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Polygenic Score May Help Personalize Induction Chemo, Improve Black Pediatric AML Patients' Outcomes

NEW YORK – Researchers have used a pharmacogenetic-based polygenic score to shed light on why Black pediatric patients with acute myeloid leukemia have historically had poorer outcomes on standard cytarabine-containing induction chemotherapy than white patients and have demonstrated the test's ability to personalize treatment in a study.

At a press conference last week ahead of the American Society of Hematology's annual meeting, Jatinder Lamba, a lead investigator of the study and associate dean for research and graduate education at the University of Florida's College of Pharmacy, said that this score may help doctors identify AML patients who would fare much better with augmented induction chemotherapy. Moreover, since scores associated with poor treatment outcomes appear to be more prevalent in Black patients, the use of such testing, when it is ready for clinical application, may also provide an opportunity to improve outcomes for this group, she suggested.

On Saturday, Jeffrey Rubnitz, the senior investigator of the study and a pediatric hematologist-oncologist at St. Jude Children's Research Hospital, presented data from a retrospective analysis involving 86 Black and 359 white, newly diagnosed, pediatric AML patients who had received one of three cytarabine-containing induction therapies in the AML02 and AML08 trials: a low dose of cytarabine, daunorubicin, and etoposide (LDAC), which is the standard treatment in pediatric patients; a high dose of cytarabine, daunorubicin, and etoposide (HDAC); or cytarabine combined with the purine nucleoside analog clofarabine (Clo/AraC).

Cytarabine, or AraC for short, has been a standard backbone of induction chemotherapy in AML for decades, but according to some estimates, up to 15 percent of pediatric patients don't achieve remission with such treatment, and 40 percent of those who do eventually relapse. Researchers led by Rubnitz, who had been a principal investigator in the original AML02 and AML08 trials, wanted to better understand differences in patient outcomes by race on cytarabine-containing induction regimens.

Prior research has shown that among adult and young AML patients, those who are Black have worse overall survival and event-free survival compared to their white counterparts. Another study, published last year, found that Black AML patients 18 to 29 years old had worse five-year overall survival, higher rates of early death, unique genomic features associated with poorer outcomes, and reduced responses to induction chemotherapy compared to white patients. The findings point to the need for "systematic changes" to how pediatric Black AML patients are treated, wrote researchers led by Ohio State University Comprehensive Cancer Center's Ann-Kathrin Eisfeld in Blood Advances

St. Jude's Rubnitz and colleagues, however, found no significant differences in five-year event-free survival between Black and white patients when they considered outcomes across the three treatment regimens in their analysis. Black patients had slightly lower five-year overall survival than white patients, but the difference wasn't statistically significant.

Even though Rubnitz's group did not find the same differences in treatment outcomes seen in prior studies among young Black and white AML patients, they wanted to use pharmacogenomics to better understand the biological differences that might be causing these historical disparities. To do this, they analyzed samples from Black and white patients in the AML02 and AML08 studies using a PGx-based polygenic score.

Lamba and colleagues described in a 2022 Journal of Clinical Oncology paper how they identified and combined 10 PGx SNPs into a polygenic score predictive of cytarabine response. Some of these SNPs included in the so-called ACS10 score had previously shown to predict minimal residual disease and event-free survival in AML patients, while others had been associated with ara-C triphosphate (ara-CTP) levels. Cytarabine is a prodrug that has to be activated to ara-CTP to be effective, and therefore, a patient's ability to form ara-CTP is key to their ability to respond to this chemotherapy.

In this earlier JCO paper, Lamba's team reported that AML patients with low ACS10 scores (zero or less) were poor cytarabine activators and had worse outcomes on standard chemo regimens than those with high scores (above zero), who were efficient cytarabine activators. They concluded that patients with low scores are likely to fare better on a higher dose of cytarabine or a regimen containing Pfizer's antibody-drug conjugate Mylotarg (gemtuzumab ozogamicin).

Lamba's team further observed that Black patients were more likely than white patients to have low ACS10 scores. They attributed this to the fact that three of the SNPs included in the score showed up more frequently in the Black population.

In the study presented at the ASH annual meeting, Rubnitz and colleagues confirmed these earlier findings and further showed that ACS10 scores were distributed differently across Black and white patients. In fact, 73 percent of Black patients had low ACS10 scores compared to 30 percent of white patients.

When researchers dug into the interaction between race, ACS10 scores, and specific treatments, they found that Black and white patients with low scores had shorter event-free survival on LDAC compared to patients with high scores, but given the greater prevalence of low scores in Black patients, outcomes in this population were particularly poor on LDAC.

However, these outcome differences were mitigated for patients with low scores when they received more intense cytarabine therapy through Clo/AraC or HDAC. While the data suggest that Black and white patients with low ACS10 scores can benefit from more intense cytarabine treatment, this also presents an opportunity to "reduce racial disparities in outcomes," Lamba said. After adjusting for other factors, like age, risk group, and leukocyte count, Clo/AraC induction therapy turned up as the best treatment option in terms of event-free survival for Black patients with low ACS10 scores, followed by HDAC.

"All in all, this reflects that maybe having a higher abundance of low ACS10 score is contributing towards historically observed inferior outcomes in Black AML patients," Lamba said.

Her team looked at the worldwide distribution of the ACS10 score using 1,000 Genomes Project data and estimated that approximately 90 percent of the population in Africa has low scores. In the Asian population, they estimated between 50 percent and 70 percent have low scores. "In these groups of patients, we can modify the treatment by giving them either high-dose AraC or the clofarabine and AraC combination in order to improve their treatment outcomes," Lamba said.

While the researchers developed ACS10 using the available data in genomic databases, Lamba acknowledged that with more diverse datasets, the score could be improved and made more accurate for different racial groups. For example, even within the African population there are sure to be other variants that can influence cytarabine response in individuals from different regions of the continent. "We don't have the numbers of patients [needed] to screen all the SNPs that may be present in some specific ethnicity or race group," Lamba said. "We have gone with what we had available."

Not just in this study but across clinical trials, researchers are often disappointed they are unable to meet accrual targets when it comes to Black and other minority patients, Lamba acknowledged. But she is reassured by the fact that across multiple studies, researchers have found low ACS10 scores to be more prevalent in Black AML patients than in white patients and that low scores have shown to predict inferior outcomes for Black patients on standard induction chemotherapy. She highlighted that at this same meeting, researchers are presenting similar validation data on the ACS10 score after testing Black AML patients treated at other institutions.

As to the commercial applicability of this polygenic score, Lamba and Rubnitz noted that with further validation and improvements in turnaround time, the pathology labs at the University of Florida and St. Jude may start performing the ACS10 score to guide AML patients' treatment decisions. Currently, Lamba's lab can produce these scores the same day for research purposes. "It would be great if we could develop a clinical assay, but we're not there yet," Rubnitz said.

If such a test eventually becomes commercially available, it could be particularly impactful in developing countries where cancer patients so often can't afford the medicines they need. Cytarabine is not as expensive as clofarabine or other newer therapies for AML. "If we can look at the patients in Africa, and if 90 percent … have a low ACS10 score, you can start their therapy with high-dose AraC and have better results without increasing as much of the economic burden," Lamba said.