Inotuzumab Ozogamicin in Combination with Low-Intensity Chemotherapy (mini-hyper-CVD) Vs. Standard Intensive Chemotherapy (hyper-CVAD) As Frontline Therapy for Older Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (ALL): A Propensity Score Analysis
Authors: Sasaki Koji , Kantarjian Hagop M. , Short Nicholas J , Ravandi Farhad , Khouri Maria , Garcia-Manero Guillermo , Daver Naval G. , Kadia Tapan M. , Konopleva Marina Y. , Jain Nitin , Issa Ghayas C. , Jacob Jovitta , Garris Rebecca E. , Yilmaz Musa , Thompson Philip A. , Nasnas Patrice , Pemmaraju Naveen , Cortes Jorge E. , O'Brien Susan M. , Jabbour Elias J. 
Published: October 2019

Abstract
Background:
The combination of inotuzumab ozogamicin with low-intensity therapy was shown to be safe and highly effective in elderly patients with newly diagnosed Philadelphia-negative ALL. There is no standard of care for these patients, and the optimal frontline therapy remains unknown. The aim of this study is to compare outcome of elderly patients with newly diagnosed Philadelphia-negative ALL treated with the combination of inotuzumab ozogamicin with low-intensity chemotherapy (mini-HCVD) (Kantarjian et al. Lancet Oncol. 2018; 19 (2): 240-248.) to those who received standard hyper-CVAD (HCVAD).
Methods:
We analyzed 135 elderly patients, 60 years and older at diagnosis with newly diagnosed Philadelphia-negative ALL who were treated with frontline HCVAD (N=77) or the combination of inotuzumab ozogamicin with mini-HCVD (N=58). Mini-HCVD comprised 50% dose reduction of cyclophosphamide and dexamethasone, 75% dose reduction of methotrexate, and 83% dose reduction of cytarabine without anthracyclines compared to the dose of standard HCVAD. Multiple imputations were performed to minimize bias due to missing variables. Propensity score analysis with 1:1 matching was performed with the nearest neighbor matching method using calipers of width equal to 0.2. Propensity scores were calculated with logistic regression from baseline covariates including age, performance status, white blood cell count, percentage of blasts in peripheral blood and bone marrow, cytogenetics, percentage of CD20 and CD22 positive blasts at diagnosis, and presence of central nervous system disease. Event-free survival (EFS) was calculated from the time of treatment initiation until date of no response (after 2 cycles), relapse, or death. Overall survival (OS) was calculated from the time of treatment initiation until death. Using pre-matched cohorts, univariate and multivariate Cox proportional hazards regression was performed to identify prognostic factors for OS with a p-value cutoff of 0.100. Time from therapy to allogeneic stem cell transplant was handled as a time-dependent variable.
Results:
Overall, 58 patients (43%) and 77 patients (57%) were treated with mini-HCVD + inotuzumab ozogamicin and HCVAD, respectively (Table 1). The median follow-up was 66 months (range, 0.4-191). Median age at the start of therapy was 68 years (range, 60-81) and 69 years (range, 60-83), respectively (p= 0.483). In the pre-matched cohort, CR/CRi/CRp rate was 98% and 88%, respectively (p= 0.037); early death rate was 0% and 8%, respectively (p= 0.030). The 3-year EFS rates for mini-HCVD + inotuzumab ozogamicin and HCVAD were 47% and 29%, respectively (p=< 0.001); the 3-year OS rates were 54% and 32%, respectively (p=0.001). The median EFS was 34 months and 8 months in the mini-HCVD + inotuzumab ozogamicin and HCVAD, respectively (p=0.002) (Figure 1A); the median OS was not reached and 15.8 months, respectively (p= 0.002) (Figure 2A).
Propensity score matching identified 38 patients in each cohort. Baseline differences were minimized without statistical significance between cohorts. With propensity score matching, CR/CRi/CRp rate was 97% and 90%, respectively (p= 0.361); early death rate was 0% and 5%, respectively (p= 0.493). The 3-year EFS rates for mini-HCVD + inotuzumab ozogamicin and HCVAD were 64% and 34%, respectively (p= 0.001) (Figure 1B); the 3-year OS rates were 63% and 34%, respectively (p= 0.001) (Figure 2B). Using the pre-matched cohorts, multivariate Cox proportional regression confirmed therapy with mini-HCVD + inotuzumab ozogamicin (p= 0.020; hazard ratio [HR], 0.550; 95% confidence interval [95% CI], 0.332-0.911), and age at the start of therapy (p= 0.019; HR, 1.045; 95% CI, 1.007-1.085) as prognostic factors for OS (Table 2).
Conclusion:
The combination of inotuzumab ozogamicin with low-intensity therapy is safe and effective in elderly patients with newly diagnosed Philadelphia-negative ALL, and confers better outcome when compared with standard HCVAD chemotherapy.

Disclosures
Sasaki: Otsuka Pharmaceutical: Honoraria. Short:Takeda Oncology: Consultancy. Ravandi:Macrogenix: Honoraria, Research Funding; Sunesis: Honoraria; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Xencor: Research Funding; Xencor: Research Funding; Macrogenix: Honoraria, Research Funding; Jazz: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Abbvie: Research Funding; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Orsenix: Honoraria; Seattle Genetics: Research Funding; Jazz: Honoraria; Orsenix: Honoraria. Daver:Pfizer: Consultancy; Alexion: Consultancy; Incyte: Research Funding; Karyopharm: Consultancy; ARIAD: Research Funding; Sunesis: Consultancy; Kiromic: Research Funding; ImmunoGen: Consultancy; Karyopharm: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Incyte: Consultancy; Otsuka: Consultancy; BMS: Research Funding; Sunesis: Research Funding; Novartis: Consultancy. Kadia:Amgen: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Research Funding; BMS: Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy; Novartis: Consultancy; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy; Celgene: Research Funding. Konopleva:Stemline Therapeutics: Research Funding. Jain:Seattle Genetics: Research Funding; Astra Zeneca: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genentech: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: 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; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; ADC Therapeutics: Research Funding; Abbvie: Research Funding; Cellectis: Research Funding; BMS: Research Funding; Verastem: Research Funding; Infinity: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Seattle Genetics: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Celgene: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Incyte: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Cellectis: Research Funding; Pfizer: Research Funding; Infinity: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Servier: Research Funding; BMS: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Pharmacyclics: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Thompson:Pharmacyclics: 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; Adaptive Biotechnologies: Research Funding; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding. Pemmaraju:plexxikon: Research Funding; samus: Research Funding; novartis: Research Funding; abbvie: Research Funding; celgene: Consultancy, Honoraria; stemline: Consultancy, Honoraria, Research Funding; daiichi sankyo: Research Funding; cellectis: Research Funding; SagerStrong Foundation: Research Funding; Affymetrix: Research Funding. Cortes:Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding. O'Brien:Kite Pharma: Research Funding; Acerta: Research Funding; Aptose Biosciences Inc.: Consultancy; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Astellas: Consultancy; Vaniam Group LLC: Consultancy; Gilead: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Alexion: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Regeneron: Research Funding; Pfizer: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding. Jabbour:Takeda: Consultancy, Research Funding; Novartis: Research Funding; Pfizer: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Abbvie: Research Funding.