Venetoclax-Based Combinations for the Treatment of Newly Diagnosed Acute Myeloid Leukemia

Abstract

Elderly and/or unfit patients with acute myeloid leukemia have historically been challenging to manage as they were ineligible for what was considered standard of care treatment with induction chemotherapy. The emergence of venetoclax with hypomethylating agents or low-dose cytarabine has substantially improved outcomes in the frontline setting with manageable toxicity. However, this regimen can be challenging to deliver given its differences from standard intensive chemotherapy. In this review, we summarize the landmark trials that established venetoclax-based combinations as a new standard of care for patients with acute myeloid leukemia not suitable for intense chemotherapy, provide practical clinical pearls for managing patients on these therapies, and offer a brief overview of modifications to these regimens under development to improve their efficacy and/or applicability.

A Clinical Phase 1B Study of the CD3xCD123 Bispecific Antibody APVO436 in Patients with Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

“…The greatest challenge in the field of AML therapy is achieving deep CRs and longterm leukemia-free survival in R/R AML patients [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Despite the fact that we have…”

“…The greatest challenge in the field of AML therapy is achieving deep CRs and longterm leukemia-free survival in R/R AML patients [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Despite the fact that we have gained new insights and a better understanding of cell-intrinsic drivers of AML and new drugs have been developed for targeting select somatic mutations, the majority of R/R AML patients die of leukemia [8][9][10][11][12][13][14][15][16].…”

“…Older patients with newly diagnosed AML respond poorly to standard induction chemotherapy and have a poor survival. For newly diagnosed older AML patients, new treatment regimens have been developed in recent years, such the combination of the BCL-2 homology 3 (BH3)-mimetic compound; Venetoclax with HMA (e.g., azacitidine/AZA and decitabine/DAC); or the combination of the Hedgehog pathway inhibitor Glasdegib with LDARAC, both of which showed significant clinical activity with reduction in the risk of death in randomized phase II clinical trials [3,4,11,59]. Older patients with relapsed AML have a dismal prognosis and are in urgent need for new salvage treatment strategies for their chemo-resistant leukemia.…”

“…The rate of new cases of AML is 4.3 per 100,000 men and women per year, and the death rate is 2.8 per 100,000 men and women per year. Several targeted medicines, such as FLT3 inhibitors, IDH1/2 inhibitors, and BCL-2 inhibitor Venetoclax, as well as biotherapeutics (e.g., antibody-drug conjugates) for AML therapy have been developed and approved by the FDA over the last 10 years [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Despite these recent advances in therapy, more than 50% of patients who achieve a remission eventually relapse, and the five-year overall survival remains at 29.5%.…”

The Ups and Downs of STAT Inhibition in Acute Myeloid Leukemia

“…Final results of the clinical trial are still awaited; however, the authors suggest that this approach could be an alternative to aggressive chemotherapy for obtaining CR prior to allogenic hematopoietic stem cell transplant [127]. A recent approval of a combination of Decitabine with BCL2 inhibitor Venetoclax, which is also directed to AML patients who are not eligible for intensive chemotherapy, diminishes the attractivity of this novel combinatorial approach of Ruxolitinib and Decitabine [127,129]. In particular, preclinical studies have shown promising results upon combining Venetoclax with Ruxolitinib.…”