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2903 Cladribine, High-Dose AraC, Plus Gemtuzumab Ozogamicin (CLAG-GO) As Frontline Intensive Therapy for Fit Patients with Core-Binding Factor Acute Myeloid Leukemia: Preliminary Results

Program: Oral and Poster Abstracts
Session: 615. Acute Myeloid Leukemias: Commercially Available Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster II
Hematology Disease Topics & Pathways:
Acute Myeloid Malignancies, AML, Combination therapy, Diseases, Therapies, Myeloid Malignancies
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Georgina Gener-Ricos1*, Gautam Borthakur, MD1, Koji Sasaki, MD1, Guilin Tang, MD, PhD2*, Guillermo Montalban-Bravo, MD1, Elias Jabbour1, Maro Ohanian, DO1*, Musa Yilmaz, MD1*, Fadi G. Haddad, MD1*, Kelly S. Chien, MD1, Jo Ishizawa, MD, PhD1, Nicholas J. Short, MD1, Abhishek Maiti, MD1, Mahesh Swaminathan, MD1, Guillermo Garcia-Manero, MD3, Naval Daver, MD1, Courtney D. DiNardo, MD, MSc1, Farhad Ravandi, MD, MBBS1 and Tapan M. Kadia, MD1

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
3University of Texas MD Anderson Cancer Center, Houston, TX

Background: Core-binding factor (CBF) acute myeloid leukemias (AML) are associated with favorable outcomes when treated with intensive therapy regimens, particularly based on high-dose cytarabine. In addition, gemtuzumab-ozogamicin (GO) added to frontline chemotherapy showed improved survival in patients with CBF-AML in a meta-analysis of five randomized trials (Hills RK, et all. 2014). Since then, GO has been incorporated to the intensive regimen [traditional ‘3+7’ or fludarabine-cytarabine and GCSF (FLAG)] and has become the standard approach for CBF-AML.

Methods: Fit patients with newly diagnosed AML with inv(16) or t(16;16), CBFB::MYH11 [AML -inv(16)] and AML with t(8;21), RUNX1::RUNX1T1 [AML -t(8;21)] were eligible to receive cladribine, cytarabine, GCSF and GO (CLAG-GO) regimen as frontline intensive chemotherapy. We evaluated baseline patient’s characteristics, disease features, and early molecular-response dynamics, including qPCR for each CBF-AML, along with count recovery after cycle 1 (C1) and 2 (C2). Response criteria were standard as defined by the European Leukemia Net (ELN) 2022.

Results: Fifteen patients (pts) diagnose with CBF-AML were included, with a median age 47 years (range, 20 - 66 years), 53% were males. Median WBC were 15.5x10^9/L (range, 2.4 - 103). Eleven pts (73%) had AML -inv(16) and 4 pts (27%) had AML -t(8;21). Nine of 11 AML -inv(16) had a CBFB::MYH11 fusion transcript variant A and 2 of 11 pts had a CBFB::MYH11 fusion transcript variant non-A. Median CBF transcript level by qPCR at diagnose was 54.5% (range, 29.5 - 63.6) for AML -inv(16) and median qPCR of 100% (range, 100 – 100) for AML -t(8;21). Median number of co-mutations was 2 (range, 0 - 5), commonly kinase signaling mutations in components of the RAS/MAPK pathway (Figure 1). All pts received induction therapy with cladribine 5mg/m2 (D1-D5), cytarabine 2g/m2 (D1-D5), GCSF (D1 and D5) and GO 3mg/m2 (D1 or D2). If responses were achieved, subsequent consolidation cycles (up to 6 cycles) could be given with CLAG-GO (CLAG on D1-D3 and GO on D1 of C3 and C5). Thirteen pts (87%) were evaluable after induction therapy. Of the 2 non-evaluable pts, one died during induction, and 1 patient is still receiving induction therapy at the last cut off. All pts (13/13) achieved a complete remission (CR) with full count recovery (complete remission -CR- 100%). Twelve of them had minimal residual disease (MRD) assessed by flow cytometry (FC), and 11/12 (91%) pts achieved MRD negative (MRD-ve). One patient had MRD positive (0.7%) after C1. In one patient, MRD is unavailable. Twelve of 15 pts were monitored using qPCR for variant A CBFB::MYH11 or RUNX1::RUNX1T1 in different times points throughout C1. One patient died and 2 pts carried non-A variant CBFB::MYH11 fusion transcript hence qPCR was not available. Molecular MRD at D14 of C1 showed that 6/7 (86%) pts achieved qPCR <1, and by the end-of-induction 8/12 (67%) achieved qPCR <0.1 (Figure 2). There was 1 death (4-week mortality = 6%) during induction in a patient with intracranial bleeding secondary to thrombocytopenia and platelet-refractoriness. Thirteen of the 13 recovered their counts following C1, with median time to absolute neutrophil count (ANC) ≥1.0x10^9/L of 20 days (range, 13 - 23) and platelets ≥100x10^9/L of 21 days (range, 17 - 28). Ten pts received C2 of therapy in our institution. One patient was transferred to another hospital, one patient just finished induction therapy and 1 patient started consolidation regimen with FLAG-GO per physician discretion. Nine of 10 pts were evaluable after C2, and all them (100%) sustained a CR, all were MRD-ve by FC (including a patient that previously was positive) and 7 of 8 pts achieved qPCR <0.05. After C2, median days to ANC ≥1.0x10^9/L of 16 days (range, 0 - 27) and platelets ≥100x10^9/L of 21 days (0 - 37). In general, CLAG-GO was well tolerated in induction with only 1 patient had grade 3 increased alanine transferase and 1 patient had grade 3 increased aspartate transferase (both related to GO), which resolved spontaneously; and 9 pts of 15 have had an episode of neutropenic fever (3 of them infection was proved). After a median follow-up of 5 months, overall survival is 92%.

Conclusions: CLAG-GO is highly effective and safe when treating CBF-AML as frontline therapy and seems encouraging treatment. More patients need to be treated and longer follow up is needed to confirm these preliminary results.

Disclosures: Borthakur: Catamaran Bio, Abbvie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding; Pacylex, Novartis, Cytomx, Bio Ascend:: Membership on an entity's Board of Directors or advisory committees. Montalban-Bravo: Takeda: Research Funding; Rigel: Research Funding. Jabbour: Ascentage Pharma Group: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Hikma Pharmaceuticals: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Astex: Honoraria, Research Funding. Yilmaz: Pfizer: Research Funding; Daiichi-Sankyo: Research Funding. Chien: AbbVie: Consultancy; Rigel Pharmaceuticals: Consultancy. Short: AstraZeneca: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy; Stemline therapeutics: Research Funding; Astellas: Research Funding; Pfizer: Consultancy; Amgen: Honoraria. Maiti: Celgene: Research Funding; Lin BioScience: Research Funding. Garcia-Manero: Bristol Myers Squibb: Other: Medical writing support, Research Funding; Genentech: Research Funding; AbbVie: Research Funding. Daver: Celgene: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Jazz: Consultancy; Shattuck Labs: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Servier: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Trovagene: Research Funding; Hanmi: Research Funding; Kite, a Gilead company: Consultancy, Research Funding; Glycomimetics: Research Funding; Novimmune: Research Funding; Novartis: Consultancy; Agios: Consultancy; AROG: Consultancy; Genentech: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Syndax: Consultancy; FATE: Research Funding; Kronos Bio: Research Funding. DiNardo: AbbVie/Genentech: Honoraria; Servier: Honoraria; ImmuniOnc: Honoraria; Astellas: Honoraria; Fogham: Honoraria; BMS: Honoraria; Notable Labs: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Schrödinger: Consultancy. Ravandi: Abbvie: Consultancy, Honoraria, Research Funding; Syros: Consultancy, Honoraria, Research Funding; Xencor: Research Funding; Astex/taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomea fusion: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Prelude: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding. Kadia: Glycomimetics: Research Funding; Delta-Fly Pharma, Inc.: Research Funding; Janssen Research and Development: Research Funding; Astellas Pharma Global Development: Research Funding; AstraZeneca: Research Funding; Pinotb-Bio: Consultancy; Servier: Consultancy; Iterion: Research Funding; GenFleet Therapeutics: Research Funding; BMS: Consultancy, Research Funding; Daiichi Sankyo, Genentech, Inc., Genzyme, Jazz Pharmaceuticals, Liberum, Novartis, Pfizer, PinotBio, Inc, Pulmotect, Inc, Sanofi-Aventis, Servier: Consultancy; Hikma Pharmaceuticals: Speakers Bureau; Agios: Consultancy; Pulmotect, Inc.: Consultancy, Research Funding; Liberum: Consultancy; Novartis: Consultancy; Genentech: Consultancy, Research Funding; Genzyme: Honoraria; Biologix, Cure, Hikma Pharmaceuticals: Speakers Bureau; Pfizer: Consultancy, Research Funding; AbbVie, Amgen, Inc, Ascentage Pharma Group, Astellas Pharma Global Development, Astex, AstraZeneca, BMS, Celgene, Cellenkos Inc, Cyclacel, Delta-Fly Pharma, Inc, Genentech, Inc., Genfleet, Glycomimetics, Iterion, Janssen Research and Development: Research Funding; Jazz Pharmaceuticals, Pfizer, Pulmotect, Inc, Regeneron Pharmaceuticals, SELLAS Life Sciences Group: Research Funding; Ascentage Pharma Group: Research Funding; Celgene: Research Funding; Cellenkos Inc.: Research Funding; Cure: Speakers Bureau; Amgen, Inc.: Research Funding; Cyclacel: Research Funding; Regeneron Pharmaceuticals: Research Funding; Sanofi-Aventis: Consultancy; SELLAS Life Sciences Group: Research Funding; Astex: Honoraria.

*signifies non-member of ASH