Treatment of myeloid malignancies relapsing after allogeneic hematopoietic stem cell transplantation with venetoclax and hypomethylating agents—a retrospective multicenter analysis on behalf of the German Cooperative Transplant Study Group

Abstract

Treatment of relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) remains a great challenge. Aiming to evaluate the combination of venetoclax and hypomethylating agents (HMAClax) for the treatment of relapse of myeloid malignancies after alloHSCT, we retrospectively collected data from 32 patients treated at 11 German centers. Venetoclax was applied with azacitidine (n = 13) or decitabine (n = 19); 11 patients received DLI in addition. HMAClax was the first salvage therapy in 8 patients. The median number of cycles per patient was 2 (1–19). All but 1 patient had grade 3/4 neutropenia. Hospital admission for grade 3/4 infections was necessary in 23 patients (72%); 5 of these were fatal. In 30 evaluable patients, overall response rate (ORR) was 47% (14/30, 3 CR MRDneg, 5 CR, 2 CRi, 1 MLFS, 3 PR). ORR was 86% in first salvage patients versus 35% in later salvage patients (p = 0.03). In 6 patients with molecular relapse (MR), ORR was 67% versus 42% in patients with hematological relapse (HR) (n = 24, p = n.s.). After a median follow-up of 8.4 months, 25 patients (78%) had died and 7 were alive. Estimated median overall survival was 3.7 months. Median survival of patients with HMAClax for first versus later salvage therapy was 5.7 and 3.4 months (p = n.s.) and for patients with MR (not reached) compared to HR (3.4 months, p = 0.024). This retrospective case series shows that venetoclax is utilized in various different combinations, schedules, and doses. Toxicity is substantial and patients who receive venetoclax/HMA combinations for MR or as first salvage therapy derive the greatest benefit.

Azacitidine for relapse of acute myeloid leukemia or myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation, multicenter PALG analysis

“…Recently, a report on a combination of HMA (either decitabine or azacitidine) with venetoclax has been published, with a median OS of 5.7 vs 3.4 months for first versus later salvage therapy. It needs to be elucidated whether the addition of venetoclax can result in a survival advantage in comparison to azacitidine alone 24 …”

Treatment of AML Relapse After Allo-HCT

“…Venetoclax-containing regimens induce remissions in 28-31% of relapsed AML after allo-HCT without appreciable differences in response among patients who receive DLI, but significantly increased response rates when such regimens are used as the first post-transplant salvage treatment. In these studies, OS was significantly improved in responding patients and those treated for molecular relapse ( 61 , 63 ). As the combination of HMAs and venetoclax can induce remissions post-transplant, it may serve as a useful bridge to subsequent cellular therapy.…”

“…In practice the rates of serious and fatal infectious complications have proven much higher in post-transplant and relapsed/refractory than newly diagnosed AML patients treated with HMAs and venetoclax, but the regimen consistently induces remissions post-transplant, even in the absence of DLI. When used in the post-transplant setting, the incidence of fatal infectious complications in patients treated with HMAs and venetoclax is 16%, while the incidence of invasive fungal infections with such regimens more broadly in the relapsed/refractory setting is 19% ( 61 , 62 ). Thus the use of appropriate, broad antimicrobial prophylaxis is critical in patients treated with HMAs and venetoclax for post-allo-HCT relapse.…”

Management of Acute Myeloid Leukemia: Current Treatment Options and Future Perspectives

“…HMA plus venetoclax is also considered in relapsed AML following alloHSCT. A retrospective analysis of 32 patients demonstrated satisfying response rates when HMA/venetoclax is applied as salvage treatment or early at molecular relapse [65,66]. Using prior to al-loHSCT HMA/venetoclax has shown an excellent ORR of 68.8% in a small cohort of 32 patients (including 19 with r/r AML and 13 with de novo AML), providing a feasible strategy of remission induction [67].…”