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. 2022 Jun 14;14(12):2934.
doi: 10.3390/cancers14122934.

Phase 1/2 Trial of CLAG-M with Dose-Escalated Mitoxantrone in Combination with Fractionated-Dose Gemtuzumab Ozogamicin for Newly Diagnosed Acute Myeloid Leukemia and Other High-Grade Myeloid Neoplasms

Colin D Godwin  1   2 , Eduardo Rodríguez-Arbolí  1 , Megan Othus  3 , Anna B Halpern  1   2 , Jacob S Appelbaum  1   2 , Mary-Elizabeth M Percival  1   2 , Paul C Hendrie  1   2 , Vivian G Oehler  1   2 , Siobán B Keel  1   2 , Janis L Abkowitz  1   2 , Jason P Cooper  1   2 , Ryan D Cassaday  1   2 , Elihu H Estey  1   2 , Roland B Walter  1   2   4   5
Affiliations

Phase 1/2 Trial of CLAG-M with Dose-Escalated Mitoxantrone in Combination with Fractionated-Dose Gemtuzumab Ozogamicin for Newly Diagnosed Acute Myeloid Leukemia and Other High-Grade Myeloid Neoplasms

Colin D Godwin et al. Cancers (Basel). .

Abstract

Gemtuzumab ozogamicin (GO) improves outcomes when added to intensive AML chemotherapy. A meta-analysis suggested the greatest benefit when combining fractionated doses of GO (GO3) with 7 + 3. To test whether GO3 can be safely used with high intensity chemotherapy, we conducted a phase 1/2 study of cladribine, high-dose cytarabine, G-CSF, and dose-escalated mitoxantrone (CLAG-M) in adults with newly diagnosed AML or other high-grade myeloid neoplasm (NCT03531918). Sixty-six patients with a median age of 65 (range: 19-80) years were enrolled. Cohorts of six and twelve patients were treated in phase 1 with one dose of GO or three doses of GO (GO3) at 3 mg/m2 per dose. Since a maximum-tolerated dose was not reached, the recommended phase 2 dose (RP2D) was declared to be GO3. At RP2D, 52/60 (87%) patients achieved a complete remission (CR)/CR with incomplete hematologic recovery (CRi), 45/52 (87%) without flow cytometric measurable residual disease (MRD). Eight-week mortality was 0%. Six- and twelve-month event-free survival (EFS) were 73% and 58%; among favorable-risk patients, these estimates were 100% and 95%. Compared to 186 medically matched adults treated with CLAG-M alone, CLAG-M/GO3 was associated with better survival in patients with favorable-risk disease (EFS: p = 0.007; OS: p = 0.030). These data indicate that CLAG-M/GO3 is safe and leads to superior outcomes than CLAG-M alone in favorable-risk AML/high-grade myeloid neoplasm.

Keywords: CD33; CLAG-M; acute myeloid leukemia (AML); adults; antibody-drug conjugate; chemotherapy; gemtuzumab ozogamicin; phase 1/2 trial.

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Conflict of interest statement

C.D.G. received laboratory research grants and/or clinical trial support from Pfizer and ImmunoGen and has current employment and equity ownership with Bristol Myers Squibb. A.B.H. received clinical trial support from Bayer, Gilead, Imago, Incyte, Jazz, and Novartis, and is a consultant to AbbVie. J.S.A. received research support from 2seventy bio. M.-E.M.P. received clinical trial support from AbbVie, Biosight, Bristol Myers Squibb, Cardiff, Glycomimetics, Oscotec, Pfizer, and Trillium. V.G.O. received research support from Pfizer. S.B.K. is a consultant to Discmedicine. R.D.C. received clinical trial support from Amgen, Kite/Gilead, Merck, Pfizer, Servier, and Vanda Pharmaceuticals; consulting/honoraria from Amgen, Kite/Gilead, and Pfizer; serves on a data safety monitoring board for Pepromene Bio; and his spouse is employed by and owns stock in Seagen. R.B.W. received laboratory research grants and/or clinical trial support from Agios, Amgen, Aptevo, Arog, BioLineRx, Celgene, ImmunoGen, Janssen, Jazz, Kura, MacroGenics, Pfizer, Selvita, and Stemline; has ownership interests in Amphivena; and is (or has been) a consultant to Agios, Amgen, Amphivena, Aptevo, Astellas, BioLineRx, Boston Biomedical, Bristol Myers Squibb, Celgene, Genentech, GlaxoSmithKline, Janssen, Jazz, Kite, Kronos, MacroGenics, New Link Genetics, Pfizer, and Race. The other authors declare no competing financial interests.

Figures

Figure 1
Figure 1
Estimates of (A) cumulative incidence of relapse, (B) event-free survival, and (C) overall survival for the 60 patients who received CLAG-M/GO3 as well as, separately, the 28 patients age <65 years and the 32 patients age ≥65 years in this cohort.
Figure 2
Figure 2
Estimates of (A) cumulative incidence of relapse, (B) event-free survival, and (C) overall survival for the 60 patients who received CLAG-M/GO3 and 186 medically matched patients who received CLAG-M without GO.
Figure 3
Figure 3
Estimates of (A,D,G) cumulative incidence of relapse, (B,E,H) event-free survival, and (C,F,I) overall survival for the 60 patients who received CLAG-M/GO3 and medically matched patients who received CLAG-M without GO, stratified by favorable (A–C), intermediate (D–F), and adverse (G–I) cytogenetic/molecular disease risk (ELN 2017 classification).
See this image and copyright information in PMC

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