Evolving Approaches in the Treatment of AML and MDS - Episode 4

Genomics Guide Treatment, But Novel Agents Generate Excitement in AML and HR-MDS

New data ranging from up-front approaches with targeted therapy to maintenance therapy, as well as emerging findings with novel agents continue to push the paradigm forward in acute myeloid leukemia and higher-risk myelodysplastic syndromes.

New data ranging from up-front approaches with targeted therapy to maintenance therapy, as well as emerging findings with novel agents continue to push the paradigm forward in acute myeloid leukemia (AML) and higher-risk myelodysplastic syndromes (MDS), explained faculty from an OncLive® moderated by Gustavo Rivero, MD.1

Rivero, an associate professor in the Department of Medicine and Section of Hematology/Oncology at Baylor College of Medicine, was joined by fellow colleagues:

  • Hetty Carraway, MD, MBA, professor of oncology, director of the Leukemia Program, vice chair of strategy and director of Leukemia, Cleveland Clinic
  • Elizabeth Griffiths, MD, associate professor of medicine, SUNY Buffalo, associate member, Roswell Park Comprehensive Cancer Center
  • Elias Jabbour, MD, professor of medicine, The University of Texas MD Anderson Cancer Center
  • Catherine Lai, MD, MPH, associate professor, University of Pennsylvania, physician leaders, Leukemia, Abramson Cancer Center
  • Selina Luger, MD, FRCPC, professor of medicine, University of Pennsylvania, Hospital of the University of Pennsylvania
  • Daniel Pollyea, MD, associate professor of medicine, hematology, University of Colorado
  • David Sallman, MD, assistant professor, Department of Malignant Hematology, Morsani College of Medicine, assistant member, Myeloid, Moffitt Cancer Center
  • Aditi Shastri, MD, associate professor, Montefiore Einstein Cancer Center, attending physician, Montefiore Medical Center

During the workshop, the faculty reviewed testing practices and the importance of novel biomarkers, the role of maintenance therapy, and emerging treatment strategies in AML and HR-MDS.

Testing in AML and HR-MDS

The National Comprehensive Cancer Network (NCCN) recommends testing 8 genes as part of the diagnostic workup of patients with newly diagnosed AML: c-KIT, FLT3-ITD and FLT3-TKD, NPM1, CEBPA, IDH1 and IDH2, RUNX1, AXSL1, and TP53. Repeat testing is recommend at relapse.

FLT3

The importance of such practices has been emphasized by findings from several trials. For example, long-term follow-up from the phase 3 ADMIRAL trial (NCT02421939) confirmed overall survival (OS) benefit with gilteritinib (Xospata) in relapsed/refractory FLT3-mutant AML (HR, 0.665; 95% CI, 0.518-0.853; P = .0013). Moreover, findings from the phase 3 QuANTUM-R trial (NCT02039726) showed similar superiority in OS with quizartinib vs salvage chemotherapy (HR, 0.76; 95% CI, 0.58-0.98; P = .02).

Additionally, in the phase 3 QuANTUM-First trial (NCT02668653), frontline quizartinib plus standard induction therapy was reported to have met its primary end point of improved OS in FLT3-ITD–positive AML, according to a press release.

The triplet of azacitidine, venetoclax (Venclexta), and gilteritinib also demonstrated promising results in FLT3-mutated AML in a phase 1/2 trial (NCT04140487).

IDH1/2

Preferred NCCN options for patients with IDH1- and IDH2-mutant AML at least 60 years of age who are not candidates for intensive therapy include ivosidenib (Tibsovo) and enasidenib (Idhifa), respectively, or the combination of venetoclax and a hypomethylating agent (HMA).

Findings from a phase 1 study (NCT02074839) showed ivosidenib elicited deep, durable remissions in newly diagnosed IDH1-mutant AML, findings which were replicated in the phase 3 AGILE trial (NCT03173248). In AGILE, patients with untreated, IDH1-mutant AML were randomized to ivosidenib plus azacitidine or placebo plus azacitidine. Enrollment was halted based on efficacy findings, which showed a significant improvement in event-free survival ([EFS] HR, 0.33; 95% CI, 0.16-0.69; P = .0011) and OS (HR, 0.44; 95% CI, 0.27-0.73; P = .0005) with ivosidenib-based therapy.

“I think [the AGILE study] gives us a nice option to consider for patients. However, we’re talking about a subset of AML patients for whom this is relevant,” Pollyea said. “If we’re just talking about IDH1, which is [present in] somewhere around 10% of patients, for a non-intensive chemotherapy candidate, you are going to be essentially not treating 90% of your patients with ivosidenib plus azacitidine. How long do we wait for results to come back for 1 in 10 patients to get started on treatment?”

On March 7, 2022, the FDA granted priority review to a supplemental new drug application seeking the approval of ivosidenib in combination with azacitidine in the treatment of patients with previously untreated IDH1-mutated AML based on findings from AGILE.22

In the randomized phase 1/2 AG-221-AML-005 study (NCT02677922), enasidenib showed benefit in EFS (HR, 0.59; 95% CI, 0.30-1.13; P = .11) but not OS (HR, 0.99; 95% CI, 0.52-1.87; P = .97) in untreated, IDH2-mutant AML.

Maintenance Treatment

In the phase 3 QUAZAR AML-001 trial (NCT01757535), patients at least 55 years of age with AML and intermediate- or poor-risk cytogenetics who achieved a complete response (CR) or CR with incomplete hematologic recovery after intensive chemotherapy with or without consolidation were randomized to oral azacitidine or placebo. Findings from the trial showed a median OS of 24.7 months (95% CI, 18.7-30.5) with oral azacitidine vs 14.8 months (95% CI, 11.7-17.6) with placebo (P < .001).

Notably, oral azacitidine reduced the risk of death by 30% and the risk of relapse by 41% vs placebo, regardless of baseline characteristics.

“The data with oral azacitidine is encouraging. The trouble that I have is with the patient population and the eligibility because there are very few patients [who] aren’t going to transplant or that aren’t just stopping chemotherapy that would then go on [oral azacitidine], so it’s a very select population,” Lai said.

Regarding tolerability, Griffiths explained that gastrointestinal toxicity has been the predominant concern. As such, she recommended routine anti-nausea prophylaxis with between 4 mg and 8 mg of Zofran 30 minutes before taking the medication. For diarrhea and/or constipation, she advised adopting a prune-heavy diet in the days leading up to each treatment cycle and/or the use of laxative therapies including but not limited to Miralax and Lactulose

On the Horizon in AML and HR-MDS

With respect to new agents, the faculty pointed to magrolimab, tamibarotene, and sabatolimab.

In September 2020, the FDA granted a breakthrough therapy designation to magrolimab for the treatment of patients with newly diagnosed MDS.3

In May 2021, the FDA granted fast track designation for sabatolimab for the treatment of adult patients with MDS defined with a Revised International Prognostic Scoring System risk category of high or very high risk in combination with HMAs.4

“It’s all hands on deck, and we’re excited to enroll [patients] in clinical trials. The long and short of it is that that’s exactly where we sit in the myeloid malignancies space; we need to continue to contribute and put clinical trials at the forefront for our patients,” Carraway concluded.

References

  1. Evolving approaches in the treatment of AML and MDS: an OncLive® Scientific Interchange & Workshop. Accessed April 6, 2022.
  2. Servier announces FDA filing acceptance and priority review for TIBSOVO (ivosidenib tablets) in combination with azacitidine for patients with previously untreated IDH1-mutated acute myeloid leukemia. News release. Servier Pharmaceuticals; March 7, 2022. Accessed April 6, 2022. https://prn.to/3CtMlJy
  3. Gilead’s magrolimab, an investigational anti-CD47 monoclonal antibody, receives FDA breakthrough therapy designation for treatment of myelodysplastic syndrome. News release. Gilead Sciences, Inc. September 15, 2020. Accessed April 22, 2022. https://bit.ly/2RwPUrw
  4. Novartis receives FDA fast track designation for sabatolimab (MBG453) in myelodysplastic syndromes. News release. Novartis. May 25, 2021. Accessed April 22, 2022. https://bit.ly/3xOUpEb