Q1 2023: Additional information and data in acute leukemia
AML
Intensive chemotherapy before alloHCT doesn not improve survivail in AML: data from the phase III ASAP trial presented at the 64th ASH Annual Meeting and Exposition showed no benefit to undergoing intensive remission induction chemotherapy before alloHCT compared to watchful waiting and sequential conditioning before alloHCT. (Ref: Schetelig J, Stelljes M, Middeke JM, et al. In patients with relapsed/refractory AML sequential conditioning and immediate allogeneic stem cell transplantation (allo-HCT) results in similar overall and leukemia-free survival compared to intensive remission induction chemotherapy followed by allo-HCT: results from the randomized phase III ASAP trial. Abstract #4. Presented at the 2022 American Society of Hematology Annual Meeting and Exposition; December 11, 2022; New Orleans, Louisiana.)
Co-mutation patterns allowed for updated risk stratification of NPM1-mutated AML: many patients with NPM1-mutated AML carry at least three gene mutations, and consideration of these co-mutational patterns is necessary for accurate risk stratification, according to data presented at the 64th ASH Annual Meeting and Exposition. (Ref: Hernández Sánchez A, Ramiro AV, Strang E, et al. Machine learning allows the identification of new co-mutational patterns with prognostic implications in NPM1 mutated AML – results of the European Harmony Alliance. Abstract #304. Presented at the 2022 American Society of Hematology Annual Meeting and Exposition; December 10, 2022; New Orleans, Louisiana).
Impact of IDH1 and IDH2 mutation detection at diagnosis and in remission in patients with AML receiving allogeneic transplantation: a study shows that the diagnostic presence of IDH mutations in AML did not have a strong prognostic impact following HSCT consolidation, the presence, especially of IDH1 R132 and IDH2 R172 mutations at higher MRD levels in remission, associated with an increased risk of relapse following HSCT (inferior outcomes). (Ref: https://doi.org/10.1182/bloodadvances.2021005789)
Enasidenob vs conventional care in older patient with late-stage mutant-IDH2 relapsed/refractory AML: the open-label, randomized, phase 3 trial (NCT02577406) compared enasidenib, an oral IDH2 inhibitor with conventional care regimens in patients aged ≥60 years with late-stage, mutant-IDH2 AML R/R to 2 or 3 prior AML-directed therapies did not meet its primary study endpoint was not met, but OS was confounded by early dropout and subsequent AML-directed therapies. Enasidenib provided meaningful benefits in EFS, TTF, ORR, HI, and RBC-TI in this heavily pretreated older mutant-IDH2 R/R AML population. (Ref: https://doi.org/10.1182/blood.2021014901)
Early initiation of low-dose gilterinib maintenance impoves posttransplant outcomes in patients with R/R FLT3 mutated AML: A recent study showed preliminary but promising results for the early initiation of gilteritinib maintenance in patients with FLT3-mutated AML post-SCT in clinical practice. Despite poor patient backgrounds and MRD-positive peri-SCT statuses, early initiation of gilteritinib maintenance with reduced doses resulted in improved RFS and OS. Based on these results, we would suggest careful adjustments to the starting timing and dose modification of gilteritinib maintenance therapy for each patient to further improve the outcome of patients with R/R FLT3-mutated AML with residual MRD peri-SCT. Subsequent studies are warranted to validate our results and to elucidate the detailed mechanisms underlying our new insights. (Ref: https://doi.org/10.1182/bloodadvances.2022008991)
Acquired mutations in BAX confer resistance to BH3-mimetic therapy in AML: Randomized trials in AML have demonstrated improved survival by the BCL-2 inhibitor venetoclax combined with azacitidine in older patients, and clinical trials are actively exploring the role of venetoclax in combination with intensive chemotherapy in fitter patients with AML. As most patients still develop recurrent disease, improved understanding of relapse mechanisms is needed. The study showed that acquired mutations in BAX during venetoclax-based therapy represent a novel mechanism of resistance to BH3-mimetics and a potential barrier to the long-term efficacy of drugs targeting BCL-2 in AML. (Ref. https://doi.org/10.1182/blood.2022016090)
Clinical outcomes associated with NMP1 mutations in R/R AML patients: Mutations in Nucleophosmin 1 (NPM1) are associated with a favorable prognosis in newly diagnosed AML, however, their prognostic impact in R/R settings are unknown. A recent study showed that AML with NPM1c is associated with poor outcomes at relapse but has no impact on the risk of relapse or death. The use of HI regimens and/or the addition of venetoclax to salvage therapy was associated with improved outcomes in patients with NPM1c in this setting. Combination strategies incorporating emerging novel therapies should be rapidly evaluated to further improve outcomes and long-term survival. (Ref: https://doi.org/10.1182/bloodadvances.2022008316)
A prospective, observational study enrolled patients presenting for treatment of AML at 13 institutions to analyze associations between hematopoietic cell transplantation (HCT) and survival, quality of life, and function in: the entire cohort, those aged ≥65 years, those with high comorbidity burden, intermediate cytogenetic risk, adverse cytogenetic risk, and first complete remission with or without measurable residual disease.
Key points:
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Models adjusted for AML and patient-specific variables showed no benefit of allogeneic HCT in patients that are older or medically infirm.
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Current practice of offering HCT to older and medically infirm patients with AML is not evidence based, which calls for randomized trials.
Ref: https://doi.org/10.1182/blood.2022016916
ALL
Use of the anti-CD19 bispecific T-cell engaging antibody blinatumomab given in conjunction with the tyrosine kinase inhibitor (TKI) dasatinib may provide an alternative to allogenic transplant for older adults with Ph+ALL. What was unique about the trial is that it strictly included patients older than 65 years, allowed comorbidities, and only one patient proceeded to allogenic transplant. Moreover, previous research used ponatinib in conjunction with blinatumomab, but ponatinib may not be a good option for older patients given its risk for cardiovascular events. (Ref. Advani AS, Moseley A, O’Dwyer KM, et al. Dasatinib/prednisone induction followed by blinatumomab/dasatinib in Ph+ acute lymphoblastic leukemia [published online, 2022 Nov 2]. Blood Adv. doi: 10.1182/bloodadvances.2022008216.)
It was identified that CD22low/Bcl-2high is a dual-marker signature that reliably predicts poor response to Inotuzumab ozogamicin (InO). Furthermore, this approach also identifies dynamic changes of tumor composition after InO and suggests venetoclax as a promising drug with the potential for synergistic clinical efficacy, suggesting a patient-stratified approach for InO combinatorial treatments. (Ref: https://doi.org/10.1182/bloodadvances.2021006810)
CAR-T
Children living in poverty experience excessive relapse and death from newly diagnosed ALL. A recent study has shown that CAR T-cell therapy produces equivalent survival for children with r/r ALL, regardless of household poverty or neighborhood opportunity. Also CAR T-cell therapy may ameliorate factors influencing disparate outcomes observed in other treatment settings for children with ALL. (Ref: https://doi.org/10.1182/blood.2022017866)
Fertility
An advanced practitioner-driven fertility preservation initiative introduced at a community oncology practice resulted in a more than two-fold increase in referrals for fertility preservation consultation with a reproductive endocrinologist among adolescents and young adults (AYAs, age 15-39) at risk for infertility. (Valdez C. Early identification for fertility preservation improves referrals in a community oncology practice. Presented at JADPRO Live 2022, Aurora, Colorado).