To complement The ASCO Post’s comprehensive coverage of the 2019 American Society of Hematology (ASH) Annual Meeting & Exposition, here are several abstracts selected from the meeting proceedings focusing on novel therapeutic regimens for acute myeloid leukemia (AML). For full details of these study abstracts, visit hematology.org/Annual-Meeting.
ABSTRACT 13: Time from diagnosis to treatment does not affect outcome in intensively treated (7+3) patients with newly diagnosed AML (ClinicalTrials.gov identifier NCT03188874)1
Methods: The investigators analyzed the influence of the time from diagnosis to treatment on complete remission, early death, and overall survival in univariable analyses for each day of treatment delay, in groups of 0 to 5, 6 to 10, 11 to 15, and more than 15 days of the time from diagnosis to treatment. The start of treatment was defined by the first day of cytarabine, whereas single-agent hydroxyurea (4% of the patients) was labeled as pretreatment. Patients with acute promyelocytic leukemia were excluded.
Syed A. Abutalib, MD
Margaret Kasner, MD, MSCE
Results: Unadjusted complete remission rates for the patient groups with the time from diagnosis to treatment of 0 to 5, 6 to 10, 11 to 15, and more than 15 days were 80%, 77%, 74%, and 76%, respectively (P = .317). In multivariable analyses accounting for the influence of European Leukemia Network risk, age, white blood cell count, lactate dehydrogenase level, de novo vs secondary AML and Eastern Cooperative Oncology Group status, the overall response for each additional day of the time from diagnosis to treatment was 0.99 (95% confidence interval [CI] = 0.97–1.00; P = .124). Four percent of patients died within the first 30 days from the start of treatment. In multivariable analysis, the overall response for the time from diagnosis to treatment was 1.01 (95% CI = 0.98–1.05; P = .549). After a median follow-up of 40 months, the 2-year overall survival of all patients was 51%. The hazard ratio (HR) for each day of treatment delay was 1.00 (95% CI = 0.99–1.01; P = .317).
GUEST EDITORS
Dr. Abutalib is Assistant Director, Hematology and Hematopoietic Cell Transplantation Director, Hematopoietic Cell Transplant Apheresis Service, Cancer Treatment Centers of America, Zion, Illinois, Editor-in-Chief, Advances in Cell & Gene Therapy. Dr. Kasner is Associate Professor, Director, Acute Leukemia Program, Department of Medical Oncology, Division of Hematologic Malignancy and Stem Cell Transplantation, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia
In multivariable Cox regression analysis, the hazard ratio for time from diagnosis to treatment as a continuous variable was 1.00 (95% CI = 0.99–1.01; P = .689). When overall survival was analyzed separately and stratified for age (≤ 60 and > 60 years), no significant differences between the time from diagnosis to treatment groups were observed.
Clinical Implications: As treatment stratification in intensive first-line treatment of AML evolves, the time from diagnosis to treatment (retrospective) data suggest that it may not be deleterious to wait in most circumstances. A reasonable approach might be to wait for genetic results to assign “clinically stable” patients to the best treatment option. A bias toward a longer time from diagnosis to treatment intervals in patients judged to be clinically stable by the treating physician cannot be excluded entirely in this study.
ABSTRACT 15: Genetic characteristics and outcomes by mutation status in a phase III study of CPX-351 (daunorubicin and cytarabine liposome) vs 7+3 in older adults (aged 60–75) with newly diagnosed, high-risk/secondary AML (NCT01696084)2
Methods: The investigators performed targeted sequencing of 112 genes in pretreatment blood or bone marrow samples from available patient samples (n = 169 of total 309 patients in original study), including 84 treated with CPX-351 and 85 treated with standard 7+3.
Results: Individual gene mutations were associated with specific AML subtypes. Among patients with secondary AML (defined as antecedent myelodysplastic syndromes [MDS] or chronic myelomonocytic leukemia), secondary-type mutations (such as ASXL1, SRSF2, STAG2, and ZRSR2) were more common than in other AML subgroups (nominal P < .05). By contrast, the frequency of TP53 mutations was higher among patients with therapy-related AML (57.6%) and de novo AML (defined as de novo AML with MDS karyotype; 51.2%) than in those with secondary AML (19.4%; nominal P < .0001). Activated signaling genes (FLT3, NRAS, KRAS, PTPN11, CBL, NF1, RIT1, KIT) were more common in the secondary AML subgroup than the other AML subgroups (nominal P = .047). In a univariate analysis, TET2 (38.2% vs 19.3%; nominal P = .014) and EZH2 (12.7% vs 2.6%; nominal P = .014) were more common in patients between the ages of 70 and 75 than in those between the ages of 60 and 69.
OF NOTE
Watch future issues of The ASCO Post for more selected abstracts from the 2019 ASH Annual Meeting & Exposition. Visit ASCOPost.com for interviews with experts filmed live during the ASH Annual Meeting.
There was an association between individual gene mutation(s) and clinical outcomes, focusing on genes mutated in at least 20% of patients. Using a univariable Cox model, median overall survival was longer in the CPX-351 vs 7+3 arms among patients with DNMT3A (12.6 vs 5.5 months; HR = 0.41 [95% CI = 0.19–0.89]) and TET2 (9.1 vs 3.7 months; HR = 0.47 [95% CI = 0.23–0.93]) mutations. Median overall survival was similar among patients with TP53 mutations treated with CPX-351 and 7+3 (4.5 vs 5.1 months; HR = 1.19 [95% CI = 0.70–2.05]). Median overall survival among patients with ASXL1 mutations treated with CPX-351 vs 7+3 was 9.10 vs 6.29 months (HR = 0.67 [95% CI = 0.35–1.27]), and for those with RUNX1 mutations, it was 8.87 vs 4.09 months (HR = 0.58 [95% CI = 0.30–1.11]), respectively.
Clinical Implications: Within the U.S. Food and Drug Administration (FDA)-approved indications of CPX-351 in AML, among patients with high-risk mutations, rates of complete remission or complete remission with incomplete hematology recovery were similar compared with the 7+3 control arm. TP53 mutations were associated with a poor prognosis, irrespective of treatment arm, whereas median overall survival was longer with CPX-351 vs 7+3 among patients with DNMT3A and TET2 (statistically significant) and ASXL1 and RUNX1 (P value trend) mutations.
ABSTRACT 115: Maintenance decitabine (20 mg/m2 for 3 days/month x 12 months) improves disease-free and overall survival after intensive therapy for AML in older adults (median age of 69 years), particularly in FLT3-ITD–negative patients: ECOG-ACRIN (E-A) E2906 randomized study (NCT02085408)3
Methods: The abstract reports the Step 3 part of the parent E2906 study (observation vs maintenance decitabine) with 1:1 randomization (stratified by induction therapy, cytogenetic risk group, age < 70 years). This phase was designed as a phase II pilot randomized study, with target accrual of 172 patients, allowing 90% power to detect a 36% reduction in disease free–survival hazard ratio with decitabine maintenance for 1 year, assuming 140 events and 2 years of follow-up from randomization. However, further accrual to E2906 was suspended in February 2015 by the independent data and safety monitoring committee) due to superior overall survival observed in the standard arm (7+3 [daunorubicin at 60 mg/m2] and intermediate-dose cytarabine consolidation. Thus, ‘Step 3’ completed just 70% (n = 120) of the target accrual. P values reported are two-sided by convention unless specified otherwise.
Results: The median number of decitabine cycles received was six, and analysis was in the intent-to-treat population. Median follow-up was 49.8 months. There were 90 disease free–survival events (47 observation, 43 decitabine), with 82 deaths (46 observation, 36 decitabine). The multivariate Cox model confirmed a superior hazard rate for disease free–survival (one-sided P = .10) and overall survival (one-sided P = .07) in the decitabine arm. The FLT3-ITD status was available for 96 patients; 84 patients were FLT3-ITD–negative (46 observation, 38 decitabine). Superior overall survival was observed in the FLT3-ITD–negative individuals in the decitabine arm (P = .039).
Clinical Implications: There was a significant impact on overall survival for the FLT3-ITD–negative population. The investigators acknowledged study limitations: incomplete accrual due to early termination of the parent E2906 trial and inherent weakness of phase II design. Still, these data support a phase III randomized study of decitabine maintenance, focused on the FLT3-ITD–negative patients who are otherwise transplant-ineligible. Outside of a clinical trial, and due to lack of better maintenance therapies, this might be a reasonable strategy to adopt in clinical practice in select patients with AML.
ABSTRACT 175: Precision medicine treatment in older adults (≥ 60 years) with newly diagnosed AML: Results of multicenter BEAT AML Master trial (NCT03013998)4
Methods: The BEAT AML trial was designed to assess the feasibility of using genetic profiling (local cytogenetics and Foundation Medicine) to assign older adults to molecularly defined, subtype-specific therapies within 7 days of the initial diagnosis in a multicenter clinical trial setting and to delineate the role of molecularly informed first-line treatment of AML with mechanism-based novel therapies. Treatment assignment was made centrally using a predetermined algorithm considering somatic cytogenetic and molecular alterations in the dominant clone, available targeted therapeutics for specific AML subsets, and the likelihood of cure with intensive chemotherapy.
Results: The median age of eligible patients was 72 years, with 38% 75 years of age or older, and 16% had treatment-related AML. Of the 395 eligible patients, 374 (94.7%) were assigned to the different cytogenetic/genomic groups within 7 days. The most common groups were TP53-mutated (19%) and marker-negative (18%) molecular groups.
The BEAT AML trial is dynamic by design, thereby allowing different arms to open over time; all trial arms are designed to evaluate substantial clinical efficacy in small, molecularly defined patient subsets. Overall, 224 patients (57%) had a treatment assignment and consented to a BEAT AML substudy. Of the remaining 171 patients, 103 received standard therapy defined as induction therapy (7+3) or hypomethylating agents, 28 received an alternative investigational agent, 38 received palliative care, and 2 had an unknown treatment status and were grouped with those receiving palliative care in subsequent analyses; 9 patients died before treatment assignment (2 who received standard therapy and 7, palliative care).
Overall survival was significantly longer for patients enrolled in a targeted-therapy arm compared with those who elected standard therapy (P < .0001). The 30-day estimated death rate was 3.7% (95% CI = 1.9%–7.2%) for patients electing treatment on a BEAT AML substudy, 20.4% (95% CI = 13.0%–31.2%) for those receiving standard therapy, 0% for those receiving an investigational therapy, and 72.6% (95% CI = 57.8%–85.7%) for the palliative care group.
Clinical Implications: These data support the feasibility of a rapid precision medicine approach in older adults with previously untreated AML (non–acute promyelocytic leukemia). Patients with AML who elected treatment based upon cytogenetic and molecular alterations in the dominant clone using a novel precision medicine approach, had significantly improved overall survival vs those who elected standard-of-care treatment. With the rapidly expanding therapeutic armamentarium, this novel trial strategy allows precise trial assignment to move anti-AML agents into clinical practice more efficiently.
ABSTRACT LBA-3: The QUAZAR AML-001 maintenance trial: Results of a phase III international, randomized, double-blind, placebo (n = 234)-controlled study of CC-486 (oral azacitidine; n = 238) in patients with AML in first complete remission 1 (NCT01757535]) who were initially ineligible for allogeneic hematopoietic stem cell transplantation (allo-HCT)5
Methods: Within 4 months of attaining first complete remission or complete remission with incomplete hematologic recovery, patients were randomly assigned 1:1 to receive oral azacitadine at 300 mg or placebo once daily on days 1 to 14 of repeated 28-day cycles. A 21-day dosing schedule was permitted for patients who experienced AML relapse with 5% to 15% blasts in blood or marrow while on study. Treatment could continue indefinitely until the presence of more than 15% blasts, unacceptable toxicity, or patients became eligible and received allo-HCT. The primary endpoint was overall survival.
Results: Following induction, 81% of patients achieved a complete remission and 19% achieved complete remission with incomplete hematologic recovery; 80% of patients had received consolidation chemotherapy. At a median follow-up of 41.2 months, overall survival was significantly improved with CC-486 vs placebo: median overall survival was 24.7 months vs 14.8 months from the time of randomization, respectively (P = .0009; HR = 0.69 [95% CI = 0.55–0.86]). Median relapse-free survival was 10.2 months in the CC-486 arm, compared with 4.8 months in the placebo arm (P = .0001; HR = 0.65 [95% CI = 0.52–0.81]).
CC-486 had a manageable safety profile generally consistent with that of injectable azacitidine. Median exposure to CC-486 was 12 cycles and to placebo, 6 cycles. Few adverse events led to treatment discontinuation, most often gastrointestinal events.
Clinical Implications: CC-486 (oral azacitadine) is the first therapy used in the maintenance setting to provide statistically significant and clinically meaningful improvements in both overall– and relapse-free –survival. Oral CC-486 has a manageable safety profile; once approved by the FDA, it is expected to become the standard of care for the patient population studied in this trial.■
DISCLOSURE: Dr. Abutalib is an advisor for AstraZeneca and has served on the advisory board of Jazz Pharmaceuticals. Dr. Kasner has served on the advisor board of and received research funding from Jazz Pharmaceuticals; has served as a consultant or advisor to Daiichi Sankyo, Jazz Pharmaceuticals, Otsuka US, and Partner Therapeutics; and has received research funding from Astellas Pharma, Daiichi Sankyo, Genentech, Otsuka, and Pfizer.
REFERENCES
1. Röllig C, et al: Time from diagnosis to treatment does not affect outcomes in intensively treated patients with newly diagnosed acute myeloid leukemia. 2019 ASH Annual Meeting & Exposition. Abstract 13. Presented December 7, 2019.
2. Lindsley RC, et al: Genetic characteristics and outcomes by mutation status in a phase 3 study of CPX-351 versus 7+3 in older adults with newly diagnosed, high-risk/secondary acute myeloid leukemia. 2019 ASH Annual Meeting & Exposition. Abstract 15. Presented December 7, 2019.
3. Foran JM, et al: Maintenance decitabine improves disease-free and overall survival after intensive therapy for acute myeloid leukemia in older adults, particularly in FLT3-ITD-negative patients. 2019 ASH Annual Meeting & Exposition. Abstract 115. Presented December 7, 2019.
4. Burd A, et al: Precision medicine treatment in older AML. 2019 ASH Annual Meeting & Exposition. Abstract 175. Presented December 7, 2019.
5. Wei AH, et al: The QUAZAR AML-001 maintenance trial. 2019 ASH Annual Meeting & Exposition. Abstract LBA-3. Presented December 10, 2019.
