When it is dark enough, you can see the stars.” —Ralph Waldo Emerson
Low-intensity therapy for older or unfit patients with acute myeloid leukemia (AML) was introduced in the early 2000s in the form of low-dose cytarabine or hypomethylation therapy (azacitidine or decitabine). Recent studies documented the benefit of hypomethylation therapy plus venetoclax; this is now an established standard of care in older or unfit patients with AML. Experts still debate the best definition of older/unfit patients with AML, whether lower-intensity therapy can be further improved (with the addition of other targeted therapies), and whether such therapies can be used even in subsets of younger/fit patients with AML. Several recent abstracts from the European Hematology Association (EHA) Congress and the ASCO Annual Meeting add to this knowledge.
Induction Therapy: Low-Intensity Regimen vs Intensive Chemotherapy
EHA Abstract P570:Real-world efficacy outcomes of venetoclax plus azacitidine vs intensive chemotherapy for induction therapy in mainly older adults with AML.1
Background: Intensive chemotherapy is commonly used to achieve remission in young adults with newly diagnosed AML. The combination of venetoclax plus azacitidine is approved for the treatment of patients with newly diagnosed AML aged ≥ 75 years or with comorbidities that preclude the use of intensive chemotherapy in younger adults.2 Patients with AML in randomized controlled trials often do not reflect the population seen in clinical practice due to strict eligibility criteria; therefore, analysis of real-world databases is important.
Syed Ali Abutalib, MD
Farhad Ravandi, MD
Methods: This retrospective study compared U.S. real-world outcomes for the use of venetoclax plus azacitidine vs intensive chemotherapy, particularly in an older population. Of 7,484 patients in the Flatiron databasea with newly diagnosed AML, 1,188 met the selection criteria and 436 were propensity score–matched, resulting in 218 patients per treatment group. In the matched venetoclax-plus-azacitidine vs intensive chemotherapy cohorts, patients had a mean age of 70 vs 69 years and a mean Charlson Comorbidity Indexb of 0.5 vs 0.7, respectively.
Results: The rates of patients with complete remission and those who proceeded to allogeneic hematopoietic cell transplantation (allo-HCT) were significantly lower with venetoclax plus azacitidine vs intensive chemotherapy at 46% vs 62% (P = .001) and 16% vs 31% (P < .001), respectively. Patients aged 59 or younger had better overall survival with intensive chemotherapy (hazard ratio [HR] = 2.19). Median overall survival for venetoclax plus azacitidine vs intensive chemotherapy in the matched population was 13.0 vs 17.2 months (P = .263), respectively, and with censoring for allo-HCT, it was 11.0 vs 15.6 months (P = .410). Among patients aged 75 years or older, the hazard ratio favored lower-intensity therapy (HR = 0.66). The same was observed in patients with NPM1 mutations (HR = 0.35, 95% confidence interval [CI] = 0.10–1.24) and IDH1 mutations (HR = 0.47, 95% CI = 0.13–1.66). A suboptimal number of bone marrow biopsies were performed in the low-intensity group.
Clinical Implications: This retrospective study highlights the importance of proper selection of patients for different therapies. Although intensive chemotherapy produced better outcomes in younger patients, lower-intensity therapy proved better in older patients and in patients with some AML molecular subsets.
EHA Abstract P584: Overall survival with intensive chemotherapy vs nonintensive chemotherapy in patients with newly diagnosed AML from the Connect Myeloid Disease Registry ineligible for randomized clinical trials.2
Background: Another important retrospective study presented at the EHA Congress 2022 analyzed the Connect Myeloid Disease Registry database (ClinicalTrials.gov identifier NCT01688011) and compared outcomes of patients who would have been considered eligible or ineligible per criteria used in the VIALE-A trial (a randomized trial of azacitidine vs venetoclax plus azacitidine × 7 days).
Methods: The investigators analyzed registry data by categorizing patients into three groups (median age = 71 years): (1) “eligible” patients (n = 192; 26%), who would have met all VIALE-A inclusion criteria; (2) “unfit” patients (n = 327; 45%), who would have been ineligible for VIALE-A due to at least one of the following: abnormal liver/kidney function, high Eastern Cooperative Oncology Group (ECOG) performance status, recent prior malignancy, comorbidities score ≥ 2 by ACE-27, hepatic grade ≥ 1, AIDS grade ≥ 1; and (3) “fit” patients (n = 215; 29%), who would have been ineligible for a venetoclax-based regimen in VIALE-A because they would have qualified for intensive chemotherapy (defined as age ≤ 74 years, low ECOG performance status, no apparent cardiovascular/renal comorbidities, and did not meet any group 2 criteria).
Results: The investigators reported the following findings:
Group 1: Low-intensity venetoclax based therapy (n = 27) was superior to intensive chemotherapy (n = 31; median overall survival = 23 vs 13 months, HR = 1.45, 95% CI = 0.66–3.17; P value not significant).
Group 2: Among unfit patients, those receiving intensive chemotherapy had significantly longer overall survival compared with patients receiving a venetoclax-based regimen (median overall survival = 14 vs 6 months; HR = 0.51, 95% CI = 0.27–0.98; P = .042. Unfit patients who received intensive chemotherapy went on to transplant more frequently than those who received venetoclax-based therapies (16% [n = 17] vs 1% [n = 1]).
Group 3: Among fit patients, median overall survival was 19 months for those receiving intensive chemotherapy (n = 69) and could not be estimated for patients receiving venetoclax-based therapies due to the small sample size (n = 10).
Clinical Implications: This analysis suggests that randomized controlled trials may be excluding patients who appear “unfit” but can potentially tolerate intensive chemotherapy and experience improved survival.
EHA Abstract S125: Decitabine × 10 days (n = 303) vs conventional chemotherapy (7 + 3 regimen; n = 303) followed by allo-HCT in medically fit patients ≥ 60 years with AML: Randomized phase III study of the EORTC leukemia group, GIMEMA, CELG, and GMDS-SG (54 centers; NCT02172872).3
Background: Older patients with AML have a poor prognosis, with 5-year overall survival less than 20%, after intensive chemotherapy. The majority of these patients are unable to receive curative allo-HCT. The rationale of this study was to use a milder AML front-line approach with reduced toxicity and allow a greater opportunity for allo-HCT.
“In patients with AML who have adverse cytogenetics, CPX-351 did not improve response, overall survival, or event-free survival compared with FLAG-Ida but was associated with better duration of remission and relapse-free survival.”— Syed Ali Abutalib, MD and Farhad Ravandi, MD
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Methods: The primary endpoint was overall survival. Patients fit for intensive chemotherapy were randomly assigned 1:1 (n = 606) to the decitabine group and the conventional chemotherapy group. They were stratified by de novo AML vs secondary AML, age (60–64 vs 65–70 vs ≥ 70 years) and by institution. Median follow-up was 4 years. Median patient age was 68 years. A median of three decitabine cycles and two intensive chemotherapy cycles were administered.
Results: The complete response/complete response with incomplete blood cell count recovery rate was 48% with decitabine and 61% with intensive chemotherapy. Access to allo-HCT was similar, 40% vs 39%, and the 3-year overall survival rate was similar, 30% vs 33%. In patients aged 70 or older, overall survival was better with decitabine × 10 days (HR = 0.84; P = .58).
Notable differences in the incidence of grade 3 to 5 adverse events were reported (before allo-HCT) favoring decitabine over intensive chemotherapy. The incidence of grade 5 treatment-related adverse events after allo-HCT was comparable in both treatment arms (25% with decitabine and 22% with intensive chemotherapy). The 30-day mortality rate was 3.6% with decitabine and 6.4% with intensive chemotherapy.
Clinical Implications: This large multicenter randomized study demonstrated similar overall survival, fewer toxicities with less time in the hospital, and better quality of life with decitabine compared with intensive chemotherapy. The allo-HCT rates were similar in both arms. On subgroup analysis, the overall survival benefit favored intensive chemotherapy in patients up to age 64, especially in those with NPM1 mutations. In patients aged 70 or older, the survival benefit favored decitabine × 10 days.
Some unanswered questions that require further investigation include the following:
- Can hypomethylating agents plus venetoclax further improve survival compared with the 3 + 7 regimen in these different age groups?
- How do overall survival results with decitabine × 10 days with or without venetoclax compare with CPX-351 (liposomal daunorubicin plus cytarabine) therapy in secondary AML?
Young Adults With High-Risk AML and Myelodysplastic Syndromes
EHA Abstract S128: Randomized trial of CPX-351 and FLAG-Ida (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin) in high-risk AML or myelodysplastic syndromes (> 10% blasts): Results from the NCRI AML19 trial -(ISRCTN78449203).4
Background: Gradual but definite progress has been made in the treatment of younger adults with AML, except the 25% to 30% with high-risk AML. CPX-351 has shown a survival advantage for older patients (aged 60–75) with secondary AML compared with conventional, 3 + 7 chemotherapy; however, in younger patients, there is a lack of randomized evidence for benefit.5
Methods: The trial included 635 patients (mainly up to age 60 with high-risk AML or myelodysplastic syndromes [>10% blasts]) who were treated with CPX-351 or FLAG-Ida. Three groups of high-risk patients were randomly assigned 2:1 in favor of CPX-351, with the aim of proceeding to allo-HCT. The investigators presented results for group 1 (n = 195), which included patients with known adverse-risk cytogenetics. Patients were randomly assigned at diagnosis to four courses of CPX-351 and two courses of FLAG-Ida followed by MACE/MidAC (amsacrine [not available in the United States], cytarabine, etoposide, and then mitoxantrone/cytarabine) consolidation. This group included 49.2% with de novo AML, 20.3% with secondary AML, and 30.5% with high-risk myelodysplastic syndromes. Group 1 was not powered to claim statistical significance; therefore, these results are intended to be exploratory and hypothesis-generating.
Results: The overall response rate (complete response or complete response with incomplete blood cell count recovery) was 64.8% with CPX-351 and 74.4% with FLAG-Ida (univariate odds ratio = 0.57, 95% CI = 0.30–1.10, P = .09). Overall survival rates at 3 years were 32% and 24%, with a median overall survival of 13.3 months vs 10.2 months (univariate hazard ratio = 0.83, 95% CI = 0.58–1.18, P = .3) with CPX-351 and FLAG-Ida, respectively.
Event-free survival was not significantly different (hazard ratio = 0.91 95% CI = 0.50–1.64, P = .76). Relapse-free survival rates at 3 years were 43% and 28%, and median relapse-free survival was 22.1 vs 14 months (univariate hazard ratio = 0.66, 95% CI = 0.41–1.06, P = .09) with CPX-351 and FLAG-Ida, respectively. The median duration of remission favored CPX-351 and was 319.5 days vs 167 days (P = .046) with CPX-351 vs FLAG-Ida, respectively. Hematologic toxicity was greater in course 1 with CPX-351, but day 30 and day 60 mortality did not significantly differ between the arms.
Clinical Implications: In patients with AML who have adverse cytogenetics, CPX-351 did not improve response, overall survival, or event-free survival compared with FLAG-Ida but was associated with a better duration of remission and relapse-free survival. More patients receiving CPX-351 underwent transplantation (50.5% vs 41.5%), with a median number of two courses given prior to transplant in both arms. Further follow-up is needed to determine the clinical significance of those differences.
Maintenance Therapy for AML
ASCO Abstract e19018: Phase II study of intravenous azacitidine and venetoclax as maintenance therapy for patients with AML in remission after high- or low-intensity therapy, including those who are not immediately candidates for allo-HCT (NCT04062266).6
Background: Although remission rates for newly diagnosed AML have improved with modern therapies, relapse remains a major cause of treatment failure and death. Postremission maintenance therapy in AML seeks to prevent relapses, with the goal of improving survival. From a historical cohort, among patients who did not receive allo-HCT in first remission, the median relapse-free survival has been 10, 8, and 5.7 months for those who received intensive therapy, those who received lower-intensity therapy, and those with detectable measurable residual disease (MRD), respectively. In the QUAZAR AML-001 trial, oral azacitidine was shown to be effective in improving relapse-free and overall survival in older AML patients (> aged 55) in first complete remission following intensive chemotherapy.7
“Maintenance therapy with oral azacitidine and venetoclax yields encouraging median relapse-free survival and overall survival durations with minimal toxicity in first complete remission.”— Syed Ali Abutalib, MD and Farhad Ravandi, MD
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Methods: The primary outcome was modified relapse-free survival (enrollment to relapse or death). Maintenance consisted of intravenous azacitidine at 50 mg/m2 on days 1 to 5 and venetoclax at 400 mg on days 1 to 14 every 28 days, for up to 24 cycles. Patients who became eligible for allo-HCT were taken off study and censored at the time of allo-HCT. The median patient age at diagnosis was 52 years. Prior therapy with venetoclax was given in 58% of patients.
Results: Median relapse-free survival was not reached in both the high- and low-intensity therapy cohorts: 1-year median relapse-free survival 73.9% and 58.3%, respectively. Median overall survival was not reached in both the high- and low-intensity therapy cohorts. The 1-year overall survival rate was 93.8% vs 53.3%, respectively. Median relapse-free survival was numerically higher in patients with prior venetoclax exposure, with a 1-year median relapse-free survival rate of 79.1% vs 55.6% in non–venetoclax-exposed patients (P = .067).
In the safety analysis, 12% of patients required venetoclax dose reduction for cytopenias. In addition, there were eight relapses and six deaths (all after relapse or allo-HCT) had occurred. Overall, 15% of patients went off protocol for allo-HCT.
Clinical Implications: Maintenance therapy with intravenous azacitidine and venetoclax yields encouraging median relapse-free survival and overall survival durations with minimal toxicity in first complete remission. Longer follow-up and comparative studies (with intravenous azacitidine) are needed to confirm and compare these initial results with alternative strategies, respectively.
Patients With AML Who Are Unfit for Conventional Therapies or Clinical Trials
EHA Abstract P581: Phase II study of lower-intensity front-line therapy for newly diagnosed patients with AML who are unfit or otherwise not eligible for front-line clinical trials (n = 25; NCT01515527).8
Background: Patients with AML frequently present with abnormal organ function, a poor performance status, concurrent active malignancies, and active infections. These factors often preclude these patients from enrollment on front-line clinical trials, since standard eligibility criteria routinely exclude them.
Methods: The primary objective of this study was 60-day survival rate. Eligibility criteria included either creatinine ≥ 2 mg/dL, total bilirubin ≥ 2 mg/dL, ECOG performance status of 3 or 4, or ineligibility for participation in a higher-priority protocol. Also, patients with active concurrent malignancies and ongoing infection related to AML could be enrolled. Induction therapy consisted of intravenous cladribine at 5 mg/m2 on days 1 to 5, subcutaneous cytarabine at 20 mg twice daily on days 1 to 10, followed by consolidation with intravenous cladribine at 5 mg/m2 on days 1 to 3 and subcutaneous cytarabine at 20 mg twice daily on days 1 to 10 alternating with intravenous decitabine at 20 mg/m2 daily on days 1 to 5. The median age of patients was 73 years.
Results: In all, 10 of 25 patients (40%) achieved a complete response and 7 of 25 patients (28%) achieved a complete response with incomplete blood cell count recovery. Among responders, six patients (35%) achieved MRD-negative status by flow cytometry. Of seven patients with no response, all were European LeukemiaNet (ELN) adverse risk. The 30- and 60-day mortality rates were 8% and 16%, respectively. At a median follow-up of 9.4 months, the median overall survival and event-free survival were both 8.3 months, with both a 60-day overall survival (primary endpoint) and event-free survival rate of 83% and a median relapse-free survival of 5.8 months.
Clinical Implications: In an unfit patient population with a high comorbidity burden ineligible for other clinical trials, induction therapy with cladribine plus low-dose cytarabine was feasible. Treating this patient population on a clinical trial can allow some patients to achieve remission and move on to effective postremission therapy. The benefit was not observed in the ELN adverse-risk group, but the sample size was small.
DISCLOSURE: Dr. Abutalib has served on an advisory board for AstraZeneca. Dr. Ravandi has received research funding from BMS/Celgene, Amgen, Astex/Taiho, Xencor, Syros, Prelude, AbbVie, and Biomea Fusion. He has also received consultancy/advisory board fees from Celgene/BMS, Novartis, Genentech/AbbVie, Syros, and Astellas.
a Flatiron Health is an independent affiliate of the Roche Group. Flatiron’s database contains more than 3 million patient records available for research, with 75% from community practices and 25% of the data from academic cancer centers. To learn more about Flatiron, visit flatiron.com.
b The Charlson Comorbidity Index assesses the relevance of comorbid diseases in the prediction of 1-year mortality. The index applies a weighted score to each of 17 comorbidities, based on the relative risk of 1-year mortality. The sum of the index score is an indicator of disease burden and a strong estimator of mortality.
REFERENCES
1. Zeidan AM, Pollyea DA, Borate U, et al: Real-world efficacy outcomes of venetoclax plus azacitidine vs intensive chemotherapy for induction therapy in adult patients with acute myeloid leukemia. EHA Congress 2022. Abstract P570. Presented June 10, 2022.
2. Erba H, Pollyea D, Sekeres M, et al: Overall survival with intensive chemotherapy (IC) vs non-IC in patients with newly diagnosed AML from the Connect Myeloid Disease Registry ineligible for randomized clinical trials. EHA Congress 2022. Abstract P584. Presented June 10, 2022.
3. Lübbert M, Wijermans P, Kicinski M, et al: 10-day decitabine vs. conventional chemotherapy (‘3+7’) followed by allografting in AML patients ≥ 60 years: A randomized phase III study of the EORTC leukemia group, GIMEMA, CELG, and GMDS-SG. EHA Congress 2022. Abstract S125. Presented June 11, 2022.
4. Russell N, Wilhelm-Benartzi Charlotte, Knapper S, et al: A randomised comparison of CPX-351 and FLAG-Ida in high risk acute myeloid leukaemia: Results from the NCRI AML19 Trial. EHA Congress 2022. Abstract S128. Presented June 11, 2022.
5. Lancet JE, Uy GL, Cortes JE, et al: CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol 36:2684-2692, 2018.
6. Bazinet A, Kantarjian H, Borthakur G, et al: Phase 2 study of azacitidine and venetoclax as maintenance therapy for acute myeloid leukemia patients in remission. 2022 ASCO Annual Meeting. Abstract e19018.
7. Wei AH, Döhner H, Pocock C, et al: Oral azacitidine maintenance therapy for acute myeloid leukemia in first remission. N Engl J Med 383:2526-2537, 2020.
8. Venugopal S, Jabbour E, Pemmaraju N, et al: Phase II study of lower-intensity frontline therapy for newly diagnosed patients with AML who are unfit or otherwise not eligible for frontline clinical trials. EHA Congress 2022. Abstract P581. Presented June 10, 2022.
Dr. Abutalib is Co-Director of the Hematology and BMT/Cellular Therapy Programs and Director of the Clinical Apheresis Program at the Cancer Treatment Centers of America and NMDP Midwest Apheresis Program, Zion, Illinois; Associate Professor at Rosalind Franklin University of Medicine and Science; and Founder of Advances in Cell and Gene Therapy. Dr. Ravandi is Janiece and Stephen A. Lasher Professor of Medicine and Chief of Section of Developmental Therapeutics in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, Houston.
