AML Research From ASH 2022: Novel Combinations and Evidence That “Less is More”

Studies presented at the 2022 ASH Annual Meeting may inform the treatment of acute myeloid leukemia (AML), with 2 studies highlighting promising combination regimens and 2 studies suggesting certain patients may benefit from less intensive treatment. 

The phase 3 ASAP trial showed that intensive remission induction chemotherapy does not provide a benefit over watchful waiting and sequential conditioning prior to allogeneic hematopoietic stem cell transplant (allo-HSCT) in patients with AML.¹

The phase 3 DaunoDouble trial showed that neither a higher dose of daunorubicin nor a second induction improve outcomes for patients with newly diagnosed AML.²

In a phase 1b/2 study, treatment with pivekimab sunirine, azacitidine, and venetoclax led to a favorable response rate in high-risk AML patients.³

And updated results from a phase 2 trial revealed high response rates in younger, newly diagnosed AML patients treated with venetoclax plus cladribine, idarubicin, and cytarabine.⁴

Allo-HSCT in AML: Start the Donor Search ASAP

In the phase 3 ASAP trial, intensive remission induction chemotherapy before allo-HSCT did not provide a benefit in disease-free survival (DFS) or overall survival (OS), when compared with watchful waiting followed by sequential conditioning and allo-HSCT.¹

The trial (ClinicalTrials.gov Identifier: NCT02461537) enrolled adult AML patients with a poor response after first induction therapy or AML relapse who had an HLA-compatible donor. Patients were randomly assigned to a remission induction strategy (RIST) or a disease control (DISC) strategy.

Patients assigned to the RIST arm received cytarabine at 3 g/m² (1 g/m² for patients older than 60 years) twice daily on days 1-3 plus mitoxantrone at 10 mg/m² on days 3-5, followed by conditioning and allo-HSCT. 

Patients assigned to the DISC arm underwent watchful waiting or received low-dose cytarabine and single doses of mitoxantrone for disease control as needed, prior to sequential conditioning and allo-HSCT. 

The intent-to-treat (ITT) population included 137 patients in the RIST arm and 139 in the DISC arm. The per-protocol population included 134 patients in the RIST arm and 138 in the DISC arm. 

In the DISC arm, 76% of patients were kept on watchful waiting until the start of conditioning, and 24% needed disease control measures before conditioning. In the RIST arm, 46% of patients achieved a complete response (CR). Five patients received a second course of intensive chemotherapy, and the remaining patients proceeded to allo-HSCT with no additional attempt to induce a CR. 

The primary endpoint was DFS at day 56 after allo-HSCT. In the ITT population, the DFS rate at day 56 was 83.5% in the DISC arm and 81.0% in the RIST arm (P for noninferiority =.054). In the per-protocol population, the DFS rate at day 56 was 84.1% in the DISC arm and 81.3% in the RIST arm (P for noninferiority =.047). 

The median follow-up from randomization was 37 months. Among patients who met the primary endpoint, there was no significant difference between the RIST and DISC arms in leukemia-free survival from day 56 (P =.61). In the ITT population, there was no significant difference between the arms in OS from randomization (P =.47). 

Grade 3 or higher adverse events (AEs) occurred in 23% of patients in the DISC arm and 64% of those in the RIST arm (P <.001). The mean number of days in the hospital prior to allo-HSCT was 19 days in the DISC arm and 42 days in the RIST arm (P <.001).

The DISC approach may be the preferred treatment option for these patients if a stem cell donor is readily available, said study presenter Johannes Schetelig, MD, of the University Hospital TU Dresden in Germany.

He added that, if no donor is readily available and a prolonged donor search is needed, intensive salvage chemotherapy, targeted therapy for FLT3-mutant AML, or treatment with a BCL2 inhibitor and hypomethylating agent are all options. 

“The most important takeaway for adult AML patient therapy is that medical providers should start the donor search as early as possible, preferably at the time of diagnosis or after the receipt of genetic risk profiling when it becomes clear that a patient does suffer from nonfavorable-risk AML,” Dr Schetelig said.

The results of this study “challenge the concept that complete blast eradication is necessary for optimal outcome with hematopoietic stem cell transplantation,” said John Mascarenhas, MD, of the Icahn School of Medicine and the Tisch Cancer Institute at Mount Sinai in New York, New York, who was not involved in this study. 

“This could impact the management of relapsed/refractory AML and limit the amount of cytotoxic therapy prior to transplant, which would reduce toxicity and potential added morbidity and mortality,” Dr Mascarenhas added.  

“The only counterargument for this study is that the reinduction regimen used also contained high-dose cytarabine and anthracycline for patients who already failed cytarabine and an anthracycline, and we can’t help but wonder if targeted therapies or introducing other reinduction [regimens] like FLAG [fludarabine, cytarabine, and granulocyte colony stimulating factor] would have made a difference,” said Maher Abdul Hay, MD, of NYU Langone’s Perlmutter Cancer Center, who was not involved in the study. 

This article originally appeared on Cancer Therapy Advisor