-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

588 Inotuzumab Ozogamicin in Combination with Low-Intensity Chemotherapy (mini-hyper-CVD) As Frontline Therapy for Older Patients with Acute Lymphoblastic Leukemia (ALL): Interim Result of a Phase II Clinical TrialClinically Relevant Abstract

Acute Lymphoblastic Leukemia: Clinical Studies
Program: Oral and Poster Abstracts
Type: Oral
Session: 612. Acute Lymphoblastic Leukemia: Clinical Studies: Molecular Features, Toxicity of Therapy, and New Approaches to Immunotherapy
Monday, December 5, 2016: 8:15 AM
Marriott Grand 2-4 (Marriott Marquis San Diego Marina)

Koji Sasaki, MD1, Elias J. Jabbour, MD2, Susan M. O'Brien, MD3, Farhad Ravandi, MD2, Deborah A Thomas, MD2, Guillermo Garcia-Manero, MD2, Naval Daver, MD2, Gautam Borthakur, MD2, Nitin Jain, MD2, Marina Konopleva, MD, PhD2, Nicholas J. Short, MD1, Naveen Pemmaraju, MD2, Yesid Alvarado, MD2, Jovitta Jacob, RN2*, Rebecca Garris, MS2*, Philip A Thompson, MBBS2*, Jorge E. Cortes, MD2 and Hagop M. Kantarjian, MD2

1Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
3Chao Family Comprehensive Cancer Center, University of California, Irvine, Orange, CA

Background: Older patients (pts) with ALL have a worse outcome than younger pts due to poor tolerance of intensive therapy. CD22 expression is present in >90% of pts with B-cell ALL. Inotuzumab ozogamicin (InO) is a CD22 monoclonal antibody bound to a toxin, calecheamicin, and has shown single-agent activity in relapsed/refractory ALL (Kantarjian et al. NEJM 2016). Addition of targeted therapy to effective low-intensity therapy might improve outcome.

Methods: Pts ≥ 60 years with newly diagnosed B-cell ALL were eligible for the chemotherapy with 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) in combination with InO given on Day 3 of each of the first 4 courses. Rituximab (in patients whose cells were CD20 positive) and intrathecal chemotherapy were given for the first 4 courses. The first 6 pts received InO 1.3 mg/m2 for cycle 1 followed by 0.8 mg/m2 for subsequent cycles; Pts 7 onwards received 1.8 mg/m2 for Cycle 1 followed by 1.3 mg/m2 for subsequent cycles. After the occurrence of veno-occlusive disease (VOD) in 4 pts, the dose of InO was modified to 1.3 mg/m2 for Cycle 1 followed by 1.0 mg/m2 for subsequent cycles after Pt #33. Maintenance therapy consists of daily 6-MP and weekly methotrexate for 3 years, and monthly vincristine and 5-day prednisone for the first 1 year. 

Results: Forty-six pts with a median follow-up of 24 months were treated (range 1-51 months) (Table 1). Median age is 68 years (range 60-81). Of the 42 pts evaluable for response (4 started in CR), 40 (95%) achieved complete response (CR)/ CR with incomplete platelet recovery (CRp) (35 CR, 5 CRp). All 22 pts with baseline abnormal karyotype achieved a complete cytogenetic response; of the 44 pts assessed for minimal residual disease (MRD) by 6-color multiparameter flow cytometry, 41 (93%) achieved negative MRD (71% of them at CR). Median time to platelet and neutrophil recovery was 23 days (11-91), and 16 days (0-49) after induction, and was 22 days (0-64), and 17 days (0-49) after subsequent cycles. Grade 3-4 toxicities ≥10% included prolonged thrombocytopenia (n=34; 74%), infections during consolidation (n=34; 74%), infections during induction (n=25; 54%), hyperglycemia (n=24; 52%), hypokalemia (n=16; 35%), hyperbilirubinemia (n=8; 17%), increased ALT/AST (n=9; 20%), and hemorrhage (n=6; 13%). VOD was observed in 4 pts (9%) after a median of 2 courses (2-4); all were in CR with negative MRD. Two were Grade 2 (one of them post matched related allogeneic stem cell transplantation (ASCT) using a conditioning regimen with fludarabine and busulfan after 4 cycles of mini-hyper-CVD + InO) and 2 were Grade 5. No VOD was observed after the InO dose adjustment. At the last follow-up, 30 (65%) are alive and 28 (61%) in CR. Three (7%) pts are currently receiving consolidation chemotherapy with a median of 4 cycles (1-8); 19 (41%) are receiving POMP maintenance therapy; 3 (7%) completed POMP maintenance therapy; 1 (2%) is under observation after completion of consolidation therapy. Of the 6 pts who relapsed, 2 (4%) pts are alive on salvage therapy. Three (7%) pts underwent an ASCT: 2 of them are alive in CR.  Sixteen pts (35%) died: 1 had primary refractory ALL and died after the first salvage; 4 relapsed after initial response and died of disease progression; 10 (22%) died in CR from sepsis (n=4), VOD (n=2), gunshot wound (n=1), dementia (n=1), kidney dysfunction (n=1), unknown cause (n=1); and 1 died of ASCT-related complications. The 3-year complete remission duration, and overall survival rates were 76% and 52%, respectively (Figure 1a). The mini-hyper-CVD + InO +/- rituximab (n=46) results appear superior to the historical data with HCVAD +/- rituximab (n=46) in a similar patients’ population (3-year overall survival (OS) rates of 52% and 36%, respectively, p=0.05); Figure 1b). This advantage was mainly observed in patients with CD20 expression ≥20% (all patients received rituximab; p=0.05) (Figure 1c); while no superiority was observed when compared to hyper-CVAD alone (in patients with CD20 expression <20%).

Conclusions: The combination of InO with low-intensity mini-hyper-CVD chemotherapy is safe and shows encouraging results in the frontline setting in older pts with ALL. These results appear to be better than those achieved with hyper-CVAD +/- rituximab and may become the new standard of care for frontline treatment of older pts with ALL.

Disclosures: Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. O'Brien: Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Daver: Kiromic: Research Funding; Otsuka: Consultancy, Honoraria; Ariad: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Karyopharm: Honoraria, Research Funding; Sunesis: Consultancy, Research Funding. Jain: Novimmune: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Genentech: Research Funding; Novartis: Consultancy, Honoraria; BMS: Research Funding; Celgene: Research Funding; Infinity: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Abbvie: Research Funding; Seattle Genetics: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding. Konopleva: Calithera: Research Funding; Cellectis: Research Funding. Pemmaraju: stemline: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria; Cellectis: Research Funding; Incyte: Consultancy, Honoraria. Thompson: Pharmacyclics: Consultancy, Honoraria. Cortes: ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

<< Previous Abstract | Next Abstract
*signifies non-member of ASH