Acute myeloid leukemia (AML) is a highly heterogeneous hematologic malignancy, presenting significant challenges in treatment strategies and prognosis management for clinicians. At this year’s ASCO conference, several AML studies were presented. This article highlights three of them, covering the importance of frailty assessment, exploration of shortened treatment regimens, and interim results of new therapeutic agents. These advancements not only offer new insights into treatment strategies but also bring hope to patients.01. Frailty Risk Assessment and Its Impact on Treatment Outcomes in AML Patients (FRAIL-AML): A Population-Based Study from Ontario, Canada (Abstract #6506)
Background: In AML, treatment decisions, particularly between intensive and non-intensive therapies, depend on clinicians’ assessment of the patient’s fitness. Frailty, a broader concept of fitness, is associated with poor prognosis in various cancers. Integrating frailty assessment into cancer treatment choices provides precision beyond disease-related factors. However, the impact of frailty on AML treatment outcomes has not been fully studied.
Methods: This retrospective cohort study utilized the Ontario population health administrative database (ICES) and included all AML patients aged 18 and above who received treatment within 90 days of diagnosis between 2006 and 2021. The McIsaac Frailty Index (MFI) was used to assess frailty. Patients were classified as Fit (FT), Pre-Frail (PFR), or Frail (FR) based on MFI tertiles. Treatment intensity was categorized as Intensive (IT) or Non-Intensive (NIT) based on standard practice. The primary endpoint was overall survival (OS), and Cox regression was used to measure the association between frailty and OS in both IT and NIT AML groups.
Results: Among 5450 patients, the median age was 65 years (IQR 54-74), with 55.8% males and 44.2% females. 65% (n=3543) received intensive treatment, with 29.4% and 35.5% of these being frail and pre-frail, respectively. The remaining 35% (n=1907) received non-intensive treatment, with 41.1% frail and 32.3% pre-frail. The median OS (95% CI) for the entire cohort, intensive treatment group, and non-intensive treatment group were 12.5 (12.0-13.2), 16.7 (15.7-18.2), and 7.6 (7.0-8.2) months, respectively. Frail patients had significantly lower OS than fit patients in both IT and NIT groups (P<0.0001). Frailty, older age, and non-AML malignancies were identified as risk factors for poor OS in both treatment groups through univariate and multivariate analyses.
Conclusion: Higher frailty is independently associated with poor OS in AML patients, even after adjusting for age. There is a mismatch in treatment intensity allocation based on frailty status, with about 30% of frail patients receiving intensive treatment and over 25% of fit patients receiving non-intensive treatment. This study underscores the need for standardized frailty assessments in AML patients to optimize treatment decisions.
02. Shortened “7+7” Regimen vs. Standard Hypomethylating Agents (HMA) + Venetoclax in Newly Diagnosed Elderly or Unfit AML Patients: A Retrospective Comparison (Abstract #6507)
Background: HMA + Venetoclax (VEN) is the standard treatment for elderly or chemotherapy-intolerant AML patients. While the VEN label recommends a continuous 28-day cycle, a shortened VEN cycle may reduce cytopenia and improve tolerability. The efficacy and safety of shorter VEN cycles compared to standard HMA + VEN regimens remain unclear.
Methods: A retrospective comparison was conducted at seven French centers (n=82) for newly diagnosed (ND) AML patients treated with Azacitidine (AZA) 7 days plus VEN 7 days (“7+7” regimen), compared with patients from U.S. centers (n=173) receiving standard-dose HMA + VEN (s-HMA/VEN), which typically includes 21-28 days of VEN. Comprehensive complete remission rates (CRc, including CR and CRi), overall survival (OS), event-free survival (EFS), and bone marrow suppression were compared between the two groups.
Results: 59% of s-HMA-VEN patients received 10 days of Decitabine (DAC), with the remainder receiving 5 days of DAC or 7 days of AZA. CRc rates were similar between “7+7” (72%) and s-HMA/VEN (71%) (P=0.89). Both groups had a median of one cycle to first response, but 42% of “7+7” responders required more than one cycle for the first response compared to almost all s-HMA-VEN responders (99%) after one cycle. The median cycles to best response were two for “7+7” and one for s-HMA/VEN (P=0.02). Four-week mortality was similar (2% “7+7” vs. 6% s-HMA-VEN; P=0.24), but eight-week mortality was higher in the s-HMA-VEN group (17%) than in the “7+7” group (6%) (P=0.02). Median OS was 11.2 months for “7+7” (28% 2-year survival) and 10.1 months for s-HMA/VEN (33% 2-year survival) (P=0.93). Fewer “7+7” patients required platelet transfusions in the first cycle compared to s-HMA/VEN patients (62% vs. 77%, P=0.01). Rates of febrile neutropenia and red blood cell transfusion requirements in the first cycle were similar between groups.
Conclusion: Although this multicenter retrospective comparison has limitations, no significant efficacy difference was observed between the “7+7” regimen and the standard HMA + VEN regimen in newly diagnosed AML. The “7+7” regimen was associated with lower platelet transfusion needs and eight-week mortality.
03. Interim Safety and Efficacy of BP1001 in Phase II Study for AML (Abstract #6511)
Background: Oncogenic tyrosine kinases induce AML progression through the growth factor receptor-bound protein-2 (Grb2). BP1001, a liposomal antisense oligonucleotide targeting Grb2, enhances cancer cell sensitivity to chemotherapeutics like Decitabine (DEC) and Venetoclax (VEN). A multicenter, open-label Phase II study was initiated to evaluate whether BP1001 + DEC + VEN offers higher response rates than previously reported DEC + VEN in newly diagnosed AML (including secondary AML) or refractory/relapsed (R/R) AML patients unfit for intensive therapy.
Methods: From day 4, BP1001 was administered intravenously at 60 mg/m² twice weekly for eight doses over a 28-day cycle. DEC was given at 20 mg/m² intravenously on days 1-5. VEN was administered orally at 100 mg on day 1, 200 mg on day 2, and 400 mg from day 3 to day 14 or 21. Eligible patients were deemed unfit or declined intensive therapy, with ECOG performance status of 0-2. The interim analysis was conducted on January 24, 2024, for patients enrolled between July 28, 2020, and December 26, 2023.
Results: Cohort 1 included 31 newly diagnosed patients; 20 evaluable patients (9 males, 45%), median age 75 (range 69-84), received at least one cycle of BP1001 + DEC + VEN. They had poor-risk (n=12, per ELN 2017 classification) or secondary AML (sAML; n=7) derived from myelodysplastic syndrome (MDS, n=4), chronic myelomonocytic leukemia (CMML, n=1), or therapy-related AML (n=2). 15 patients (75% of evaluable, 54% of enrolled) achieved complete remission/complete remission with incomplete hematologic recovery/complete remission with incomplete platelet recovery (CR/CRi/CRh); 2 patients had partial remission (PR), and 2 had stable disease (SD).
Cohort 2 included 38 R/R patients; 23 evaluable patients (13 males, 57%), median age 63 (range 24-89), received at least one cycle of BP1001 + DEC + VEN, with poor-risk (n=13) or sAML (n=5). 12 patients (55% of evaluable, 32% of enrolled) achieved CR/CRi/CRh; 1 patient had PR, 8 had SD, and 1 treatment failure.
Adverse events were consistent with those expected from DEC, VEN, and/or AML, including fatigue (72%), anemia (60%), and neutropenia (49%), with the most common severe adverse events being febrile neutropenia (26%) and sepsis (5%).
Conclusion: BP1001 + DEC + VEN has been safely administered with no drug-related toxicity observed. With at least half of the patients in both cohorts achieving a response, the study will continue, aiming to enroll 98 and 54 evaluable patients in cohorts 1 and 2, respectively. The efficacy data is encouraging for patients with poor-risk, sAML, and R/R AML.
These studies highlight significant advances in AML treatment, from the importance of frailty assessment to novel therapeutic regimens and promising new drugs, offering new hope for improved patient outcomes.
