Phase I Trial Combining Venetoclax with Cladribine, Cytarabine, G-CSF, and Mitoxantrone (CLAG-M) for Patients with Acute Myeloid Leukemia (AML) and High-Grade Myeloid Neoplasms
Authors: Raychaudhuri Suravi , Gooley Ted , Rasmussen Allegra , Quach Kim , Gill Zach , Halpern Anna B. , Appelbaum Jacob S. , Ghiuzeli Cristina Maria , Hendrie Paul C. , Cassaday Ryan D. , Walter Roland B. , Estey Elihu , Percival Mary-Elizabeth M. 
Published: December 2024

Background:
The oral BCL2 inhibitor venetoclax is safe and effective when combined with low dose cytarabine or hypomethylating agents for the treatment of patients with newly diagnosed (ND) AML who are unfit to receive intensive induction chemotherapy. Previous studies have successfully combined venetoclax with fludarabine, cytarabine, idarubicin, and G-CSF (DiNardo et. al, AJH, 2022). Combining venetoclax with intensive chemotherapy regimens may increase response rates and improve long-term outcomes for a high-risk population of AML patients. We report the results of a phase I study of venetoclax in combination with the high-intensity induction regimen, CLAG-M, for fit patients with ND adverse-risk or relapsed/refractory (R/R) AML or high-grade myeloid neoplasms (NCT04797767).
Methods:
Eligible participants were diagnosed with AML or high-grade myeloid neoplasm (≥10% myeloid blasts in bone marrow or peripheral blood) and had either (1) ND adverse-risk disease by European LeukemiaNet 2017 guidelines or (2) R/R disease. Dose level (DL) 1 was G-CSF 5 mcg/kg days 0-5, cladribine 5 mg/m2 days 1-5, cytarabine 1.5 g/m2 days 1-5, mitoxantrone 10 mg/m2 days 1-3, and venetoclax 200 mg days 1-14 with 4-day ramp-up. DL 2 increased venetoclax to 400 mg daily. DL 3 increased mitoxantrone to the standard 16 or 18 mg/m2 days 1-3 for R/R and ND disease respectively. DL 4 increased cytarabine to the standard 2 g/m2 days 1-5.
Dose-limiting toxicity (DLT) was defined as (1) any grade &gt;4 non-hematologic toxicity, (2) neutrophil count &lt;500/μL or platelet count &lt;50,000/μL, for &gt;49 days after initiation of CLAG-M, in conjunction with bone marrow showing no evidence of disease, or (3) any grade &gt;3 non-heme toxicity lasting &gt;48h and resulting in a treatment delay after day 56. Two participants started at DL 2 and a Bayesian optimal interval (BOIN) design was used to recommend subsequent dose levels, with a targeted true DLT rate of 30%. All patients received standard neutropenic prophylaxis, and venetoclax was dose-adjusted for concomitant use of CYP3A4 inhibitors. A second cycle of induction with CLAG-M and venetoclax was allowed for residual disease after the first cycle. Those with complete remission (CR) or CR with incomplete hematologic recovery (CRi) and no measurable residual disease (MRD) were eligible to receive up to 4 consolidation cycles of venetoclax plus cladribine and cytarabine at the same dose level as induction. 20 participants were enrolled with the primary objective of determining the recommended phase 2 dose (RP2D). Secondary outcomes included CR+CRi rate, overall survival (OS), and event-free survival (EFS), with events defined as death, relapse, or persistent disease on post-induction evaluation. The study was approved by the IRB and participants were consented in accordance with the Declaration of Helsinki.
Results:
Median age was 61 (range: 30-74) years. Six were ND and 14 were R/R. Two participants enrolled at DL 1, 6 at DL 2, 10 at DL 3, and 2 at DL 4 per the BOIN design. Six DLTs occurred: grade 4 respiratory failure at DL 2, grade 4 sepsis at DL3 (n=2), grade 4 respiratory failure at DL 4, myelosuppression &gt;49 days at DL 4, and grade 5 sepsis at DL 3. 28-day mortality was 5%. Sixteen participants received 1 cycle and 4 received 2.
Counting best response after 1-2 cycles of induction, overall response rate (CR + CRi) was 65%. For ND: 2 participants achieved CR without MRD, 1 CR with MRD, 2 CRi with MRD, and 1 had refractory disease. For R/R: 3 participants achieved CR without MRD, 2 CRi without MRD, 3 CRi with MRD, 3 MLFS without MRD, 2 had persistent disease, and 1 died before evaluation. Median time from starting induction 1 to recovering neutrophils &gt;500/μL or platelet count &gt;50,000/μL was 37 and 40 days respectively. Median OS from treatment start was 9.6 months (95% CI 5.1 months - not reached). Median follow up of survivors was 7.8 months. Median EFS was 3.9 months (95% CI 1.6 - 9.6 months). Five patients (2 ND, 3 R/R) went on to receive allogeneic hematopoietic stem cell transplant.
Discussion:
The recommended phase 2 dose is DL 3: G-CSF 5 mcg/kg days 0-5, cladribine 5 mg/m2 days 1-5, cytarabine 1.5 g/m2 days 1-5, mitoxantrone 16 or 18 mg/m2 days 1-3, and venetoclax 400 mg days 1-14. The results of this phase 1 trial support the design and implementation of a planned phase 2 trial to examine the efficacy of combining CLAG-M and venetoclax.