Individualized Sequential Allogeneic Stem Cell Transplantation for Relapsed or Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome Patients with Active Disease
Authors: Zucenka Andrius , Kevličius Lukas , Smalinskaitė Tautvilė , Daukėlaitė Guoda , Davainis Linas , Trociukas Igoris , Slobinas Artūras , Jucaitienė Renata , Šlepikienė Inga , Čekauskienė Rita , Jaraminė Vaida , Strumskytė Justė , Jakubauskas Artūras , Griškevičius Laimonas 
Published: December 2024

BACKGROUND
Salvage therapies for relapsed or refractory acute myeloid leukemia (R/R AML) or high-risk myelodysplastic syndromes (R/R HR-MDS) are rarely curative due to the suboptimal efficacy, short lasting responses, and toxicity. Herein, we report a sequential salvage treatment consisting of Venetoclax-based preconditioning followed by conventional conditioning and allogeneic stem cell transplantation (alloSCT) for patients with active R/R AML or HR-MDS in a real-world setting.
METHODS
This was a retrospective, single-center study. Patients were 18 years of age or older with active R/R AML or HR-MDS. Informed consent and Institutional Ethics Committee treatment approval was obtained in all cases.
The preconditioning regimens consisted of 10-day Venetoclax containing regimens which were individualized based on the patient's status, age, prior treatment and genomics. Five backbones were used for preconditioning: De-ACTIVE (Decitabine 20 mg/m2 on days 1-10, Actinomycin D 12.5 mcg/kg on days 1-3 + Cytarabine 20 mg/m2 on days 1-10, Venetoclax 600 mg/d on days 1-10), ACTIVE (Actinomycin D 12.5 mcg/kg + Cytarabine 20 mg/m2 + Venetoclax 600 mg/d), De-CAVE (Decitabine 20 mg/m2 + Cytarabine 20 mg/m2 + Venetoclax 600 mg/d), Ven + HMA (Venetoclax 400 mg/d + Decitabine 20 mg/m2 or Azacitidine 75 mg/m2) or Ven + LDAraC (Venetoclax 600 mg/d + Cytarabine 20 mg/m2). 5-day regimens were used for patients with ECOG 2-3 or age &gt;70 years. Additional Gilteritinib, Trametinib, Dasatinib, Navitoclax, and Cladribine were used based on AML genomics and FAB classification. After the preconditioning patients proceeded to conditioning and stem cell infusion.
We collected data on patients' baseline characteristics, genomics, prior therapies, and transplant-related parameters. For efficacy analysis CR, CRp, MLFS, and MRD negativity (multiparameter flow cytometry (&lt;0.1%) rates were collected after the preconditioning and post-engraftment. Survival and toxicity data consisted of overall survival (OS), relapse-free survival (RFS), time to neutrophil (ANC) engraftment, grade 3-5 non-hematological toxicity, day 30, and day 60 mortality rates.
RESULTS
Thirty-five patients (22 male) were enrolled in the study. The median age was 56 years (21-72) and the median ECOG was 1 (0-3). AML and HR-MDS were diagnosed in 80% (28/35) and 20% (7/35), respectively. Most patients (86%, 30/35) were stratified to the ELN 2022 adverse risk group, 40% (14/35) had adverse cytogenetics, and 31% (11/35) had TP53 mutations. Fifty-four percent (19/35) were previously treated with one prior therapy, whereas 26% (9/35) and 20% (7/35) had received 2 or ≥3 prior therapies, respectively. Venetoclax exposure and previous alloSCT were recorded in 54% (19/35) and 29% (10/35), respectively. The median blast percentage before treatment was 18% (4-97).
De-ACTIVE, ACTIVE, De-CAVE, Ven + HMA and Ven + LDAraC were used as preconditioning backbones in 51% (18/35), 23% (8/35), 14% (5/35), 6% (2/35), and 6% (2/35), respectively. Additional agents were administered in 66% (22/35). The MLFS rate after the preconditioning was 77% (27/35). All patients proceeded to either MAC (23%, 8/35) or RIC (77%, 27/35) after a median of 1 wash-out day (0-19). Haploidentical, matched-related, matched-unrelated, and mismatched donors were used in 51% (18/35), 23% (8/35), 20% (7/35), 6% (2/35), respectively.
The CR + CRp rate after alloSCT was 90% (28/31) with an MRD negativity rate of 88% (23/26) in evaluable cases. The median time from the start of the preconditioning to ANC engraftment was 38 days (28-57).
Day 30 and day 60 mortality was 11% (4/35) and 14% (5/35), respectively. Grade 3-5 infectious complications were observed in 86% (30/35). Hepatic toxicity was notable with 9% (3/35), 6% (2/35), and 17% (6/35) developing VOD, grade 3 bilirubin increase, or grade 3 ALT/AST elevation, respectively.
The median OS was 8.1 months (95% CI 5.5-10.8), and 24-month OS was 36% (SE 11.3) in all patients. The median RFS was 9.5 months (95% CI 3.3-9.5) and 24-month RFS was 45% (SE 12.4) in responders.
CONCLUSIONS
Sequential alloSCT with Venetoclax-based low intensity preconditioning followed by conditioning and alloSCT demonstrates high antileukemic efficacy in difficult-to-treat R/R AML or HR-MDS patients with active disease in a real-world setting. However, the treatment was associated with high rates of severe infectious complications and notable hepatic toxicity.