Purpose: Treatment outcomes in patients with relapsed/refractory (R/R) myelodysplastic syndrome (... more Purpose: Treatment outcomes in patients with relapsed/refractory (R/R) myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) remains dismal. On the basis of both extensive preclinical data and emerging clinical data, treatment with bromodomain and extra-terminal domain inhibitors (BETi) is a potential approach for patients with high-risk myeloid malignancies. Patients and Methods: We conducted a phase I trial to study the safety and efficacy of PLX51107 (BETi) and azacitidine combination therapy in patients with R/R AML and high-risk (HR) MDS and studied mechanisms of resistance to the combination therapy. Results: Thirty-seven patients with HR R/R MDS (n = 4) and R/R AML (n = 33) were treated. Sixteen patients (43%) had MECOM gene rearrangement and 7 other patients had TP53 mutation. Median prior number of therapies was three (range 1–9); 97% had received prior hypomethylating agent and 84% prior venetoclax. Overall response rate was 8/37 (22%): complete remission with incomplete platelet recovery (n = 1); morphologic leukemia-free state (n = 2); hematologic improvement (n = 5). The most common nonhematologic toxicities were febrile neutropenia and pneumonia in 12 (32%) patients each; 6 patients (17%) had severe hyperbilirubinemia. RNA-sequencing analysis of mononuclear cells harvested on treatment (day 3) versus pretreatment showed significant changes in mRNA expressions in responders: downregulation of MYC, BCL2, IL7R, and CDK6 and upregulation of HEXIM1, CD93, DCXR, and CDKN1A. Immunoblot analyses confirmed reduction in protein levels of c-Myc, CDK6, BCL2, and BCL-xL, and induction of BRD4 and HEXIM1 protein levels in responders. Conclusions: In a heavily pretreated patient cohort with R/R MDS and AML, PLX51107+ azacitidine was well-tolerated and resulted in modest clinical benefit.
Background: Hypomethylating agents (HMAs) are the standard of care for patients with higher-risk ... more Background: Hypomethylating agents (HMAs) are the standard of care for patients with higher-risk myelodysplastic syndrome (MDS), but their role in those with lower-risk MDS has not been well-established. A randomized phase 2 study evaluating low-dose decitabine and low-dose azacitidine in patients with lower-risk MDS showed that treatment with attenuated dose schedules of HMA therapy are both well-tolerated and effective in patients with lower-risk MDS (Jabbour E, Blood 2017). However, their use as early intervention in transfusion-independent patients with lower-risk MDS remains unknown. Consequently, we performed a retrospective analysis of a cohort of transfusion-independent lower-risk MDS patients to evaluate the safety and clinical activity of low-dose HMAs in this patient population. Methods: Fifty-four adult patients with low-risk or intermediate-1-risk disease by the International Prognostic Scoring System (IPSS) and transfusion-independence at baseline treated on clinical trial NCT01720225 from November 2012 to February 2016 were included in the analysis. Patients were treated with either decitabine 20 mg/m2 intravenously (IV) daily for 3 days or azacitidine 75 mg/m2 IV daily for 3 days every 28 days. Dose reductions for grade 3 or 4 toxicities were allowed on the clinical trial, and responding patients were allowed to continue therapy indefinitely. Results: Patient characteristics included a median age of 70 with 38 males (70%) and median bone marrow (BM) blast percentage of 3%. Twelve patients (22%) had low-risk disease and 42 patients (78%) had intermediate-1-risk disease by IPSS, and risk groups by revised IPSS (IPSS-R) included very low-risk in 8 patients (15%), low-risk in 22 patients (41%), intermediate-risk in 12 patients (24%), and high-risk in 11 patients (20%). The most commonly observed mutations were TET2 (26%), RUNX1 (9%), ASXL1 (7%), and TP53 (7%). Thirty-three patients (61%) were treated with decitabine while 21 patients (39%) were treated with azacitidine. Grade 3 or 4 adverse events included pneumonia (4%), syncope (4%), myalgias/joint pains (2%), dizziness (2%), and neutropenia (2%). Otherwise, the most common toxicities were grade 1-2 fatigue (17%), nausea (13%), and constipation (11%). No early mortality was observed during the first 60 days. Of the 54 patients included in the analysis, 50 patients (93%) were evaluable for response based on BM blast percentage and cytopenias. Of the 17 patients with BM blasts > 5%, 11 patients achieved complete remission (CR), 4 patients reached marrow CR, and 2 patients had no response. Of the 33 patients with BM blasts ≤ 5% and at least 1 cytopenia, 13 patients demonstrated hematological improvement, 10 patients exhibited stable disease, 8 patients did not respond, and 2 patients progressed. At a median follow-up of 37 months, the median overall survival was not reached, and the median event-free survival was 24.9 months. Four patients (7%) eventually became transfusion-dependent, and 5 patients (9%) ultimately transformed to acute myeloid leukemia (AML). Conclusions: Overall, attenuated doses of decitabine and azacitidine were safe and tolerated in patients with transfusion-independent lower-risk MDS. Higher rates and longer durations of response with improved survival and lower rates of AML transformation were observed. Though patients with lower-risk MDS who are transfusion-independent have traditionally undergone surveillance, early intervention with low-dose HMAs may be beneficial in these patients. Prospective studies, such as with clinical trial NCT02269280, are warranted. Disclosures Jabbour: Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Ravandi:Menarini Ricerche: Research Funding; Macrogenix: Consultancy, Research Funding; Xencor: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding. Kadia:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Borthakur:FTC Therapeutics: Membership on an entity's…
7001Background: HMAs are the standard of care for most pts with higher risk MDS. However, the rol... more 7001Background: HMAs are the standard of care for most pts with higher risk MDS. However, the role of the therapy is not well defined in lower risk MDS. Data from our center has indicated that atte...
Introduction: Although pts with lower risk MDS have longer OS and transformation free survival th... more Introduction: Although pts with lower risk MDS have longer OS and transformation free survival than pts with higher risk disease, a subset of pts with lower risk MDS have higher risk cytogenetics. There is scarce data on the impact of cytogenetic abnormalities on response to HMAs in this patient population, the ability of these agents to induce cytogenetic responses along with the prognostic relevance of clonal evolution in this subset of pts. Methods: Pts with lower risk MDS treated with HMAs between 2012 and 2015 were evaluated. Information regarding baseline cytopenias, prior malignancy or chemotherapy, initial and on therapy bone marrow cytogenetic findings and response to therapy by IWG criteria were collected. Pts were stratified according to IPSS/IPSS-R cytogenetic groups and MDACC Lower risk model. Data regarding time to cytogenetic response, clonal evolution and clinical evolution was also reviewed. Statistical analysis included Chi-squared for categorical variables, T-student for continuous variables and Kaplan-Meier for OS and EFS. Results: A total of 83 pts were evaluated. Pt characteristics are in Table 1. Overall response rate was 61% with 39% CR, 10% CRn, 2% CRp, 1% CRi and 10% pts showing hematological improvement only. No significant difference in response rates (68% vs 61%, p=0.51) to HMAs was observed between pts with or without cytogenetic abnormalities. In pts with abnormal karyotype, 10 (26%) had complete cytogenetic response (CCyR) and 12 (31%) had partial cytogenetic response (PCyR) after a median of 7 months of therapy (range 2-18). Clonal evolution during therapy was observed in 12 (14%) pts after a median time of 8 months, and was associated with loss of response in 6 (50%) pts. There was no correlation between the achievement of a CR and cytogenetic response (p=0.36).The median follow-up was 13 months (2-30 months). Stratification of pts by IPSS or IPSS-R cytogenetic scores did not significantly predict differences for EFS (p=0.31 and p=0.47) nor OS (p=0,52 and p=0.18). By applying the MDACC low-risk scoring system, the 13-month survival rate was 100%, 83%, and 73%, for pts with categories 1, 2, and 3 respectively (p=0.35). No differences in EFS were observed between these groups. The 1-year EFS and OS rates were 79% vs 24%…
Background: The prognosis of patients with lower-risk MDS is heterogeneous; many have poor surviv... more Background: The prognosis of patients with lower-risk MDS is heterogeneous; many have poor survival (Leukemia. 2008;22:538-543). Hypomethylating agents (HMA) improve the outcomes of patients with higher-risk MDS. Recent Phase I/II studies suggested that HMA doses below current standards of care retain activity in MDS, potentially with a better toxicity profile (JCO. 2009;27:1850-1856). We hypothesized that lower doses of HMA may be active and well tolerated in patients with lower-risk MDS. Aim: This is a phase II randomized trial to evaluate the efficacy and tolerability of low-dose regimens of either DAC or AZA in patients with low- or intermediate-1-risk MDS. Materials and Methods: Eligible patients were adults older than 18 years with de novo or secondary IPSS low- or intermediate-1-risk MDS, including CMML, with normal organ function. Patients were randomized on a Bayesian design to receive DAC 20 mg/m2 IV or AZA 75 mg/m2 IV/SC per day for 3 consecutive days every 28 days. The primary efficacy end point is overall improvement rate (OIR: complete remission [CR], partial remission [PR], marrow CR [mCR], or hematologic improvement [HI]). Secondary end points are HI, transfusion independence, cytogenetic response, overall survival (OS), and time to acute myeloid leukemia or death. Chi-square test and independent t-test were performed to evaluate differences of patients’ characteristics. OS was estimated with the Kaplan-Meier method. A log-rank test was used for statistical analysis, and p<0.05 was considered statistically significant. Results: Between 11/2012 and 4/2014, 68 patients were enrolled. Eleven patients have not been on-study long enough for response assessment. Fifty-seven patients are currently evaluable in this study; 28 patients received DAC, and 29 patients received AZA. Median duration of follow-up is 9 months (range, 0-18+). Median age at enrollment was 71 years (33-85). Median time from diagnosis to therapy was 1.5 months (range, 0.2-63.4). Baseline patient demographic and clinical characteristics did not differ significantly between groups. Of the 28 patients in the DAC arm, 13 (46%) had diploidy, and 2 (7%) had complex karyotypes; 3 (11%) were low-risk and 25 (89%) were intermediate-1-risk by IPSS. Of the 29 patients in the AZA arm, 17 (59%) had diploidy, and 1 (3%) had complex karyotype; 5 (17%) were low-risk and 24 (83%) were intermediate-1-risk by IPSS (2006). Six (21%) patients in the DAC arm and 7 (24%) in the AZA arm received growth factor support prior to therapy. Overall, 19 (33%) patients achieved CR, 2 (4%) CRp, 6 (11%) mCR, and 5 (9%) HI. In the DAC arm, 15 (54%) achieved OIR, 10 (36%) CR, 1 (4%) CRp, 3 (11%) mCR, and 1 (4%) HI. In the AZA arm, 16 (56%) achieved OIR, 9 (31%) CR, 1 (3%) CRp, 3 (10%) mCR, and 3 (10%) HI. Median response duration is 13 months (range, 0-16+). In the DAC group, 1 (8%) out of 12 initially RBC-dependent patients became RBC independent, 3 of 5 RBC/platelet-dependent patients became RBC/platelet-independent, and 1 (7%) of 14 transfusion-independent patients became RBC-dependent. In the AZA group, 3 (27%) of 11 initially RBC-dependent patients became RBC-independent, and 1 (7%) of 14 transfusion-independent patients became dependent. The median number of courses is 7 (range, 2-17+). Treatment has been well tolerated, and only 3 (5%) patients had dose reduction due to grade 3-4 myelosuppression. No death is observed during therapy but 9 deaths in total (16%) were observed after HMA failure; 3 (10%) in AZA and 1 (3%) in DAC in patients who failed to respond and discontinued therapy before death; 2 (7%) in AZA and 3 (11%) in DAC in patients who progressed to higher grade of MDS and changed therapy before death. The 1-year survival rates for the DAC and AZA were 80% and 67%, respectively (p=0.478). Median OS has not been reached, and no difference was noted between groups. Analyzing survival by the MDA lower-risk scoring system (Leukemia. 2008;22:538-543), the median survival was not reached for patients with low-risk disease, not reached for patients with intermediate-risk disease, and 272…
Purpose: Treatment outcomes in patients with relapsed/refractory (R/R) myelodysplastic syndrome (... more Purpose: Treatment outcomes in patients with relapsed/refractory (R/R) myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) remains dismal. On the basis of both extensive preclinical data and emerging clinical data, treatment with bromodomain and extra-terminal domain inhibitors (BETi) is a potential approach for patients with high-risk myeloid malignancies. Patients and Methods: We conducted a phase I trial to study the safety and efficacy of PLX51107 (BETi) and azacitidine combination therapy in patients with R/R AML and high-risk (HR) MDS and studied mechanisms of resistance to the combination therapy. Results: Thirty-seven patients with HR R/R MDS (n = 4) and R/R AML (n = 33) were treated. Sixteen patients (43%) had MECOM gene rearrangement and 7 other patients had TP53 mutation. Median prior number of therapies was three (range 1–9); 97% had received prior hypomethylating agent and 84% prior venetoclax. Overall response rate was 8/37 (22%): complete remission with in...
Background: Bromodomain and extra-terminal domain (BET) family proteins represent a novel target ... more Background: Bromodomain and extra-terminal domain (BET) family proteins represent a novel target class for patients (pts) with myeloid malignancies. Pharmacologic inhibition of BET proteins transcriptionally downregulates critical pro-survival and anti-apoptotic genes. We hypothesized that combination of BET inhibitor (BETi) with hypomethylating agent (HMA) azacitidine (AZA) could lead to clinical benefit for high-risk (HR) pts with R/R MDS and AML. Methods: We conducted an investigator-initiated, single-center, phase I, 3+3 dose-escalation and cohort expansion study of PLX51107 (BETi) + AZA in pts with R/R HR MDS (intermediate-2 score or >10% blasts) or R/R AML. PLX51107 was administered PO on days 1-21 and AZA 75 mg/m2 IV on days 8-14 of a 28-day cycle. Dose-escalation phase of PLX51107 doses included: 40mg (n=4), 80mg (n=3), and 120mg; ultimately, no formal MTD was reached, therefore the 120mg dose was administered to the remaining 30 pts treated on study. Results: 37 pts were...
We conducted a phase Ib/II multi-arm, parallel cohort study to simultaneously evaluate various im... more We conducted a phase Ib/II multi-arm, parallel cohort study to simultaneously evaluate various immunotherapeutic agents and combinations in relapsed/refractory acute myeloid leukemia (AML). Overall, 50 patients were enrolled into one of 6 arms: (A) single agent PF-04518600 (OX40 agonist monoclonal antibody), (B) azacitidine + venetoclax + gemtuzumab ozogamicin (GO), (C) azacitidine + avelumab (anti-PD-L1 monoclonal antibody) + GO, (D) azacitidine + venetoclax + avelumab, (E) azacitidine + avelumab + PF-04518600, and (F) glasdegib + GO. Among all regimens evaluated, azacitidine + venetoclax + GO appeared most promising. In this arm, the CR/CRi rates among venetoclax-naïve and prior venetoclax-exposed patients were 50% and 22%, respectively, and the 1-year OS rate was 31%. This study shows the feasibility of a conducting a multi-arm trial to efficiently and simultaneously evaluate novel therapies in AML, a needed strategy in light of the plethora of emerging therapies. This trial was registered at www.clinicaltrials.gov as NCT03390296.
Background: Several novel agents, including venetoclax (VEN), gemtuzumab ozogamicin (GO), and gla... more Background: Several novel agents, including venetoclax (VEN), gemtuzumab ozogamicin (GO), and glasdegib have shown promise in newly diagnosed AML. However, their role in relapsed/refractory (R/R) AML and their optimal combination with other agents has not been established. We therefore designed a multi-arm, parallel cohort, phase Ib/II study to evaluate various novel combinations of these agents in pts with R/R AML. Methods: Adults ≥18 years of age with R/R AML or with AML from antecedent hematologic malignancy previously treated with hypomethylating agents (HMAs) who had performance status of ≤2 and adequate organ function were eligible. Pts were assigned at the treating physician's discretion to one of 5 concomitantly enrolling arms: A.) azacitidine (AZA) + VEN + GO, B.) AZA + VEN + avelumab (anti-PDL1 mAb), C.) AZA + avelumab + GO, D.) OX40 agonist mAb (PF-04518600), or E.) glasdegib + GO. Treatment regimens are shown in Table 1. In arms containing VEN, a bone marrow (BM) ass...
7001Background: HMAs are the standard of care for most pts with higher risk MDS. However, the rol... more 7001Background: HMAs are the standard of care for most pts with higher risk MDS. However, the role of the therapy is not well defined in lower risk MDS. Data from our center has indicated that atte...
Background: Hypomethylating agents (HMAs) are the standard of care for patients with higher-risk ... more Background: Hypomethylating agents (HMAs) are the standard of care for patients with higher-risk myelodysplastic syndrome (MDS), but their role in those with lower-risk MDS has not been well-established. A randomized phase 2 study evaluating low-dose decitabine and low-dose azacitidine in patients with lower-risk MDS showed that treatment with attenuated dose schedules of HMA therapy are both well-tolerated and effective in patients with lower-risk MDS (Jabbour E, Blood 2017). However, their use as early intervention in transfusion-independent patients with lower-risk MDS remains unknown. Consequently, we performed a retrospective analysis of a cohort of transfusion-independent lower-risk MDS patients to evaluate the safety and clinical activity of low-dose HMAs in this patient population. Methods: Fifty-four adult patients with low-risk or intermediate-1-risk disease by the International Prognostic Scoring System (IPSS) and transfusion-independence at baseline treated on clinical t...
Introduction: Although pts with lower risk MDS have longer OS and transformation free survival th... more Introduction: Although pts with lower risk MDS have longer OS and transformation free survival than pts with higher risk disease, a subset of pts with lower risk MDS have higher risk cytogenetics. There is scarce data on the impact of cytogenetic abnormalities on response to HMAs in this patient population, the ability of these agents to induce cytogenetic responses along with the prognostic relevance of clonal evolution in this subset of pts. Methods: Pts with lower risk MDS treated with HMAs between 2012 and 2015 were evaluated. Information regarding baseline cytopenias, prior malignancy or chemotherapy, initial and on therapy bone marrow cytogenetic findings and response to therapy by IWG criteria were collected. Pts were stratified according to IPSS/IPSS-R cytogenetic groups and MDACC Lower risk model. Data regarding time to cytogenetic response, clonal evolution and clinical evolution was also reviewed. Statistical analysis included Chi-squared for categorical variables, T-stud...
Background: The prognosis of patients with lower-risk MDS is heterogeneous; many have poor surviv... more Background: The prognosis of patients with lower-risk MDS is heterogeneous; many have poor survival (Leukemia. 2008;22:538-543). Hypomethylating agents (HMA) improve the outcomes of patients with higher-risk MDS. Recent Phase I/II studies suggested that HMA doses below current standards of care retain activity in MDS, potentially with a better toxicity profile (JCO. 2009;27:1850-1856). We hypothesized that lower doses of HMA may be active and well tolerated in patients with lower-risk MDS. Aim: This is a phase II randomized trial to evaluate the efficacy and tolerability of low-dose regimens of either DAC or AZA in patients with low- or intermediate-1-risk MDS. Materials and Methods: Eligible patients were adults older than 18 years with de novo or secondary IPSS low- or intermediate-1-risk MDS, including CMML, with normal organ function. Patients were randomized on a Bayesian design to receive DAC 20 mg/m2 IV or AZA 75 mg/m2 IV/SC per day for 3 consecutive days every 28 days. The p...
Purpose: Treatment outcomes in patients with relapsed/refractory (R/R) myelodysplastic syndrome (... more Purpose: Treatment outcomes in patients with relapsed/refractory (R/R) myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) remains dismal. On the basis of both extensive preclinical data and emerging clinical data, treatment with bromodomain and extra-terminal domain inhibitors (BETi) is a potential approach for patients with high-risk myeloid malignancies. Patients and Methods: We conducted a phase I trial to study the safety and efficacy of PLX51107 (BETi) and azacitidine combination therapy in patients with R/R AML and high-risk (HR) MDS and studied mechanisms of resistance to the combination therapy. Results: Thirty-seven patients with HR R/R MDS (n = 4) and R/R AML (n = 33) were treated. Sixteen patients (43%) had MECOM gene rearrangement and 7 other patients had TP53 mutation. Median prior number of therapies was three (range 1–9); 97% had received prior hypomethylating agent and 84% prior venetoclax. Overall response rate was 8/37 (22%): complete remission with incomplete platelet recovery (n = 1); morphologic leukemia-free state (n = 2); hematologic improvement (n = 5). The most common nonhematologic toxicities were febrile neutropenia and pneumonia in 12 (32%) patients each; 6 patients (17%) had severe hyperbilirubinemia. RNA-sequencing analysis of mononuclear cells harvested on treatment (day 3) versus pretreatment showed significant changes in mRNA expressions in responders: downregulation of MYC, BCL2, IL7R, and CDK6 and upregulation of HEXIM1, CD93, DCXR, and CDKN1A. Immunoblot analyses confirmed reduction in protein levels of c-Myc, CDK6, BCL2, and BCL-xL, and induction of BRD4 and HEXIM1 protein levels in responders. Conclusions: In a heavily pretreated patient cohort with R/R MDS and AML, PLX51107+ azacitidine was well-tolerated and resulted in modest clinical benefit.
Background: Hypomethylating agents (HMAs) are the standard of care for patients with higher-risk ... more Background: Hypomethylating agents (HMAs) are the standard of care for patients with higher-risk myelodysplastic syndrome (MDS), but their role in those with lower-risk MDS has not been well-established. A randomized phase 2 study evaluating low-dose decitabine and low-dose azacitidine in patients with lower-risk MDS showed that treatment with attenuated dose schedules of HMA therapy are both well-tolerated and effective in patients with lower-risk MDS (Jabbour E, Blood 2017). However, their use as early intervention in transfusion-independent patients with lower-risk MDS remains unknown. Consequently, we performed a retrospective analysis of a cohort of transfusion-independent lower-risk MDS patients to evaluate the safety and clinical activity of low-dose HMAs in this patient population. Methods: Fifty-four adult patients with low-risk or intermediate-1-risk disease by the International Prognostic Scoring System (IPSS) and transfusion-independence at baseline treated on clinical trial NCT01720225 from November 2012 to February 2016 were included in the analysis. Patients were treated with either decitabine 20 mg/m2 intravenously (IV) daily for 3 days or azacitidine 75 mg/m2 IV daily for 3 days every 28 days. Dose reductions for grade 3 or 4 toxicities were allowed on the clinical trial, and responding patients were allowed to continue therapy indefinitely. Results: Patient characteristics included a median age of 70 with 38 males (70%) and median bone marrow (BM) blast percentage of 3%. Twelve patients (22%) had low-risk disease and 42 patients (78%) had intermediate-1-risk disease by IPSS, and risk groups by revised IPSS (IPSS-R) included very low-risk in 8 patients (15%), low-risk in 22 patients (41%), intermediate-risk in 12 patients (24%), and high-risk in 11 patients (20%). The most commonly observed mutations were TET2 (26%), RUNX1 (9%), ASXL1 (7%), and TP53 (7%). Thirty-three patients (61%) were treated with decitabine while 21 patients (39%) were treated with azacitidine. Grade 3 or 4 adverse events included pneumonia (4%), syncope (4%), myalgias/joint pains (2%), dizziness (2%), and neutropenia (2%). Otherwise, the most common toxicities were grade 1-2 fatigue (17%), nausea (13%), and constipation (11%). No early mortality was observed during the first 60 days. Of the 54 patients included in the analysis, 50 patients (93%) were evaluable for response based on BM blast percentage and cytopenias. Of the 17 patients with BM blasts > 5%, 11 patients achieved complete remission (CR), 4 patients reached marrow CR, and 2 patients had no response. Of the 33 patients with BM blasts ≤ 5% and at least 1 cytopenia, 13 patients demonstrated hematological improvement, 10 patients exhibited stable disease, 8 patients did not respond, and 2 patients progressed. At a median follow-up of 37 months, the median overall survival was not reached, and the median event-free survival was 24.9 months. Four patients (7%) eventually became transfusion-dependent, and 5 patients (9%) ultimately transformed to acute myeloid leukemia (AML). Conclusions: Overall, attenuated doses of decitabine and azacitidine were safe and tolerated in patients with transfusion-independent lower-risk MDS. Higher rates and longer durations of response with improved survival and lower rates of AML transformation were observed. Though patients with lower-risk MDS who are transfusion-independent have traditionally undergone surveillance, early intervention with low-dose HMAs may be beneficial in these patients. Prospective studies, such as with clinical trial NCT02269280, are warranted. Disclosures Jabbour: Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Ravandi:Menarini Ricerche: Research Funding; Macrogenix: Consultancy, Research Funding; Xencor: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding. Kadia:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Borthakur:FTC Therapeutics: Membership on an entity's…
7001Background: HMAs are the standard of care for most pts with higher risk MDS. However, the rol... more 7001Background: HMAs are the standard of care for most pts with higher risk MDS. However, the role of the therapy is not well defined in lower risk MDS. Data from our center has indicated that atte...
Introduction: Although pts with lower risk MDS have longer OS and transformation free survival th... more Introduction: Although pts with lower risk MDS have longer OS and transformation free survival than pts with higher risk disease, a subset of pts with lower risk MDS have higher risk cytogenetics. There is scarce data on the impact of cytogenetic abnormalities on response to HMAs in this patient population, the ability of these agents to induce cytogenetic responses along with the prognostic relevance of clonal evolution in this subset of pts. Methods: Pts with lower risk MDS treated with HMAs between 2012 and 2015 were evaluated. Information regarding baseline cytopenias, prior malignancy or chemotherapy, initial and on therapy bone marrow cytogenetic findings and response to therapy by IWG criteria were collected. Pts were stratified according to IPSS/IPSS-R cytogenetic groups and MDACC Lower risk model. Data regarding time to cytogenetic response, clonal evolution and clinical evolution was also reviewed. Statistical analysis included Chi-squared for categorical variables, T-student for continuous variables and Kaplan-Meier for OS and EFS. Results: A total of 83 pts were evaluated. Pt characteristics are in Table 1. Overall response rate was 61% with 39% CR, 10% CRn, 2% CRp, 1% CRi and 10% pts showing hematological improvement only. No significant difference in response rates (68% vs 61%, p=0.51) to HMAs was observed between pts with or without cytogenetic abnormalities. In pts with abnormal karyotype, 10 (26%) had complete cytogenetic response (CCyR) and 12 (31%) had partial cytogenetic response (PCyR) after a median of 7 months of therapy (range 2-18). Clonal evolution during therapy was observed in 12 (14%) pts after a median time of 8 months, and was associated with loss of response in 6 (50%) pts. There was no correlation between the achievement of a CR and cytogenetic response (p=0.36).The median follow-up was 13 months (2-30 months). Stratification of pts by IPSS or IPSS-R cytogenetic scores did not significantly predict differences for EFS (p=0.31 and p=0.47) nor OS (p=0,52 and p=0.18). By applying the MDACC low-risk scoring system, the 13-month survival rate was 100%, 83%, and 73%, for pts with categories 1, 2, and 3 respectively (p=0.35). No differences in EFS were observed between these groups. The 1-year EFS and OS rates were 79% vs 24%…
Background: The prognosis of patients with lower-risk MDS is heterogeneous; many have poor surviv... more Background: The prognosis of patients with lower-risk MDS is heterogeneous; many have poor survival (Leukemia. 2008;22:538-543). Hypomethylating agents (HMA) improve the outcomes of patients with higher-risk MDS. Recent Phase I/II studies suggested that HMA doses below current standards of care retain activity in MDS, potentially with a better toxicity profile (JCO. 2009;27:1850-1856). We hypothesized that lower doses of HMA may be active and well tolerated in patients with lower-risk MDS. Aim: This is a phase II randomized trial to evaluate the efficacy and tolerability of low-dose regimens of either DAC or AZA in patients with low- or intermediate-1-risk MDS. Materials and Methods: Eligible patients were adults older than 18 years with de novo or secondary IPSS low- or intermediate-1-risk MDS, including CMML, with normal organ function. Patients were randomized on a Bayesian design to receive DAC 20 mg/m2 IV or AZA 75 mg/m2 IV/SC per day for 3 consecutive days every 28 days. The primary efficacy end point is overall improvement rate (OIR: complete remission [CR], partial remission [PR], marrow CR [mCR], or hematologic improvement [HI]). Secondary end points are HI, transfusion independence, cytogenetic response, overall survival (OS), and time to acute myeloid leukemia or death. Chi-square test and independent t-test were performed to evaluate differences of patients’ characteristics. OS was estimated with the Kaplan-Meier method. A log-rank test was used for statistical analysis, and p<0.05 was considered statistically significant. Results: Between 11/2012 and 4/2014, 68 patients were enrolled. Eleven patients have not been on-study long enough for response assessment. Fifty-seven patients are currently evaluable in this study; 28 patients received DAC, and 29 patients received AZA. Median duration of follow-up is 9 months (range, 0-18+). Median age at enrollment was 71 years (33-85). Median time from diagnosis to therapy was 1.5 months (range, 0.2-63.4). Baseline patient demographic and clinical characteristics did not differ significantly between groups. Of the 28 patients in the DAC arm, 13 (46%) had diploidy, and 2 (7%) had complex karyotypes; 3 (11%) were low-risk and 25 (89%) were intermediate-1-risk by IPSS. Of the 29 patients in the AZA arm, 17 (59%) had diploidy, and 1 (3%) had complex karyotype; 5 (17%) were low-risk and 24 (83%) were intermediate-1-risk by IPSS (2006). Six (21%) patients in the DAC arm and 7 (24%) in the AZA arm received growth factor support prior to therapy. Overall, 19 (33%) patients achieved CR, 2 (4%) CRp, 6 (11%) mCR, and 5 (9%) HI. In the DAC arm, 15 (54%) achieved OIR, 10 (36%) CR, 1 (4%) CRp, 3 (11%) mCR, and 1 (4%) HI. In the AZA arm, 16 (56%) achieved OIR, 9 (31%) CR, 1 (3%) CRp, 3 (10%) mCR, and 3 (10%) HI. Median response duration is 13 months (range, 0-16+). In the DAC group, 1 (8%) out of 12 initially RBC-dependent patients became RBC independent, 3 of 5 RBC/platelet-dependent patients became RBC/platelet-independent, and 1 (7%) of 14 transfusion-independent patients became RBC-dependent. In the AZA group, 3 (27%) of 11 initially RBC-dependent patients became RBC-independent, and 1 (7%) of 14 transfusion-independent patients became dependent. The median number of courses is 7 (range, 2-17+). Treatment has been well tolerated, and only 3 (5%) patients had dose reduction due to grade 3-4 myelosuppression. No death is observed during therapy but 9 deaths in total (16%) were observed after HMA failure; 3 (10%) in AZA and 1 (3%) in DAC in patients who failed to respond and discontinued therapy before death; 2 (7%) in AZA and 3 (11%) in DAC in patients who progressed to higher grade of MDS and changed therapy before death. The 1-year survival rates for the DAC and AZA were 80% and 67%, respectively (p=0.478). Median OS has not been reached, and no difference was noted between groups. Analyzing survival by the MDA lower-risk scoring system (Leukemia. 2008;22:538-543), the median survival was not reached for patients with low-risk disease, not reached for patients with intermediate-risk disease, and 272…
Purpose: Treatment outcomes in patients with relapsed/refractory (R/R) myelodysplastic syndrome (... more Purpose: Treatment outcomes in patients with relapsed/refractory (R/R) myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) remains dismal. On the basis of both extensive preclinical data and emerging clinical data, treatment with bromodomain and extra-terminal domain inhibitors (BETi) is a potential approach for patients with high-risk myeloid malignancies. Patients and Methods: We conducted a phase I trial to study the safety and efficacy of PLX51107 (BETi) and azacitidine combination therapy in patients with R/R AML and high-risk (HR) MDS and studied mechanisms of resistance to the combination therapy. Results: Thirty-seven patients with HR R/R MDS (n = 4) and R/R AML (n = 33) were treated. Sixteen patients (43%) had MECOM gene rearrangement and 7 other patients had TP53 mutation. Median prior number of therapies was three (range 1–9); 97% had received prior hypomethylating agent and 84% prior venetoclax. Overall response rate was 8/37 (22%): complete remission with in...
Background: Bromodomain and extra-terminal domain (BET) family proteins represent a novel target ... more Background: Bromodomain and extra-terminal domain (BET) family proteins represent a novel target class for patients (pts) with myeloid malignancies. Pharmacologic inhibition of BET proteins transcriptionally downregulates critical pro-survival and anti-apoptotic genes. We hypothesized that combination of BET inhibitor (BETi) with hypomethylating agent (HMA) azacitidine (AZA) could lead to clinical benefit for high-risk (HR) pts with R/R MDS and AML. Methods: We conducted an investigator-initiated, single-center, phase I, 3+3 dose-escalation and cohort expansion study of PLX51107 (BETi) + AZA in pts with R/R HR MDS (intermediate-2 score or >10% blasts) or R/R AML. PLX51107 was administered PO on days 1-21 and AZA 75 mg/m2 IV on days 8-14 of a 28-day cycle. Dose-escalation phase of PLX51107 doses included: 40mg (n=4), 80mg (n=3), and 120mg; ultimately, no formal MTD was reached, therefore the 120mg dose was administered to the remaining 30 pts treated on study. Results: 37 pts were...
We conducted a phase Ib/II multi-arm, parallel cohort study to simultaneously evaluate various im... more We conducted a phase Ib/II multi-arm, parallel cohort study to simultaneously evaluate various immunotherapeutic agents and combinations in relapsed/refractory acute myeloid leukemia (AML). Overall, 50 patients were enrolled into one of 6 arms: (A) single agent PF-04518600 (OX40 agonist monoclonal antibody), (B) azacitidine + venetoclax + gemtuzumab ozogamicin (GO), (C) azacitidine + avelumab (anti-PD-L1 monoclonal antibody) + GO, (D) azacitidine + venetoclax + avelumab, (E) azacitidine + avelumab + PF-04518600, and (F) glasdegib + GO. Among all regimens evaluated, azacitidine + venetoclax + GO appeared most promising. In this arm, the CR/CRi rates among venetoclax-naïve and prior venetoclax-exposed patients were 50% and 22%, respectively, and the 1-year OS rate was 31%. This study shows the feasibility of a conducting a multi-arm trial to efficiently and simultaneously evaluate novel therapies in AML, a needed strategy in light of the plethora of emerging therapies. This trial was registered at www.clinicaltrials.gov as NCT03390296.
Background: Several novel agents, including venetoclax (VEN), gemtuzumab ozogamicin (GO), and gla... more Background: Several novel agents, including venetoclax (VEN), gemtuzumab ozogamicin (GO), and glasdegib have shown promise in newly diagnosed AML. However, their role in relapsed/refractory (R/R) AML and their optimal combination with other agents has not been established. We therefore designed a multi-arm, parallel cohort, phase Ib/II study to evaluate various novel combinations of these agents in pts with R/R AML. Methods: Adults ≥18 years of age with R/R AML or with AML from antecedent hematologic malignancy previously treated with hypomethylating agents (HMAs) who had performance status of ≤2 and adequate organ function were eligible. Pts were assigned at the treating physician's discretion to one of 5 concomitantly enrolling arms: A.) azacitidine (AZA) + VEN + GO, B.) AZA + VEN + avelumab (anti-PDL1 mAb), C.) AZA + avelumab + GO, D.) OX40 agonist mAb (PF-04518600), or E.) glasdegib + GO. Treatment regimens are shown in Table 1. In arms containing VEN, a bone marrow (BM) ass...
7001Background: HMAs are the standard of care for most pts with higher risk MDS. However, the rol... more 7001Background: HMAs are the standard of care for most pts with higher risk MDS. However, the role of the therapy is not well defined in lower risk MDS. Data from our center has indicated that atte...
Background: Hypomethylating agents (HMAs) are the standard of care for patients with higher-risk ... more Background: Hypomethylating agents (HMAs) are the standard of care for patients with higher-risk myelodysplastic syndrome (MDS), but their role in those with lower-risk MDS has not been well-established. A randomized phase 2 study evaluating low-dose decitabine and low-dose azacitidine in patients with lower-risk MDS showed that treatment with attenuated dose schedules of HMA therapy are both well-tolerated and effective in patients with lower-risk MDS (Jabbour E, Blood 2017). However, their use as early intervention in transfusion-independent patients with lower-risk MDS remains unknown. Consequently, we performed a retrospective analysis of a cohort of transfusion-independent lower-risk MDS patients to evaluate the safety and clinical activity of low-dose HMAs in this patient population. Methods: Fifty-four adult patients with low-risk or intermediate-1-risk disease by the International Prognostic Scoring System (IPSS) and transfusion-independence at baseline treated on clinical t...
Introduction: Although pts with lower risk MDS have longer OS and transformation free survival th... more Introduction: Although pts with lower risk MDS have longer OS and transformation free survival than pts with higher risk disease, a subset of pts with lower risk MDS have higher risk cytogenetics. There is scarce data on the impact of cytogenetic abnormalities on response to HMAs in this patient population, the ability of these agents to induce cytogenetic responses along with the prognostic relevance of clonal evolution in this subset of pts. Methods: Pts with lower risk MDS treated with HMAs between 2012 and 2015 were evaluated. Information regarding baseline cytopenias, prior malignancy or chemotherapy, initial and on therapy bone marrow cytogenetic findings and response to therapy by IWG criteria were collected. Pts were stratified according to IPSS/IPSS-R cytogenetic groups and MDACC Lower risk model. Data regarding time to cytogenetic response, clonal evolution and clinical evolution was also reviewed. Statistical analysis included Chi-squared for categorical variables, T-stud...
Background: The prognosis of patients with lower-risk MDS is heterogeneous; many have poor surviv... more Background: The prognosis of patients with lower-risk MDS is heterogeneous; many have poor survival (Leukemia. 2008;22:538-543). Hypomethylating agents (HMA) improve the outcomes of patients with higher-risk MDS. Recent Phase I/II studies suggested that HMA doses below current standards of care retain activity in MDS, potentially with a better toxicity profile (JCO. 2009;27:1850-1856). We hypothesized that lower doses of HMA may be active and well tolerated in patients with lower-risk MDS. Aim: This is a phase II randomized trial to evaluate the efficacy and tolerability of low-dose regimens of either DAC or AZA in patients with low- or intermediate-1-risk MDS. Materials and Methods: Eligible patients were adults older than 18 years with de novo or secondary IPSS low- or intermediate-1-risk MDS, including CMML, with normal organ function. Patients were randomized on a Bayesian design to receive DAC 20 mg/m2 IV or AZA 75 mg/m2 IV/SC per day for 3 consecutive days every 28 days. The p...
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