Relapsed or refractory ALL is a challenging situation. “Adults with relapsed or refractory ALL have a five-year survival rate of less than 10%, making these patients particularly difficult to treat. To see remission rates and two-year survival rate that are more than doubled compared to standard of care chemotherapy is very gratifying. We believe these data add to the growing body of evidence that supports inotuzumab ozogamicin as an important potential treatment option in adults with relapsed or refractory ALL,” said Mace Rothenberg, MD, Chief Development Officer, Oncology, Pfizer Global Product Development.3
Inotuzumab ozogamicin is an antibody-drug conjugate comprising of a monoclonal anti-CD22 antibody bound to calicheamicin, a cytotoxic antibiotic agent. The target, CD22, is expressed in almost all of the patients with B-cell ALL. When inotuzumab ozogamicin binds to the CD22 on malignant B-cells, calicheamicin is delivered intracellularly and causes leukemia cell apoptosis.2
The INO-VATE trial recruited 326 patients with relapsed or refractory ALL to assess the clinical activity and safety of this agent. Patients were randomly assigned to receive either intravenous inotuzumab ozogamicin (n=164) at 1.8mg/m2 per cycle for up to six cycles or investigator’s choice of chemotherapy (n=162) with FLAG (the combination of fludarabine, cytarabine and granulocyte colony-stimulating factor), cytarabine plus mitoxantrone, or high-dose cytarabine.1,2
Of the first 218 enrolled patients (109 in each group) who made up the intention-to-treat population for the primary analysis of complete remission, the rate of complete remission or complete remission with incomplete hematologic recovery was 80.7% (95%CI: 72.1-87.7) in the inotuzumab ozogamicin group, vs 29.4% (95%CI: 21.0-38.8) in the standard therapy group (p<0.001).1,2
Among patients who achieved a complete remission, a higher percentage of patients in inotuzumab ozogamicin group had results below the threshold for minimal residual disease (0.01% marrow blasts), at 78% vs 28.1% in the standard group (p<0.001), and also longer median duration of remission, at 4.6 months vs 3.1 months in the control arm (HR=0.55, 95%CI: 0.31-0.96; p<0.034).1,2
Significantly more patients proceeded to stem-cell transplant after inotuzumab ozogamicin than after standard chemotherapy (41% vs 11%, p<0.001).2
Complete remission is often a pre-requisite for subsequent allogeneic stem-cell transplantation, however, only 5% to 30% of patients could proceed to transplantation due to low rates of complete remission associated with current chemotherapy.
“It’s a big deal in the setting of ALL treatment”, said lead author Hagop M. Kantarjian, MD, chair of leukemia at MD Anderson Cancer Center. “Given that stem cell transplant is considered the only curative treatment option, the ability of inotuzumab ozogamicin to increase the number of patients able to bridge to transplant is encouraging.”1
Inotuzumab ozogamicin also improved survival outcomes. In the total study population (n=326), median progression-free survival was significantly longer in the inotuzumab ozogamicin arm than in the control arm, at 5.0 months vs 1.8 months respectively (HR=0.45, 97.5%CI: 0.34-0.61, p<0.001).1,2
Median overall survival was also longer in the inotuzumab ozogamicin arm, at 7.7 months [95%CI, 6.0-9.2] vs. 6.7 months [95%CI, 4.9-8.3] in the control arm (HR=0.77, 95.5%CI:0.58-1.03, p=0.04), but the difference did not meet the pre-specified criteria for significance (p<0.0208).2
The study reported moderate side effects. Thrombocytopenia and febrile neutropenia of at least grade 3 occurred less often in the inotuzumab ozogamicin group than in the control group, at 37% vs 59% and 24% vs 49%, respectively.2 But veno-occlusive liver disease within 2 years of randomisation was more common among patients who received inotuzumab ozogamicin, at 11% vs 1%.2 Dr Kantarjian explained, however, that veno-occlusive liver disease occurred mainly after subsequent allogeneic stem cell transplantation, and can be avoided by not using double alkylator-preparative regimens and through preventive measures.
These results suggest inotuzumab ozogamicin, if approved, could be a valuable new addition to currently available treatment options for relapsed/ refractory ALL patients.1