Syed Ali Abutalib, MD
Farhad Ravandi, MD
To complement The ASCO Post’s continued comprehensive coverage of the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition, here are several abstracts selected from the meeting proceedings focusing on acute myeloid leukemia (AML), such as the use of venetoclax added to cladribine plus low-dose cytarabine alternating with azacitidine in newly diagnosed patients; the prognostic effect of IDH mutations on patient outcomes; and early results with a first-in-class anti-CD47 antibody (magrolimab) with azacitidine in patients unfit for intensive chemotherapy. For full details of these study abstracts, visit ashpublications.org.
Venetoclax-Based Therapy for Newly Diagnosed AML
ABSTRACT 25: Phase II MD Anderson Cancer Center study (n = 48): Venetoclax added to cladribine and low-dose cytarabine alternating with azacitidine in older (≥ 60 years) and younger unfit (for induction) patients (n = 1) with newly diagnosed AML (excluding acute promyelocytic and core-binding factor leukemias).1
Background: Investigators have previously reported on a low-intensity backbone of cladribine and low-dose cytarabine alternating with a hypomethylating agent for older adults with AML, yielding higher rates of complete response and improved outcomes compared with a hypomethylating agent alone. Recently, the addition of the BCL2 inhibitor venetoclax to a hypomethylating agent was shown, in a randomized study, to improve survival over a hypomethylating agent alone.2 On October 16, 2020, the U.S. Food and Drug Administration approved venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine for newly diagnosed adults with AML aged 75 or older and for those unfit for intensive induction chemotherapy.2,3 Investigators of this study hypothesized that the addition of venetoclax to the low-intensity cladribine-plus-cytarabine backbone may further improve response rates and outcomes.
Methods: Induction consisted of cladribine at 5 mg/m2 intravenously over 30 minutes on days 1 to 5 with cytarabine at 20 mg subcutaneously twice a day on days 1 to 10. Consolidation/maintenance consisted of 2 cycles of cladribine at 5 mg/m2 on days 1 to 3 plus cytarabine at 20 mg subcutaneously twice a day on days 1 to 10, alternating with 2 cycles of azacitidine at 75 mg/m2 on days 1 to 7, for a total of 18 cycles. Venetoclax at 400 mg was added on days 1 to 21 of each cycle, with dose adjustments for concomitant CYP3A inhibitors. One cycle was 4 weeks, and up to two cycles of induction were allowed.
Results:
A total of 37 patients (77%) achieved a complete remission, and 8 (17%) had a complete remission with incomplete blood cell count recovery, for a combined rate of 94%.
The median number of cycles to response was 1 (1–3), and 36 patients (80%) had measurable residual disease (also known as minimal residual disease) negativity by multiparameter flow cytometry at the time of complete remission/complete remission with incomplete blood cell count recovery.
Among patients with secondary AML or an adverse karyotype, the complete remission and complete remission with incomplete blood cell count recovery rates were 83% and 83%, respectively.
The regimen was reported to be well tolerated, with 4- and 8-week mortality rates of 0% and 6%, respectively.
Of the 45 responding patients, 11 (24%) proceeded to allogeneic hematopoietic cell transplantation.
The median relapse-free survival was not reached, with 6- and 12-month relapse-free survival rates of 79% and 64%, respectively.
With a median follow-up of 11+ months, the median overall survival has not been reached, with 6- and 12-month overall survival rates of 86% and 70%, respectively.
Clinical Implications: Cladribine and low-dose cytarabine alternating with azacitidine plus venetoclax is a highly effective and relatively nontoxic regimen that appears to produce superior results compared with the current standard of care. This combination therapy is likely to be examined with the addition of other targeted agents in specific subsets of patients with AML in an attempt to improve outcomes even further.
IDH Mutations and Patient Age
ABSTRACT 388: De novo IDH mutations in AML—Characteristics and prognostic effects of IDH mutations across the age spectrum in AML: A collaborative analysis from COG, SWOG, and ECOG.4
Background: Somatic mutations in the IDH genes are common in AML. Mutations occur at active site arginine residues in IDH1 (R132) and IDH2 (R140, R172). IDH inhibitors, ivosidenib (IDH1) and enasidenib (IDH2), have shown improved clinical outcomes in patients with relapsed or refractory IDH-mutant AML and are approved for use in this setting; investigations of these agents in combination with chemotherapy are under way in de novo AML and myelodysplastic syndromes (MDS). The prognostic significance of IDH mutations remains controversial.
“If similar activity is confirmed in larger trials, [magrolimab] has the potential for being combined in a number of regimens in myeloid malignancies….”— Syed Ali Abutalib, MD, and Farhad Ravandi, MD
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Methods: The total cohort (n = 3,588) included patients aged younger than 1 month to 88 years. Patients were analyzed according to three defined age groups: 0–29 (n = 2,401); 30–59 (n = 819); and ≥ 60 (n = 319). The prevalence of IDH mutations, co-occurring mutations, and outcomes (5-year event-free survival) were analyzed across the three age groups.
Results: The prevalence of IDH mutations was strongly correlated with increased age. According to the age-defined cohorts, IDH mutations were present in 4.0% (n = 82), 15.2% (n = 126), and 20.3% (n = 65) of the 0 to 29, 30 to 59, and ≥ 60 age groups, respectively (P < .001). Given the favorable prognostic significance of NPM1, investigators analyzed outcomes of this dual-mutant group; they found that NPM1 mutations retained favorable prognostic impact in the context of patients with IDH-mutant disease in the first two age groups but not in the older age group. Those with IDH-mutant/NPM1-mutant disease had a favorable event-free survival compared with those who had IDH-mutant/NPM1 wild-type disease for those in the group up to age 29 (76% vs 24%, P < .001) and for those between ages 30 and 59 (43% vs 15%, P = .001); however, this favorable effect was not seen in the older age group (29% vs 34%, P = .456). Among those aged 30 to 59, outcomes were further stratified by DNMT3A status; those with IDH-mutant/NPM1-mutant/DNMT3A-mutant disease experienced an inferior event-free survival of 25% vs 57% in those with IDH-mutant/NPM1-mutant disease (P = .003).
Clinical Implications: This large retrospective data set confirms the lack of prognostic effect of IDH mutations on outcomes of patients with AML treated with conventional cytotoxic regimens. Analyses confirm age-associated prevalence of IDH mutations and frequent co-occurrence with NPM1 mutation in all ages. Co-occurrence of NPM1 and IDH mutations favorably impacts outcomes in patients younger than age 60 with AML, particularly in the absence of DNMT3A mutation. These data support that IDH inhibitors may be of particular interest in older adults and in patients younger than age 60, according to co-occurring NPM1 and DNMT3A mutations.
First-in-Class Anti-CD47 Antibody With Azacitidine
ABSTRACT 330: Magrolimab and azacitidine: The first-in-class anti-CD47 antibody magrolimab combined with azacitidine is well tolerated and effective in patients with AML (n = 52): Phase Ib results of treatment-naive patients with AML unfit for intensive chemotherapy (ClinicalTrials.gov identifier NCT03248479).5
Background: CD47 is a potent “don’t eat me” signal on cancer cells and impairs tumor cell phagocytosis by engaging the inhibitory macrophage receptor SIRPα. Magrolimab (Hu5F9-G4) is an antibody blocking CD47. Magrolimab induces tumor phagocytosis and eliminates putative leukemia stem cells. Azacitidine synergizes with magrolimab by inducing “eat me” signals on leukemic blasts, thereby enhancing phagocytosis. The combination of magrolimab plus azacitidine has been shown to be clinically effective in AML and MDS.
Methods: A magrolimab priming dose-escalation regimen (1–30 mg/kg given intravenously weekly followed by 30 mg/kg every 2-week dosing in cycle 3 and beyond) was utilized to mitigate on-target anemia. Azacitidine dosing was 75 mg/m2 on days 1 to 7 on a 28-day cycle.
Results:
Efficacy was seen in both patients with wild-type and TP53-mutant AML.
The median overall survival for patients with TP53 wild-type AML (n = 16) was 18.9 months (95% confidence interval [CI] = 4.34 months to not reached).
Efficacy was particularly encouraging in TP53-mutant AML, with a 71% response rate (15 of 21), including a complete response rate of 48%, and a median overall survival of 12.9 months (95% CI = 6.24 months to not reached).
On-target anemia was generally transient and reversible, with no observed grade 4 or 5 adverse events.
Treatment-related adverse events (≥ 15% of patients) for magrolimab/azacitidine were anemia (31%), fatigue (19%), blood bilirubin increase (19%), neutropenia (19%), thrombocytopenia (17%), and nausea (15%).
Two patients (3.8%) discontinued therapy due to a treatment-related adverse event.
Putative leukemic stem cells, as defined by CD34+CD38– expression, were eliminated by the combination therapy in 71% of all responding patients with AML.
Clinical Implications: Magrolimab is a novel immunotherapy that blocks a key macrophage checkpoint. The combination of magrolimab plus azacitidine has been reported to be well tolerated, with no immune-related adverse events. On-target anemia is mitigated by a priming/maintenance dose strategy. Expansion cohorts in AML are ongoing, and a phase III randomized trial evaluating magrolimab/azacitidine (ENHANCE-2) in untreated patients with TP53-mutant AML is planned. If similar activity is confirmed in larger trials, this agent has the potential for being combined in a number of regimens in myeloid malignancies due to its relatively manageable toxicity. Of particular importance is the combination’s potential efficacy in TP53-mutant AML and MDS, a population of patients with limited therapeutic strategies.
DISCLOSURE: Dr. Abutalib has served on the advisory board for AstraZeneca. Dr. Ravandi has received honoraria and been a member of advisory boards for Celgene, Bristol Myers Squibb, Astellas, Agios, Novartis, Taiho, Amgen, Orsenix, Jazz, AstraZeneca and has received research funding from Amgen, Xencor, Taiho, Prelude, Astex, and Menarini.
REFERENCES
1. Kadia TM, Borthakur G, Pemmaraju N, et al: Phase II study of venetoclax added to cladribine + low dose AraC alternating with 5-azacitidine demonstrates high rates of minimal residual disease negative complete remissions and excellent tolerability in older patients with newly diagnosed acute myeloid leukemia. 2020 ASH Annual Meeting & Exposition. Abstract 25. Presented December 5, 2020.
2. DiNardo CD, Jonas BA, Pullarkat V, et al: Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med 383:617-629, 2020.
3. Wei AH, Montesinos P, Ivanov V, et al: Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: A phase 3 randomized placebo-controlled trial. Blood 135:2137-2145, 2020.
4. Zarnegar-Lumley S, Alonzo TA, Othus M, et al: Characteristics and Prognostic Effects of IDH Mutations across the Age Spectrum in AML: A collaborative analysis from COG, SWOG, and ECOG. 202 ASH Annual Meeting & Exposition. Abstract 388. Presented December 6, 2020.
5. Sallman DA, Asch AS, Kambhampati S, et al: The first-in-class anti-CD47 antibody magrolimab combined with azacitidine is well-tolerated and effective in AML patients: Phase 1b results. 2020 ASH Annual Meeting & Exposition. Abstract 330. Presented December 6, 2020.
Dr. Abutalib is Associate Director of the Hematology and BMT/Cellular Therapy Programs and Director of the Clinical Apheresis Program at the Cancer Treatment Centers of America, Zion, Illinois; Associate Professor at Rosalind Franklin University of Medicine and Science; and Founder of Advances in Cell and Gene Therapy. Dr. Ravandi is the Janiece and Stephen A. Lasher Professor of Medicine and Chief of the Section of Acute Myeloid Leukemia in the Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston.
