Allogeneic Transplant Improves AML Outcomes Compared to Maintenance Venetoclax and Azacitidine Following Response to Initial Venetoclax and Azacitidine Therapy
Authors: Pollyea Daniel A. , Winters Amanda , Jordan Craig T. , Smith Clayton , Gutman Jonathan A. 
Published: February 2021

Venetoclax and azacitidine (ven/aza) is our institutional preference for initial treatment of non-core binding factor AML patients age ≥60. Given potential durability of response in these patients, the role of transplant (SCT) in patients who achieve response to ven/aza is uncertain. To examine the potential contribution of SCT, we identified 119 patients age ≥60 who received ven/aza as initial AML therapy at our center between 1/2015 and 1/2020. We then compared outcomes for these patients based on whether they were deemed eligible or ineligible for SCT; for those deemed eligible, we compared outcomes between patients who received SCT and those who did not due to personal preference. SCT consults were generally conducted within 2 cycles of initiation of ven/aza but were delayed in some patients achieving CR until evidence of persistent or recurrent measurable residual disease (MRD).

Among the 119 patients, 61 (median age 76 (61-90)) were not SCT candidates due to age or comorbidities (n=44) or early death due to primary refractory disease/acute toxicity (n=17). 60 patients were potential SCT candidates. 21 patients median age 65 (60-73) underwent SCT. 2 of these patients had MDS prior to developing AML and underwent SCT consult before developing AML and initiating ven/aza. For the remaining 19 patients, consult occurred median of 50 days (20-287) from diagnosis. 2 patients relapsed after initiating ven/aza prior to transplant, underwent induction, and then went on to SCT. SCT occurred median 176 (69-643) days from diagnosis and median 133 (49-615) days from SCT consult. 37 patients median age 72 (64-78) had SCT consults but did not undergo SCT. 5 of these patients had refractory disease and never achieved SCT eligibility, one patient was deemed not an SCT candidate after consult due to social issues, and one patient was lost to follow up. The remaining 30 patients median age 72 (64-78) achieved adequate response for SCT but elected to defer. 2 of these 30 patients had MDS prior to developing AML and underwent SCT consult before developing AML and initiating ven/aza. Among the 28 patients who had SCT consults after initiating ven/aza and deferred SCT, SCT consult occurred median of 64 days (14-222) from diagnosis.

Details of ELN risk status and disease status at time of SCT consult, time of SCT, and best disease response for non-SCT patients are provided in Table 1. MRD positivity included disease detected by cytogenetics, FISH, flow cytometry, or digital droplet PCR (ddPCR). Donor sources were cord (n=11), haplocord (n=3), and matched related donor (n=7). Conditioning regimens included 7 non-myeloablative, 12 reduced-intensity, and 2 myeloablative.

Overall survival (OS) was significantly greater among SCT patients (median survival not reached) versus patients undergoing SCT consult and deferring SCT (median 588 days) (p=0.01) versus patients not considered SCT candidates due to age or comorbidities (median 291 days) (p=&lt;0.001). OS was significantly greater for patients undergoing SCT consult and deferring SCT versus patients not considered SCT candidates due to age or comorbidities (p=0.01) (Figure 1). Among patients SCT eligible but deferring SCT, OS trended toward improved among patients with best disease response of CR or CRi without MRD (n=22 median 811 days) versus patients whose best disease response continued to include MRD (n= 8 median 443 days) (p=0.13). Favorable ELN status (n=10) was associated with improved OS compared to intermediate or unfavorable (n=20) (p=0.036, median survival 871 versus 443 days). Among SCT patients, OS was comparable whether patients went to SCT with (n=14) or without MRD (n=7) (p=0.49). ELN status did not impact OS; only 3 patients had favorable status. Median survival was not reached in any arm.

For SCT eligible patients, SCT appears to improve outcomes among patients who respond to ven/aza compared to patients who defer SCT. Preliminary data suggests that outcomes may be improved for patients going to transplant with MRD following initial therapy with ven/aza as compared to traditional chemotherapy induction. Ongoing data to further refine the significance of MRD, molecular and cytogenetic prognostic factors, and optimal timing of SCT, as well as standardized tools to assess MRD, are necessary.

Disclosures

Pollyea: Syndax: Consultancy; Glycomimetics: Other; Syros: Consultancy; Abbvie: Consultancy, Research Funding; Karyopharm: Consultancy; Takeda: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Celgene/BMS: Consultancy; Pfizer: Consultancy; 47: Consultancy, Research Funding; Janssen: Consultancy; Amgen: Consultancy; Genentech: Consultancy; Novartis: Consultancy.