A Phase I/II Study of Inotuzumab Ozogamicin in Combination with Low-Intensity Chemotherapy (mini-hyper-CVD) for Older Patients with Newly Diagnosed Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia

Background: Elderly patients (pts) with acute lymphocytic leukemia (ALL) have a poor outcome, in part due to toxicity with intensive chemotherapy. Inotuzumab ozogamicin (INO), a CD22 monoclonal antibody bound to a toxin, calicheamicin, has single-agent activity in relapsed/refractory ALL. The addition of INO to low-intensity chemotherapy might improve outcomes in older pts with newly diagnosed ALL. Methods: Pts ≥60 years of age with newly diagnosed Philadelphia chromosome (Ph)-negative pre-B ALL were eligible. Pts were required to have a performance status of ≤3, total bilirubin ≤1.5 mg/dl, AST/ALT ≤3x ULN and creatinine ≤2 mg/dl. Pts received 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) for up to 8 cycles, given every 4 weeks as permitted by count recovery. INO was given at a dose of 1.3-1.8mg/m2 on day 3 of cycle 1 and 0.8-1.3mg/m2 on day 3 of cycles 2-4. The first 6 pts received 1.3 mg/m2 for cycle 1 followed by 0.8 mg/m2 for subsequent cycles; pt 7 onwards received the phase II dose of 1.8 mg/m2 for cycle 1 followed by 1.3 mg/m2 for subsequent cycles. After the observation of veno-occlusive disease (VOD), the protocol was amended in 9/2015 to use lower doses of INO. After this amendment (pt 35+), INO was given at 1.3 mg/m2 for cycle 1 followed by 1 mg/m2 for subsequent cycles. Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles. Responding pts received POMP maintenance for up to 3 years. Results: 52 pts have been treated, 4 of whom were in CR at enrollment. Median age was 68 years (range, 60-81 years) and median CD22 expression was 97% (range, 27-100%). 31 pts (60%) were CD20+ and received rituximab. Among 48 pts evaluable for morphologic response, 47 (98%) response (CR, n=39; CRp, n=7; CRi, n=1). Only 1 pt did not respond. MRD negativity by 6-color flow cytometry was achieved in 36/46 pts (78%) after 1 cycle and 49/51 pts (96%) overall. Median times to platelet and ANC recovery in cycle 1 were 23 and 16 days, respectively, and for subsequent cycles were 22 and 17 days, respectively. Prolonged thrombocytopenia (>6 weeks) occurred in 42 pts (81%). The 30-day and 60-day mortality rates were 0% and 4%, respectively. Infections occurred in 27 pts (52%) during induction and in 36 during (69%) during consolidation; 28 pts (54%) had grade 3-4 hyperglycemia, 16 (31%) had grade 3-4 hypokalemia; 10 (19%) had grade 3-4 transaminase elevation, 9 (17%) had grade 3-4 hyperbilirubinemia, and 7 (13%) had grade 3-4 hemorrhage. 4 pts (8%) developed VOD, 1 after subsequent allogeneic SCT. Two of the VOD cases were severe and resulted in death. Among 51 responders, 6 (12%) relapsed, 3 (6%) underwent allogeneic SCT in CR1, 29 (57%) remain on treatment or have completed maintenance, and 12 (24%) died in CR/CRp. Causes of death for pts in CR/CRp included: sepsis (n=5), VOD (n=1), gunshot wound (n=1), dementia and deconditioning (n=1), end stage renal disease (n=1) and unknown causes (n=3). With a median follow-up of 29 months (range, 1-66 months), 35 pts (67%) were alive, 30 of whom (58%) were in CR and MRD negative status. The 3-year continued remission and OS rates were 74% and 56%, respectively (Figure 1). Compared to a similar historical cohort of older pts treated with hyper-CVAD ± rituximab (n=78), mini-hyper-CVD + INO resulted in significantly higher 3-year OS (54% vs 32%; P=0.004). Conclusions: Mini-hyper-CVD plus INO is safe and effective in elderly pts with newly diagnosed Ph-negative ALL and appears to improve outcomes compared to hyper-CVAD. A prospective study of this regimen is warranted. Disclosures Kantarjian: Bristol-Meyers Squibb: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Pfizer: Research Funding. Jain: Abbvie: Research Funding; Incyte: Research Funding; Pfizer: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Verastem: Research Funding; Celgene: Research Funding; Novartis: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Daver: Incyte Corporation: Honoraria, Research Funding; Jazz: Consultancy; Kiromic: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Otsuka America Pharmaceutical, Inc.: Consultancy; Pfizer Inc.: Consultancy, Research Funding; Immunogen: Research Funding; Karyopharm: Consultancy, Research Funding; Daiichi-Sankyo: Research Funding; Bristol-Myers Squibb Company: Consultancy, Research Funding; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding. Thomas: Amgen: Honoraria; Pfizer: Honoraria. Pemmaraju: cellectis: Research Funding; roche diagnostics: Consultancy, Honoraria; affymetrix: Research Funding; Incyte Corporation: Consultancy, Honoraria; novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria; abbvie: Research Funding; stemline: Consultancy, Honoraria, Research Funding. Khoury: Stemline Therapeutics: Research Funding; Pfizer: Research Funding; Angle: Research Funding; Kiromics: Research Funding. Cortes: Sun Pharma: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Burger: Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Wierda: Emergent: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; GSK/Novartis: Consultancy, Honoraria, Research Funding; Karyopharm: Research Funding; Celgene: Consultancy, Honoraria; The University of Texas MD Anderson Cancer Center: Employment; AbbVie: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Acerta: Research Funding; Juno: Research Funding; Kite: Research Funding; Janssen: Research Funding; Genentech/Roche: Consultancy, Honoraria, Research Funding. DiNardo: AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. O9Brien: GSK: Consultancy; TG Therapeutics: Consultancy, Other: Research Support: Honorarium, Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy; Astellas: Consultancy; CLL Global Research Foundation: Membership on an entity9s Board of Directors or advisory committees; Pharmacyclics: Consultancy, Other: Research Support: Honorarium, Research Funding; ProNAI: Other: Research Support: Honorarium, Research Funding; Acerta: Other: Research Support: Honorarium, Research Funding; Aptose Biosciences, Inc.: Consultancy; Janssen: Consultancy; Regeneron: Other: Research Support: Honorarium, Research Funding; Vaniam Group LLC: Consultancy; Celgene: Consultancy; AbbVie: Consultancy; Sunesis: Consultancy; Alexion: Consultancy; Gilead Sciences, Inc.: Consultancy, Other: Research Support: Honorarium, Research Funding. Jabbour: Bristol-Myers Squibb: Consultancy.