Old rivals become new friends

In this issue of Blood, Jabbour et al report on the use of inotuzumab ozogamicin (InO) in the setting of measurable residual disease (MRD) in patients with B-cell acute lymphoblastic leukemia (ALL).¹ InO (Besponsa) is an antibody-drug conjugate approved for the treatment of relapsed/refractory B-cell ALL (R/R B-ALL) in adults.² InO consists of a CD22-targeting immunoglobulin G4 humanized monoclonal antibody conjugated to calicheamicin, similar to the anti-CD33 antibody-drug conjugate gemtuzumab ozogamicin (GO, Mylotarg).

After initial development in R/R aggressive B-cell non-Hodgkin lymphoma, InO moved to CD22⁺ R/R B-ALL. Important points emerged from phase 2 studies of InO such as the dosing regimen and increased sinusoidal obstruction syndrome (SOS) rate when combined with chemotherapy despite a better response rate. As seen with GO, splitting the dose into 2 to 3 days of administration per cycle (0.8, 0.5, 0.5 mg/m²; day 1, day 8, and day 15) resulted in a better tolerance without affecting efficacy, which was a major step forward. In 2016, the results of the registration phase 3 study, the INO-VATE (INotuzumab Ozogamicin trial to inVestigAte Tolerability and Efficacy) study were reported.³ Although the benefit in survival was not significantly different between the 2 arms, complete remission (CR) rates (80.7% vs 29.4%) and MRD negativity rates (78.4% vs 28.1%) were higher with InO compared with chemotherapy, with improved median event-free survival (EFS) in favor of InO (5 months vs 1.8 months). Thrombocytopenia and veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) were the major AEs significantly associated with InO. The 11% VOD/SOS rate was thought to be due to hepatic toxicity related to previous therapy and impacted by the number of administered cycles and conditioning regimen in case of allogenic stem cell transplantation (allo-SCT). As in salvage therapies other than chimeric antigen receptor T (CAR-T) cellular therapies, the benefit reported by INO-VATE was modest, but the data resulted in InO registration and a renewed interest in the antibody-drug conjugate.

InO was next explored in frontline treatment for patients ineligible for intensive or pediatric-inspired regimens. The final results of the first-line combination of InO plus mini-hyper-CVD (cyclophosphamide, vincristine, and dexamethasone) in 80 patients with B-ALL were recently published.⁴ A paradigm shift occurred with a CR rate of 94% and a 2-year overall survival rate of 64%, which was even more remarkable given the median age of 68. The VOD/SOS rate was 8% overall; however, the InO dosing evolved during the trial and the final dose level 4 used fractionated doses (0.6, 0.3 mg/m², day 2, day 8, cycle 1; and 0.3, 0.3 mg/m², day 2, day 8, cycles 2-4). Other studies that are ongoing suggest that the VOD/SOS rate may be further reduced with the use of low-intensity chemotherapy (EWALL [European Working Group for Adult Acute Lymphoblastic Leukemia]-InO trial, NCT03249870) or no chemotherapy at all (Initial-1 trial, NCT03460522).⁵ 

Jabbour et al now report the use of InO for the treatment of MRD in patients with B-cell ALL in first complete remission (CR1, 73%) or beyond (CR2⁺, 27%). Twenty-six patients received fractionated dose of Ino at 0.6 mg/m² on day 1 and 0.3 mg/m² on day 8 of cycle 1, then at 0.3 mg/m² on days 1 and 8 of cycles 2 to 6 without chemotherapy. Although the population of patients was heterogeneous (CR1 and CR2⁺, Ph⁺ and Ph⁻ ALL) and MRD assessment varied (flow cytometry ± polymerase chain reaction ± next-generation sequencing), 18 (69%) patients achieved MRD negativity mostly after the first cycle and 6 of them underwent allo-SCT (vs only 1 in the nonresponder group). Responses translated into a median relapse-free survival (RFS) of 41 months, with a 2-year RFS rate of 54% (median follow-up of 24 months). Only 2 patients (8%) had VOD/SOS. A similar study conducted by the GIMEMA (Gruppo Italiano Malattie Ematologiche dell’Adulto/Italian Adult Haematological Diseases) group (ALL2418, NCT03610438) reported results on the first 39 patients.⁶ Two 28-day cycles of InO were planned (at 0.5 mg/m² on days 1, 8, and 15). A 35% MRD rate (centrally assessed) was observed in evaluable patients, and only 1 case of VOD/SOS has been observed to date (2.5%).

Does this strategy compare favorably with blinatumomab (Blina; CD19-targeting bispecific T-cell engagers [CD19-BiTE]) immuno-oncotherapy?

The first report of the BLAST (Blinatumomab for MRD in Adults with B-Cell Precursor Acute Lymphoblastic Leukemia) study (NCT01207388) on 116 patients with CD19⁺ B-ALL and MRD positivity showed an MRD clearance rate of 78% after one 28-day cycle of Blina, and RFS was 54% with a median follow-up of 30 months.⁷ The transplant rate was 67%. Final results were recently published with a median follow-up of 59.8 months.⁸ Estimated 5-year survival was 43% overall and 50% for complete MRD responders.

Having 2 options in patients with B-ALL with MRD positivity would be in the patient’s interest, assuming InO obtains regulatory approval for CD22⁺ B-ALL with MRD positivity (see figure). Neither of the 2 options (Blina or InO) can be considered superior to the other in the absence of a head-to-head comparison. The logical next question will then be: why not give combination therapy with both agents? As B-ALL relapses post Blina may became CD19⁻, having a CD22 targeting agent may reduce the chance for the leukemic blasts to escape and vice versa. The frontline setting is probably the best situation to evaluate the combination of InO and Blina, which should decrease the toxicity, especially for older patients. This story is ongoing with studies testing a sequential administration of both antibodies (Alliance A041703 trial, NCT03739814) or a simultaneous administration (Ino + Blina MDACC [MD Anderson Cancer Center] trial, NCT02877303).

Conflict-of-interest disclosure: The Clinical Research Department of Centre Hospitalier de Versailles received a research grant to conduct the EWALL-InO trial.