ANTI-CD22 ANTIBODY FOR ALL

VIENNA — The investigational drug inotuzumab ozogamicin (Pfizer) significantly improved complete remission rates in patients with refractory or relapsed acute lymphoblastic leukemia (ALL), compared with standard intensive chemotherapy, according to results from an ongoing trial.

"The results, based on the first primary end point of this phase 3 clinical trial, suggest that inotuzumab ozogamicin may be a promising new treatment option for relapsed or refractory ALL," said presenting author Daniel J. DeAngelo, MD, PhD, a hematologist at the Dana-Farber Cancer Institute in Boston.

"In terms of safety, we found no new toxicities," he reported.

The results were presented here at the 20th Congress of the European Hematology Association (EHA).

Even with the standard of care — an intensive, long-term chemotherapy regimen — the cure rate for ALL, which is an aggressive leukemia, is only about 20% to 40%, and the 5-year overall survival rate for refractory ALL is less than 10%.

Inotuzumab ozogamicin (INO), a humanized anti-CD22 antibody drug conjugate linked to the potent cytotoxic agent calicheamicin, has shown previous efficacy and safety in the treatment of ALL.

"What has been particularly remarkable is that the vast majority of patients achieving remission in two previous trials achieved a minimal residual disease [MRD]-negative status," Dr. DeAngelo said.

He reported the primary outcomes of complete remission or complete remission with incomplete hematologic recovery (CRi) for the first 218 of 326 patients randomized in the ongoing study.

The study met its first primary end point. Rates of complete remission or CRi were better in patients treated with INO than in those treated with standard chemotherapy (80.7% vs 33.3%; P < .0001).

Rates of complete remission or CRi with MRD-negativity were also higher with INO than with standard chemotherapy (78.4% vs 28.0%; P < .0001).

All the study participants had relapsed or treatment refractory ALL. Median age in the study cohort was 47 years, but the oldest patient was 79 years. More than half the patients had a remission duration of less than 12 months, which is considered to be an adverse prognostic feature.

For the 109 patients randomized to INO, the starting dose was 1.8 mg/m² per cycle on days 1 to 15. Once complete remission or CRi was achieved, the dose was reduced to 1.5 mg/m² per cycle.

The 109 patients randomized to standard chemotherapy received one of three standard-of-care regimens: fludarabine plus cytarabine (ara-C) plus granulocyte colony-stimulating factor (FLAG); ara-C plus mitoxantrone; or high-dose ara-C.

In both groups, complete remission or CRi was achieved in most patients in cycle 1.

The rate of complete remission or CRi that lasted 12 months or more was higher in the INO group than in the chemotherapy group (86.8% vs 45.5%).

Dr. DeAngelo noted that approximately two-thirds of the patients in the INO group who achieved complete remission had undergone previous stem cell transplantation.

In addition, for patient who were Philadelphia chromosome-positive, a complete response or CRi was achieved by 11 of 14 patients in the INO group, compared with eight of 15 in the chemotherapy group (79% vs 53%; P < .14). Dr. DeAngelo attributed the fact that this did not reach statistical significance to the small number of patients in the two groups.

Patients treated with INO underwent a median of three cycles of treatment, whereas patients treated with standard chemotherapy underwent a median of one cycle, regardless of the type of treatment.

Despite the differences, the overall incidence of treatment-emergent adverse events of any grade was similar in the two groups, according to a safety analysis of 259 patients.

"All-cause treatment events were similar between the inotuzumab ozogamicin and standard chemotherapy arms, in spite of the fact that the inotuzumab ozogamicin patients received, on average, three times as much therapy," Dr. DeAngelo noted.

Discontinuation rates were similar in the INO and chemotherapy groups (83% vs 89%), but discontinuation in the INO group was primarily because of complete remission (35%), whereas in the chemotherapy group, it was primarily because of resistant ALL (40%).

Febrile neutropenia was the most common serious adverse event in both the INO and chemotherapy groups (12% vs 18%).

There were more deaths during treatment in the INO group than in the chemotherapy group (17 vs 11). In the INO group, four deaths were deemed to be related to treatment and two were the result of veno-occlusive liver disease (VOD), which was related to transplantation that occurred after the study period.

Overall, more patients in the INO group than in the chemotherapy group developed VOD (15 vs 1). In the INO group, five developed it during therapy and 10 developed it after poststudy transplantation.

On multivariate analysis, the biggest risk factor for VOD was use of a dual-alkylator preparative regimen during transplantation (P = .03).

In terms of other adverse events, hyperbilirubinemia was more common in the INO group than in the chemotherapy group (15% vs 10%).

More patients in the INO group than in the chemotherapy group proceeded to allogeneic stem cell transplantation (48 vs 20).

Because this study is ongoing, the overall survival data are still blinded and will likely not be available until January 2016, Dr. DeAngelo reported.

In terms of improvement, the findings are particularly impressive in tough-to-treat cases such as Philadelphia chromosome-positive patients, said session comoderator Anthony Moorman, PhD, professor of genetic epidemiology at the Northern Institute of Cancer Research at Newcastle University in the United Kingdom.

"They are the largest high-risk genetic subgroup, and are now routinely treated with a tyrosine kinase inhibitor [TKI]," Dr. Moorman told Medscape Medical News.

"The fact that inotuzumab can achieve responses among Philadelphia chromosome-positive patients who have acquired resistance to TKIs is a plus-point for the drug because of size and nature of this genetic subtype," he explained.

"Overall, I thought this was an impressive study," he added, noting the encouraging results and a good number of patients.

"Although the duration of remission was modest, these were refractory/relapse patients, and 4.6 months is significantly longer than standard of care," he pointed out.

'Like all these types of study, it represents an incremental improvement, which can be built upon in subsequent trials," Dr. Moorman added.

The study was sponsored by Pfizer. Dr. DeAngelo has received research support from Sigma Tau and has been a consultant for Novartis, Sigma Tau, BMS, Amgen, and Pfizer. Dr. Moorman has disclosed no relevant financial relationships.

20th Congress of the European Hematology Association (EHA): Abstract LB2073. Presented June 14, 2015.