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Inotuzumab Ozogamicin Yields Anti-Leukemia Activity in Young Patients With R/R ALL

Single-agent inotuzumab ozogamicin demonstrated anti-leukemia activity in heavily pre-treated pediatric patients with CD22-positive relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL), according to data presented by Erica Brivio, MD, Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands, at the virtual 62nd American Society of Hematology Annual Meeting and Exposition. 

“Inotuzumab ozogamicin (InO) was well tolerated and demonstrated anti-leukemia activity in heavily pre-treated pediatric patients with CD22-positive relapsed/refractory acute lymphoblastic leukemia in the Phase (Ph) I ITCC-059 study. With the established recommended phase 2 dose (RP2D) (1.8 mg/m2/course, as in adults) a consecutive Ph II study has been performed, sponsored by Erasmus MC and supported by Pfizer (NTR57360),” explained Dr Brivo et al. 

A total of 33 patients with R/R CD22-positive BCP-ALL were enrolled in the study, after obtaining, inclusion criteria included M2/M3 marrow and adequate liver and kidney function.

The trial consisted of a single-stage design to test the null hypotheses (H0) overall response rate (ORR) less than or equal to 30% and the alternative hypotheses of ORR greater than 55%. The Kaplan-Meier method was used for survival analysis, results were based on a database snapshot from June 2020.

The primary endpoint was ORR, including complete remission (CR), complete remission with incomplete platelet recovery (CRp; ANC >500/µL but PLT ≤50.000/µL), and complete remission with incomplete hematologic recovery (CRi; ANC ≤500/µL and or PLT ≤50,000/µL). Secondary endpoints were safety, minimal residual disease (MRD) levels, and durability of response.

Of the patients enrolled, 6 (21.5%) were primary refractory, 16 (57%) had ≥2nd relapse, 6 (21.5%) had 1st relapse post-HSCT (median 2 prior regimens, range 2-7), while 50% of the patients had received a previous HSCT, 3 (11%) CAR T-cell therapy and 7 (25%) blinatumomab. 

At the time of data snapshot, 48 courses of inotuzumab ozogamicin were administered (range 1-4 per pt); one pt was still receiving inotuzumab ozogamicin. A total of 27 patients were evaluable for efficacy analyses.

Following the first cycle, 22 patients achieved a response, with the ORR being 81.5% (95% CI, 61.9%, 93.7%; CR, n=14, CRp, n=1, CRi, n=7). 21 (95%) of patients achieved MRD-negativity as the best response. 
When you combine these results with those from patients treated at the RP2D in the phase 1 study (n=13), 33 out of 40 patients (82.5%) achieved a response (94% of whom achieved MRD-negativity). Three of the 9 (33%) primary refractory patients from phases 1 and 2 did not respond to inotuzumab ozogamicin.
The event-free survival (EFS) at 6 and 12 months was 57.9% (95% CI: 40.3−83.3) and 24.8% (95% CI: 9.8−62.9), respectively, while the median EFS was reached at 6.34 months (95% CI 2.53, NA). Overall survival (OS) at 6 months was 61.6% (95% CI: 43.3−87.8), and 54.8% (95% CI: 35.9−83.6) at 12 months.

9 of 22 responding patients underwent HSCT, 4 of which are still in CR. Three responders received consolidation with CAR-T (52, 55, and 215 days after last inotuzumab ozogamicin dose), all are still in CR. 3 patients died in CR (2 due to HSCT complications, 1 due to neurological deterioration considered related to previous CNS leukemia and prolonged intrathecal treatment).

All patients experienced at least 1 adverse event (AE), with 19 reporting at least 1 grade 3-4 AE. The most common AE was fever.

Four cases of VOD/SOS were reported, one during treatment. Three (33%) of the 9 transplanted patients had post-HSCT SOS. None received prophylactic defibrotide. One patient, who was previously transplanted and treated with CAR-T, received 1 course of inotuzumab ozogamicin treatment before a second HSCT and developed SOS, ongoing at the time of death due to multi-organ failure

“InO was well tolerated in this Ph II study which confirmed remarkable activity in these heavily pretreated patients. The ORR was 81.5% with 95% MRD-negativity; 55% of patients remained alive after 1 year. Twelve patients proceeded to consolidation treatment (either HSCT or CAR T)," concluded Dr Brivo and colleagues.—Alexandra Graziano

Brivio E, Locatelli F, Thanoi A, et al. A Phase II Study of Single-Agent Inotuzumab Ozogamicin in Pediatric CD22-Positive Relapsed/Refractory Acute Lymphoblastic Leukemia: Results of the ITCC-059 Study. Presented at: the 62nd ASH Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 164.

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