Feasibility of Azacitidine Added to Standard Chemotherapy in Older Patients with Acute Myeloid Leukemia — A Randomised SAL Pilot Study

Introduction: Older patients with acute myeloid leukemia (AML) experience short survival despite intensive chemotherapy. Azacitidine has promising activity in patients with low proliferating AML. The aim of this dose-finding part of this trial was to evaluate feasibility and safety of azacitidine combined with a cytarabine- and daunorubicin-based chemotherapy in older patients with AML. Trial Design: Prospective, randomised, open, phase II trial with parallel group design and fixed sample size. Patients and Methods: Patients aged 61 years or older, with untreated acute myeloid leukemia with a leukocyte count of ,20,000/ml at the time of study entry and adequate organ function were eligible. Patients were randomised to receive azacitidine either 37.5 (dose level 1) or 75 mg/sqm (dose level 2) for five days before each cycle of induction (7+3 cytarabine plus daunorubicine) and consolidation (intermediate-dose cytarabine) therapy. Dose-limiting toxicity was the primary endpoint. Results: Six patients each were randomised into each dose level and evaluable for analysis. No dose-limiting toxicity occurred in either dose level. Nine serious adverse events occurred in five patients (three in the 37.5 mg, two in the 75 mg arm) with two fatal outcomes. Two patients at the 37.5 mg/sqm dose level and four patients at the 75 mg/sqm level achieved a complete remission after induction therapy. Median overall survival was 266 days and median event-free survival 215 days after a median follow up of 616 days. Conclusions: The combination of azacitidine 75 mg/sqm with standard induction therapy is feasible in older patients with AML and was selected as an investigational arm in the randomised controlled part of this phase-II study, which is currently halted due to an increased cardiac toxicity observed in the experimental arm. Trial Registration: This trial is registered at clinical trials.gov (identifier: NCT00915252)

Elotuzumab, lenalidomide, and dexamethasone in RRMM: final overall survival results from the phase 3 randomized ELOQUENT-2 study

Prolonging overall survival (OS) remains an unmet need in relapsed or refractory multiple myeloma (RRMM). In ELOQUENT-2 (NCT01239797), elotuzumab plus lenalidomide/dexamethasone (ERd) significantly improved progression-free survival (PFS) versus lenalidomide/dexamethasone (Rd) in patients with RRMM and 1–3 prior lines of therapy (LoTs). We report results from the pre-planned final OS analysis after a minimum follow-up of 70.6 months, the longest reported for an antibody-based triplet in RRMM. Overall, 646 patients with RRMM and 1–3 prior LoTs were randomized 1:1 to ERd or Rd. PFS and overall response rate were co-primary endpoints. OS was a key secondary endpoint, with the final analysis planned after 427 deaths. ERd demonstrated a statistically significant 8.7-month improvement in OS versus Rd (median, 48.3 vs 39.6 months; hazard ratio, 0.82 [95.4% Cl, 0.68–1.00]; P = 0.0408 [less than allotted α of 0.046]), which was consistently observed across key predefined subgroups. No additional safety signals with ERd at extended follow-up were reported. ERd is the first antibody-based triplet regimen shown to significantly prolong OS in patients with RRMM and 1–3 prior LoTs. The magnitude of OS benefit was greatest among patients with adverse prognostic factors, including older age, ISS stage III, IMWG high-risk disease, and 2–3 prior LoTs

Safety and efficacy of oral panobinostat plus chemotherapy in patients aged 65 years or younger with high-risk acute myeloid leukemia

The role of histone deacetylase inhibitors in the treatment of acute myeloid leukemia (AML) is not well characterized. The current study evaluated the safety and efficacy of panobinostat in combination with idarubicin and cytarabine in newly diagnosed patients aged ≤65 years with primary or secondary high-risk AML based on cytogenetic classification. Treatment included fixed dose idarubicin (12 mg/m2/d, IV; day 1–3) and cytarabine (100 mg/m2/d, continuous IV infusion; day 1–7) and escalating oral doses of panobinostat at 15 mg, 20 mg, and 25 mg, thrice weekly starting at week 2 of a 28-day cycle. Forty-six patients were enrolled (primary AML [n = 36], secondary AML [n = 10]). The median age was 55 years. The most common all-grade AEs were diarrhea (54.3%), nausea (39.1%), vomiting, and decreased appetite (each, 21.7%), stomatitis (19.6%), and fatigue (17.4%). The overall response rate was 60.9%, 43.5% achieved a complete remission (CR), and 17.4% achieved CR with incomplete count recovery. The event-free survival at 1-year was 78.3%. Panobinostat in combination with idarubicin and cytarabine demonstrated tolerable safety and efficacy in younger patients with high-risk AML. The recommended phase 2 dose of panobinostat in this combination was 20 mg. ClinicalTrials.gov registry no: NCT01242774, and European Trial Registry EudraCT no: 2009-016809-42.The study was sponsored by Novartis Pharmaceuticals Corporation

Genome-wide association study identifies susceptibility loci for acute myeloid leukemia

Publisher Copyright: © 2021, The Author(s).Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 x 10(-8); KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 x 10(-10); HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA). Genome wide association studies in cancer are used to understand the heritable genetic contribution to disease risk. Here, the authors perform a genome wide association study in European patients with acute myeloid leukemia and identify loci associated with risk of developing the disease.Peer reviewe

Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma

Presented at the 50th Annual American Society of Clinical Oncology Meeting (2014), the 56th American Society of Hematology Annual Meeting (2014), the 20th Congress of the European Hematology Association (2015), the 15th International Myeloma Workshop (2015), and the 57th American Society of Hematology Annual Meeting (2015).Patients with relapsed and/or refractory multiple myeloma (RRMM) have poor prognosis. The STRATUS study assessed safety and efficacy of pomalidomide plus low-dose dexamethasone in the largest cohort to date of patients with RRMM. Patients who failed treatment with bortezomib and lenalidomide and had adequate prior alkylator therapy were eligible. Pomalidomide 4 mg was given on days 1-21 of 28-day cycles with low-dose dexamethasone 40 mg (20 mg for patients aged >75 years) on days 1, 8, 15, and 22 until progressive disease or unacceptable toxicity. Safety was the primary end point; secondary end points included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Among 682 patients enrolled, median age was 66 years, and median time since diagnosis was 5.3 years. Median number of prior regimens was 5. Most patients were refractory to both lenalidomide and bortezomib (80.2%). Median follow-up was 16.8 months; median duration of treatment was 4.9 months. Most frequent grade 3/4 treatment-emergent adverse events were hematologic (neutropenia [49.7%], anemia [33.0%], and thrombocytopenia [24.1%]). Most common grade 3/4 nonhematologic toxicities were pneumonia (10.9%) and fatigue (5.9%). Grade 3/4 venous thromboembolism and peripheral neuropathy were rare (1.6% each). The ORR was 32.6%, and the median DOR was 7.4 months. Median PFS and OS were 4.6 months and 11.9 months, respectively. We present the largest trial to date evaluating pomalidomide plus low-dose dexamethasone in patients with RRMM, further confirming that this regimen offers clinically meaningful benefit and is generally well tolerated.This study was funded by Celgene Corporation.Peer Reviewe