Inotuzumab Ozogamicin in Combination with Low-Intensity Chemotherapy (mini-hyper-CVD) As Frontline Therapy for Older Patients (≥60 years) with Acute Lymphoblastic Leukemia (ALL)

Background: 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).

Methods: 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/m²for subsequent cycles.

Results: Twenty-seven pts (15 men, 12 women) have been treated so far. Pts characteristics and outcome are summarized in Table 1. Median age is 68 yrs (range 60-79). Median follow-up is 13 months (mos). Of the 26 pts evaluable for response (one pt started with CR that she had achieved with single-agent prednisone), 25 pts (96%) achieved CR/CRp (21 CR, 4 CRp). All pts achieving CR have also achieved flow-cytometric MRD negative status, in 77% at the time of CR achievement. Grade 3-4 toxicities included infections (n=23; 85%), prolonged thrombocytopenia (n=17; 65%), hyperglycemia (n=12; 44%); increased bilirubin (n=6; 22%); intracranial hemorrhage (n=4; 15%), increased ALT (n=3; 11%), hematuria (n=2; 7%), headache (n=1; 4%), cognitive disturbance (n=1; 4%), ascites (n=1; 4%), and diarrhea (n=1; 4%). No dose-limiting toxicity was observed. At the last follow-up, 20 (74%) pts are alive in CR. Seven (26%) pts died: 1 was primary refractory an died after the first salvage; 2 relapsed after receiving 3 and 2 courses only due to prolonged myelossuppression and died of disease progression; and 4 in CR from pneumonia complications (n=1), sepsis and multiple organ failure (n=1), gun shot wound (n=1), and renal failure and metabolic encephalopathy (n=1). No pts received allogeneic stem cell transplantation. The 1-year progression-free and overall survival rates were 86% and 81%, respectively. The mini-hyper-CVD (n=27) appears superior to the historical HCVAD +/- rituximab (n=46) in similar patients’ population. The 1-year survival rates were 78% and 60%.

Conclusions: The combination of IO with low-intensity mini-hyper-CVD chemotherapy is safe and shows very encouraging results (96% 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.