Beat-AML 2024 ELN-Refined Risk Stratification for Older Adults with Newly Diagnosed AML Given Lower-Intensity Therapy.

While the 2022 European LeukemiaNet (ELN) acute myeloid leukemia (AML) risk classification reliably predicts outcomes in younger patients treated with intensive chemotherapy, it is unclear whether it applies to adults ≥ 60 years treated with lower-intensity treatment (LIT). We aimed to test the prognostic impact of ELN risk in patients with newly diagnosed (ND) AML ≥ 60 years given LIT and to further refine risk stratification for these patients. A total of 595 patients were included: 11% had favorable-risk, 11% had intermediate-risk, and 78% had adverse-risk AML as defined by ELN. ELN risk was prognostic for overall survival (OS) (P<0.001) but did not stratify favorable-risk from intermediate-risk (P=0.71). Within adverse-risk AML, the impact of additional molecular abnormalities was further evaluated. Multivariable analysis was performed on a training set (N=316) and identified IDH2 mutation as an independent favorable prognostic factor, and KRAS, MLL2, and TP53 mutations as unfavorable (P<0.05). A "mutation-score" was calculated for each combination of these mutations, assigning adverse-risk patients into two risk groups: -1 to 0 points ("Beat-AML-intermediate") vs 1+ points ("Beat-AML-adverse"). In the final refined risk classification, the ELN favorable- and intermediate-risk groups were combined into a newly defined "Beat-AML-favorable-risk", in addition to mutation scoring within the ELN adverse-risk. This approach redefines risk for older ND AML and proposes refined Beat-AML-favorable- (22%), Beat-AML-intermediate- (41%), and Beat-AML-adverse-risk (37%) groups with improved discrimination for OS (2-year OS: 48% vs 33% vs 11%, respectively, P<0.001; C-index: 0.60 vs 0.55 for ELN), providing patients and providers additional information for treatment decision-making.

Phase 1 dose escalation study of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine in patients with myeloid malignancies.

BACKGROUND: Mouse double minute-2 homolog (MDM2) plays a key role in downregulating p53 activity in hematologic malignancies, and its overexpression is associated with poor outcomes. METHODS: This phase 1 study assessed the safety and efficacy of different dosing regimens of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine (AZA) in patients with relapsed or refractory acute myeloid leukemia or high-risk myelodysplastic syndromes. RESULTS: Seventy-four patients (monotherapy, n = 57; milademetan-AZA combination, n = 17) were treated. The maximum tolerated dose of milademetan was 160 mg once daily given for the first 14-21 days of 28-day cycles as monotherapy and on Days 5-14 in combination with AZA. Dose-limiting toxicities were gastrointestinal, fatigue, or renal/electrolyte abnormalities. Treatment-emergent adverse events related to milademetan occurred in 82.5% and 64.7% of participants in the monotherapy and AZA combination arms, respectively. Two participants (4.2%) in the monotherapy arm achieved complete remission (CR), and 1 (2.1%) achieved CR with incomplete blood count recovery (CRi). Two participants (13.3%) achieved CRi in the combination arm. New TP53 mutations, detected only during milademetan monotherapy, were found pre-existing below standard detection frequency by droplet digital polymerase chain reaction. INTERPRETATION: Milademetan was relatively well tolerated in this population; however, despite signals of activity, clinical efficacy was minimal.

Venetoclax and Cobimetinib in Relapsed/Refractory AML: A Phase 1b Trial.

BACKGROUND: Therapies for relapsed/refractory acute myeloid leukemia remain limited and outcomes poor, especially amongst patients who are ineligible for cytotoxic chemotherapy or targeted therapies. PATIENTS AND METHODS: This phase 1b trial evaluated venetoclax, a B-cell lymphoma-2 (BCL-2) inhibitor, plus cobimetinib, a MEK1/2 inhibitor, in patients with relapsed/refractory acute myeloid leukemia, ineligible for cytotoxic chemotherapy. Two-dimensional dose-escalation was performed for venetoclax dosed daily, and for cobimetinib dosed on days 1-21 of each 28-day cycle. RESULTS: Thirty patients (median [range] age: 71.5 years [60-84]) received venetoclax-cobimetinib. The most common adverse events (AEs; in ≥40.0% of patients) were diarrhea (80.0%), nausea (60.0%), vomiting (40.0%), febrile neutropenia (40.0%), and fatigue (40.0%). Overall, 66.7% and 23.3% of patients experienced AEs leading to dose modification/interruption or treatment withdrawal, respectively. The composite complete remission (CRc) rate (complete remission [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery) was 15.6%; antileukemic response rate (CRc + morphologic leukemia-free state/partial remission) was 18.8%. For the recommended phase 2 dose (venetoclax: 600 mg; cobimetinib: 40 mg), CRc and antileukemic response rates were both 12.5%. Failure to achieve an antileukemic response was associated with elevated baseline phosphorylated ERK and MCL-1 levels, but not BCL-xL. Baseline mutations in ≥1 signaling gene or TP53 were noted in nonresponders and emerged on treatment. Pharmacodynamic biomarkers revealed inconsistent, transient inhibition of the mitogen-activated protein kinase (MAPK) pathway. CONCLUSION: Venetoclax-cobimetinib showed limited preliminary efficacy similar to single-agent venetoclax, but with added toxicity. Our findings will inform future trials of BCL-2/MAPK pathway inhibitor combinations.

A study to assess the efficacy of enasidenib and risk-adapted addition of azacitidine in newly diagnosed IDH2-mutant AML.

ABSTRACT: Enasidenib (ENA) is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML substudy, we applied a risk-adapted approach to assess the efficacy of ENA monotherapy for patients aged ≥60 years with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated that mutant IDH2 was in the dominant leukemic clone. Patients for whom ENA monotherapy did not induce a complete remission (CR) or CR with incomplete blood count recovery (CRi) enrolled in a phase 1b cohort with the addition of azacitidine. The phase 2 portion assessing the overall response to ENA alone demonstrated efficacy, with a composite complete response (cCR) rate (CR/CRi) of 46% in 60 evaluable patients. Seventeen patients subsequently transitioned to phase 1b combination therapy, with a cCR rate of 41% and 1 dose-limiting toxicity. Correlative studies highlight mechanisms of clonal elimination with differentiation therapy as well as therapeutic resistance. This study demonstrates both efficacy of ENA monotherapy in the upfront setting and feasibility and applicability of a risk-adapted approach to the upfront treatment of IDH2-mutant AML. This trial is registered at www.clinicaltrials.gov as #NCT03013998.

Association of geriatric measures and global frailty with cognitive decline after allogeneic hematopoietic cell transplantation in older adults.

INTRODUCTION: Allogeneic hematopoietic cell transplantation (alloHCT) is increasingly offered to older adults, and its potential impact on cognition in this population is understudied. This work aims to evaluate the ability of cancer-specific geriatric assessments (cGA) and a global frailty index based on accumulation of deficits identified in the cGA to predict the risk of cognitive decline after alloHCT in older adults. MATERIALS AND METHODS: AlloHCT recipients aged 50 years or older completed a cGA, including a cognitive evaluation by the Blessed Orientation Memory Concentration (BOMC) test, at baseline prior to alloHCT and then at 3, 6, and 12 months after transplant. Baseline frailty was assessed using a deficit accumulation frailty index (DAFI) calculated from the cGA. A multinomial logit model was used to examine the association between predictors (individual cGA measures, DAFI) and the following three outcomes: alive with stable or improved cognition, alive with cognitive decline, and deceased. In post-hoc analyses, analysis of variance was used to compare BOMC scores at baseline, 3, 6, and 12 months across frailty categories. RESULTS: In total, 148 participants were included, with a median age of 62 (range 50-76). At baseline, 12% had cognitive impairment; at one year, 29% of survivors had improved BOMC scores, 33% had stable BOMC, and 37% had worse BOMC. Prior to transplant, 25% were pre-frail and 11% were frail. Individual baseline cGA measures were not associated with cognitive change at one year as assessed by BOMC. Adjusting for age, sex, and education, those who were frail at baseline were 7.4 times as likely to develop cognitive decline at one year than those who were non-frail, although this finding did not reach statistical significance (95% confidence interval [CI] 0.74-73.8, p = 0.09). The probability of being alive with stable/improved cognition at 12 months for the non-frail, pre-frail, and frail groups was 43%, 34%, and 8%, respectively. DISCUSSION: Baseline geriatric measures and frailty were not significantly associated with cognitive change as assessed by BOMC in adults aged 50 or older after alloHCT. However, the study was underpowered to detect clinically meaningful differences, and future work to elucidate potential associations between frailty and cognitive outcomes is warranted.

Evaluation of venous thromboembolism prophylaxis protocol in hematopoietic cell transplant patients.

Hematopoietic cell transplant (HCT) recipients are at risk for thromboembolic and bleeding complications. There is limited evidence regarding the optimal approach to managing venous thromboembolism (VTE) prophylaxis in hospitalized patients undergoing HCT. In this retrospective cohort study, we evaluated the incidence of bleeding and VTE events in hospitalized HCT patients who received VTE prophylaxis per our institution's VTE Prophylaxis Protocol (VPP), with either enoxaparin 40 mg subcutaneously daily or heparin 5 000 units subcutaneously twice daily, compared to historical controls who did not receive VTE prophylaxis. The primary outcome was a composite of major bleeding events, clinically relevant non-major bleeding (CRNMB), and minor bleeding. The secondary outcome was a composite of VTE events. A total of 614 patients were evaluated, including 278 prior to and 336 after implementation of VPP. VTE prophylaxis resulted in no difference in bleeding events (15.1% in the pre-VPP group vs. 14.6% in the post-VPP group, p = 0.86) or composite of major and CRNMB events (0.72% vs. 0.30%, p = 0.59). There was a trend toward lower incidence of VTE events in the post-VPP group which did not reach statistical significance (8.6% vs. 6.0%, p = 0.20). We conclude that VTE prophylaxis does not pose additional bleeding risk in HCT patients.

Acute Myeloid Leukemia, Version 3.2023, NCCN Clinical Practice Guidelines in Oncology.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States. Like AML, blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a myeloid malignancy. It is a rare malignancy characterized by the aggressive proliferation of precursors of plasmacytoid dendritic cells that frequently involves the bone marrow, skin, central nervous system, and other organs and tissues. This discussion section focuses on the diagnosis and management of BPDCN as outlined in the NCCN Guidelines for AML.

The Transplantation Ecosystem: A New Concept to Improve Access and Outcomes for Older Allogeneic Hematopoietic Cell Transplantation Patients.

Allogeneic hematopoietic cell transplantation (HCT) is increasingly offered to older adults with hematologic malignancies, even though nonrelapse mortality remains a major concern in older patients owing to more comorbidities and greater frailty compared with their younger counterparts. The importance of patient fitness, a well-matched donor, and disease control to the success of allogeneic HCT have been well documented; however, these factors fail to account for the impact of the complex transplantation ecosystem (TE) that older adult HCT candidates must navigate. We propose a definition of the TE modeled after the social determinants of health. Furthermore, we outline a research agenda aimed at increasing understanding of the roles of individual social determinants of transplantation health in the larger ecosystem and how they may benefit or harm older adult HCT candidates. Herein we define the TE and its individual tenets, the social determinants of transplantation health. We review the available literature while incorporating the expertise of the membership of the American Society for Transplantation and Cellular Therapy (ASTCT) Special Interest Group for Aging. The membership of the ASTCT Special Interest Group for Aging identify knowledge gaps and strategies to address them for each of the described social determinants of transplantation health. The ecosystem is an essential but underappreciated pillar for transplant access and success. We put forth this novel research agenda seeking to gain a better understanding of the complexity of HCT in older adults and develop strategies to improve access to HCT, survival, and quality of life.

Entospletinib with decitabine in acute myeloid leukemia with mutant TP53 or complex karyotype: A phase 2 substudy of the Beat AML Master Trial.

BACKGROUND: Patients with acute myeloid leukemia (AML) who have tumor protein p53 (TP53) mutations or a complex karyotype have a poor prognosis, and hypomethylating agents are often used. The authors evaluated the efficacy of entospletinib, an oral inhibitor of spleen tyrosine kinase, combined with decitabine in this patient population. METHODS: This was a multicenter, open-label, phase 2 substudy of the Beat AML Master Trial (ClinicalTrials.gov identifier NCT03013998) using a Simon two-stage design. Eligible patients aged 60 years or older who had newly diagnosed AML with mutations in TP53 with or without a complex karyotype (cohort A; n = 45) or had a complex karyotype without TP53 mutation (cohort B; n = 13) received entospletinib 400 mg twice daily with decitabine 20 mg/m2 on days 1-10 every 28 days for up to three induction cycles, followed by up to 11 consolidation cycles, in which decitabine was reduced to days 1-5. Entospletinib maintenance was given for up to 2 years. The primary end point was complete remission (CR) and CR with hematologic improvement by up to six cycles of therapy. RESULTS: The composite CR rates for cohorts A and B were 13.3% (95% confidence interval, 5.1%-26.8%) and 30.8% (95% confidence interval, 9.1%-61.4%), respectively. The median duration of response was 7.6 and 8.2 months, respectively, and the median overall survival was 6.5 and 11.5 months, respectively. The study was stopped because the futility boundary was crossed in both cohorts. CONCLUSIONS: The combination of entospletinib and decitabine demonstrated activity and was acceptably tolerated in this patient population; however, the CR rates were low, and overall survival was short. Novel treatment strategies for older patients with TP53 mutations and complex karyotype remain an urgent need.