VIENNA (FRONTLINE MEDICAL NEWS) – The investigational agent inotuzumab ozagamicin more than doubled complete remission rates compared with standard therapy in relapsed or refractory acute lymphoblastic leukemia, preliminary results from the INO-VATE study show.

The co-primary endpoint of complete remission or CR with incomplete hematologic recovery (CRi) by independent review was achieved by 80.7% of patients treated with inotuzumab and 33.3% treated with standard of care (SOC) (P < .0001).

Significantly more CR/CRi responders treated with inotuzumab were minimal residual disease (MRD)-negative by multicolor flow cytometry (78.4% vs. 28.1%; P < .0001), Dr. Daniel DeAngelo reported in a late-breaking abstract (LBA2073) at the annual congress of the European Hematology Association.

“The fact that the response rate was astronomically high with a high MRD-negative status really allows this or this should be an opportunity for patients with relapsed/refractory disease,” he said in an interview.

Inotuzumab ozagamicin is an investigational anti-CD22 antibody conjugated to calicheamicin, an antitumor antibiotic. CD22 is expressed on the surface of about 90% of B-cell ALL cells.

Previous phase II studies reported strong initial antitumor activity and safety with inotuzumab in relapsed or refractory ALL, Dr. DeAngelo , of the Dana Farber Cancer Institute in Boston, said.

The ongoing phase III trial randomized 326 patients with relapsed/refractory CD22-positive ALL due for salvage 1 or 2 therapy to inotuzumab or SOC: either the FLAG regimen (fludarabine (Fludara)/cytarabine (Ara-C)/granulocyte colony-stimulating factor), Ara-C plus mitoxantrone (Novantrone), or high-dose Ara-C. The starting dose for inotuzumab was 1.8 mg/m2/cycle and was reduced to 1.5 mg/m2/cycle once CR/CRi was achieved. Patients were stratified by duration of first remission, salvage 1 or 2, and age.

The first 218 randomized patients were included in the intention-to-treat CR/CRi analysis, which was modified after excluding 13 patients from the SOC arm who refused to start treatment.

The patients’ median age was 47 years (ranging up to 79 years), two-thirds were salvage 1, and more than half had a remission duration of less than 12 months, an adverse prognostic feature.

Data for the co-primary endpoint of overall survival in all 326 patients are still blinded and not expected to mature until 2016, Dr. DeAngelo said.

CR/CRi analyses significantly favored inotuzumab in all stratification factors and baseline factors including peripheral blasts and CD22 expression. Cytogenetics are still being evaluated, but 11 of 14 (79%) patients with Philadelphia-positive karyotype achieved a CR or CRi, he said.

Median duration of remission among responders was 4.6 months in the inotuzumab arm and 3.1 months in the SOC arm (hazard ratio, 0.55; P = .016).

Safety assessed in 259 patients who received at least one dose of study drug showed similar incidence of grade 3 or higher adverse events in the inotuzumab and SOC arms (91% vs. 95%). There were 2 fatal events in the SOC arm and 4 in the inotuzumab arm: 2 veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS), both after poststudy transplant, 1 intestinal ischemia/septic shock, and 1 acute respiratory distress syndrome as a terminal event of pneumonia. In multivariate analysis, dual alkylator conditioning was the only significant covariate of VOD/SOS (P = .039), Dr. DeAngelo said.

An audience member chided the author for the short duration of remission, but session co-moderator Dr. Anthony Moorman , of Newcastle University, Newcastle upon Tyne, England, said it is not that concerning because of the aggressive nature of ALL.

“For all patients that have relapsed or refractory adult ALL, their responses are incredibly low. So any kind of complete remission is a major achievement in this patient population, especially if they are refractory or relapse after tyrosine kinase inhibitors or Philadelphia-positive,” he said in an interview.

“When you have an active agent that works with relapsed refractory disease, in this case leukemia, the goal is to move it up front,” Dr. DeAngelo told this publication.

Indeed, updated results presented at the meeting from M.D. Anderson Cancer Center of frontline inotuzumab added to low-intensity chemotherapy (Mini-hyper CVD) in elderly ALL patients were “provocative,” he added. CR rates reached 97% in the study, according to the abstract (S114).

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