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

ABSTRACT: 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.

SUBMITTER: DeAngelo DJ

PROVIDER: S-EPMC7108400 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

DeAngelo Daniel J DJ Walker Alison R AR Schlenk Richard F RF Sierra Jorge J Medeiros Bruno C BC Ocio Enrique M EM Röllig Christoph C Strickland Stephen A SA Thol Felicitas F Valera Sue-Zette SZ Dasgupta Kohinoor K Berkowitz Noah N Stuart Robert K RK

Leukemia research 20190801

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/m<sup>2</sup>/d, IV; day 1-3) and cytarabine (100 mg/m<sup>2</sup>/d, continuous IV infusion; day 1 ...[more]

PMID: 31541945

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Project description:OBJECTIVE:To evaluate the safety and efficacy of intravenous golimumab + methotrexate (MTX) in patients with active rheumatoid arthritis (RA) aged <?65?years and those ??65?years who were enrolled in the GO-FURTHER study. METHODS:In the phase III, double-blind, randomized, placebo-controlled GO-FURTHER trial, patients with active RA were randomized to intravenous (IV) golimumab 2?mg/kg + MTX or placebo + MTX at weeks 0 and 4, then every 8?weeks thereafter (with crossover to golimumab at week 16 [early escape] or week 24 [per-protocol]). The final golimumab infusion was at week 100. Assessments included American College of Rheumatology (ACR) 20/50/70 response criteria. Efficacy and adverse events (AEs) were monitored through 2 years. Efficacy and AEs were summarized for patients aged <?65?years or ??65?years; AEs were also summarized for patients < or ??70?years and patients < or ??75?years. RESULTS:In GO-FURTHER, 592 patients were randomized to receive placebo (n?=?197) or golimumab (n?=?395), 515 were aged <?65?years and 77 were ??65?years. At week 24, ACR20 response rates were greater for golimumab + MTX patients compared with placebo + MTX for patients <?65?years (61.6% vs 31.3%, p?<?0.001) and those ??65?years (69.5% vs 33.3%; p?<?0.01). Infections were the most common AE through week 112 (51.6% in patients <?65?years; 55.3% in patients ??65?years); upper respiratory infections were the most common infection in patients <?65?years (13.2%) and those ??65?years (11.8%). Serious AEs occurred in 17.7% in patients <?65?years and 25.0% of patients ??65?years and included malignancies, pneumonia, fractures, acute pancreatitis, cellulitis, and bacterial arthritis. CONCLUSIONS:In GO-FURTHER, ACR response rates were similar between patients <?65?years and patients ??65?years within each treatment group. AEs in elderly patients were similar to the known safety profile of IV golimumab. Immunosenescence is known to increase the risk of infections in the elderly. Elderly patients had a numerically higher incidence of serious infections. Six malignancies occurred in golimumab-treated patients, all in patients <?65?years. TRIAL REGISTRATION:clinicaltrials.gov: NCT00973479 . Registered September 9, 2009.

Project description:BACKGROUND:Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population. METHODS:We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles (ITD [high] and ITD [low], respectively). Allogeneic transplantation was allowed. The primary end point was overall survival. RESULTS:A total of 717 patients underwent randomization; 360 were assigned to the midostaurin group, and 357 to the placebo group. The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7% in the midostaurin group vs. 59.4% in the placebo group were women, P=0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P=0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P=0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of midostaurin was consistent across all FLT3 subtypes. The rate of severe adverse events was similar in the two groups. CONCLUSIONS:The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with AML and a FLT3 mutation. (Funded by the National Cancer Institute and Novartis; ClinicalTrials.gov number, NCT00651261 .).

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

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

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