Venetoclax and hypomethylating agents in octogenarians and nonagenarians with acute myeloid leukemia.

Venetoclax (VEN) plus a hypomethylating agent (HMA) regimen is the standard of care for older adults with acute myeloid leukemia (AML); however, it is associated with significant myelosuppression and complications, potentially limiting its use in those who are very old. We performed a multicenter retrospective analysis of VEN-HMA treatment in octogenarians and nonagenarians to further understand the tolerability, feasibility, dosing considerations, and clinical efficacy in this unique group. Patients with AML aged ≥80 years who received VEN-HMA between March 2015 and April 2022 were reviewed.

Therapy-related myelodysplastic syndromes and acute myeloid leukemia.

Progress always comes at a price: the field of oncology has seen unprecedented progress in treatment options recently for many solid and hematologic cancers. Unfortunately, these long-term survivors of prior cancer and cytotoxic therapy exposure are at higher risk of therapy-related myelodysplastic syndromes/acute myeloid leukemia (t-MDS/AML.) T-MDS/AML is a myeloid malignancy which occur after exposure to chemotherapy or radiation therapy for unrelated malignancy.

Outcomes of Patients With Newly Diagnosed AML and Hyperleukocytosis.

Purpose: AML presenting with hyperleukocytosis is associated with poor outcomes. We aim to understand the factors associated with early mortality and overall survival (OS) to help guide management and improve early mortality.

Methods: We retrospectively reviewed data from 129 consecutive patients with newly diagnosed AML and a WBC count ≥100 × 10/L between January 2010 and April 2020.

Oral decitabine plus cedazuridine and venetoclax in patients with higher-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia: a single-centre, phase 1/2 study.

Background: Hypomethylating agents are approved in higher-riskmyelodysplastic syndromes. The combination of a hypomethylating agent with venetoclax is standard of care in acute myeloid leukaemia. We investigated the safety and activity of the first totally oral combination of decitabine plus cedazuridine and venetoclax in patients with higher-risk-myelodysplastic syndromes and chronic myelomonocytic leukaemia.

The future paradigm of HMA + VEN or targeted inhibitor approaches: sequencing or triplet combinations in AML therapy.

The routine use of next-generation sequencing methods has underscored the genetic and clonal heterogeneity of acute myeloid leukemia (AML), subsequently ushering in an era of precision medicine-based targeted therapies exemplified by the small-molecule inhibitors of FLT3, IDH1/IDH2, and BCL2. This advent of targeted drugs in AML has broadened the spectrum of antileukemic therapies, and the approval of venetoclax in combination with a hypomethylating agent has been a welcome addition to our AML patients unable to tolerate intensive chemotherapy. Mounting evidence demonstrates that molecularly targeted agents combined with epigenetic therapies exhibit synergistic augmented leukemic cell kill compared to single-agent therapy.

Current State and Future Prospects of Diagnosis and Management of TP53-Mutated Myeloid Neoplasms.

TP53-mutated myeloid neoplasms including acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS) are notoriously treatment resistant with uniformly poor outcomes. TP53 status is an important prognostic indicator and early knowledge of the TP53 mutation/allelic state may assist in appropriate management including clinical trial enrollment for eligible patients. Thus far, no therapy has shown to demonstrate durable response or incremental survival benefit in TP53-mutated AML or MDS.

Oral therapy for myelodysplastic syndromes/neoplasms and acute myeloid leukemia: a revolution in progress.

Introduction: Patients with myeloid neoplasms such as myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML) are generally older, and many are not eligible for curative intent intensive therapies and/or allogeneic hematopoietic stem cell transplantation. While lower intensity, hypomethylating agent (HMA)-based therapies such as azacitidine+venetoclax have improved patient outcomes significantly, responses are not durable, and most patients die from disease-related complications. The approvals of oral HMAs such as cedazuridine-decitabine (C-DEC) and oral azacitidine (CC-486) have kindled the hope that myeloid malignancies may soon be treated with total oral therapy.

Olutasidenib: from bench to bedside.

The discovery of isocitrate dehydrogenase 1 (IDH1) mutations in acute myeloid leukemia (AML) and the resounding success of molecularly targeted therapies in related myeloid malignancies swiftly prompted the development of IDH1mut inhibitors. Olutasidenib (formerly known as FT-2102) is an orally administered novel IDH1mut inhibitor that entered clinical development in 2016, proceeded briskly through the developmental process, and was granted regular approval to treat patients with R/R IDH1mut AML on 1 December 2022. Single agent olutasidenib, a potent and selective IDH1mut inhibitor, demonstrated highly durable remission rates along with meaningful outcomes, such as transfusion independence, in patients with R/R IDH1mut AML.

An overview of novel therapies in advanced clinical testing for acute myeloid leukemia.

Introduction: The past decade has seen a sea change in the AML landscape with vastly improved cognizance of molecular pathogenesis, clonal evolution, and importance of measurable residual disease. Since 2017, the therapeutic armamentarium of AML has considerably expanded with the approval of midostaurin, enasidenib, ivosidenib, gilteritinib, and venetoclax in combination with hypomethylating agents and others. Nevertheless, relapse and treatment refractoriness remain the insurmountable challenges in AML therapy.

A retrospective study of cladribine and low-dose cytarabine-based regimens for the treatment of chronic myelomonocytic leukemia and secondary acute myeloid leukemia.

Background: Patients with higher risk chronic myelomonocytic leukemia (CMML) have limited therapeutic options beyond hydroxyurea and hypomethylating agents (HMAs). Regimens based on a backbone of cladribine (CLAD), low-dose cytarabine (LDAC), and an HMA are effective low-intensity therapies for acute myeloid leukemia (AML).

Methods: The authors conducted a retrospective chart review to evaluate the efficacy of CLAD/LDAC/HMA in CMML and secondary acute myeloid leukemia (sAML) arising from CMML.

Clinical outcomes associated with NPM1 mutations in patients with relapsed or refractory AML.

Mutations in Nucleophosmin 1 (NPM1) are associated with a favorable prognosis in newly diagnosed acute myeloid leukemia (AML), however, their prognostic impact in relapsed/refractory (R/R) settings are unknown. In a retrospective analysis, we identified 206 patients (12%) with mutated NPM1 (NPM1c) and compared their outcomes to 1516 patients (88%) with NPM1 wild-type (NPM1wt). NPM1c was associated with higher rates of complete remission or complete remission with incomplete count recovery compared with NPM1wt following each line of salvage therapy (first salvage, 56% vs 37%; P < .

Differential prognostic impact of RUNX1 mutations according to frontline therapy in patients with acute myeloid leukemia.

RUNX1-mutated (mRUNX1) acute myeloid leukemia (AML) has historically been associated with poor outcomes in the setting of conventional chemotherapy. The prognostic impact of mRUNX1 AML is not well-established in the current era of lower-intensity treatment regimens incorporating venetoclax. We retrospectively analyzed 907 patients with newly diagnosed AML, including 137 patients with mRUNX1 AML, who underwent first-line therapy with intensive chemotherapy (IC), low-intensity therapy without venetoclax (LIT without VEN), or LIT with VEN.

Targeted therapy with the mutant IDH2 inhibitor enasidenib for high-risk IDH2-mutant myelodysplastic syndrome.

The isocitrate dehydrogenase enzyme 2 (IDH2) gene is mutated in ∼5% of patients with myelodysplastic syndrome (MDS). Enasidenib is an oral, selective, mutant IDH2 inhibitor approved for IDH2-mutated (mIDH2) relapsed/refractory acute myeloid leukemia. We designed a 2-arm multicenter study to evaluate safety and efficacy of (A) the combination of enasidenib with azacitidine for newly diagnosed mIDH2 MDS, and (B) enasidenib monotherapy for mIDH2 MDS after prior hypomethylating agent (HMA) therapy.

The odyssey of pacritinib in myelofibrosis.

Myelofibrosis (MF) can present with symptomatic splenomegaly and/or cytopenias including thrombocytopenia. Disease-related thrombocytopenia is a poor prognostic factor with a median overall survival of less than 2 years. Currently approved JAK1/2 inhibitors have not been evaluated in patients with platelets ≤ 50 × 109/L and in fact could potentiate thrombocytopenia because of their combined JAK1/2 inhibitory activity.

BTK inhibitor selection for chronic lymphocytic leukemia: which drug for which patient?

Introduction: The development of BTK inhibitors has revolutionized the management of CLL. Currently, there are 3 BTK inhibitors available to treat CLL: ibrutinib, acalabrutinib, and zanubrutinib (the latter not yet approved for this disease but included in the NCCN guidelines). In this review, we will elucidate our approach to the selection of BTK inhibitor and provide insight into the future of BTK directed therapy.

Impact of frontline treatment approach on outcomes in patients with secondary AML with prior hypomethylating agent exposure.

Background: Treated secondary acute myeloid leukemia (ts-AML)-i.e., AML arising from a previously treated antecedent hematologic disorder-is associated with very poor outcomes.