Two separate studies presented at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition provide preliminary evidence that triplet combinations may have a role in the treatment of acute myeloid leukemia (AML). Both triplets were based on the addition of a third drug to standard therapy with an azacitidine/venetoclax backbone.

In the first presentation, magrolimab—an anti-CD47 monoclonal antibody—showed encouraging activity as front-line treatment in high-risk patients with de novo and secondary AML.¹ In the second abstract, the antibody-drug conjugate pivekimab sunirine showed activity in high-risk patients with relapsed or refractory AML.²

Azacitidine plus venetoclax is currently a front-line standard for the treatment of AML in older patients and those unfit for transplantation, but the 2-year survival rate is 35% to 40%. Patients with TP53 mutations have poor outcomes, with a median survival of 5 to 7 months. Triplets that build on standard therapy are being explored in this setting in the hope of improving outcomes.

Azacitidine/Venetoclax/Magrolimab

A phase I/II trial showing that the addition of magrolimab to azacitidine/venetoclax achieved high complete response rates with good tolerability as front-line therapy in high-risk de novo and secondary AML, regardless of TP53 mutation status.¹ However, response rates in the relapsed/refractory cohort were much lower, and the combination probably will not move forward in the relapsed/refractory setting.

All patients included in the trial were deemed to be at high risk, with 95% classified as adverse risk according to European Leukemia Network (ELN) 2017 criteria and 65% having adverse cytogenetics. Magrolimab is a first-in-class investigational anti-CD47 monoclonal antibody under development for hematologic cancers. In preclinical models, the addition of magrolimab to azacitidine and venetoclax demonstrated synergistic activity.

“The combination of azacitidine, venetoclax, and magrolimab was safe in the front-line setting in this very high–risk population,” said lead study author Naval Daver, MD, Associate Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, Houston. “Activity in relapsed/refractory AML was modest.”

Naval Daver, MD

In the front-line population, the rate of complete response or complete response with incomplete hematologic recovery was 72%. The measurable residual disease (MRD)-negative rate was 67%. Cytogenetic responses were seen in 52%. The median time to platelet count recovery was 32 days, and for absolute neutrophil counts, 36 days. At 4 and 8 weeks, no deaths were reported.

In the relapsed/refractory cohort, the rate of complete response or complete response with incomplete hematologic recovery was 11% in venetoclax-exposed patients and 44% in venetoclax-naive patients. One patient without prior venetoclax exposure achieved a morphologic leukemia-free state, for an objective response rate of 49%.

The phase I dose-finding portion of the trial identified the recommended phase II dose of magrolimab as 1 mg/kg on days 1 and 4, 15 mg/kg on day 8, and 30 mg/kg on day 11 of the first cycle and thereafter for subsequent doses. Once the recommended dose was established, phase II allowed both front-line and relapsed/refractory patients. The median age was 70 years,37% were female, and 93% had a European Cooperative Oncology Group performance status of 1 or 2. Dr. Daver emphasized that 91% had adverse risk and 65% had adverse cytogenetics.

At a median follow-up of 14.5 months, the median duration of response in the front-line de novo population was not reached in patients with TP53-mutant and TP53 wild-type disease. The 18-month response rates were 52% and 74%, respectively.

Eight patients with de novo TP53-mutant disease and one patient with secondary, untreated TP53-mutant disease underwent transplantation. The median relapse-free -survival was 16.3 months in transplanted patients vs 4.2 in nontransplanted patients. Similarly, median overall survival was improved in transplanted patients, at 16.6 months vs 9.8 months in nontransplanted patients.

In the relapsed/refractory population, at a median follow-up of 17.9 months, median relapse-free survival was 3.1 months in venetoclax-exposed patients vs 7.5 months in venetoclax-naive patients. The median overall survival was 3.1 months and 5.6 months in venetoclax-exposed and venetoclax-naive patients, respectively.

“The triplet was well tolerated. There were no unexpected adverse events, no immune-related adverse events, and no discontinuations due to treatment-related adverse events,” Dr. Daver said.

All patients experienced at least one adverse event, and 90% had at least one grade 3 or greater adverse event. Eight patients (10%) experienced infusion reactions, which were managed with dexamethasone prior to the next doses of therapy. A total of 18 patients (23%) had grade 3 or greater anemia on study, none of which led to life-threatening events or deaths, but this suggests monitoring is needed, he noted.

Dr. Daver reported that two phase III trials of magrolimab in combinations are now underway: ENHANCE-2 (mutation-agnostic patients with AML, front-line treatment with triplet vs backbone) and ENHANCE-3 (TP53-mutated patients, those suited for nonintensive therapy randomly assigned to venetoclax/azacitidine vs magrolimab/azacitidine; for intensive therapy, magrolimab/azacitidine vs 7 + 3 chemotherapy).

Pivekimab Sunirine in Relapsed/Refractory AML

The second study also presented by Dr. Daver, focused on an ongoing multicenter phase Ib/II trial of the addition of the investigational antibody-drug conjugate pivekimab sunirine to azacitidine/venetoclax in patients with relapsed or refractory CD123-positive AML.² Patients received pivekimab sunirine, azacitidine, and venetoclax escalated over a 28-day cycle. Two doses of pivekimab sunirine were selected from the phase I part of the study: 15 μg/kg given intravenously or 45 μg/kg given intravenously. The recommended phase II dose moving forward will be 45 μg/kg for pivekimab sunirine plus azacitidine at 75 mg and venetoclax for 14 days. The study is just beginning to enroll front-line patients, so Dr. Daver focused on the relapsed/refractory cohort.

“CD123 is expressed in the majority of AML blasts and leukemic stem cells yet minimally expressed on normal hematopoietic stem cells. Pivekimab sunirine is a first-in-class CD123-targeted antibody-drug conjugate and may have less toxicity,” Dr. Daver explained. In preclinical studies, synergy was seen for pivekimab sunirine and azacitidine and/or venetoclax.

“In this trial, [pivekimab sunirine] had tolerable safety and encouraging activity in venetoclax-naive patients in first relapse and in those with IDH2 and FLT3 mutations. The phase II dose of 14-plus days of venetoclax was not associated with excessive toxicity and was well tolerated,” he said.

The median age of patients was 67 years. About three-quarters had de novo AML, and one-quarter had secondary AML. About 53% were classified as ELN 2017 adverse risk. About 48% had more than two lines of prior treatment, 25% had undergone allogeneic hematopoietic cell transplantation, and 50% had received prior venetoclax.

Overall, the regimen was well tolerated. No cases of tumor-lysis syndrome, veno-occlusive disease, capillary leak syndrome, or cytokine-release syndrome were reported, “making this an attractive combination,” Dr. Daver said. The most frequently reported grade 3 or higher adverse events included febrile neutropenia (29%), thrombocytopenia (20%), and dyspnea (6%).

A total of 91 patients were enrolled. The overall response rate was 45%, and for the cohort receiving the recommended phase II dose, 38%. The median time to response was 1.1 months, but responses could be seen up to 6 months after treatment initiation. The duration of complete response was close to 8 months, “which is quite encouraging in a salvage population,” he said. The 37 patients receiving the recommended phase II dose had similar response rates to the overall population.

About 32% of treated patients achieved MRD-negative status, “which is quite remarkable in a relapsed/refractory setting,” he said. About 25% went on to allogeneic transplantation.

The objective response rate in venetoclax-naive patients was 53%. Patients treated with prior venetoclax continue to do poorly, with an objective response rate of 36% and a composite complete response rate of 11%. Responses in patients with FLT3-ITD mutations showed an encouraging preliminary signal, with a composite complete response rate of 64%, but the numbers were small.

Front-line patients were just enrolling at the time of the 2022 ASH meeting. Dr. Daver presented preliminary data on the first 10 such patients. “This is the cohort that will tell us if we are going forward with this combination. It is too early to draw conclusions,” he said.

Triplet vs Sequential Therapy

During the discussion following the presentation of both studies looking at triplets in AML, the question was raised as to whether triplets should be the way forward, or should investigators study sequential doublets.

Dr. Daver responded: “The sequential approach is attractive, but it is difficult, because we need good rapid MRD assessment to determine that the drugs are working. We need to study both approaches going forward. It may be that for high-risk patients with FLT3 or TP53 mutations, we should start with triplets and then drop down when response is assured. On the other hand, low-risk patients may want to start treatment with a doublet. We need to study both approaches, come back in 2 years, and decide which is best for selected patients.” 

DISCLOSURE: Dr. Daver has received research funding from GlycoMimetics, Amgen, Hanmi, Novimmune, Astellas, Gilead Sciences, Genentech, Servier, FATE Therapeutics, Trovagene, Trillium, ImmunoGen, AbbVie, Daiichi Sankyo, Pfizer, and BMD; and has served as a consultant to Celgene, Novartis, Amgen, Arog, Jazz, Hanmi, Shattuck, Syndax, Agios, Astellas, Gilead Sciences, Genentech, Servicer, Trillium, Immunogen, AbbVie, Daiichi Sankyo, Pfizer, and BMS.

REFERENCES

1. Daver N, Senapati J, Maiti A, et al: Phase I/II study of azacitidine with venetoclax and magrolimab in patients with newly diagnosed older/unfit or high-risk acute myeloid leukemia (AML) and relapsed/refractory AML. 2022 ASH Annual Meeting and Exposition. Abstract 61. Presented December 10, 2022.

2. Daver NG, Montesinos P, Arbi A, et al: Broad activity for the pivekimab sunirine (PVEK, IMGN632), azacitidine and venetoclax triplet in high-risk patients with relapsed/refractory and frontline acute myeloid leukemia. 2022 ASH Annual Meeting and Exposition. Abstract 62. Presented December 10, 2022.