMedianRangep-valueCYP3A5rs776746AA89.35.0-16.8<0.00287.75.5-13.30.01GG12211.03.1-27.012210.64.9-33.8GA409.43.9-16.2408.22.8-16.4
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Khaled:Sequenom: Research Funding. Off Label Use: Use of tacrolimus and sirolimus immunosuppressants for prevention of graft-versus-host disease following allogeneic hematopoietic stem cell transplantation..
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Philadelphia (Ph) chromosome t(9;22) was reported as a rare recurrent balanced translocation among therapy-related acute leukemia (N=10, 2%) Gene Chromosomes Cancer. 2002. Here, we conducted a ...retrospective analysis of therapy-related acute leukemia with Ph chromosome (Ph+ t-AL) to better understand this entity. We included cases diagnosed at our institution between 2000 and 2016, excluding patients with CML in blastic phase. We defined Ph+ t-AL as acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) harboring Ph chromosome that developed after prior exposure to cytotoxic therapy (chemotherapy, radiation or both).
Of the 330 patients with Ph+ AL, 28 cases (8.4%) met our definition of Ph+ t-AL, including 25 (89%) B-cell ALL, 1 case of T-cell ALL, and 2 cases of AML. The median age at diagnosis was 56 years (range: 29-79), and 64% (N=18) of them were female. Breast cancer was the most common prior malignancy N=8, 29%, followed by lymphoma N=6, 21% and sarcoma N=4, 14%. Prior cytotoxic therapy consisted of chemotherapy (32%), radiotherapy (29%) and chemoradiation (39%). Among 20 patients who had prior chemotherapy, 70% had received alkylating agents (i.e., cyclophosphamide, temozolomide), 70% had received topoisomerase II inhibitors (i.e., etoposide, anthracycline), 40% had received antimetabolites, (i.e., methotrexate) and 50% both alkylators and topoisomeraseII inhibitor. The median interval between prior malignancy and Ph+ t-AL diagnosis was 6.8 years (range: 2.5-19.6) and was not different according to prior cytotoxic therapy modality chemotherapy/radiotherapy vs. either chemotherapy or radiotherapy alone (P = 0.66). The median white blood cells count at presentation was 20 x103/µL (range: 1.4-230). Myelodysplastic syndrome preceded one case of AML. Among 22 patients with available standard cytogenetics, 7 (32%) had Ph chromosome as the sole abnormality, while 15 (68%) had an additional cytogenetic abnormality (ACA). Complex (≥ 3 abnormalities) or monosomal karyotypes were observed respectively in 12 and 9 cases. Chromosome 7 abnormality was observed in 6 (27%) cases, including 5 of them with monosomy 7. In 18 patients (ALL = 17; AML = 1) with available molecular study for BCR/ABL1, all were positive for p190 fusion transcript, including 3 patients who carried both p210 and p190 (ALL =2; AML =1). The median time from prior diagnosis to AL onset was not different according to cytogenetics (isolated Ph chromosome vs. complex/monosomy karyotype) (P> 0.99). However, prior exposure to topoisomeraseII inhibitor was more common among patients with isolated Ph chromosome compared to patients with complex/monosomy karyotype (86% vs. 33%, P= 0.02).
Tyrosine-kinase inhibitor (TKI) was administered as part of initial induction regimen to all patients except 4 (N= 24, 86%), who received TKI only upon leukemia relapse/progression. Of the 28 patients, 25 (89%) achieved complete remission (CR) with induction, and 17 (61%) patients subsequently underwent alloHCT; of them, 13 (76%) were in CR1. The 2-year overall survival and event-free survival were respectively 48% and 36% for all patients, and 63% and 41% for those who underwent alloHCT, respectively. The 2-year cumulative incidence rates of relapse and non-relapse mortality for transplanted patients were 19% and 25%, respectively.
In conclusion, Ph+ chromosome is a recurrent therapy-related chromosomal aberration presenting most often as a B-cell ALL phenotype, and only rarely as T-cell ALL or AML. Ph+ t-AL is associated with high incidence of ACA, including complex and monosomal karyotype as well as chromosome 7 abnormalities, similar to therapy-related myeloid neoplasms. Similar to de novo Ph+ ALL, a high response rate to TKI-based regimen was observed among Ph+ t-AL. Given its therapeutic implication, presence of Ph chromosome should be excluded in all cases of t-AL.
Song:Seattle Genetics: Consultancy. Ali:Incyte Corporation: Research Funding. Salhotra:Alexion: Consultancy. Snyder:Ariad: Consultancy; Novartis: Consultancy. Stein:Amgen: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding. Forman:Mustang Therpapeutics: Other: Construct licensed by City of Hope.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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