In February 2017, the U.S. Food and Drug Administration granted inotuzumab ozogamicin priority review for the treatment of adult patients with relapsed/refractory B-cell precursor acute lymphocytic leukemia (ALL), based on results of the phase III INO-VATE 1022 trial, which showed that inotuzumab ozogamicin lowered the risk of disease progression and death, compared with standard-of-care chemotherapy.
Because older patients with ALL typically do not tolerate standard, intensive chemotherapy well, researchers, led by Nicholas Short, MD, of the MD Anderson Cancer Center in Houston, Texas, evaluated whether treatment with inotuzumab ozogamicin and lower-intensity chemotherapy (mini-hyper-CVD) would similarly benefit older patients with ALL, while limiting toxicity associated with higher-intensity regimens. Dr. Short presented the findings of the phase I/II trial at the 2017 ASCO Annual Meeting.
“This is a particularly difficult population to treat,” Dr. Short told ASH Clinical News. “When treated with full-intensity chemotherapy, they have a relatively unacceptable early mortality from induction and from myelosuppression-related infections, and their long-term survival has been quoted around 20 to 40 percent, largely because of the toxicity of the regimen.”
The trial enrolled 52 patients (median age = 68 years; range = 60-81 years) who were newly diagnosed with Philadelphia-negative B-cell precursor ALL. Patients received treatment with:
- mini-hyper-CVD: cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, and cytarabine 0.5 g/m2
- inotuzumab ozogamicin: 1.3-1.8 mg/m2 on day 3 of cycle 1 and 0.8-1.3 mg/m2 on day 3 of cycles 2-4
All patients received prophylactic intrathecal chemotherapy for the first four cycles; patients who were CD20-positive received rituximab. Patients who responded to treatment received maintenance therapy with a combination of 6-mercaptopurine, vincristine, methotrexate, and prednisone (POMP) for up to 3 years.
Patients were followed for a median of 29 months. Among the 48 patients who were evaluable for response at the time of data presentation, the overall response rate was 98 percent, with 39 patients achieving complete response (CR; 81%), seven achieving CR with incomplete platelet recovery (CRp; 15%), and one achieving CR with incomplete hematologic recovery (CRi; 2%). One patient did not respond to treatment.
The 3-year rates of CR and overall survival were 74 percent and 56 percent, respectively. “Compared to a historical cohort of older patients treated with hyper-CVAD with or without rituximab, mini-hyper-CVD plus inotuzumab ozogamicin resulted in significantly higher 3-year OS (54% vs. 31%; p=0.007),” Dr. Short reported.
The researchers also assessed minimal residual disease (MRD), measured by 6-color flow cytometry, and found that the majority of evaluable patients were MRD-negative after one treatment cycle (n=36/46; 78%). Overall, 49 of 51 responders (96%) achieved MRD-negativity.
“We found excellent response rates, which were driven in part by a relatively high rate of MRD-negativity, which we know is a good surrogate for long-term outcomes,” Dr. Short said.
The median times to platelet and absolute neutrophil count recovery in cycle 1 were 23 days (range = 11-91 days) and 16 days (range = 0-49 days), respectively, and 22 days (range = 14-64 days) and 17 days (range = 13-49 days) for subsequent cycles.
The most common adverse event (AE) associated with inotuzumab ozogamicin and mini-hyper-CVD was prolonged thrombocytopenia (lasting >6 weeks), which occurred in 81 percent of patients. Infections during induction and consolidation treatment were also common (52% and 69%, respectively).
Four patients (8%) developed veno-occlusive disease (VOD) – one following allogeneic hematopoietic cell transplantation (AHCT) and three unrelated to AHCT. The authors noted that “only one patient developed severe VOD.”
Among the entire cohort of 46 responders, six relapsed (13%) and three underwent AHCT in first CR (7%). Twenty-seven patients (59%) remained on treatment or completed maintenance and 10 died in CR/CRp.
The study’s findings are limited by the small population and its non-randomized design. Dr. Short noted that the trial is still accruing patients and future research will focus on altering the dosing of inotuzumab ozogamicin to minimize toxicity.
Short NJ, Kantarjian HM, O’Brien SM, et al. Updated results of a phase I/II study of inotuzumab ozogamicin in combination with low-intensity chemotherapy (mini-hyper-CVD) as frontline therapy for older patients with acute lymphoblastic leukemia. Abstract #7014. Presented at the 2017 American Society of Clinical Oncology Annual Meeting, June 5, 2017; Chicago, Illinois.