Outcome of Therapy-Related Myeloid Neoplasms with Venetoclax-Based Therapy
Authors: Shah Mithun V. , Chhetri Rakchha , Dholakia Ruchita , Alkhateeb Hassan B. , Al-Kali Aref , Patnaik Mrinal M. , Gangat Naseema , Wei Andrew H. , Tiong Ing Soo , Begna Kebede H. , Hiwase Devendra 
Published: November 2021

Introduction: Therapy-related myeloid neoplasm (t-MN) is defined as the development of a myeloid neoplasm in the context of prior DNA damaging therapies. t-MN is an aggressive disease with no effective therapies. BCL2-inhibitor venetoclax (VEN) represents a novel treatment for acute myeloid leukemia (AML) patients including those with high-risk features. Available VEN studies included only a small portion of t-AML patients, and its efficacy in t-MDS is not known. Our aim was to study the efficacy and outcomes of VEN in t-MN.

Methods: Patients diagnosed with t-MN based on the WHO criteria who received VEN were identified. Minimal residual disease (MRD) assessment was performed in a subset of patients by multiparametric flow cytometry or molecular marker as available. Best response to VEN was divided into 3 categories: 1) MRD(-) complete remission (CR); 2) other CR [including complete morphological remission, MRD(+) CR, and CR with incomplete count recovery]; and 3) partial response/progressive disease/stable disease (PR/PD/SD). Progression-free (PFS) and overall survival (OS) were calculated from the time of initiation of VEN therapy using Kaplan-Meier analysis using Wilcoxon test. Logistic regression analysis was performed using Cox Proportional Hazard method. Statistical analysis was performed using JMP (v14.1, SAS Institute) and significance was defined as P&lt;0.05.

Results: Of 332 t-MN patients identified (248 at Mayo Clinic, 84 at the Central Adelaide Health Network), 65 (19.6%) received VEN. Clinical and pathological characteristics of patients that received VEN and did not receive VEN (non-VEN) were matched except: a higher proportion of VEN patients had t-AML (49.2% vs. 32.6%, P=0.004), higher peripheral (2% vs. 0%, P=0.02), and bone marrow blasts (18% vs. 8%, P=0.02). VEN patients had a higher proportion of abnormality of chromosome 17, complex karyotype, and monosomal karyotype compared to non-VEN patients. The proportion of patients with pathogenic/likely pathogenic variant (PV) in TP53 or RAS genes was not different. The proportion of patients receiving stem cell transplant for t-MN was not different (Table 1).

The indication for VEN was treatment naïve t-MN, relapsed/refractory (R/R) disease, and maintenance in 31 (47.7%), 32 (49.2%), and 2 (3.1%) patients respectively. Prior to VEN, patients received a median of 1 (range 0-4) lines of therapy. The median duration of VEN exposure was 3 cycles (IQR 1-4). VEN was administered with azacitidine, decitabine, low dose cytarabine, intensive chemotherapy, single agent, and &gt;1 agents in 37.9%, 40.9%, 12.1%, 4.5%, 4.5%, and 2.9% respectively. The best and the final responses to VEN are shown in Table 2. Median PFS and OS from initiation of VEN was 5 months (IQR 2-9.5, Fig. A) and 6.5 months (2-14.5, Fig. B) respectively.

Female sex (vs. male, χ 2 9.6, P=0.03), VEN as the 1 st line of therapy (vs. other line of therapy, χ 2 8.3, P=0.02), and hypomethylating agent (HMA)-backbone (vs. other, χ 2 12.1, P=0.02) were associated with a significantly higher likelihood of achieving CR. Abnormality of chromosome 7 was associated with a shorter PFS (3.5 vs. 6 months, P=0.03) and OS (4.7 vs. 10.5 months, P=0.02). Using VEN as the 1 st line therapy was associated with an improved PFS (5.5 vs. 2.7 months, P&lt;0.01) and a trend towards improved OS (9.3 vs. 5.1 months, P=0.06). Using HMA (n=51), Ara-C based (n=8), and single agent VEN (n=3) was associated with median PFS of 5.5, 4.2, and 1.5 months (P&lt;0.01) and OS of 9.1, 4, and 1.5 months (P&lt;0.01, Fig. C) respectively. Achieving MRD(-) CR (n=7), other CR (n=17), and PR/PD/SD (n=36) was associated with a median PFS of 7.7, 9.5, and 2 months (P&lt;0.001) and median OS not reached, 12.9, and 2.9 months respectively (P&lt;0.01, Fig. D). Finally, best response rate, PFS, and OS did not differ based on morphological diagnosis [t-MDS vs. t-AML] at diagnosis or bone marrow blast percent [&lt;20% vs. ≥20%] at the start of VEN therapy. On multivariate analysis, only the best response remained an independent predictor of PFS and OS.

Conclusion: VEN induced remission, including MRD(-) remission, in a subset of patients. However, progression was noted in 83% patients with continued use, and PFS and OS were overall short. The morphological diagnosis of t-MDS/t-AML or blast percentage at the start of VEN therapy did not impact outcome. Earlier use of VEN, using HMA-based therapies, and achieving deeper responses were associated with improved outcomes.

Figure 1 Figure 1.

Disclosures

Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution. Patnaik: StemLine: Research Funding; Kura Oncology: Research Funding. Wei: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Macrogenics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Tiong: Pfizer: Consultancy; Amgen: Speakers Bureau; Servier: Consultancy, Speakers Bureau. Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure:

venetoclax is not approved in the treatment of myelodysplastic syndrome.