Inotuzumab Ozogamicin In Combination With Low-Intensity Chemotherapy (Mini-hyper-CVD) As Frontline Therapy For Older Patients (≥60 years) With Acute Lymphoblastic Leukemia (ALL)

Older patients (pts) with ALL have a significantly worse outcome. This is primarily due to poor tolerance of intensive chemotherapy. Addition of targeted non-myelosuppressive therapy to effective low-intensity chemotherapy might improve outcome. CD22 expression occurs in >90% of pts with ALL. Inotuzumab ozogamicin (IO) is a CD22 monoclonal antibody bound to a toxin, calecheamicin, and has shown single-agent activity in relapsed/refractory ALL (Kantarjian et al. Lancet Oncology 2012).

Pts ≥60 years (yrs) with newly-diagnosed B-cell ALL were eligible. The chemotherapy was lower intensity than conventional hyper-CVAD and 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). Rituximab and intrathecal chemotherapy were given for first 4 courses. IO was given on day 3 of each of the first 4 courses. The first 6 pts received 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.

Fifteen pts (10 men, 5 women) have been treated so far. Median age is 69 yrs (range 60-79). Median follow-up is 10.8 months (mos). Grade 3-4 non-hematological toxicity included 2 pts with grade 3 LFT elevation. Eleven pts had one or more infections. Six patients were switched early to maintenance therapy due to thrombocytopenia. No dose-limiting toxicity was observed. Of the 14 patients evaluable for response (one patient started with CR that she had achieved with single-agent prednisone), 13 patients (93%) achieved CR/CRp (12 CR, 1 CRp). All pts achieving CR have also achieved flow-cytometric MRD negative status and all except one continue to be on study in CR anywhere from 0.1 to 19.2 mos. There has been one relapse in a patient who received only 3 intensive chemotherapy cycles due to prolonged thrombocytopenia. She relapsed at the 1-year mark and is currently receiving salvage chemotherapy. One patient did not achieve CR and died 2 mos later after receiving a salvage regimen. This is the only death on the study. One-year disease-free and overall survival are 83% and 93%, respectively.

The combination of IO with low-intensity mini-hyper-CVD chemotherapy is safe and shows very encouraging results (93% CR/CRp) in the frontline setting in older pts with ALL. These results appear to be better than those achieved with a chemotherapy only approach and may become the new standard of care for frontline treatment of older pts with ALL.

Off Label Use: Inotuzumab is a antibody drug conjugate targeting CD22 on ALL cells. Ravandi:Pfizer: Honoraria. Kantarjian:Bristol-Myers Squibb, Novartis, Pfizer: Research Funding.