Patients with Philadelphia chromosome–positive acute lymphoblastic or chronic myeloid leukemias in lymphoid blast phase may have longer event-free and overall survival with a combination of inotuzumab ozogamicin (Besponsa) and bosutinib (Bosulif) than with standard chemotherapy combined with a targeted agent, investigators in a phase 1/2 study reported.
Among patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) or chronic myeloid leukemia (Ph+ CML) in lymphoid blast phase treated with inotuzumab ozogamicin (Besponsa) and bosutinib (Bosulif), the median overall survival was 15.4 months. In contrast, median overall survival for similar patients treated with chemotherapy and a tyrosine kinase inhibitor (TKI) was less than 6 months, reported, and colleagues from the University of Texas MD Anderson Cancer Center in Houston.
The study was presented in a scientific poster session as part of the virtual annual congress of the European Hematology Association.
“Patients with relapsed/refractory Philadelphia chromosome–positive ALL/CML in lymphoid blast crisis are also best managed with a TKI targeting the constitutively active ABL kinase with the TKI selected based on presence of ABL kinase mutations and prior TKI history,” commented, a leukemia specialist at the Dana-Farber Cancer Institute in Boston.
“A critical question for this patient population is whether these two approaches [TKI and inotuzumab ozogamicin] can be administered safely in combination. I congratulate MD Anderson for completion of this Phase I trial which demonstrates that inotuzumab and bosutinib can be safely combined with identification of a maximum tolerated dose of bosutinib 400 mg daily when administered in combination. I look forward to further studies that explore the efficacy of combination versus the approved single-agent regimen,” she said in an interview.
To see whether they could improve the dismal outcomes for patients with Ph+ ALL or Ph+ CML in lymphoid blast phase, they studied the combination of inotuzumab ozogamicin, an anti-CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin, and bosutinib, an inhibitor of the ABL kinase. Inotuzumab is approved in the United States for treatment of adults with relapsed or refractory B-cell precursor ALL, bosutinib is approved for the treatment of patients with newly-diagnosed chronic phase Ph+ CML and for adults with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.
The investigators enrolled 16 patients with Ph+ ALL and 2 with Ph+ CML with bone marrow blasts greater than 5%, CD22 expressed on at least 20% of blasts, and good to fair performance status. The patients also had adequate organ function as measured by liver enzyme, total bilirubin, and serum creatinine levels. Patients with the T315I mutation, prior anti-CD22 therapy, active graft-versus-host disease, or liver disease were excluded.
The patients received inotuzumab 0.8 mg/m2 intravenously on day 1, they received 0.5 mg/m2 on days 8 and 15 of cycle 1, and they received 0.5 mg/m2 on days 1, 8, and 15 of cycles 2 through 6. Each cycle was 4 weeks. Patients who had a complete remission (CR), had complete cytogenetic remission (CCyR), or became negative for minimal residual disease (MRD) continued on 1 mg/m2 every 4 weeks. Bosutinib was dosed continuously day starting on the first day of cycle 1 and continued until disease progression or toxicity.
After a median follow-up of 36.7 months, 11 of the 18 patients had CRs, and 4 had CRs with incomplete recovery of hematologic counts. In addition, 13 of 16 patients with without diploid cytogenetics at the start of the study had CCyr; 14 patients had major molecular remission; 10 had complete molecular remission, and 11 were negative by flow cytometry.
As noted before, the median overall survival was 15.4 months. Event-free survival – time to lack of response, relapse, MRD relapse requiring therapy, or death – was 8 months. The event-free survival data were not censored for allogeneic stem cell transplant. Six patients underwent transplant while in remission.
The primary objective of the phase 1 trial was to evaluate safety of the combination and determine the maximum tolerated dose of bosutinib, which was determined to be 400 mg daily. At this dose level, one patient had a dose-limiting toxicity in the form of a grade 3 skin rash.
The most frequent adverse events were diarrhea and rash, in 50% of patients each, and nausea in 39% of patients. Grade 3 adverse events included were rash in three patients and reversible alanine aminotransferase and hyponatremia in one patient each. No patients developed veno-occlusive disease, and there no deaths within 30 days of the start of therapy.
Dr. Jain disclosed consultancy, honoraria, advisory board/committee activity, and research funding from Pfizer, maker of inotuzumab ozogamicin and bosutinib. Dr. Luskin reported no relevant disclosures.
SOURCE: Jain N et al. EHA25, .