scholarly journals Ponatinib and Chemotherapy in Adults with De Novo Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. Final Results of Ponalfil Clinical Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1230-1230
Author(s):  
Josep-Maria Ribera ◽  
Olga Garcia ◽  
Jordi Ribera ◽  
Pau Montesinos ◽  
Isabel Cano ◽  
...  
Keyword(s):  
Propensity Score ◽  
Research Funding ◽  
Response To Therapy ◽  
High Dose ◽  
Molecular Response ◽  
Hepatic Toxicity ◽  
Cns Involvement ◽  
Hematopoietic Stem ◽  
Central Retina ◽  
T315i Mutation

Abstract Background and objective. The combination of HyperCVAD and ponatinib resulted in a high molecular response rate and survival in adults with Ph+ ALL, suggesting improved outcome compared with combinations of chemotherapy with first- or second-generation tyrosine kinase inhibitors (TKI) (Jabbour E, et al, Lancet Haematol. 2018;5:e618-e627). The Spanish PETHEMA group conducted the phase 2 PONALFIL trial, which incorporates ponatinib to the same chemotherapy as that of the ALL Ph08 trial that used imatinib as TKI (Ribera JM et al. Cancer 2019;125:2810-17). Final results of this trial are reported. Patients and method. PONALFIL trial (NCT02776605) combined ponatinib (30 mg/d) and induction chemotherapy (vincristine, daunorubicin, prednisone) followed by consolidation (high-dose methotrexate, high-dose ARA-C, mercaptopurine, etoposide) and allogeneic hematopoietic stem cell transplantation (alloHSCT). Ponatinib was scheduled after alloHSCT only for patients (pts) with persistence/reappearance of MRD. Response to therapy (complete morphological [CR], molecular [complete -CMR- or major -MMR-] after induction and before alloHSCT) (assessed by centralized BCR-ABL1/ABL1 ratio), disease-free survival (DFS), overall survival [OS]) and toxicity were analyzed. The following genetic studies were performed: 1. Additional gene abnormalities (Copy Number Alteration [CNA] analysis by SNP array Affymetrix 750K), 2. ABL1 mutation status at diagnosis (Sanger sequencing), 3. T315I mutation at diagnosis (allele-specific PCR). A propensity score comparison with the results of the ALL Ph08 trial was performed. Results. Median age was 49 (19-59) years (y), and 13/30 pts were female. One pt showed CNS involvement at diagnosis. ECOG score was <2 in 90% of pts. Median WBC count was 6.4 x10 9/L (0.6-359.3), Hb 90 g/L (63-145), platelets 38 x10 9/L (11-206). Immunologic phenotype was common in 26 cases, with p190 isoform in 20 pts (67%), p210 in 9 (30%) and p230 in 1 (3%). CR was attained in 30/30 pts, CMR in 14/30 (47%), MMR in 5/30 (17%) and no molecular response in 11/30 (37%). Two pts withdrew the trial during induction (thrombosis of central retina artery and severe intestinal infection, one case each). Consolidation was given to 28 pts, 2 pts withdrew the trial (physician's decision and lack of molecular response, one case each) and 26 pts received alloHSCT (20 in CMR, 6 in MMR). No relapses before HSCT were detected. One pt died by severe GVHD and two withdrew the trial (grade IV hepatic toxicity:1, protocol deviation after molecular relapse:1). One pt relapsed in BM after HSCT. Ponatinib was given after HSCT in 4/26 pts and dasatinib in 1/26 due to MRD reappearance, and 1/26 received dasatinib in CMR because of refusal to receive CNS prophylaxis, whereas 20/26 pts did not receive any TKI therapy after HSCT. Twenty-nine pts are alive (median follow-up 2.3y, range 1.3-4). 2y DFS and OS probabilities were 97% (91%-100%) and 97% (91%-100%) (Figure 1). Among 7/16 pts without CMR after consolidation and genetic material available, 4 showed IKZF1 deletion (IKZF1 plus in 2), 1 showed CDKN2A/B and PAX5 deletion and 2 did not show any CNA. Among 5/19 pts with molecular relapse, 3 showed IKZF1 deletion (1 being IKZF1 plus), and 2 pts did not show any CNA. No ABL1 mutations or T315I mutation at diagnosis were found. Propensity score with 1:1 matching identified 30 pts in each cohort (variables: age, gender, ECOG, WBC, CNS involvement, cytogenetic risk and BCR/ABL isoform). 2y DFS rates for PONALFIL and ALL Ph08 trials were 97% and 62%, (p=0.005), and 2y OS rates were 97% and 66% (p=0.001) (Figure 2). 107 adverse events (AE) were registered in 20 pts (21 severe in 11 pts), prompting to withdrawn of the trial in 3 (thrombosis of central retina artery, severe bowel infection, grade IV hepatic toxicity). The most frequent AE were hematologic (28%), gastrointestinal (14%), hepatic (11%), infections (7%), and cutaneous (5%). Cardiovascular events occurred in 2 patients (angor pectoris and thrombosis of central artery of the retina). Conclusions. The results of the PONALFIL trial show a high antileukemic efficacy with acceptable toxicity profile and compare favorably with the same chemotherapy schedule and imatinib. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation. Figure 1. OS (A) and DFS (B). PONALFIL. Figure 2. OS (A) and DFS (B). PONALFIL vs. ALL Ph08. Figure 1 Figure 1. Disclosures Ribera: AMGEN: Consultancy, Research Funding, Speakers Bureau; NOVARTIS: Consultancy, Speakers Bureau; TAKEDA: Consultancy, Research Funding, Speakers Bureau; ARIAD: Consultancy, Research Funding, Speakers Bureau; SHIRE: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Esteve: Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Abbvie: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Novartis: Research Funding; Jazz: Consultancy; Astellas: Consultancy. Mercadal: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences, Inc.: Honoraria, Speakers Bureau. Martínez-López: Roche, Novartis, Incyte, Astellas, BMS: Research Funding; Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy. OffLabel Disclosure: This trial includes Ponatinib in off-label indication.

Long Term Outcomes of Rituximab, Temozolamide, and High-Dose Methotrexate for Lymphoma Involving the Central Nervous System

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2701-2701
Author(s):  
Sarah Jordan Nagle ◽  
Nirav N. Shah ◽  
Alex Ganetsky ◽  
Daniel J. Landsburg ◽  
Sunita Dwivedy Nasta ◽  
...  
Keyword(s):  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Initial Response ◽  
Response Assessment ◽  
Response To Therapy ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Cns Involvement ◽  
Dose Methotrexate

Abstract Background Management of patients (pts) with primary central nervous system lymphoma (PCNSL) and those with secondary CNS involvement by diffuse large B cell lymphoma (DLBCL) present a therapeutic challenge. There is no clear standard of care but traditionally initial treatment of PCNSL involves induction with intravenous high-dose methotrexate (HD-MTX) followed by consolidation including whole brain radiation therapy (WBRT), cytarabine, or autologous stem cell transplant. This approach has been associated with significant toxicities, especially the risk of cognitive dysfunction with WBRT. Treatment of secondary CNS involvement by DLBCL may depend on the extent of concomitant systemic disease, but HD-MTX is often the backbone of therapy. We report results of our institutional approach in pts with PCNSL and secondary involvement of the CNS by DLBCL using a prolonged course of rituximab, temozolamide, and HD-MTX (RTM) without consolidation. Methods We conducted a retrospective cohort study describing outcomes of pts with PCNSL or secondary CNS DLBCL who were treated on the RTM protocol. Eligible pts are treated with rituximab 375 mg/m2 on day 1 in combination with HD-MTX 8 g/m2 (days 1 and 15) and temozolamide 150 mg/m2 (days 1-5) in 28-day cycles. HD-MTX is administered with leucovorin rescue and adjusted for creatinine clearance. Initial response assessment is usually after 2 cycles with brain MRI. Once a complete response (CR) has been achieved, the day 15 HD-MTX is omitted from future cycles. Pts typically complete a total of 6-12 cycles, at the discretion of the clinician, without further planned consolidation. Descriptive and survival analyses using the Kaplan-Meier methodology were performed (STATA 13). The primary endpoints, overall survival (OS) and progression free survival (PFS) were estimated from the date of the first treatment with RTM to death, progression, or date of last follow-up. A log-rank test was utilized to compare OS/PFS between pts with PCNSL versus secondary CNS DLBCL. A Cox proportional hazard analysis was performed to evaluate the effect of patient level variables on OS. Clinical response was evaluated using International Workshop on Response Criteria for PCNSL (Abrey, J Clin Oncol 2005). Results We identified 46 pts who received RTM at our institution between 2009 and 2014. Twenty-seven (59%) pts had PCNSL and 19 (41%) pts had secondary CNS DLBCL. The median age at diagnosis was 61 years (range 21-85) with 50% males. Treatment was well tolerated. Two (4%) pts discontinued treatment prematurely and 7 (15%) pts required a dose reduction in HD-MTX due to toxicity. Toxicities included transaminitis, acute renal failure, infection, fatigue, and cytopenias. In pts with PCNSL, all received RTM as their initial treatment. Best response to therapy in this group was as follows: 19 (70%) had a CR, 3 (11%) had PR, 3 (11%) had SD and 2 (7%) had PD. The overall response rate was 81%. All patients with secondary CNS DLBCL had received prior systemic therapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone. Best CNS response to therapy in this group was as follows: 7 (37%) had CR, 2 (11%) had PR, 1 (5%) had SD, and 9 (47%) had PD. The overall response rate was 47%. For the entire cohort, the median OS was 41 months (m) and median PFS was 8 m. Compared with secondary CNS DLBCL, patients with PCNSL had a significantly longer median OS (54 m vs. 5 m; p<0.01) (Figure 1). PFS was also significantly longer for pts with primary versus secondary CNS DLBCL (22 m vs. 2 m; p=0.02) (Figure 2). Univariate cox analysis demonstrated that sex and age did not impact OS but pts who were in a CR or PR at initial response assessment compared to SD or PD had a hazard ratio for OS of 0.12 (95% CI: 0.05 to 0.29, P<0.01). Conclusions In our cohort, pts with PCNSL had excellent outcomes using a prolonged course of the RTM regimen without the toxicities of consolidation with radiation or high dose chemotherapy. These outcomes did not translate to pts with secondary CNS DLBCL, which may be consistent with the different biology and aggressive nature of this subgroup in addition to the prior therapies received. Early response assessment is vital to assess prognosis pts as those who respond within 2 cycles of therapy have an improved OS. This data suggests that RTM without further consolidation is an acceptable alternative regimen for PCNSL. Future prospective studies are needed to validate our findings. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Ganetsky: Onyx: Speakers Bureau. Dwivedy Nasta:Millenium: Research Funding; BMS: Research Funding. Mato:Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding; Pronai Pharmaceuticals: Research Funding; Celgene Corporation: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; TG Therapeutics: Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy. Schuster:Gilead: Research Funding; Janssen: Research Funding; Hoffman-LaRoche: Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Svoboda:Celgene: Research Funding; Seattle Genetics: Research Funding; Immunomedics: Research Funding; Celldex: Research Funding.

Outcome of High Dose Melphalan with Autologous Hematopoietic Stem Cell Transplant In Myeloma Associated with AL Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2400-2400
Author(s):  
Simrit Parmar ◽  
Mubeen Khan ◽  
Gabriela Rondon ◽  
Nina Shah ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Research Funding ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
High Dose ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
High Dose Melphalan

Abstract Abstract 2400 Background: Approximately 10% of patients with multiple myeloma (MM) have clinically overt primary systemic light-chain (AL) amyloidosis, and about 30% have concurrent occult AL amyloidosis. The impact of concurrent AL amyloidosis on the prognosis of myeloma is not well known. High-dose melphalan followed by autologous hematopoietic stem cell transplant (auto HCT) has shown significant activity in both MM and AL amyloidosis. Methods: We performed a retrospective analysis of patients who had concurrent MM and AL amyloidosis and underwent auto HSCT with high dose Melphalan at MDACC between 01/1998 to 05/2010. We identified 41 patients with concurrent MM and AL amyloidosis. Patient characteristics are summarized in Table 1. Twenty -six patients had occult AL amyloid, while 15 had clinically overt disease. Results: Median age at auto HSCT was 56 years (39-77), 58.5% being male with median follow up of 58.7 months from the time of diagnosis and 42.5 months from auto HCT. The median time from diagnosis to auto HCT was 8.9 mos (2.7-102.4 mos). 39% had Salmon Durie Stage III disease and 36.6% had more than one involved site at the time of transplant.Cytogenetic abnormalities were detected in 24.4% of patients. Post transplant hematologic responses were as follows: ≥CR=10 (24%), ≥VGPR=16 (39%), >PR=33 (80.5%), ≥stable disease= 40 (97.6%). Among the patients with overt organ involvement, one had early death. Of the 15 evaluable patients, organ responses were scored using the published consensus guidelines for amyloidosis and were as follows: PR=5 (33.3%), ≥SD=7 (46.7%). No correlation was seen between organ response and hematologic response. The 100-day treatment related mortality (TRM) was 0 and 1-year TRM of 2.4% which is comparable to patients transplanted for MM alone at our center. The median progression-free (PFS) and overall survival (OS) from auto HCT were 33.8 and 58.3 months, respectively.The median PFS and OS from diagnosis were 49.8 and 96 mos, respectively. In multivariate analysis, creatinine ≥ 2mg/dl was associated with a shorter PFS (p=0.043) and hemoglobin <10g/dl showed a trend towards a shorter PFS (p=0.093). None of these variables (Hb <10g/dl, Age>60yrs, Creatinine≥2mg/dl, B2M >3.5mg/l, BM plasma cells>30%) emerged as significant predictors of OS. There was no significant difference in outcome between patients with occult or symptomatic AL amyloidosis for OS (p=0.24) or PFS (P=0.9) Conclusion: In this analysis the outcome of patients with concurrent MM and AL amyloidosis was comparable to patients with MM alone. We believe these patients are acceptable candidates for auto HCT. Disclosures: Shah: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Novartis: Research Funding. Weber: novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; celgene- none for at least 2 years: Honoraria; millenium-none for 2 years: Honoraria; celgene, Millenium, Merck: Research Funding. Orlowski: Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding.

EUTOS Score Is Not Predictive for Survival and Outcome in Patients (pts) with Chronic Myeloid Leukemia in Early Chronic Phase (CML-CP) Treated with Tyrosine Kinase Inhibitors (TKIs) At MD Anderson Cancer Center (MDACC),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3769-3769
Author(s):  
Aziz Nazha ◽  
Elias Jabbour ◽  
Jorge E. Cortes ◽  
Susan O'Brien ◽  
Jenny Shan ◽  
...  
Keyword(s):  
Research Funding ◽  
Kinase Inhibitors ◽  
Standard Dose ◽  
Chronic Phase ◽  
Cancer Center ◽  
High Dose ◽  
Molecular Response ◽  
Phase Ii Trials ◽  
Free Survival ◽  
Eutos Score

Abstract Abstract 3769 Background: Until recently, prognosis of pts with CML treated with TKI was based on scores developed in the chemotherapy and interferon era. Hasford and colleagues [Blood. 2011;(118):686–692] have identified the EUTOS score, using the percentage of basophils and spleen size, as a significant tool to predict the probability of achieving 18-month complete cytogenetic response (CCyR) and progression-free survival in patients treated with imatinib. Aims: To validate the EUTOS score in an independent MDACC cohort of pts, with early CML-CP treated with standard-dose imatinib, high-dose imatinib, dasatinib, and nilotinib, and its ability to predict transformation-free survival (TFS), event-free survival (EFS) and overall survival (OS). Methods: 465 consecutive pts with newly diagnosed CML–CP (0 – 6 months from diagnosis to TKI treatment) were treated with imatinib 400 mg daily (n=71), imatinib 800 mg daily (n=208), and 2nd TKIs (n=186; dasatinib n=88, nilotinib n=98) in sequential phase II trials. Entry criteria were similar for all trials. EUTOS score = (7 x basophils %) + (4 x spleen cm BCM). A EUTOS score of >87 indicates high-risk and ≤87 low-risk. Results: 465 pts with CML-CP were assessed. Median age was 47 years (range, 15–85). Median time from diagnosis to TKI therapy was 1 month (range, 0 to 6). 319 (69%), 112 (24%), and 34 (7%) pts were in low, intermediate, and high-Sokal score category, respectively. Median basophils percentage at baseline was 3 (range, 0 to 19). Median splenomegaly size was 0 cm (range, 0 to 30). 118 pts (25%) received previous cytoreduction therapy. Median follow-up was 117 months (range, 16 to 130) for pts receiving standard-dose imatinib, 88 months (range, 4 to 118) for those receiving high-dose imatinib, and 30 months (range, 3 to 69) for those receiving 2nd TKI. The overall CCyR rates were 87%, 91%, and 95%, respectively. The 4-year EFS, TFS, and OS rates for the whole group were 84%, 94%, and 95%, respectively. Overall, of the 465 pts, 427 (92%) were in low EUTOS score category (Table 1). Pts with low EUTOS score had higher rates of CCyR at anytime compared to pts with high EUTOS score (93% versus 81%, p=0.02). This difference was mainly significant among pts receiving 2nd TKI (p=0.03) while it was not different among pts receiving imatinib (p=0.27). There was no difference in the rates of major molecular response (85% versus 81%, p=0.48) between pts with low and high EUTOS score. There was no difference in TFS, EFS, and OS rates between pts with low and high EUTOS score, overall and among specific therapy (Table 1). Conclusion: Eight percent of pts with CML-CP treated at MDACC are of high EUTOS score. In this population, the EUTOS score was not predictive for overall MMR, TFS, EFS, and OS. Disclosures: Cortes: BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

A Phase I Study of Myeloablative I-131-Anti CD-20 (Tositumomab) Radioimmunotherapy with Escalating Doses of Fludarabine Followed by Autologous Hematopoietic Stem Cell Transplantation (ASCT) for Adults ≥ 60 Years of Age with High-Risk or Relapsed/Refractory B-Cell Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 663-663
Author(s):  
Ajay K. Gopal ◽  
Ted Gooley ◽  
Joseph Rajendran ◽  
John M. Pagel ◽  
Darrell R. Fisher ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
B Cell ◽  
Radiation Exposure ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Nucleoside Analogs ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Hematopoietic Stem

Abstract Abstract 663 Background: The majority of patients with relapsed or refractory B-cell, non-Hodgkin's lymphoma (NHL) are over 60 years of age, yet many are denied potentially curative high-dose regimens due to concerns of excessive toxicity. We have shown that myeloablative anti-CD20 radioimmunotherapy (RIT) can safely deliver effective radiation doses to tumor sites while limiting exposure to normal organs in older adults requiring high-dose therapy, however, not all patients in this series remained progression-free (Gopal, JCO 2007). Preclinical data suggest that improved anti-tumor activity may be attained by the concurrent administration of nucleoside analogs (fludarabine, cytarabine) which synergize with RIT (Johnson, Int J Cancer; Gopal, BBMT, 2006). We hypothesized that a prolonged regimen of fludarabine could be administered concurrently with myeloablative RIT and ASCT to safely augment the efficacy of this approach. We present the phase I data evaluating this strategy. Methods: Patients were eligible if they were 60 years of age or older, had mantle cell lymphoma (MCL) in first remission or relapsed/refractory B-NHL, an ECOG PS of 0–1, acceptable organ function, >2×106 autologous CD34+ peripheral blood stem cells/kg collected, <20 Gy prior radiation to critical organs, and no human-anti-mouse-antibodies (HAMA). All patients underwent outpatient biodistribution studies for dosimetry using tositumomab (1.7 mg/kg, n=3 or 485mg flat dose, n=33) labeled with ∼10mCi I-131 followed by serial quantitative gamma camera imaging to calculate individualized organ-specific absorbed dose estimates. Patients then received therapeutic infusions of I-131-tositumomab to deliver 27Gy to the critical normal organ receiving the highest radiation exposure. Forty-eight hours later fludarabine was administered in escalating doses to patients (Table) to define a regimen associated with a dose limiting toxicity (DLT = grade III/IV Bearman toxicity) rate of <25%. ASCT occurred when radiation exposure was estimated to be <2mR/hr at 1meter. Filgrastim at 5μg/kg/day or pegfilgrastim at 6mg × 1 was started on day 1. Response was scored using standard criteria. Results: Between July 2005 and May 2011 36 patients were treated. Baseline characteristics included: median age 65 yrs (range 60–76), stage III/IV = 34 (94%), median number of prior regimens = 2 (range 1–9), chemoresistant disease (defined as < a partial response [PR] to the most recent regimen) = 12 (33%), >1 extranodal site = 14 (39%), elevated LDH at treatment = 13 (36%), IPI score at transplant 3–5 = 53%. Histology: MCL = 23, diffuse large B-cell = 8 (with 5 transformed from follicular lymphoma [FL]), FL=3, and marginal zone = 1, Waldenstrom's = 1. Dose limiting organs receiving up to 27Gy included lung (30), kidney (4), and liver (2) with a median administered I-131 activity of 471 mCi (range 260–1620). Fludarabine was escalated from 10 mg/m2/day × 5 days to 30 mg/m2 × 7 days without observation of a DLT (Table). The median CD34 dose was 5.42 ×106/kg with neutrophil (ANC>500μl) and platelet (>20 K/μl) engraftment occurring a median on 10 and 12 days after ASCT, respectively. Only 2 patients developed grade 4 NCI-CTC grade 4 non-hematologic toxicities (hypokalemia/hypophosphatemia, depression), 25 (69%) remained outpatients after discharge from radiation isolation, and there were no non-relapse deaths in the first 100 days after transplant. Responses to therapy were as follows: CR/CRu = 26 (79%), PR = 2 (6%), SD = 4 (11%), and PD = 4 (11%). Currently, 23 (64%) patients are alive with 22 (61%) progression free. The estimated 3 yr overall survival, progression-free survival, relapse, and non-relapse mortality are 54%, 53%, 41%, and 7%, respectively (median follow up of 2.5yrs after ASCT, Figure). Improved survival was associated with <2 prior regimens (HR=.08, p=.02) and chemosensitive disease (HR=.35, p=.07). Conclusions: High-dose (27 Gy) I-131 tositumomab can safely be administered concurrently with up to 210 mg/m2 fludarabine in an older, high-risk patient population. This strategy warrants further investigation as a method to safely augment the antitumor activity of myeloablative RIT. Disclosures: Gopal: GSK: Research Funding; Spectrum: Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Research Funding; Piramal: Research Funding; Cephalon: Research Funding; Millenium: Speakers Bureau; Abbott: Research Funding; Pfizer: Research Funding; SBio: Research Funding; Bio Marin: Research Funding; Biogen-Idec: Research Funding. Off Label Use: High-dose use of I-131-tositumomab. Maloney:GSK: Consultancy, Honoraria.

C-MYC Rearrangement: A Marker for High-Risk Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4989-4989
Author(s):  
Isabella C. Glitza ◽  
Gary Lu ◽  
Su Chen ◽  
Robert Z. Orlowski ◽  
Muzaffar H. Qazilbash
Keyword(s):  
Stem Cell ◽  
Plasma Cell ◽  
Response To Therapy ◽  
Chromosome 8 ◽  
Plasma Cell Leukemia ◽  
Disease Stage ◽  
High Dose ◽  
Cell Leukemia ◽  
Hematopoietic Stem ◽  
Conventional Cytogenetics

Abstract Abstract 4989 Background: The proto-oncogene c-MYC encodes a transcription factor that regulates cell proliferation, growth, and apoptosis. c-MYC is mapped to the 8q24. 1 on the long arm of chromosome 8 and its rearrangement has been reported in 15% of myeloma patients independent of the disease stage (Avet-Loiseau et al. Blood 2001). However, the clinical significance of c-MYC rearrangement is not well described. Here we report the characteristics and outcome of myeloma patients with c-MYC rearrangements that were treated at our institution. Methods: We identified 18 patients (11 males, 7 females) with c-MYCrearrangements either on fluorescence in situ hybridization (FISH) analyses or conventional cytogenetics, who were treated at the M.D. Anderson Cancer Center. The primary objective was to describe the patient characteristics, response to therapy, time to progression (TTP), and overall survival (OS). Results: Median age at diagnosis was 56. 5 years (21–72). Overall, 8 patients (44%) presented with or progressed to either plasma cell leukemia (PCL: 6) or plasmablastic myeloma (PBM: 2). Abnormalities involving chromosome 8q24. 1, the c-MYC locus, were detected on conventional cytogenetics in all 18 patients, including t(8;14)(q24. 1;q32) in 6 cases, t(2;8)(p12;q24. 1) in 3 cases, t(8;22) (q24. 1;q11. 2) in 4 cases, t(8;20)(q24. 1;q13. 3) in one case, and an abnormal chromosome 8 with unknown material attached to the 8q24. 1 region in 4 cases. Five patients (27%) had a del(13)(q14. 1)/RB1, one of whom had a del(17)(p13)/TP53, while 3 other patients had t(11;14)(q13;q32) involving CCND1-XT/IGHrearrangements. Twelve patents (66%) received induction with a novel agent: bortezomib-based = 8 (44%) and thalidomide- based = 4 (22%). Six patients (33%) received induction with conventional chemotherapy regimens: CVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone) = 2, pulsed steroids only = 2, EPOCH (Etoposide, doxorubicin, vincristine, prednisone, cyclophosphamide) = 1 and melphalan + prednisone =1. Nine patients achieved a partial response (PR, 50%) and 4 patients achieved a very good partial remission (VGPR, 22%), with an overall response rate of 72% to induction. Thirteen patients (72%) went on to receive high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT). Four patients died of disease progression before auto-HCT while one patient opted for stem cell harvest and cryopreservation only. Median time to auto-HCT was 7. 1 months (3. 6–12. 7). Median follow up in all patients was 13 months (range 3. 4–105). Fifteen patients had progressed, with a median TTP of 7. 1 months and a median OS of 20. 2 months. Patients with PCL or PBM had significantly shorter OS (p=0. 04). Conclusion: This is the first report describing clinical characteristics of myeloma patients with c-MYC rearrangements. c-MYC rearrangement is associated with a higher incidence of plasma cell leukemia or plasmablastic myeloma, short TTP and OS. Disclosures: No relevant conflicts of interest to declare.

Achievement Of a MR5.0 Within the Randomized CML-Study IV: Feasibility, Differences Between Treatment Arms, and Prognostic Implications

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4008-4008
Author(s):  
Martin C. Müller ◽  
Michael Lauseker ◽  
Rüdiger Hehlmann ◽  
Benjamin Hanfstein ◽  
Christian Dietz ◽  
...  
Keyword(s):  
Internal Control ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Cox Model ◽  
High Dose ◽  
Molecular Response ◽  
Molecular Monitoring ◽  
Cox Models ◽  
Excellent Outcome ◽  
Real Time Quantitative Pcr

Abstract Introduction Depth of molecular remission on tyrosine kinase inhibitor (TKI) treatment is of rising importance for chronic myeloid leukemia (CML) patients (pts) with regard to possible treatment discontinuation and competing TKIs available to improve molecular response. At present, it is unknown which level of deep molecular response is necessary for optimal prognosis and for successfully stopping therapy. The aim of this work is both to evaluate the technical feasibility of molecular monitoring at the mentioned level and to search for factors allowing to predict MR5.0 in pts on imatinib (IM)-based treatment. Methods Real-time quantitative PCR on mRNA BCR-ABL transcripts in addition to total ABL transcripts as internal control has been performed on a LightCycler platform in 1,442 pts within the randomized CML-Study IV and adapted according to the International Scale (IS). In order to qualify for MR5.0 the BCR-ABLIS expression should meet one of the following criteria: a positive result ≤0.001% or a negative result with a minimum sample quality of 100,000 ABL copies (Cross et al., Leukemia 2012). Calculating cumulative incidences of remission or progression, the competing risks progression and/or death before possible progression were considered. Cox models were estimated for the multivariate analysis. Results In 1,198 of the 1,442 molecularly examined pts at least one sample fulfilled the sensitivity criteria for a MR5.0 (8,266 of 24,101 samples, 34.3%). Cumulative incidence of MR5.0 was 51% at 8 years. The median time to MR5.0 according to randomized treatment arms differed as follows: IM 800mg 79.7 months (mos), IM 400mg 95.0 mos, IM 400mg + IFNα 98.0 mos, IM 400mg + AraC 103.3 mos, IM 400mg after IFN failure 112.9 mos. A Cox model examining the different treatment arms compared to IM 400mg revealed a significantly higher chance for MR5.0 in the IM 800mg arm (HR 1.305, 95% CI 1.003-1.698, p=0.048). Baseline factors like thrombocytosis >450/nl were associated with better responses (HR 1.701 compared to <450/nl, 95% CI 1.405-2.059, p<0.001) and higher leukocyte counts >100/nl (HR 0.503 compared to <50/nl, 95% CI 0.400-0.632, p<0.001) and 50-100/nl (HR 0.746 compared to <50/nl, 95% CI 0.591-0.942, p=0.014) with unfavorable responses. Other upfront factors like age, gender, blasts, eosinophils, hemoglobin, and EUTOS score did not significantly influence the probability for MR5.0. Taken all treatment arms together, our analyses have shown that the chance of achieving a MR5.0 by 8 years was considerably reduced if the pts had a BCR-ABLIS >10% at 3 mos (40.2% vs 58.0%), >1% at 6 mos (40.3% vs 68.7%), >0.1% at 12 mos (37.7% vs 72.0%), and >0.1% at 24 mos (21.5% vs 60.5%). Conclusion This evaluation of a large randomized trial reveals feasibility of MR5.0 detection in the majority of pts underlining the benefits of standardized molecular monitoring on the IS with optimized highly sensitive technologies. Baseline low leukocyte count, high thrombocyte count and high dose IM treatment are predictors of future MR5.0. Further, early molecular landmarks qualify for excellent outcome giving hope to a rising number of pts to successfully discontinue treatment and avoid possible side effects or comorbidities. Disclosures: Müller: Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding. Hehlmann:BMS: Consultancy, Research Funding; Novartis: Research Funding. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding, Travel Other; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria. Saussele:Novartis: Honoraria, Research Funding, Travel Other; BMS: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria.

Central Nervous System Relapse in Patients with Diffuse Large B-Cell Lymphoma: Analysis of Incidence and Prognostic Factors

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1666-1666
Author(s):  
Masahiro Uni ◽  
Yuki Kagoya ◽  
Yasuhito Nannya ◽  
Fumihiko Nakamura ◽  
Mineo Kurokawa
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Initial Diagnosis ◽  
High Dose ◽  
Cns Involvement ◽  
Large B Cell Lymphoma ◽  
Cns Relapse ◽  
Large B Cell

Abstract The addition of rituximab to CHOP (R-CHOP; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisolone) has significantly improved the outcome of diffuse large B-cell lymphoma (DLBCL). However, its secondary involvement in the central nervous system (CNS) is still a fatal event, and optimal therapeutic strategies have remained to be established. Combined immunochemotherapy with rituximab, methotrexate, procarbazine, and vincristine (R-MPV) followed by consolidation reduced-dose whole-brain radiotherapy and high-dose cytarabine is currently in use for patients with CNS relapse, though treatment outcome has not been evaluated enough. In the present study, we aimed to analyze the incidence and prognosis of CNS relapse of aggressive B-cell lymphoma in comparison with those of systemic relapse in the era of rituximab-containing regimens. We also estimated the risk factors and prognostic factors for CNS relapse. We retrospectively analyzed 278 consecutive adult patients (≥16 years old) who were diagnosed as DLBCL or primary mediastinal large B-cell lymphoma (PMLBL) at The University of Tokyo Hospital, Tokyo, Japan, from August 2003 through August 2013. We excluded patients who had CNS or intraocular involvement at diagnosis since those patients had received high-dose methotrexate-based therapy instead of R-CHOP. Four to six courses of intrathecal administration of methotrexate were performed in patients with adrenal gland, testis or breast involvement as prophylaxis for CNS relapse. The median follow-up period was 42 months, and the median age was 66 years (range, 23-91). Overall, 67 patients (24.1%) had relapse at any site, of which 24 patients (35.8%) had CNS involvement. The median interval between initial diagnosis and the occurrence of secondary CNS involvement was 212 days, and 15 of the 24 patients (62.5%) had CNS relapse within 1 year from the initial diagnosis. Multivariate analysis revealed that multiple or diffuse extranodal involvement at initial diagnosis (hazard ratio [HR] 3.74, 95% confidence interval [CI] 1.28-10.91; P<0.01) was associated with the development of CNS relapse against non-CNS relapse. Chromosomal abnormality was investigated in 112 patients, of which 38 had abnormal karyotypes as identified by G-banding analysis for lymph nodes. Patients with CNS relapse more frequently harbored chromosomal abnormalities compared with those without relapse in univariate analysis (P=0.01). We also analyzed the survival of patients with primary CNS lymphoma (PCNSL) as a control. Only two (7%) of 27 patients with PCNSL died during the follow-up period. Five-year OS from initial diagnosis was 92.3% (95% CI: 82.5-100.0%), and was significantly better than that for patients with CNS relapse (33.9%, 95% CI: 17.3-66.3%, P<0.01). Among 24 patients with CNS relapse, eight (33%) had systemic lesions other than CNS when diagnosed as CNS relapse, and four (17%) patients newly developed systemic lesions while treated for CNS relapse. Patients without concurrent systemic lesions attained a rather good prognosis by chemo-radiotherapy, while those harboring concurrent systemic lesions had dismal outcome (one-year OS after the diagnosis of relapse: 74.0% versus 12.4%, P<0.01, Figure 1, systemic relapse was treated as a time-dependent covariate). These results indicate that controlling systemic lesions as well as CNS ones is essential for treating patients with secondary CNS involvement of DLBCL. CNS lesions would be well controlled with R-MPV implementation as salvage therapy, nevertheless we should be careful for concurrent systemic lesions which might require different therapeutic strategies. Disclosures Nannya: Chugai Pharmaceutical　CO., LTD: Speakers Bureau; Pfizer: Research Funding. Kurokawa:Chugai Pharmaceutical　CO., LTD: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding.

Long Term Efficacy and Safety Results and Analysis of Dose Correlations from the Phase I/II Peginvera Study of Ropeginterferon Alfa-2b, a Novel IFNa-2b, in Polycythemia Vera Patient

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4056-4056
Author(s):  
Heinz Gisslinger ◽  
Veronika Buxhofer-Ausch ◽  
Josef Thaler ◽  
Ernst Schlögl ◽  
Gunther Gastl ◽  
...  
Keyword(s):  
Research Funding ◽  
Dose Group ◽  
Low Dose ◽  
Term Treatment ◽  
High Dose ◽  
Individual Response ◽  
Molecular Response ◽  
Efficacy And Safety ◽  
Long Term Treatment

Abstract Background Ropeginterferon alfa-2b (AOP2014/P1101) is a novel long-acting pegylated IFN-alpha-2b, composed of mainly one isoform, resulting in longer half-life and exposure time. Reduced dosing frequencies, better tolerability, improved compliance and more favorable long-term treatment outcomes in patients with polycythemia vera (PV) are expected. The drug has Orphan designation by EMA and FDA and is currently in the phase III stage of development. Study design Efficacy and safety data are being collected in the follow-up extension stage of the study (collecting the data of both Phase I and Phase II portions of the study), after the maximum tolerated dose (MTD) of ropeginterferon alfa-2b, administered subcutaneously every 14 to 28 days, has been defined earlier. Patients with confirmed diagnosis of PV, age ≥18 years, both naïve and cytoreductively pre-treated were eligible. After establishing the MTD, an extended cohort of 25 additional patients has been planned to be recruited. Complete hematological response (CR) is defined by hematocrit (Hct)<45%, platelet count≤400*109/L, WBC count≤10*109/L, normal spleen size by sonography, and absence of thromboembolic events. Partial response (PR) is defined as Hct<45% without phlebotomy but with persistent splenomegaly or elevated (>400*109/L) platelet count, or reduction of phlebotomy requirements by at least 50%. Complete molecular response has been defined as reduction of any molecular abnormality to undetectable levels; partial molecular response as: reduction ≥ 50% in patients with < 50% mutant allele burden, or a reduction ≥ 25% in patients with > 50% mutant allele burden. The present analysis was focused on long-term tolerability and safety in correlation with the dose of ropeginterferon alfa-2b in PV. Results Data on treatment as by July, 24, 2015, are covered by the current analysis. Baseline characteristics of the study cohort during short-term treatment were already presented earlier (Gisslinger et al, ASH 2013). The full analysis set and efficacy set were composed of 51 and 47 patients, respectively. Currently, the median reported treatment duration is 138 weeks, 33 patients completed their follow up for two years, 19 for three years. Starting with the week 10, Hct-level, platelet- and WBC-counts could be constantly maintained within normal range in the majority of patients. In a group of patients with the mean administered dose of <300 µg ("low dose", n=36), CR as best individual response was achieved in 20 (56%) patients, and PR in 14 (39%) compared to the CR and PR in the high dose (>300 µg, n=11) group of 8 (73%) and 3 (27%) respectively. However, no statistical significance can be observed if correlation between the dose and response status was analyzed. 30 patients are still being treated in the study. Similarly, no association between the dose and occurrence of adverse events in the study could be observed. Complete molecular response as best individual response was observed more frequently in the high dose group 4 (36%) compared to 8 (23%) in the low dose group, while partial molecular responses were equally frequent in both dose groups (in 6/55% and 20/57%, respectively). 21 patients discontinued the study, 18 being treated with AOP2014 doses corresponding to low, and 3 to the high dose arms, corresponding to the drop-out rate of 50% and 27% in the respective arms. Interestingly, all discontinuations in the high dose group occurred within the first year of treatment (at weeks 16, 18 and 32), while the drop-outs in the low dose group (6 patients, 33%) discontinued the study after completion of their first year of treatment. Conclusions Efficacy and safety profile remain in line with expectations from other (pegylated) interferons. Overall response rate of >80% with cumulative CRs in 45-50%, accompanied by phlebotomy independence, normalization of hematological parameters and spleen size reduction in majority of patients have been observed. Significant and sustained JAK2 allelic burden decrease, starting from week 28 of treatment, was seen. No significant difference between the two mean dose levels regarding response rates or adverse events even during long-term treatment and observation could be observed. These finding are to be further verified in a larger prospective setting. Disclosures Gisslinger: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; AOP ORPHAN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Geron: Consultancy; Sanofi Aventis: Consultancy; Janssen Cilag: Honoraria, Speakers Bureau. Buxhofer-Ausch:AOP Orphan: Research Funding. Thaler:AOP Orphan: Research Funding. Schlögl:AOP Orphan: Research Funding. Gastl:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP Orphan: Research Funding. Ban:AOP Orphan: Research Funding. Egle:AOP Orphan: Research Funding. Melchardt:AOP Orphan: Research Funding. Burgstaller:AOP Orphan Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria; Mundipharma: Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Willenbacher:COMET Center ONCOTYROL: Research Funding; AOP Orphan: Research Funding. Kralovics:AOP Orphan: Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees. Zörer:AOP Orphan: Employment. Ammann-Mwathi:AOP Orphan: Employment. Kadlecova:AOP Orphan: Consultancy. Zagrijtschuk:AOP Orphan: Employment. Klade:AOP Orphan: Employment. Greil:Pfizer: Honoraria, Research Funding; GSK: Research Funding; Boehringer-Ingelheim: Honoraria; AOP Orphan: Research Funding; Celgene: Consultancy; Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Novartis: Honoraria; Astra-Zeneca: Honoraria; Amgen: Honoraria, Research Funding; Ratiopharm: Research Funding; Sanofi Aventis: Honoraria; Merck: Honoraria; Mundipharma: Honoraria, Research Funding; Eisai: Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria; Roche, Celgene: Honoraria, Research Funding.

Prediction for Sustained Deep Molecular Response of BCR-ABL Levels in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1224-1224
Author(s):  
Koji Sasaki ◽  
Hagop M. Kantarjian ◽  
Susan O'Brien ◽  
Farhad Ravandi ◽  
Marina Konopleva ◽  
...  
Keyword(s):  
Research Funding ◽  
Chronic Phase ◽  
High Dose ◽  
Molecular Response ◽  
Regression Equations ◽  
Transcript Levels ◽  
Deep Molecular Response ◽  
Best Fit ◽  
Time Point

Abstract Introduction Initial treatment with tyrosine kinase inhibitors (TKI) induces excellent response in the majority of patients with CML-CP. Current guidelines recommend periodic monitoring of BCR-ABL1 levels to monitor response. During the course of treatment, recognizing early predictors of deeper response and longer-term outcomes can help guide treatment. This is relevant not only at the specified fixed time point typically reported (i.e., 3, 6, 12 months) but at any other time point when an assessment is made. Achievement of sustained deep molecular response is a goal of increasing relevance as it opens the possibility of treatment discontinuation. The objective of this study is suggest optimal BCR-ABL transcript levels at any given time, and to suggest a prediction model for sustained molecular response 4.5 (MR4.5) (BCR-ABL ≤0.0032%) for at least 2 years according to BCR-ABL levels achieved within the first 12 months of TKI therapy. Methods Response data for 630 patients with newly diagnosed CML-CP in consecutive prospective clinical trials of frontline imatinib (n=73; NCT00048672), high-dose imatinib (n=208; NCT00038469 and NCT00050531), nilotinib (n=148; NCT00129740), dasatinib (n=150; NCT00254423), and ponatinib (n=51; NCT01570868) were analyzed. Real-time PCR analysis was performed at approximately 3 month intervals during the first year and 6 month intervals thereafter. The "best fit average" molecular response was defined by robust linear regression models, with which the estimated molecular level in patients with complete cytogenetic response (CCyR) within 1 year, major molecular response (MMR) within 1 year, and sustained MR4.5 at any point were defined. The acceptable molecular response was defined by quantile regression for the 95th percentile, with which the worst 5% BCR-ABL levels in patients with CCyR within 1 year, MMR within 1 year, and sustained MR4.5 at any point were identified. Results In 630 patients, 2512 data points of BCR-ABL levels within 1 year of TKI were identified. The median follow-up for the entire cohort was 106 months (range, 0.3-177.8). The regression equations for best fit average PCR for CCyR within 1 year was Log10(PCR) = -0.2159 x (Months) + 0.1957; for MMR within 1 year, Log10(PCR) = -0.2304 x (Months) + 0.1046; for sustained MR4.5 at any point, Log10(PCR) = -0.2154 x Months -0.1161. The regression equations for acceptable PCR for CCyR within 1 year was Log10(PCR) = -0.15796 x (Months) + 1.54839; for MMR within 1 year, Log10(PCR) = -0.20999 x (Months) + 1.54839; for sustained MR4.5, Log10(PCR) = -0.22476 x (Months) + 1.50516 (Figure 1). The best fit average PCR (i.e., estimated levels achieved by the average responder in each category) for CCyR within 1 year was 0.353%, 0.079%, 0.017%, and 0.004% at 3, 6, 9, and 12 months, respectively; for MMR within 1 year was 0.259%, 0.053%, 0.011%, and 0.002% at 3, 6, 9, and 12 months, respectively; for sustained MR4.5 at any point was 0.295%, 0.067%, 0.015%, and 0.003% at 3, 6, 9, and 12 months, respectively (Table 1). To achieve CCyR within 1 year, the acceptable PCR (i.e., levels achieved by 95% of all those who eventually reach the said endpoint) response was 11.872%, 3.987%, 1.339%, and 0.450% at 3, 6, 9, and 12 months, respectively; to achieve MMR within 1 year, 8.287%, 1.943%, 0.455%, and 0.107% at 3, 6, 9, and 12 months, respectively; to achieve sustained MR4.5 at any time, 6.774%, 1.434%, 0.304%, and 0.064% at 3, 6, 9, and 12 months, respectively. Of 289 patients who eventually achieved sustained MR4.5, 288 (99%) achieved CCyR within 1 year; 268 (93%), MMR within 1 year; 201 (70%), MR4 within 1 year; 162 (56%), MR4.5 within 1 year; 72 (25%), CMR within 1 year. Of 359 patients who achieved MMR within 1 year with a minimum follow-up of 48 months, 256 (71%) achieved sustained MR4.5; of 180 patients who achieved MR4.5 within 1 year, 151 (84%); of 72 patients who achieved CMR within 1 year, 65 (90%). Conclusion Proper interpretation of early transcript levels at any time during the course of therapy may help predict later response and outcome. Such models can be built to guide therapy for patients in a continuous basis. To achieve sustained MR4.5 for at least 2 years, deeper responses are required at each time point. Our model proposes optimal values that predict the highest probability of reaching such goal. At a minimum, CCyR within 1 year is required to achieve sustained MR4.5. Disclosures Kantarjian: Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Ravandi:Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Konopleva:AbbVie: Research Funding; Genentech: Research Funding. Wierda:Novartis: Research Funding; Abbvie: Research Funding; Acerta: Research Funding; Gilead: Research Funding; Genentech: Research Funding. Daver:Ariad: Research Funding; Karyopharm: Honoraria, Research Funding; Sunesis: Consultancy, Research Funding; BMS: Research Funding; Kiromic: Research Funding; Otsuka: Consultancy, Honoraria; Pfizer: Consultancy, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.

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