Advertisement

Beat AML Trial Seeking to Change Treatment Paradigm


Advertisement
Get Permission

William Blum, MD

William Blum, MD

The Beat AML Master Clinical Trial seeks to change the treatment paradigm and outcomes in acute myeloid leukemia (AML) by personalizing therapy and ultimately facilitating the approval of novel targeted agents. Co-investigator William Blum, MD, of the Winship Cancer Institute at the Emory University School of Medicine, described the trial at Emory’s 2018 Debates and Didactics in Hematology and Oncology conference on Sea Island, Georgia.1

What Is the Beat AML Study Protocol?

The Beat AML study enrolls newly diagnosed patients with AML who are at least 60 years of age. Patients undergo bone marrow biopsy and have marrow aspirates and/or blood analyzed within 7 days by a genomic provider looking at a panel of targetable mutations, as well as cytogenetics. Based on the results, patients are offered personalized treatment on one of several substudies to the protocol, each with arm-specific treatments with varying clinical and correlative endpoints. The substudies are currently designed for the most prominent subsets of AML, and each tests an investigational therapy.

Active trial sites now include Winship Cancer Institute of Emory University, Memorial Sloan Kettering Cancer Center, Oregon Health and Science University Knight Cancer Institute, The Ohio State University Comprehensive Cancer Center, University of Texas at Southwestern, University of Utah Huntsman Cancer Center, Mayo Clinic (three locations:Rochester, Phoenix, and Jacksonville), University of Maryland School of Medicine, UCLA Health, and University of Chicago Comprehensive Cancer Center. Dr. Blum urged conference attendees, most of whom practice in Georgia, to refer patients to Emory for this study, “because this is the right way to find the best treatment for them.”

Trial’s Importance

Dr. Blum Highlighted the poor prognosis of patients with AML, noting that fewer than 10% of older patients remain alive at 5 years with current therapies. Especially in older patients, “we have a long way to go,” he said. “There’s not a lot to champion in terms of moving forward with 7+3 chemotherapy [7 days of cytarabine and 3 days of daunorubicin, idarubicin, or mitoxantrone]. It’s not accurate even to say that everyone should get 7+3 so that, if they achieve remission, they can go on to transplant, because that’s not a reality…. We have to move forward in a different way. Transplantation is part of the solution to AML, but we have to find new roads to get there, and we have to develop options for the many older patients who don’t.”

This different direction begins with molecular subtyping, as prognosis has been shown to vary considerably based on genomics. A growing number of gene mutations are are FLT3, NPM1, and DNMT3A; many other mutations occur in small groups of patients. Though in large part they have historically been for prognosis only, increasingly several mutations present therapeutic targets. 

Beat AML seeks to change the way AML is thought about, how it is discussed with patients, and how its treatment options are presented.
— William Blum, MD

Tweet this quote

There is virtually no genomic profile for which outcomes are “very good” with 7+3 therapy, especially in older individuals, noted Dr. Blum. Even among patients 60 years of age and older treated with 7+3 in previous Cancer and Leukemia Group B (CALGB) studies—a highly selected population—in the more favorable NPM1-mutated/FLT3 wild-type subgroup, for example, the median 3-year survival is only 35%. Survival is even worse for patients with other molecular subtypes, he pointed out.

Waiting to start therapy, when appropriate, until additional information is available about an individual AML patient’s risk can have several benefits. Foremost, using genetic and cytogenetic information not just for prognosis and future therapy (such as allogeneic transplantation) but also to weigh the risks and benefits of intensive induction allows for improved counseling about options. Some patients may well still be best served by receiving intensive 7+3-type chemotherapy; others may wish additional novel treatment options to be considered. The Beat AML Master Trial is designed to do just this: to put information into the hands of patients and doctors before treatment is started and then to provide opportunities for novel therapies based on an individual patient’s leukemia cell mutation analysis.

“Beat AML seeks to change the way AML is thought about, how it is discussed with patients, and how its treatment options are presented. Drugs that show benefit in a patient with relapsed or refractory disease will be studied in newly diagnosed patients, and results will be reported within a shortened timeline,” Dr. Blum explained. “The thinking here is that one treatment does not fit all. The idea is to ‘get smarter’; to introduce new agents early on and, instead of treating all patients in a randomized phase III trial, to find the unique outliers—where a targeted drug can actually hit its target and succeed.”

How the Master Trial Works

After identification as a candidate for Beat AML, the patient undergoes a bone marrow biopsy and has samples sent for genetic screening. Results are obtained within 7 days, and the patient is assigned treatment according to his or her genetic markers. At this point, prioritization (where more than one mutation is present) is given to patients with core-binding factor alteration, NPM1 mutation (+ FLT3 wild-type), KMT2A rearrangement, isocitrate dehydrogenase-2 (IDH2) mutation, IDH1 mutation, TP53 mutation, FLT3 mutation, and TET2/WT1 mutation.

One aspect of the study that has been lauded is the 7-day turnaround time for genetic testing; this was accomplished in 97% of patients.
— William Blum, MD

Tweet this quote

The aim is to match the mutation to promising targeted agents, such as for mutations sensitive to hypomethylating agents, BI836858 (anti-CD33 antibody) plus azacitidine; for TP53-mutated disease, entospletinib (a spleen tyrosine kinase [SYK] inhibitor) plus decitabine; and for NPM1-mutated/FLT3 wild-type disease, entospletinib plus intensive chemotherapy or azacitidine (depending on the patient’s functional status).

Not all patients follow this trajectory. Some patients lack targetable mutations or, for some other reason, are not candidates for any of the available trials or do not desire it. Others remain candidates and can benefit from that standard approach. Still others lack any of the prioritized mutations and/or are not candidates for any of the substudies. Of 318 patients screened so far, 113 have enrolled, with others not participating “for various reasons,” he said.

Substudies

Dr. Blum illustrated the value of studying targeted agents in patients with matching genomic profiles by describing the activity of entospletinib. Entospletinib inhibits SYK, which is a non–receptor tyrosine kinase that is primarily expressed in hematopoietic cells; is constitutively activated in AML; and promotes leukemogenesis. Dr. Blum reported results of a 53-patient phase II substudy of entospletinib monotherapy (2 weeks) followed by entospletinib with 7+3 induction chemotherapy; single-agent activity (before chemotherapy was given) was demonstrated in patients with KMT2A rearrangements and NPM1 mutations, respectively.2 Included among Beat AML substudies are combination trials of entospletinib plus chemotherapy in these unique subsets of AML.

As an example of the trial, Dr. Blum described a 64-year-old woman with thrombocytopenia, circulating blasts, obesity, and diabetes. Her white blood cell count was 10,000/mL, and she had 12% blasts in the blood, a hemoglobin of 3.8 g/dL, a platelet count of 35,000/mL, myelodysplasia-related changes, and a complex karyotype with a TP53 mutation. The patient was enrolled on a phase II study of entospletinib plus decitabine in patients with TP53-mutated disease to attempt to improve upon her 16% chance of remission with conventional therapy.

2018 DEBATES AND DIDACTICS

  • 2018 Debates and Didactics in Hematology and Oncology
  • The Cloister, Sea Island, Georgia
  • July 25, 2018 – July 29, 2018

Two of the more promising targets in older patients with AML are IDH1 and IDH2 mutations. Ivosidenib (Tibsovo; AG-120) and enasidenib (Idhfa; AG-221) are first-in-class, oral, selective inhibitors of mutated IDH1 and IDH2 enzymes, respectively, approved by the U.S. Food and Drug Administration. “The problem is they don’t work for everybody and they don’t work as long as we’d like in relapsed patients,” he said. “The idea is to move these drugs into the upfront setting.”

Another important question is whether response to hypomethylating agents can be enhanced among patients selected for “hypomethylating agent–sensitizing” mutations. Dr. Blum is the principal investigator of a novel phase II trial of a hypomethylating agent in combination with a glycoengineered CD33 antibody, BI 836858.

Early Successes

Beat AML’s Master Screening Protocol has evaluated 318 patients as of September 2018. “I think that’s just phenomenal,” he commented. One aspect of the study that has been lauded is the 7-day turnaround time for genetic testing; this was accomplished in 97% of patients and has done much to foster enthusiasm for this study, added Dr. Blum.

The trial has been open for 18 months, and results are emerging. For the 2018 American Society of Hematology Annual Meeting & Exposition, Beat AML investigators submitted several abstracts describing trial activites so far.

Closing Thoughts

Dr. Blum emphasized the value of understanding the genetic landscape of AML, which is one of the aims of Beat AML. “There’s power in understanding the genetic underpinnings of disease…. It creates a culture of constant learning and constant reassessment of what you’re doing. This will be part of the next-generation sequencing component, recognizing that we’re likely to fail more often than we succeed, but that having the data does change behavior and provide opportunities to innovate,” he said. ■

DISCLOSURE: Dr. Blum is a consultant/advisor for Pfizer, Boehringer Ingelheim, Tolero Pharmaceuticals, and Astellas Pharma; and has received research funding from Boehringer Ingelheim and Xencor.

REFERENCES

1. Blum W: Beat AML: A new clinical trial for older patients (> 60) with previously untreated AML. 2018 Debates and Didactics in Hematology and Oncology Conference. Invited lecture. Presented July 19, 2018.

2. Walker AR, Byrd JC, Bhatnagar B, et al: Results of a phase 1B/2 study of entospletinib (GS-9973) monotherapy and in combination with induction chemotherapy in newly diagnosed patients with acute myeloid leukemia. 2018 European Hematology Association Congress. Abstract S118. Presented June 15, 2018.


Advertisement

Advertisement



;
Advertisement

By continuing to browse this site you permit us and our partners to place identification cookies on your browser and agree to our use of cookies to identify you for marketing. Read our Privacy Policy to learn more.