A phase 3b study of venetoclax and azacitidine or decitabine in an outpatient setting in patients with acute myeloid leukemia.

Venetoclax, a highly selective BCL-2 inhibitor, combined with hypomethylating agents (HMAs) azacitidine or decitabine, is approved for the treatment of newly diagnosed acute myeloid leukemia (ND AML) in patients who are ineligible to receive intensive chemotherapy. Previous clinical studies initiated venetoclax plus HMA in an inpatient setting owing to concerns of tumor lysis syndrome (TLS). This study (NCT03941964) evaluated the efficacy and safety of venetoclax plus HMA in a United States community-based outpatient setting in patients with ND AML (N = 60) who were treatment naïve for AML, ineligible to receive intensive chemotherapy, had no evidence of spontaneous TLS at screening, and were deemed as appropriate candidates for outpatient initiation of venetoclax plus HMA by the investigator. Patients received venetoclax in combination with azacitidine (75 mg/m2) or decitabine (20 mg/m2) for up to 6 cycles during the study. With a median time on study of 18.3 weeks, the best response rate of composite complete remission was 66.7%, and the overall post-baseline red blood cell (RBC) and platelet transfusion independence rate was 55.0%, consistent with results of studies in which treatment was initiated in an inpatient setting. Key adverse events included nausea, anemia, thrombocytopenia, neutropenia, and white blood cell count decrease of any grade (≥50% of patients). The observed safety profile was generally consistent with that of venetoclax plus HMA observed in inpatient AML studies. With close monitoring, 2 cases of TLS were identified, appropriately managed, and the patients were able to continue study treatment. CLINICAL TRIALS REGISTRATION: This study is registered at ClinicalTrials.gov. The registration identification number is NCT03941964.

Benefit of Early Ruxolitinib Initiation Regardless of Fibrosis Grade in Patients with Primary Myelofibrosis: A Post Hoc Analysis of the Single-Arm Phase 3b JUMP Study.

Bone marrow fibrosis (BMF) is an adverse prognostic factor for myelofibrosis (MF). The single-arm, open-label, phase 3b JUMP trial (NCT01493414) assessed the safety and efficacy of the JAK1/JAK2 inhibitor ruxolitinib in patients with symptomatic MF. This post hoc analysis investigated the impact of BMF grade on response and outcomes in patients with primary MF (PMF) from the JUMP study. BMF was assessed by biopsy and graded from 0 to 3; grades 0-1 were considered low-grade fibrosis (LGF) and grades 2-3 were considered high-grade fibrosis (HGF). Patients with LGF (n = 268) had lower rates of cytopenias at baseline but showed comparable disease burden vs. patients with HGF (n = 852). The proportion of patients achieving a spleen response was greater in the LGF group vs. the HGF group at Week 24 and at any time during the study, while overall survival estimates were improved in patients with LGF vs. patients with HGF. Early initiation of ruxolitinib therapy (within 2 years of diagnosis) was associated with increased response rates in all patients. These results highlight the efficacy of ruxolitinib in symptomatic patients with PMF, with the greatest clinical improvements observed in patients with LGF and in patients who received early treatment.

Decitabine for Treatment of Myelodysplastic Syndromes in Chinese Patients: An Open-Label, Phase-3b Study.

INTRODUCTION: The objective of this study was to evaluate the efficacy and safety of decitabine in Chinese patients with myelodysplastic syndrome (MDS). METHODS: Patients (≥18 years) who had a de novo or secondary MDS diagnosis according to French-American-British classification and an International Prognostic Scoring System score ≥0.5 were enrolled and randomized (1:1) to one of two decitabine regimens: 3-day treatment (3-h intravenous infusion of 15 mg/m(2) given every 8 h for three consecutive days/cycle/6 weeks) or 5-day treatment (1-h intravenous infusion of 20 mg/m(2) once daily on days 1-5/cycle/4 weeks). After a minimum of 30 patients were assigned to 3-day schedule, the remaining were assigned to the 5-day schedule. The primary efficacy endpoint was the overall response rate (ORR). Secondary outcome measures included hematologic improvement (HI), cytogenetic response rate, the time to acute myeloid leukemia (AML) progression, and overall survival (OS). RESULTS: In total, 132 of 135 enrolled patients (3-day treatment, n = 36; 5-day treatment, n = 99) discontinued treatment (major reasons included patient withdrawal/lack of efficacy, n = 48; adverse events, n = 23; and disease progression, n = 22). During the study, 35 of 132 (26.5%) patients from the intent-to-treat (ITT) group achieved significant (P < 0.001) ORR [3-day group (n = 10, 29.4%), P = 0.003; 5-day group (n = 25, 25.5%), P < 0.001]. The HI rate was similar between the 3-day (47.1%) and 5-day groups (48.0%). Cytogenetic response was achieved in 20 of the 30 (66.7%) patients who had a baseline cytogenetic abnormality. Fifty-three (40.2%) AML transformations or deaths occurred and the median AML-free survival time was 23.8 months for all patients from the ITT set; 24-month OS rate was 48.9%. Adverse events of myelosuppression-related disorders (85.6%) and infections (43.2%) were commonly reported. CONCLUSION: Decitabine treatment was efficacious in Chinese patients with MDS with its safety profile comparable to the global studies of decitabine conducted to date. FUNDING: Xian-Janssen Pharmaceutical Ltd. China (a company of Johnson & Johnson). TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01751867.