1. Goodwin, Peter M.

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SAN DIEGO-A synthetic retinoid has shown promising adjunctive activity in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) in a small phase II open label study reported at the 2018 ASH Annual Meeting (Abstract 2735).

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The study explored the activity of SY-1425 (tamibarotene)-an oral selective agonist of retinoic acid receptor alpha (RARA) in combination with the hypomethylating agent azacitidine or the anti-CD38 antibody daratumumab (better known as a treatment for multiple myeloma) in patients with newly diagnosed AML, or relapsed/refractory AML, or higher-risk MDS. Patients with high concentrations of RARA were analyzed separately from those with and RARA-low cell lines.


Since SY-1425 increases expression of CD38 molecule on leukemic cells, the hypothesis was that it could synergize with the anti-CD38 activity of daratumumab.


The study found promising activity in patients who were positive for the biomarker-RARA pathway activation-and who were treated with the combination of SY-1425 with daratumumab. "It's exciting. It's something that's new and different. It appears to be relatively non-toxic and we're seeing some nice responses. It makes me feel optimistic about the future for leukemia patients," said Rachel Cook, MD, Assistant Professor in the Leukemia Section at Oregon Health and Sciences University in Portland.


Study Details

The study investigated upfront treatment for older unfit patients who had been candidates for standard induction therapy, Cook told Oncology Times. "The population of people enrolled in the trial was indeed quite old and quite unfit," she said, noting that the treatment had sought "a way to get the treatment of AML to be completed in a relatively non-toxic manner."


The new regimen used the standard treatment-azacitidine-as the "backbone" on top of which was added the drug SY-1425. "The goal was to see if we could improve over what's been done historically."


When asked why daratumumab had been selected for the regimen, she said that although it had been "a bit novel" in this setting it was a rational choice since SY-1425 up-regulated the expression of CD38 expression on blast cells. "Daratumumab is a CD38 antibody. And so it makes a lot of sense that people who have up-regulation of the CD38 would then be sensitive to daratumumab-not traditionally a leukemia drug," she said.


Cook acknowledged that the numbers in the study were small, but she had been impressed by the responses. "We did actually see [that in] some of the people who started with a high level of CD38 the SY-1425 pushed it higher. Then when they got the daratumumab it actually demonstrated a response-with drugs you wouldn't typically expect in this setting."


The research studied both AML and MDS because these were judged to be good candidates for anti-CD38 therapy. "Daratumumab is a CD38 antibody so it's specifically killing off the cells that are over-expressing CD38. It's commonly used for myeloma. So we're borrowing a drug from myeloma because we're seeing that these leukemia blasts [in MDS and AML] now over-express CD38-like a myeloma cell," Cook said.


In the combination of azacitidine with SY-1425, said Cook, patients generally tolerated the addition of the oral drug very well. "It has a pretty well-tolerated side-effect profile. There were very few people who had specific toxicities related to the drug. And we did find that there were a number of people who had really nice early responses-a little bit earlier than we would expect with just standard of care azacitidine. Small numbers but it certainly seems promising.


"And we've seen a couple of early responses that we're excited about," Cook continued. "Overall in the upfront setting we found that we had a good number of people who were able to get into a complete remission," she said, noting that other patients had achieved complete remission with incomplete count recovery. "It looks pretty damn good from our perspective."


The daratumumab combination also resulted in some patients who reached a morphologic leukemia-free state, she said, which she described as promising. "It's exciting because you don't normally use daratumumab in this setting. So even seeing one person who had a really nice response peaks your interest."


Biomarker Correlation

Eleven patients had been positive and eight were negative for the biomarker of retinoic acid receptor alpha pathway over-activity. And there had been a good correlation with biomarker positivity and the effectiveness of SY-1425, she said. Furthermore the test could be turned around in 2 days. So quick clinical decision-making was possible.


Although retinoic acid pathways are associated with treatment for acute promyelocytic leukemia (APL), Cook said, there were also data on their involvement with AML. "There is some history with these types of compounds not just in APL but also in non-M3 AML. Some vitamin-A derivatives [are] used in this setting. So that pathway is also known to be important in AML."


When asked about the clinical promise of the SY-1425 she was optimistic. "Certainly any drug combination for AML that's nontoxic that can be added into our armamentarium is important." Although many new drugs had been approved cure had still not been possible, she noted. "So we're going to need to be able to sequence people's therapies over time and to learn how to use these drugs in sequence.


"I think this is a nice addition and we're trying to refine and understand which patients will most obviously benefit from this," Cook said. "We also do know that getting people into remission more quickly is valuable for patients in terms of decreasing the amount of time they're spending getting their care, and for their quality of life.


"So if there's a drug that can get people into remission more quickly we'd certainly like to advocate for that for the patient," she concluded.


Peter M. Goodwin is a contributing writer.