Polyfunctional strength index identifies responders to combination immunotherapy in acute myeloid leukemia
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ORLANDO — Polyfunctional strength index on pretherapy bone marrow CD4-positive T cells differed substantially between responders and nonresponders to azacitidine plus nivolumab for relapsed or refractory acute myeloid leukemia, according to results of a nonrandomized phase 2 study presented at ASH Annual Meeting and Exposition.
This finding may indicate an immune diversity in AML and a need for biomarker-based trials testing immunotherapies in this disease, researchers noted.
“In general, biomarker-based strategies are the way to go,” Naval G. Daver, MD, associate professor in the department of leukemia at The University of Texas MD Anderson Cancer Center, said during the presentation. “These trials are more likely to succeed ... and immune toxicities must be identified and treated rapidly with steroids.”
Previous studies have shown increased bone marrow expression of PD-1-positive CD8-positive T cells in patients with relapsed AML. PD-1 inhibition alone, however, has had limited efficacy in AML.
Azacitidine, a DNA methyltransferase inhibitor, upregulates PD-1 and PD-L1 in AML. This has led to resistance to this form of chemotherapy.
Daver and colleagues evaluated azacitidine plus the PD-1 immune checkpoint inhibitor nivolumab (Opdivo, Bristol-Myers Squibb) among a cohort of 70 patients with relapsed or refractory AML. Eligibility criteria included an ECOG performance score of 2 or less and adequate organ function.
In a second cohort, which has the same eligibility criteria and continues to accrue participants, researchers have assigned 31 patients (median age, 71 years; 49% secondary AML) to the established schedule of azacitidine and nivolumab in combination with the anti-CTLA-4 antibody ipilimumab (Yervoy, Bristol-Myers Squibb), dosed at 1 mg/kg every 6 weeks. Most of these patients (65%) had unfavorable cytogenetics according to European Leukemia Net guidelines, and 54% previously received hypomethylating agent-based therapies.
Researchers compared results of the two cohorts with those of 172 contemporary historic hypomethylating agent-based clinical trial controls at MD Anderson Cancer Center.
Median follow-up was 27.2 months for the first cohort, 11.8 months for the second cohort and 51 months for the control group.
Results showed superior overall response rates and OS among 25 evaluable patients treated with azacitidine, nivolumab and ipilimumab, as well as for the azacitidine-nivolumab group, compared with controls (ORR, 44% vs. 33% vs. 20%; median OS in all-salvage setting, 10.5 months vs. 6.4 months vs. 4.6 months).
Among the first cohort, researchers observed the largest OS improvements among patients with low pretherapy bone marrow blasts and early salvage, adding to evidence that progressive T-cell exhaustion with repeated relapses could hinder T cell-based therapies.
Patients who responded to the azacytidine-nivolumab combination had a higher frequency of CD3-positive cells in pretherapy bone marrow aspirates compared with nonresponders, with an optimal CD3-positive cutoff of 13.2%.
In addition to quantitative T-cell infiltration, researchers tested pretherapy sorted bone marrow T cells in responders vs. nonresponders using the Isoplexis 32-plex, single cell, stimulated T-cell cytokine response panel (Isoplexis).
Results showed significant differences in pretherapy bone marrow T-cell polyfunctional strength index (PSI), defined as the percentage of polyfunctional cells in the sample multiplied by the intensities of the secreted cytokines, between responders and nonresponders, particularly in CD4-positive cells (P = .0317).
All complete responders, including those with incomplete count recovery, had a pretherapy PSI greater than 10, compared with none of the nonresponders, and researchers observed a statistically significant difference in OS among those with a PSI less than vs. greater than 10 (P = .0018). This suggests there could be a more specific biomarker to prospectively select patients for T-cell therapy-based trials, according to the researchers.
Nine of the 25 evaluable patients in the second cohort achieved complete response, with or without full hematological recovery. Two patients maintained hematologic improvement for more than 6 months, six patients had stable disease and 10 did not respond to treatment.
Researchers observed no mortality in the second cohort after 4 weeks, compared with a 4% mortality rate for the first cohort and a 7% mortality rate for controls. After 8 weeks, the mortality rate was 8% in the second cohort vs. 14% in the first cohort and 20% for controls.
Researchers reported a “very encouraging” 1-year OS rate of 45% among patients treated with azacitidine, nivolumab and ipilimumab. Six of these patients experienced grade 3 and grade 4 adverse events, including rash, pneumonitis and colitis. One patient required a stay in the ICU, but none has died due to toxicity.
“What’s really interesting is that when we started this work 4 or 5 years ago, this was all very new, but now there are more and more checkpoints being identified,” Daver said. “I think we will eventually find different targets than what we have seen. We just have to keep working and see where it takes us.”– by John DeRosier
Reference:
Daver NG, et al. Abstract 830. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
Disclosures: Daver reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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James K. McCloskey, MD
It’s important that we look at each of these agents separately for two main reasons. First is safety. In AML, checkpoint inhibitors have been a bit of a disappointment compared with other malignancies. We have seen full clinical holds with these agents in the hematologic malignancies, so it’s important to set up these trials for toxicity purposes to get a sense of what they are, especially for patients who underwent prior stem cell transplant and may be at risk for graft-versus-host disease.
Secondly, we need to look at efficacy of each of the agents to see if we really need both. In the solid tumor world, there are instances in which one drug is as good as two, and we need to see if that applies here.
A couple abstracts presented at this year’s ASH Annual Meeting have looked at checkpoint inhibitors in combination with hypomethylating agents. This particular abstract shows impressive response rates, and it will be interesting to see how that translates to the real world or to a multi-institutional study. It certainly seems promising so far.
The most interesting aspect of this abstract was the PSI that the researchers incorporated into this trial. Looking at pretreatment polyfunctional T cells and the relevant cytokines present before treatment, they were able to correlate 100% of the patients to having a high PSI. Something we have lacked is a marker that may identify patients likely to respond.
The ballgame has changed a lot since this trial was designed. In our era, with the commercial approval of venetoclax (Venclexta; AbbVie, Genentech) and forthcoming phase 3 data with that drug, it may be hard to know exactly where this regimen fits because of the toxicity. We will probably need randomized data to see if this can be less toxic in what is already a frail patient population.
Hackensack University Medical Center
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