Q2 2023: Additional information and data in acute leukemia

AML

Ipilimumab plus decitabine for patients with MDS or AML in posttransplant or transplant-naïve settings: combination IPI + DEC treatment has an acceptable safety profile and has meaningful clinical activity in patients with R/R MDS/AML that does not appear to require T cell–mediated alloreactivity. IPI + DEC treatment may serve as a less-intensive bridge to transplant among potential transplant candidates. Future studies are warranted to identify rational IPI-based treatment strategies to generate prolonged responses without severe immune toxicity. (Ref: https://doi.org/10.1182/blood.2022017686)

BCL2 Inhibition: A New Paradigm for the Treatment of AML and Beyond: Altering the natural history of AML in unfit and older patients has proved a highly challenging hurdle, despite several decades of concerted clinical trial effort. The arrival of venetoclax (VEN) to the clinical stage represents the most important therapeutic advance to date for older patients with AML. In this review, we will explain how and why VEN works, summarize its remarkable pathway to regulatory approval, and highlight the key milestones that have been important for its successful development in AML. We also provide perspectives on some of the challenges associated with using VEN in the clinic, emerging knowledge regarding mechanisms of treatment failure, and current clinical research directions likely to shape how this drug and others in this new class of anticancer agents are used in the future. (Ref. HemaSphere 7(6):p e912, June 2023. | DOI: 10.1097/HS9.0000000000000912)

Availability of haploidentical donors has broadened utilization of allogeneic hematopoietic cell transplantation (allo-HCT). Peripheral blood stem cells (PBSC) are being used with increased frequency in haploidentical allo-HCT. A study evaluated extent of HLA disparity (2–3/8 versus 4/8 HLA antigen mismatches) on post-allograft outcomes when using T-cell replete PBSC from haploidentical donors for AML in first complete remission. Primary objectives entailed assessing cumulative incidence of grade 2–4 acute graft-versus-host disease (GVHD) and chronic GVHD (any grade). Pertaining to HLA-B leader matching effect, our analysis did not discern any difference in aforementioned post-allograft outcomes for this variable. However, in univariate analysis, absence of an antigen mismatch in HLA-DPB1 showed a trend for better OS. Notwithstanding inherent limitations associated with registry data, the results did not show an advantage of selecting a haploidentical donor with 2–3 of 8 HLA antigen mismatches over one with 4 of 8 HLA antigen mismatches when using PBSC as the cell source. Adverse cytogenetics remains a major adverse determinant of inferior OS and LFS and a higher RI. Using reduced-intensity conditioning yielded worse OS and LFS. (ref. DOI: 10.1097/HS9.0000000000000920)

Pevonedistat with azacitidine in older patients with TP53-mutated AML: a phase 2 study with laboratory correlates: in this phase 2 Beat AML substudy, treatment with AZA + PEVO did not induce responses  in older patients with TP53-mutated AML. These observations mirror recent results with the same combination in myelodysplatic syndrome, stand in contrast to previous results in AML, and do not support the combination as targeted therapy in TP53-mutated AML. Reports of other studies  examining the addition of venetoclax to AZA + PEVO in AML are eagerly awaited. (Ref. https://doi.org/10.1182/bloodadvances.2022008625)

ALL

Haploidentical hematopoietic cell transplantation with posttransplant cyclophosphamide (PTCy) graft-versus-host-disease (GVHD) prophylaxis yields a similar OS to HLA-matched unrelated donor (MUD) HCT with conventional prophylaxis. A study showed that despite a higher risk of relapse, younger donor haploidentical HCT with PTCy prophylaxis may be preferred over older MUD HCT with conventional prophylaxis in patients with ALL due to lower NRM and better OS. Further analysis comparing the effect of donor age in haploidentical PTCy vs MUD PTCy is warranted. (Ref. https://doi.org/10.1182/bloodadvances.2022009240)

Glucocorticoids are extensively used for the treatment of ALL as they pressure cancer cells to undergo apoptosis. Nevertheless, glucocorticoid partners, modifications, and mechanisms of action are hitherto poorly characterized. Ongoing research suggests that a better understanding of GR nuclear functions and cofactors in ALL and use of inhibitors against epigenetic cofactors or enzymes controlling posttranslational modifications in combination with GCs could be of therapeutic value in high-risk ALL cases. (Ref. DOI: 10.1097/HS9.0000000000000916)

High-risk Combinations of Additional Chromosomal Abnormalities in Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia: JALSG Ph+ALL TKI-SCT Study: Additional chromosomal abnormalities (ACAs) are found in 60%–70% of Philadelphia chromosome-positive ALL (Ph+ALL) cases. the coexistence of +der(22)t(9;22) and a complex karyotype was identified as a high-risk combination of ACAs in Ph+ALL. Multiple ACAs are often observed in Ph+ALL, leading to identifying this subgroup with a poor prognosis. It was characterized by early relapse, although remission could be achieved at the same rate as standard-risk Ph+ALL. Further molecular genetic elucidation and the establishment of effective therapeutic strategies are warranted. (Ref. HemaSphere 7(6):p e899, June 2023. | DOI: 10.1097/HS9.0000000000000899)

To determine the prognostic significance of central nervous system leukemic involvement in newly diagnosed T-cell T-ALL, outcomes on consecutive, phase 3 clinical trials were examined. (Ref: https://doi.org/10.1182/blood.2022018653)

Key findings:

• Patients with CNS-1 and CNS-2 status have similar outcomes across 2 large studies with divergent therapies, including with and without CRT.
• Patients with CNS-3 T-ALL treated with nelarabine had similar OS as CNS-1 and CNS-2, and thus should receive nelarabine as standard of care.

CAR-T

Treatment of CAR-T cell toxicities –> read here