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1437 Fla-IDA Chemotherapy with or without Venetoclax in Patients with Relapsed/Refractory Acute Myeloid Leukemia

Program: Oral and Poster Abstracts
Session: 615. Acute Myeloid Leukemias: Commercially Available Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster I
Hematology Disease Topics & Pathways:
Acute Myeloid Malignancies, AML, Combination therapy, Diseases, Therapies, Myeloid Malignancies, Minimal Residual Disease
Saturday, December 10, 2022, 5:30 PM-7:30 PM

Rabia Shahswar, MD1*, Gernot Beutel, MD1*, Razif Gabdoulline, PhD1*, Adrian Schwarzer, MD, PhD1, Arnold Kloos, PhD1*, Christian Koenecke, MD1*, Michael Stadler, MD1*, Gudrun Göhring, MD2*, Brigitte Schlegelberger, MD2, Zhixiong Li, MD1, Louisa-Kristin Dallmann1*, Clara Wienecke1*, Piroska Klement, MD1*, Catherin Albert1*, Martin Wichmann1*, Yasmine Alwie1*, Axel Benner3*, Maral Saadati, PhD4*, Arnold Ganser, MD5*, Felicitas R. Thol, MD1 and Michael Heuser, MD1

1Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
2Department of Human Genetics, Hannover Medical School, Hannover, Germany
3Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany
4Saadati Solutions, Ladenburg, Germany
5Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hanover, Germany

Introduction: Refractory and relapsed AML (R/R AML) is difficult to treat with median overall survival of 6.5-39 months in patients undergoing allogeneic hematopoietic cell transplantation (alloHCT), and 1.5-11.9 months in patients not eligible for alloHCT. Venetoclax combined with fludarabine, cytarabine, and idarubicin (FLAVIDA) induces a high response rate in R/R AML patients. However, long-term outcome of this regimen has not been compared to FLA-IDA chemotherapy only.

Objectives: To compare FLAVIDA with FLA-IDA as salvage chemotherapy in R/R AML and assess MRD response and overall survival (OS).

Methods: This retrospective single center cohort study included patients with R/R AML treated with FLAVIDA or FLA-IDA. Venetoclax was dosed 100mg/day orally (days 1–7) due to co-medication with posaconazole. Eighty-one patients that were treated with FLA-IDA between 2000 and 2018 and fulfilled the selection criteria of the FLAVIDA patients served as control. Measurable residual disease (MRD) was assessed by NGS with a cutoff of 0.01% or multicolor flow cytometry with a cutoff of 0.1%. The overall response rate was defined by complete remission (CR) + CR with incomplete hematologic recovery (CRi) + morphologic leukemia-free state (MLFS). This study was approved by the local Ethics Review Committee in accordance with the Declaration of Helsinki. and is registered with ClinicalTrials.gov, NCT03662724. The data cut-off for this analysis was December 31, 2021.

Results: Thirty-seven and 81 patients, who received one course of FLAVIDA and FLA-IDA, respectively, were included in the analysis. Baseline characteristics were balanced between FLAVIDA and FLA-IDA treated patients: median age 54 vs. 52 years; de novo AML 70% vs. 77%; 2017 ELN adverse risk 33% vs. 25%; relapsed AML 51% vs. 42%; prior alloHCT 22% vs. 28%. FLAVIDA and FLA-IDA treated patients received a median of one (range 1-5) prior lines of therapy.

The ORR was 78% (n=29/37) in the FLAVIDA compared to 47% (n=38/81) in the FLA-IDA group (P=0.001) (Figure 1A). The CR/CRi rate was 59% and 30% in FLAVIDA and FLA-IDA patients, respectively (P=0.003). MRD negative response was achieved in a similar proportion of patients treated with the two regimens (50% and 57%; P=0.65).

No differences in neutrophil and platelet recovery times were observed in the FLAVIDA compared to the FLA-IDA group. Most commonly observed treatment related toxicities of any grade were hematological adverse events (AEs) being reported in all FLAVIDA treated patients. Non-hematological AEs of all grades included bacteremia, sepsis, and fungal pneumonia occurring in 27%, 11%, and 11%, respectively.

Eighty-one and 79% of patients proceeded to alloHCT or donor lymphocyte infusion (DLI) after FLAVIDA and FLA-IDA, respectively.

Median follow up was 22.4 and 62.9 months in FLAVIDA and FLA-IDA cohorts. Despite a higher ORR in FLAVIDA patients, OS was similar between FLAVIDA and FLA-IDA-treated patients (HR 1.18; P=0.57) (Figure 1B). In the 26 responding FLAVIDA patients with available MRD data, survival was significantly longer in MRD negative patients (HR 0.1, 95%CI 0.01–0.82; P=0.009) while MRD was not prognostic for OS in responding FLA-IDA patients with available samples (n=23; HR 0.58, 95%CI 0.17–1.9; P=0.36). Subgroup analyses revealed that the only group with different EFS and OS after FLAVIDA or FLA-IDA was the non-responding patient group, in which FLA-IDA treated patients had improved EFS and OS after additional salvage treatment. Median OS from the time of non-response was significantly longer in non-responding FLA-IDA compared to non-responding FLAVIDA patients (HR 0.31, 95%CI 0.12–0.8; P=0.01), suggesting that non-responding FLA-IDA patients could be salvaged more successfully.

Conclusions: Short-term venetoclax in combination with FLA-IDA represents an effective intensive treatment regimen in R/R AML. ORR was significantly higher in FLAVIDA compared to FLA-IDA treated patients. However, OS was comparable among patients treated with FLAVIDA or FLA-IDA. MRD negative response was associated with excellent OS in FLAVIDA treated patients.

Disclosures: Shahswar: Jazz Pharmaceuticals: Honoraria; AbbVie: Honoraria. Koenecke: Novartis: Membership on an entity's Board of Directors or advisory committees. Thol: Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Heuser: BergenBio: Research Funding; Bayer Pharma AG: Research Funding; Astellas: Research Funding; Tolremo: Consultancy; Roche: Consultancy, Research Funding; PinotBio: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Kura Oncology: Consultancy; Glycostem: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; BMS: Consultancy; Agios: Consultancy, Research Funding; Takeda: Honoraria; Loxo Oncology: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Eurocept: Honoraria; Abbvie: Consultancy, Honoraria, Research Funding.

*signifies non-member of ASH