In patients with relapsed/refractory Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL), inotuzumab ozogamicin increases rates of response, remission, hematopoietic stem cell transplantation (HSCT), and progression-free survival compared with intensive chemotherapy, although it does not produce a significant improvement in overall survival.
"Historically, patients with Ph-positive ALL have had poorer prognoses, with higher rates of relapse and worse long-term survival compared with patients who have Ph-negative ALL," write the investigators in their publication in Cancer, led by first author Wendy Stock, MD, Professor of Leukemia at the University of Chicago Medicine. "Despite the improved outcomes with the use of tyrosine kinase inhibitors (TKIs), patients with Ph-positive ALL are still at high risk of relapse, especially those with suboptimal molecular responses and those who do not receive an allogeneic HSCT following first complete remission…Thus, effective treatments are needed for patients with relapsed/refractory Ph-positive ALL."
In an analysis of the phase 1/2 Study 1010 and the randomized phase 3 INO-VATE trial (Study 1022), Dr. Stock and colleagues investigated the efficacy of inotuzumab ozogamicin, a humanized anti-CD22 monoclonal antibody, in a subgroup of patients with Ph-positive ALL. Study 1010 enrolled 72 patients with relapsed/refractory CD22-positive ALL previously treated with TKIs, 16 of whom had Ph-positive disease, to receive 0.8 mg/m2 inotuzumab ozogamicin on Day 1 and 0.5 mg/m2 on Days 8 and 15 of 21-day cycles. INO-VATE enrolled 164 patients with relapsed/refractory CD22-positive ALL, 49 of whom had Ph-positive disease, to receive either inotuzumab ozogamicin or investigator's choice of chemotherapy. The primary end points of the analysis were rates of complete remission, minimal residual disease (MRD) negativity, overall survival, and progression-free survival in patients with Ph-positive ALL, with a secondary end point of the proportion of patients who subsequently received HSCT.
In Study 1010, inotuzumab ozogamicin produced a complete remission rate of 56% and an MRD negativity rate of 100%. Patients in INO-VATE receiving inotuzumab ozogamicin also experienced higher rates of complete remission (73% vs 56%), MRD negativity (81% vs 33%), HSCT (41% vs 19%), and progression-free survival (20.1% vs 4.8%) compared with those receiving chemotherapy. The improvement in median overall survival for inotuzumab ozogamicin compared with chemotherapy did not reach statistical significance (8.7 vs 8.4 months). The most common nonhematologic grade ≥3 adverse events associated with inotuzumab ozogamicin were multiorgan abnormalities (41%) in Study 1010 and gastrointestinal disorders (31%) in INO-VATE.
"The results confirm that inotuzumab ozogamicin is an important treatment option for achieving subsequent remission in patients with relapsed/refractory Ph-positive ALL, with potentially beneficial clinical effects in patients with resistant and difficult-to-treat disease in whom prior TKIs have failed," conclude Dr. Stock and colleagues. "Future studies should evaluate the impact of more sensitive MRD measurements, MRD-directed therapy prior to HSCT, and the potential combined or sequential use of targeted therapies with both novel and existing targeted TKIs or other therapeutic approaches."
For More Information
Stock W, Martinelli G, Stelljes M, et al (2020). Efficacy of inotuzumab ozogamicin in patients with Philadelphia chromosome-positive relapsed/refractory acute lymphoblastic leukemia. Cancer. [Epub ahead of print] DOI:10.1002/cncr.33321
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