Naval G. Daver, MD

Naval G. Daver, MD, associate professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, discusses a phase 1b trial evaluating the efficacy of margolimab and azacitidine (Vidaza) combination for patients with acute myeloid leukemia (AML).

There were 29 patients in the trial and 72% of those patients had poor-risk cytogenetics. Almost half of the patients had a 

 mutation. The median age was 74, and there was a patient all the way up to 89 years of age, so this is definitely a population that will not routinely be considered for intensive induction therapy, according to Daver.

The overall response rate was 64% in these patients. This included a complete remission (CR) and CR with incomplete hematologic recovery (CRi) of about 56%, as well as some partial responses. Daver believes this is encouraging because azacitidine as a single agent has been studied in multiple phase 2 and 3 trials for AML, and the CR rate has been around 15% to 18% while the CR/CRi rate is around 30% to 35%. This trial had a CR rate of about 40% and CR/CRi of about 55%.

Daver says it was especially interesting that in the 12 patients with 

-positive AML, although there were small numbers and there needs to be more data to be confident with the findings, there was a CR/Ci rate of 75% and duration of response had not been reached with a median follow-up of about 8 and a half months. Comparatively, the most effective other therapy in the setting right now of azacitidine and venetoclax (Venclexta) has a CR/CRi rate of 45% to 50% and the duration of response is around 4 and a half to 5 months.

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Naval G. Daver, MD, discusses a phase 1b trial evaluating the efficacy of margolimab and azacitidine combination for patients with acute myeloid leukemia.

Exploring the Data for AML Treated With Magrolimab and Azacitidine

Naval G. Daver, MD, an associate professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, discusses how the efficacy compares between first- and second-generation FLT3 inhibitors in acute myeloid leukemia (AML).

The first-generation agents entered the treatment landscape of AML about 15 years ago, and these included lestaurtinib, midostaurin (Rydapt), sorafenib (Nexavar), and sunitinib (Sutent). These were not developed as FLT3 inhibitors, Daver says, and were referred to as re-purposed FLT3 inhibitors. They were developed to target other pathways, but researchers later discovered that they were multikinase inhibitors that also inhibited the FLT3 kinase. Researchers also realized that

was associated with an adverse prognosis.

Second-generation inhibitors, such as gilteritinib (Xospata), quizartinib, and crenolanib, were developed to specifically target FLT3. Although they did have other targets, Daver says these agents were developed to be a very potent class of FLT3 inhibitors.

In single-agent studies, the first-generation agents induced response rates of around 5% to 10% in patients with relapsed/refractory

-mutant AML. Although these responses were modest, the agents worked better in combination with either azacitidine or induction therapy.

Naval G. Daver, MD, discusses how the efficacy compares between first- and second-generation FLT3 inhibitors in acute myeloid leukemia.

Second-Generation FLT3 Inhibitors Produce Higher Response Rates in AML

Checkpoint-based immune therapies have revolutionized the therapy of solid tumors by achieving breakthrough improvements in melanoma, lung cancer, renal cancer, bladder cancers, and head and neck tumors, among others. Recent studies have demonstrated encouraging results with immune checkpoint inhibition in hematologic malignancies, including Hodgkin lymphoma, primary central nervous system and testicular lymphoma, nasal natural killer/Tcell lymphoma, primary mediastinal lymphoma, follicular lymphoma, and multiple myeloma (MM). The optimal benefits of immune checkpoint inhibitors in the majority of patients with non-Hodgkin lymphoma and MM (who do not have a 9p24 sensitizing alteration) were obtained not by single-agent therapy but when these agents were combined with standard therapies to further improve response rates and progression-free and overall survival (OS).

We and others have noted that among a variety of checkpoint receptors evaluated in patients with acute myeloid leukemia (AML), there were significantly more PD-1positive T cells (including increased CD8+, T effector cells, and regulatory cells (Tregs) in bone marrow aspirates from patients with AML as compared with healthy donors.1,2 The same pattern was seen for OX40 on CD8+ T cells and Tregs, but was less prominent than for PD-1.

Preliminary data suggest that PD-1 inhibitors have limited single- agent activity in AML and myelodysplastic syndromes (MDS).3,4 CTLA-4 inhibition may have single-agent activity in AML/MDS, as has been shown in poststem cell transplant relapsed AML, where single-agent ipilimumab produced a durable complete response in 5 of 12 patients5 and in post&ndash;hypomethylating agent MDS, where ipilimumab (Yervoy) produced an overall response in 33% of patients.4 As with follicular lymphoma and MM, rational combinations of immune checkpoint inhibitors with other standard antileukemic agents may be needed to improve the response rates, the durability of response, and the OS in patients with AML/MDS.

Immune Response to PD Expression DNA-methyltransferase inhibitors (DNMTi), such as azacitidine, enhance the immune response to tumors by upregulating tumor-cell antigen expression, antigen presentation via histocompatibility complex class 1 molecules, and expression of costimulatory molecules, while concurrently dampening the immune response by upregulating the expression of checkpoint molecules, including PD-1, PD-L1, and PD-L2. Higher expression of PD-1, PD-L1, and PD-L2 was noted in patients with AML/MDS resistant to DNMTi therapy compared with sensitive patients, suggesting PD-1 upregulation may be involved in resistance to DNMTi.6 These findings have resulted in clinical trials combining PD-1/PD-L1 inhibitors with azacitidine in AML and MDS. Recent data presented on the combination of azacitidine with nivolumab (Opdivo) (antiPD-1) demonstrated an encouraging response rate, low early mortality, and, most important, durable responses in patients with relapsed/refractory AML, with 80% of the responders alive at 1 year.7 Both responders and nonresponders had an increase in CTLA4+ CD8+ cells in the bone marrow aspirate on therapy, suggesting that a combination blockade of these 2 major co-inhibitory pathways may improve response rate and durability. Grade 2-4 immune-related adverse events (irAEs) were observed in 23% of treated patients. There was a wide variation in the time to onset of irAEs, with irAEs observed as early as 4 days to 3.5 months from the initiation of the nivolumab therapy. The irAEs profile differed from those seen in solid tumors, with the most common being pneumonitis, nephritis, colitis, and dermatitis, as opposed to endocrine insufficiencies, skin rash, and transaminitis described frequently in solid tumor immuno-oncology trials. The irAEs were reversible with early intervention. The combination of azacitidine with nivolumab similarly produced encouraging response rates (80%) as frontline treatment for a small cohort of patients with high-risk MDS.4 In MDS patients failing DNMTi therapy, single-agent nivolumab did not demonstrate activity, but single-agent ipilimumab (anti&ndash;CTLA-4) was able to produce responses in 35% of patients.

Articles

Checkpoint-based immune therapies have revolutionized the therapy of solid tumors by achieving breakthrough improvements in melanoma, lung cancer, renal cancer, bladder cancers, and head and neck tumors, among others.

Naval G. Daver, MD | Authors

Articles

Exploring the Data for AML Treated With Magrolimab and Azacitidine

Second-Generation FLT3 Inhibitors Produce Higher Response Rates in AML

Combination Checkpoint Therapy Gains Ground in AML and MDS