A Phase 1/2 Trial of Cladribine, High-Dose Cytarabine, G-CSF, and Dose-Escalated Mitoxantrone (CLAG-M) Plus Gemtuzumab Ozogamicin in Adults with Newly-Diagnosed Acute Myeloid Leukemia (AML) or Other High-Grade Myeloid Neoplasm
Authors: Godwin Colin D. , Othus Megan , Percival Mary-Elizabeth M. , Hendrie Paul C. , Scott Bart L. , Appelbaum Jacob S. , Halpern Anna B. , Oehler Vivian G. , Orozco Johnnie J. , Keel Sioban B. , Abkowitz Janis L. , Cooper Jason P. , Cassaday Ryan D. , Orlowski Kaysey F. , Marshall Anise J. , Brown Clarisa N. , Estey Elihu H. , Walter Roland B. 
Published: November 2021

Abstract
Background: In a prior single-institution trial, CLAG-M resulted in high rates of measurable residual disease (MRD)-negative remissions for adults with previously untreated AML or high-grade myeloid neoplasms (HG-MN) with ≥10% blasts in bone marrow and/or blood (Halpern et al. Leukemia 2018;32:2352-62). The CD33 antibody-drug conjugate, gemtuzumab ozogamicin (GO), reduces relapse and improves survival when added to other intensive chemotherapy regimens, prompting this phase 1/2 study (NCT03531918) combining GO with CLAG-M as initial therapy for fit adults with newly diagnosed AML or HG-MN.
Patients and Methods: Adults ≥18 years were eligible if they had LVEF ≥45%, creatinine ≤2.0 mg/dL, bilirubin ≤2.5-times upper limit of normal, and treatment-related mortality (TRM) score of ≤13.1, previously corresponding to &lt;13.1% risk of 28-day mortality (Walter et al. J Clin Oncol 2011;29:4417-23). Patients with APL, CML in blast crisis, other illness with expected survival &lt;1 year, or uncontrolled infection were excluded. Phase 1 tested two dose levels of GO in combination with CLAG-M: "GO1": 3 mg/m 2 on day 1 and "GO3": 3 mg/m 2 on days 1, 4, and 7, with all GO doses capped at 4.5 mg. CLAG-M consisted of cladribine 5 mg/m 2/day (days 1-5), cytarabine 2 g/m 2/day (days 1-5), G-CSF 300 or 480 μg/day (for weight &lt;76 kg vs. ≥76 kg; days 0-5), and mitoxantrone (18 mg/m 2/day; days 1-3). A second course of CLAG-M (without GO) was given if MRD-negative (MRDneg) complete remission (CR) or MRDneg CR with incomplete count recovery (CRi) was not achieved. MRD was measured by multiparameter flow cytometry (MFC) and cytogenetics. One cycle of CLAG (mitoxantrone omitted) followed by 2 cycles of high-dose cytarabine was allowed as post-remission therapy. Dose escalation to GO3 was permitted if fewer than 2 dose-limiting toxicities (DLTs) were observed among 6 GO1 patients. DLT was defined as: 1) any grade 3 non-hematologic toxicity lasting &gt;48 hours that resulted in &gt;7-day delay of the subsequent treatment cycle, with the exception of febrile neutropenia/infection; 2) any grade ≥4 non-hematologic toxicity, with the exception of febrile neutropenia/infection or constitutional symptoms. The primary efficacy outcome was 6-month event-free survival (EFS).
Results: Eighteen patients (median age 66 [range: 28-77] years, median TRM score 3.92 [range: 0.14-10.3]) were treated in phase 1. One of 6 GO1 patients experienced a DLT of grade 3 left ventricular systolic dysfunction. Among 12 GO3 patients, there were 3 DLTs: 1 each of grade 4 aminotransferase level increase, grade 3 posterior reversible encephalopathy syndrome, and grade 3 intracranial hemorrhage. This established GO3 as the recommended phase 2 dose. A total of 60 patients (median age; 65 [range: 19-80] years) with either AML (n=48) or HG-MN (n=12) and a median TRM score of 3.4 (range: 0.02-11.8) were treated at GO3 in either phase 1 or phase 2. By ELN 2017 criteria, 20 had favorable-, 13 intermediate-, and 27 adverse-risk disease. Forty-six (77%) achieved CR and 6 (10%) achieved CRi for a CR/CRi rate of 87% (95% CI: 75-94%). Forty-five CR/CRi patients were negative for MRD by both MFC and cytogenetics for an overall MRDneg CR/CRi rate of 75% (95% CI: 62-85%). Two patients had morphologic leukemia free state (MFLS), 2 underwent hematopoietic stem cell transplant (HCT) in aplasia not meeting MLFS criteria, and 4 had resistant disease. With median follow-up of 15 months, 6-month EFS, 12-month EFS, 6-month overall survival (OS) and 12-month OS were 73% (95% CI: 61-85%), 59% (48-73%), 90% (83-98%) and 75% (65-89%), respectively. For patients achieving CR after cycle 1 (n=45), median time to neutrophil count of 1000/µL and platelet count of 100,000/µL was 32 days (range: 22-51) and 31 days (range: 21-48), respectively. Besides infections and neutropenic fever, hypertension and hemorrhage were the most common grade ≥3 adverse events. There were no deaths within 8 weeks of study start. Of note, 1 patient had reversible early liver injury not meeting sinusoidal obstructive syndrome (SOS) criteria, and 1/25 (4%) of patients who underwent allogeneic HCT after study therapy was diagnosed with nonfatal post-HCT SOS.
Conclusion: CLAG-M with fractionated-dose GO resulted in an MRDneg CR/CRi rate of 75% and a 6-month EFS rate of 73% in adults with newly diagnosed AML/HG-MN. Formal comparison of outcomes with institutional patients given CLAG-M alone is ongoing.

Disclosures
Godwin: Pfizer: Research Funding; Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Percival: Glycomimetics: Research Funding; Cardiff Oncology: Research Funding; BMS/Celgene: Research Funding; Biosight: Research Funding; Abbvie: Research Funding; Pfizer: Research Funding; Nohla Therapeutics: Research Funding; Oscotec: Research Funding; Trillium: Research Funding. Scott: Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Halpern: Pfizer: Research Funding; Nohla Therapeutics: Research Funding; Jazz Pharmaceuticals: Research Funding; Imago Pharmaceuticals: Research Funding; Novartis: Research Funding; Bayer: Research Funding; Tolero Pharmaceuticals: Research Funding; Agios Pharmaceuticals: Research Funding; Abbvie: Consultancy; Gilead: Research Funding; Agios: Consultancy. Oehler: BMS: Consultancy; OncLive: Honoraria; Takeda: Consultancy; Pfizer: Research Funding. Orozco: Actinium Pharmaceuticals: Other: Principal Investigator, SIERRA Trial, Actinium, Research Funding. Cassaday: Pepromene Bio: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Kite/Gilead: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Vanda Pharmaceuticals: Research Funding; Servier: Research Funding; Pfizer: Consultancy, Research Funding. Walter: Pfizer: Consultancy, Research Funding; Jazz: Research Funding; Amphivena: Consultancy, Other: ownership interests; Agios: Consultancy; Selvita: Research Funding; Astellas: Consultancy; BMS: Consultancy; Genentech: Consultancy; Janssen: Consultancy; Kite: Consultancy; Macrogenics: Consultancy, Research Funding; Immunogen: Research Funding; Celgene: Consultancy, Research Funding; Aptevo: Consultancy, Research Funding; Amgen: Research Funding.

OffLabel Disclosure:
The label for cladribine does not include acute myeloid leukemia, however cladribine is frequently used to treat AML and related conditions. In this study cladribine is used in induction chemotherapy for the treated of AML and related disorders.