Inotuzumab Ozogamicin Proves Superior to Standard Chemotherapy for Relapsed/Refractory ALL in a Long-Term Follow-up Study

Two-year follow-up confirms initial findings of the INO-VATE trial

The promising preliminary survival and remission outcomes that inotuzumab ozogamicin (INO) produced in relapsed or refractory acute lymphoblastic leukemia (ALL) patients in the antibody-drug conjugate’s Phase 3 trial have been sustained in a long-term follow-up study.

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The final report of the INO-VATE (INotuzumab Ozogamicin trial to inVestigAte Tolerability and Efficacy) trial found that INO generated greater rates of complete remission (CR) and longer median overall survival (OS), but showed a greater incidence of veno-occlusive disease (VOD), compared to results in ALL patients treated with standard-of-care chemotherapy.

“INO is a very encouraging drug in the setting of relapsed/refractory ALL and this long-term follow-up study has validated its OS advantage,” says study co-author Anjali Advani, MD, Director of Cleveland Clinic Cancer Center’s Inpatient Leukemia Program. “The main challenge we still have to deal with is the risk of VOD, but INO definitely has an advantage in patients with high-tumor burden or extramedullary disease. I also tend to favor it in patients with central nervous system disease, because it can be given with concurrent intrathecal chemotherapy.”

The original INO-VATE trial assessed the safety and efficacy of single-agent INO compared to standard chemotherapy in relapsed/refractory ALL. INO is a humanized monoclonal antibody drug conjugate that binds to CD22+ ALL cells. The antibody is conjugated to calicheamicin, a cytotoxic compound that causes DNA damage and apoptosis.

INO-VATE’s results led the Food and Drug Administration to approve the drug’s use in adults with relapsed or refractory B-cell precursor ALL.

Challenging VOD rates

The main purpose of the follow-up study was to assess if INO is superior to the standard-of-care chemotherapy over a period of 2 years.

“We looked at the response/complete remission (CR) rates, toxicity, OS, disease-free survival (DFS), minimal residual disease (MRD) negativity, and the percentage of patients that were able to go on to (hematopoietic stem cell) transplant,” says Dr. Advani.

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The two-year follow-up largely confirmed the initial findings of the INO-VATE trial, with even more impressive outcomes in terms of OS and the percentage of patients who achieved MRD negativity and proceeded to transplant.

“The difference in the OS in patients who received INO (22.8%) compared to those who received standard chemotherapy (10%) has become more pronounced after the two-year follow-up,” she says. “The outcome of patients who proceeded to transplant is even more impressive in the subgroup who received INO and went into remission, achieved MRD negativity and went on to transplant (39.6% INO vs 10.5% standard of care).”

However, the risk of VOD in patients who are transplanted remains a concern, she notes. VOD/sinusoidal obstruction syndrome (SOS) was significantly more frequent in the INO arm (14%) compared to the standard-of-care arm (2.1%).

“We are now looking at how we can decrease that toxicity by either giving these patients medications (i.e., defibrotide) prophylactically prior to transplant or reducing the dose of INO and combining it with other agents,” says Dr. Advani.

In both treatment arms, the most frequent all-grade and grade 3 or higher adverse events were hematologic.

“Hematologic events are very common with both INO and the standard-of care chemotherapy,” she says. “But the neutropenia, thrombocytopenia and anemia we saw were fairly easily manageable. For those patients who are not going on to transplant and receiving multiple cycles, the low platelet count can become an issue.”

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Next research steps

In terms of continuing research on INO, Dr. Advani says upfront use of the drug is currently being investigated in several clinical trials. In the ALLIANCE (A041501) trial, led by Daniel J. DeAngelo, MD, PhD, of the Dana Farber Cancer Institute, INO is being evaluated in combination with chemotherapy in young adults with newly diagnosed CD22+ B-cell acute lymphoblastic leukemia.

“The question we are trying to answer in this trial is, if we use the drug in the upfront setting, will we have better outcomes, lower number of relapses and maybe lower toxicity, because those patients hopefully won’t be going on to transplant,” explains Dr. Advani, who is one of the study’s principal investigators.

A second planned U.S. intergroup trial led by Elias Jabbour, MD, of the University of Texas MD Anderson Cancer Center, will randomize elderly patients with ALL to either mini-hyper-CVD (low-intensity chemotherapy) or mini-hyper-CVD plus INO.

A third trial (S1312) that has completed accrual is reviewing INO plus chemotherapy (cyclophosphamide, vincristine sulfate and prednisone, or CVP) in patients with relapsed or refractory CD22+ acute leukemia. This is a Southwest Oncology Group trial in which Dr. Advani serves as a principal investigator.

Image: Electron micrograph of human B cell, in which most forms of acute lymphoblastic leukemia arise.

Credit: National Institute of Allergy & Infectious Disease