Harnessing the benefits of available targeted therapies in acute myeloid leukaemia.

Research has resulted in regulatory approval of nine agents for acute myeloid leukaemia indications by the US Food and Drug Administration since 2017: the Bcl-2 inhibitor, venetoclax; two FLT3 inhibitors, midostaurin and gilteritinib; two IDH inhibitors, ivosidenib (IDH1 inhibitor) and enasidenib (IDH2 inhibitor); the anti-CD33 antibody-drug conjugate, gemtuzumab ozogamicin; the oral, poorly absorbable hypomethylating agent, azacitidine; the liposomal formulation of cytarabine and daunorubicin (5:1 ratio), CPX-351; and the hedgehog signalling pathway inhibitor, glasdegib. A 100% absorbable oral formulation of the hypomethylating agent decitabine was approved for the treatment of myelodysplastic syndrome and chronic myelomonocytic leukaemia, and might be used as an alternative to parenteral hypomethylating agents. Several of the approvals are as single-agent therapies or in specific combinations for narrow indications, thus offering poor treatment value.

Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial.

Background: Enasidenib is an oral inhibitor of mutant isocitrate dehydrogenase-2 (IDH2) proteins. We evaluated the safety and activity of enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia ineligible for intensive chemotherapy.

Methods: This open-label, phase 1b/2 trial was done at 43 clinical sites in 12 countries (the USA, Germany, Canada, the UK, France, Spain, Australia, Italy, the Netherlands, Portugal, Switzerland, and South Korea).

Value of measurable residual disease monitoring in patients with acute promyelocytic leukemia in the era of frontline 'chemotherapy-free' therapy.

Acute promyelocytic leukemia (APL) is characterized by the chromosomal translocation (15;17) and the resulting gene used for measurable residual disease (MRD) monitoring. Despite highly effective therapy for APL, MRD monitoring practices are not fully established. We aimed to assess the value of MRD monitoring by RT-qPCR in patients with APL treated with ATRA and arsenic trioxide +/- GO.

in Acute Myeloid Leukemia: Molecular Aspects and Patterns of Mutation.

Mutation of the tumor suppressor gene, , is associated with abysmal survival outcomes in acute myeloid leukemia (AML). Although it is the most commonly mutated gene in cancer, its occurrence is observed in only 5-10% of de novo AML, and in 30% of therapy related AML (t-AML). mutation serves as a prognostic marker of poor response to standard-of-care chemotherapy, particularly in t-AML and AML with complex cytogenetics.

The cure of leukemia through the optimist's prism.

Progress is occurring at a dizzying rate across all leukemias. Since the authors' review of the topic in Cancer in 2018, numerous discoveries have been made that have improved the therapy and outcomes of several leukemia subsets. Hairy cell leukemia is potentially curable with a single course of cladribine followed by rituximab (10-year survival, ≥90%).

Predictors of outcomes in adults with acute myeloid leukemia and KMT2A rearrangements.

Acute myeloid leukemia (AML) with rearrangement of the lysine methyltransferase 2a gene (KMT2Ar) has adverse outcomes. However, reports on the prognostic impact of various translocations causing KMT2Ar are conflicting. Less is known about associated mutations and their prognostic impact.

SOHO State of the Art Updates & Next Questions: Intensive and Non-Intensive Approaches for Adults With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) was historically considered to be a very poor-risk subtype of ALL. However, with the introduction of highly potent BCR-ABL tyrosine kinase inhibitors (TKIs), Ph+ ALL can now be considered relatively favorable-risk acute leukemia. Considering the high rates of measurable residual disease negativity and excellent long-term survival that has been achieved with regimens incorporating later-generation TKIs and particularly with ponatinib, lower-intensity and even chemotherapy-free regimens are now being evaluated for patients of all ages with Ph+ ALL.

Outcomes of acute lymphoblastic leukemia with KMT2A (MLL) rearrangement: the MD Anderson experience.

Acute lymphoblastic leukemia (ALL) with t(4;11)(q21;q23)-KMT2A-AFF1 is associated with a poor prognosis. The impact of KMT2A rearrangements other than t(4;11) is uncertain, and the benefit of allogeneic stem cell transplantation (HSCT) is unclear. We reviewed adult patients with ALL treated at our institution from 1984 to 2019 and identified 50 out of 1102 (5%) with KMT2A rearrangement, including 42 (84%) with t(4;11)/KMT2A-AFF1 and 8 (16%) with other gene partners.

Long-term outcome of hyper-CVAD-R for Burkitt leukemia/lymphoma and high-grade B-cell lymphoma: focus on CNS relapse.

Burkitt leukemia/lymphoma (BL) and high-grade B-cell lymphoma (HGBL) have a high incidence of central nervous system (CNS) involvement, which is associated with poor prognosis. The hyper-cyclophosphamide, vincristine, Adriamycin, and dexamethasone plus rituximab (CVAD-R) regimen includes systemic and intrathecal CNS-directed therapy to treat and prevent CNS disease. We report here the long-term safety and efficacy of the hyper-CVAD-R regimen in adults with BL and HGBL, focusing on its efficacy to prevent CNS relapse.

Results of a randomized phase 3 study of oral sapacitabine in elderly patients with newly diagnosed acute myeloid leukemia (SEAMLESS).

Background: Acute myeloid leukemia (AML) is fatal in elderly patients who are unfit for standard induction chemotherapy. The objective of this study was to evaluate the survival benefit of administering sapacitabine, an oral nucleoside analogue, in alternating cycles with decitabine, a low-intensity therapy, to elderly patients with newly diagnosed AML.

Methods: This randomized, open-label, phase 3 study (SEAMLESS) was conducted at 87 sites in 11 countries.

Clinical and molecular characterization of myeloid sarcoma without medullary leukemia.

Myeloid sarcoma (MS) in the setting of concomitant medullary AML is relatively well described, while much less is known about patients presenting with MS with <20% bone marrow blasts. We conducted a retrospective analysis of 56 patients with MS with <20% marrow blasts seen at MD Anderson between 2005 and 2020. The prevalence of MS without medullary AML was 1.

Development of TP53 mutations over the course of therapy for acute myeloid leukemia.

TP53 mutations in acute myeloid leukemia (AML) are associated with resistance to standard treatments and dismal outcomes. The incidence and prognostic impact of the emergence of newly detectable TP53 mutations over the course of AML therapy has not been well described. We retrospectively analyzed 200 patients with newly diagnosed TP53 wild type AML who relapsed after or were refractory to frontline therapy.

Phase II study of single-agent nivolumab in patients with myelofibrosis.

Dysregulated JAK-STAT signaling in myelofibrosis induces pro-inflammatory cytokines, which suppresses T cell proliferation and differentiation, likely responsible for disease progression. The PD-1 pathway, found to be overexpressed in myeloid malignancies, has gained great interest as a therapeutic target, where a significant unmet need exists for novel therapeutic strategies. Preclinical models showed JAK2 mutant cells had higher expression of PD-L1; furthermore, JAK2 mutant xenografts treated with PD-1 inhibition had prolonged survival and reduction in JAK2 allele burden.

Ten-day decitabine with venetoclax versus intensive chemotherapy in relapsed or refractory acute myeloid leukemia: A propensity score-matched analysis.

Background: Relapsed/refractory (R/R) acute myeloid leukemia (AML) has poor outcomes. Although lower-intensity venetoclax-containing regimens are standard for older/unfit patients with newly diagnosed AML, it is unknown how such regimens compare with intensive chemotherapy (IC) for R/R AML.

Methods: Outcomes of R/R AML treated with 10-day decitabine and venetoclax (DEC10-VEN) were compared with IC-based regimens including idarubicin with cytarabine, with or without cladribine, clofarabine, or fludarabine, with or without additional agents.

Phase II study of azacitidine with pembrolizumab in patients with intermediate-1 or higher-risk myelodysplastic syndrome.

Programmed cell death protein 1 (PD-1) and PD-ligand 1 (PD-L1) expression is upregulated in cluster of differentiation 34 (CD34) bone marrow cells from patients with myelodysplastic syndromes (MDS). Hypomethylating agent (HMA) treatment results in further increased expression of these immune checkpoints. We hypothesised that combining an anti-PD-1 antibody with HMAs may have efficacy in patients with MDS.

Venetoclax plus intensive chemotherapy with cladribine, idarubicin, and cytarabine in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome: a cohort from a single-centre, single-arm, phase 2 trial.

Background: Addition of the BCL2 inhibitor venetoclax to lower intensity therapy has been shown to improve overall survival in older (aged 75 years or older) and unfit patients with newly diagnosed acute myeloid leukaemia. The aim of this study was to investigate the activity of venetoclax combined with intensive chemotherapy in patients aged 65 years or younger with acute myeloid leukaemia.

Methods: This cohort study was done at the MD Anderson Cancer Center in the USA, as part of the single-centre, single arm, phase 2, CLIA trial.

Outcomes of TP53-mutant acute myeloid leukemia with decitabine and venetoclax.

Background: TP53 mutation (TP53 ) confers an adverse prognosis in acute myeloid leukemia (AML). Venetoclax with hypomethylating agents is a current standard for older patients; however, recent reports suggest that TP53 confers resistance to venetoclax. The authors investigated the outcomes of patients with TP53 AML who were treated with a 10-day decitabine and venetoclax (DEC10-VEN) (ClinicalTrials.

Acute promyelocytic leukemia current treatment algorithms.

In 1957, Hillestad et al. defined acute promyelocytic leukemia (APL) for the first time in the literature as a distinct type of acute myeloid leukemia (AML) with a "rapid downhill course" characterized with a severe bleeding tendency. APL, accounting for 10-15% of the newly diagnosed AML cases, results from a balanced translocation, t(15;17) (q22;q12-21), which leads to the fusion of the promyelocytic leukemia (PML) gene with the retinoic acid receptor alpha (RARA) gene.

Outcomes in patients with newly diagnosed TP53-mutated acute myeloid leukemia with or without venetoclax-based therapy.

Background: Venetoclax (VEN) in combination with a hypomethylating agent (HMA) has become the standard of care for patients aged >75 years and for those not eligible for intensive chemotherapy who have newly diagnosed acute myeloid leukemia (AML). The benefit of VEN-based therapy in patients who have newly diagnosed AML with mutations in the TP53 gene (TP53 ) over standard therapy is undefined.

Methods: In this single-institutional, retrospective analysis, the authors assessed the clinical outcomes of 238 patients with newly diagnosed TP53 AML and compared the clinical characteristics, response to different therapies, and outcomes of those who received VEN-based (n = 58) and non-VEN-based (n = 180) regimens.

Acute Myeloid Leukemia: Historical Perspective and Progress in Research and Therapy Over 5 Decades.

With the Food and Drug Administration approval of 9 agents for different acute myeloid leukemia (AML) indications, the prognosis and management of AML is evolving rapidly. Herein, we review the important milestones in the history of AML research and therapy, discuss insights regarding prognostic assessment and prediction of treatment outcome, detail practical supportive care measures, and summarize the current treatment landscape and areas of evolving research.

Optimizing the treatment of acute lymphoblastic leukemia in younger and older adults: new drugs and evolving paradigms.

In the past decade, the available treatments for patients with acute lymphoblastic leukemia (ALL) have rapidly expanded, in parallel with an increased understanding of the genomic features that impact the disease biology and clinical outcomes. With the development of the anti-CD22 antibody-drug conjugate inotuzumab ozogamicin, the CD3-CD19 bispecific T-cell engager antibody blinatumomab, CD19 chimeric antigen receptor T-cell therapy, and the potent BCR-ABL1 tyrosine kinase inhibitor ponatinib, the outlook of ALL in both younger and older adults has substantially improved. The availability of highly effective drugs raised important questions concerning the optimal combination and sequence of these agents, their incorporation into frontline regimens, and the role of hematopoietic stem cell transplantation.