Impact of Cytogenetic Abnormalities (CA) on Outcome of Patients (Pts) with Relapsed/Refractory (R-R) Acute Lymphoblastic Leukemia (ALL) Treated with Inotuzumab Ozogamicin (INO) in Combination with Low-Intensity Chemotherapy (mini-hyper-CVD) with or without Blinatumomab: Results from a Phase 2 Study
Authors: Rafei Hind , Kantarjian Hagop M. , Sasaki Koji , Short Nicholas J. , Ravandi Farhad , Huang Xuelin , Khoury Joseph D. , Wang Sa A , Jorgensen Jeffrey L. , Yin C. Cameron , Khouri Issa F. , Kebriaei Partow , Jain Nitin , Takahashi Koichi , Dabaja Bouthaina S. , Verstovsek Srdan , Kadia Tapan M. , Paul Shilpa , Rausch Caitlin R. , Garcia-Manero Guillermo , Wierda William G. , DiNardo Courtney D. , Daver Naval , Montalban-Bravo Guillermo , Yilmaz Musa , Nasnas Patrice , Khouri Rita , Kwari Monica , Jacob Jovitta , Rostykus Meagan , Garris Rebecca , Konopleva Marina , O'Brien Susan M. , Jabbour Elias 
Published: November 2020

Background:

The combination of INO with hyper-mini-CVD with or without blinatumomab offers a safe and effective treatment modality for pts with R-R ALL. However, the outcomes of some pts remain poor and the predictors of survival are not well understood. CA are frequently used as predictors of outcomes in leukemia. We present an exploratory analysis evaluating the relationship between baseline CA and outcome in pts with R-R ALL treated at our institution in a phase 2 study of INO in combination with mini-hyper-CVD with or without blinatumomab.

Methods:

Ninety-six pts with R-R ALL received low-intensity chemotherapy referred to as mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses). INO was given on Day 3 of each of the first 4 courses at 1.8-1.3 mg/m2 for course 1 followed by 1.3-1.0 mg/m2 for subsequent courses. From pt #68 onwards, INO was reduced and fractionated into biweekly doses (0.6 mg/m2 and 0.3 mg/m2 during course 1 and 0.3 mg/m2 and 0.3 mg/m2 during subsequent courses), and blinatumomab for up to 4 courses after INO therapy was added. By performing univariate and multivariate analyses of factors associated with survival, we identified 11q23 rearrangements and low hypodiploidy / near triploidy (Ho-Tr) as high-risk CA. Pts were categorized based on their CA as low-risk if they carry diploid, complex or other cytogenetics. Pts with 11q23 rearrangements and those with Ho-Tr were classified as having high-risk CA. Response rates and overall survival (OS) outcomes are compared between the two cytogenetic risk categories.

Results:

Pts characteristics are summarized in Table 1. Karyotype was diploid in 23 (24%) pts, complex in 12 (13%) pts, and other in 21 (22%) pts. Ten (10%) pts had Ho-Tr, 10 (10%) pts had KMT2A rearrangements, 3 (3%) pts had high hypertriploidy (HeH), 2 (2%) pts had near triploidy (Tt) and 15 (16%) pts had insufficient metaphases/ not determined karyotype. TP53 mutation was detected in a significantly higher proportion of pts with Ho-Tr (6 out of 7 tested pts or 86%) compared to pts with other cytogenetic abnormalities (10 out of 40 tested pts or 25%) (p=0.002). We performed univariate and multivariate analyses for the association of different cytogenetics with survival. By multivariate analysis, baseline cytogenetics independently associated with worse survival included Ho-Tr [HR= 18.262 (95% CI= 5.935-56.196); p&lt;0.001], and KMT2A [HR= 3.744 (95% CI= 1.256-11.165); p=0.018]. Based on these findings, we stratified pts based on their CA into high-risk or low-risk disease. The overall response rate (ORR) was 73% in pts with high-risk CA compared to 82% in pts with low-risk CA (p=0.316). The complete remission (CR) rate was significantly higher in pts with low-risk CA compared to those with high-risk CA, 64% vs 36% (p=0.024). The rate of MRD negativity was numerically higher both at response as well as overall in the low-risk group compared to the high-risk group; 54% vs 44% and 86% vs 69%, respectively (Table 3). Four pts underwent allogeneic stem cell transplant (ASCT) in the high-risk group (17%), compared to 40 in the low risk group (55%) (p=0.003). At a median follow-up of 36 months, the median OS for pts with high-risk CA was 4 months compared to 23 months for pts with low-risk CA (p &lt; 0.001) (Figure 1). The 3-year OS rates were 3% and 53%, respectively.

Conclusion:

Our analysis identified baseline KMT2A rearrangements and Ho-Tr as independent predictive of poor outcome in pts with R-R ALL treated with the combination therapy of INO with mini-hyper-CVD with or without blinatumomab. Pts with these poor-risk features should be considered for alternative strategies such as CAR T-cells therapies and clinical trials such as adding menin inhibitors to the regimen in pts with KMT2A rearrangement.

Disclosures

Rafei: United States Provisiona: Patents & Royalties: I have a filed patent. Kantarjian:BMS: Research Funding; AbbVie: Honoraria, Research Funding; Astex: Research Funding; Ariad: Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Jazz Pharma: Research Funding; Cyclacel: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Takeda: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Agios: Honoraria, Research Funding. Sasaki:Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Otsuka: Honoraria; Pfizer Japan: Consultancy. Short:AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; Amgen: Honoraria. Ravandi:Celgene: Consultancy, Honoraria; Macrogenics: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Khouri:Bristol Myers Squibb: Research Funding; Pfizer: Research Funding. Kebriaei:Amgen: Other: Research Support; Novartis: Other: Served on advisory board; Ziopharm: Other: Research Support; Jazz: Consultancy; Pfizer: Other: Served on advisory board; Kite: Other: Served on advisory board. Jain:Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Fate Therapeutics: Research Funding; Aprea Therapeutics: Research Funding; Pfizer: Research Funding; Cellectis: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding. Verstovsek:Gilead: Research Funding; Genentech: Research Funding; CTI Biopharma Corp: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; PharmaEssentia: Research Funding; AstraZeneca: Research Funding; ItalPharma: Research Funding; Protagonist Therapeutics: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; Celgene: Consultancy, Research Funding. Kadia:Pulmotec: Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding; Novartis: Honoraria; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Cellenkos: Research Funding; Cyclacel: Research Funding; Incyte: Research Funding; Ascentage: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Genentech: Honoraria, Research Funding. Garcia-Manero:Onconova: Research Funding; AbbVie: Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; H3 Biomedicine: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Merck: Research Funding. DiNardo:Takeda: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria; Syros: Honoraria; ImmuneOnc: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Agios: Consultancy, Honoraria, Research Funding; Calithera: Research Funding. Daver:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Yilmaz:Pfizer: Research Funding; Pint Pharma: Honoraria; Daicho Sankyo: Research Funding. Konopleva:Agios: Research Funding; Calithera: Research Funding; Ablynx: Research Funding; Eli Lilly: Research Funding; Kisoji: Consultancy; Amgen: Consultancy; Forty-Seven: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding; Ascentage: Research Funding; Sanofi: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; AstraZeneca: Research Funding; Cellectis: Research Funding. O'Brien:Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc. Vaniam Group, AbbVie, Alexion, Verastem, Eisai, Juno Therapeutics, Vida Ventures: Consultancy; Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Consultancy, Research Funding; Kite, Regeneron, Acerta: Research Funding. Jabbour:BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding.

OffLabel Disclosure:

Blinatumomab and Inotuzumab as part of a clinical trial