Hypomethylating Agents With Venetoclax Can Be Effective Bridge to Transplant in AML

New research suggests the combination of hypomethylating agents with venetoclax (Venclexta) can be a successful bridging regimen to allogeneic hematopoietic cell transplantation (alloHCT) in certain patients with acute myeloid leukemia (AML).

The article was published in the American Journal of Hematology.

Corresponding author Vanessa Kennedy, MD, of the University of California San Francisco, and colleagues, wrote that the traditional curative treatment for patients with AML is cytotoxic chemotherapy followed by alloHCT.

“Many AML patients, however, are poor candidates for cytotoxic chemotherapy due to poor performance status, multiple comorbidities, and/or refractory and chemoresistant disease,” Kennedy and colleagues wrote.

In those cases, the combination of hypomethylating agents and venetoclax (HMA/Ven) has emerged as a meaningful treatment option, both for first-line therapy and in cases of relapsed or refractory (R/R) AML.

However, there have been emerging reports suggesting that HMA/Ven might also work well as a bridge to transplant. A pair of reports found the therapy produces sufficiently deep responses in some patients to make alloHCT a safe option.

In an effort to better understand whether and when HMA/Ven could work as a bridge to transplant, Kennedy and colleagues reviewed patient characteristics and outcomes in 88 cases of AML in which patients were given HMA/Ven and then proceeded to transplant.

The cases all underwent transplant procedures between 2017 and 2020. Forty-six received HMA/Ven as their frontline therapy, and the remaining 42 received the combination for R/R disease. The median age at time of transplant was 67 years, though patients receiving frontline therapy tended to be older (70 years on average, versus 58 years in the R/R group).

About half of patients (52%) were considered to have adverse-risk disease, with 15% of patients showing FLT3 mutations, and 16% showing TP53 mutations, the authors said.

Patients’ were stratified into disease status at time of transplant, with 70% of patients achieving complete responses (CR) by transplant time, and 15% achieving CR with incomplete count recovery. The remaining 15% had attained morphologic leukemia-free state (MLFS). Of the 83% of patients who underwent measurable residual disease (MRD) assessment prior to transplant, about two-thirds (68%) were negative.

Patients who were MRD positive had a median of 4 cycles of HMA/Ven, versus 3 cycles among the MRD-negative group. Most patients (55%) received reduced intensity myeloablative conditioning, while 28% received non-reduced myeloablative conditioning and 17% received non-myeloablative conditioning.

After 100 days, 85% of patients had achieved morphologic CR and 86% were MRD-negative. Overall survival was 83% after 6 months, and 73% after a year. Cumulative incidences of relapse (CIR) were 22% at 6 months and 36% at 1 year.

Kennedy and colleagues found that only pre-transplant MRD status was a significant predictor of outcomes, with MRD negativity associated with superior outcomes in both the frontline and R/R groups.

“This finding corroborates prior studies demonstrating MRD negativity is predictive of post-alloHCT outcomes in AML and emphasizes the value of achieving MRD negativity prior to transplant,” Kennedy and colleagues wrote.

Patients with TP53 mutations were shown to have inferior outcomes, but only in patients who received frontline HMA/Ven. FLT3 was not associated with poorer outcomes.

Kennedy and colleagues concluded that their report suggests HMA/Ven as a bridge to alloHCT.

“These data are particularly relevant as use of HMA/Ven is increasing over time, as demonstrated in our cohort,” they wrote. “Elderly patients should be considered for alloHCT early during HMA/Ven treatment, as the use of low- intensity therapy does not preclude [reduced-intensity conditioning] alloHCT at any age.”

Reference

Kennedy VE, Hui G, Azenkot T, et al. Outcomes of allogeneic transplantation after hypomethylating agents with venetoclax in acute myeloid leukemia. Am J Hematol. Published online March 9, 2022. doi:10.1002/ajh.26524