Inotuzumab Ozogamicin as Single Agent in Pediatric Patients with Relapsed and Refractory Acute Lymphoblastic Leukemia: Results from a Phase II Trial

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Inotuzumab Ozogamicin (InO) is an anti-CD22 conjugated antibody that received approval for adult patients with B-cell precursor (BCP) Acute Lymphoblastic Leukemia (ALL) based on superiority in a randomized phase III trial (InO-VATE study). Available data in pediatrics are scarce. Upon trial initiation, published data mostly included a report from 51 pediatric patients treated in a compassionate use program in relapsed/refractory ALL (1), and a French retrospective cohort on 11 patients (2). Results showed that InO was effective in heavily pretreated patients and that sinusoidal obstruction syndrome (SOS) was the main safety concern. To collect data in a controlled setting, two simultaneous trials in pediatric relapsed or refractory BCP-ALL have been initiated in Europe and US (the ITCC-059 trial and the COG AALL1621) (3-4). The phase I ITCC-059 trial was the first prospective study in the context of a Pediatric Investigational Plan, and showed that the pediatric recommended phase 2 dose (1.8 mg/m2/cycle) was similar to adults, and indicated high response (CR, CRi, CRp) rates (80%; 95%CI: 59% to 93%) across the various dose-levels including minimal-residual disease negative (84%; 95%CI: 60% to 97%) complete remissions (3).

 This article concerns the ITCC-059 phase 2 part of the trial, which was a single-stage open-label study with Overall Response Rate (ORR; bone marrow M1 with or without hematological recovery) as the primary objective. Patients were treated at the RP2D of 1.8 mg/m2/cycle in three fractioned administrations, given weekly over 28 days. The study met its primary endpoint and showed an ORR of 81.5% (95%CI: 61.9%-93.7%), with an MRD negativity rate of 81.8% in patients achieving remission. Interestingly, our findings confirm the experience of the phase 1 arm of the trial, but deviate from the COG experience which estimated in the phase 2 trial a CR/CRi rate of 58.3% (90% CI: 46.5 to 69.3) (4). In general, InO was well tolerated, with liver function abnormalities and hematological toxicity as the main adverse events. Only four patients still had thrombocytopenia grade 3/4 at C1D22, of which one after day 42. SOS was confirmed to be the most relevant risk associated with InO treatment, but particularly for patients transplanted after receiving InO, and rarely occurring while on study treatment. Seven (25%, n=28) cases of SOS were reported in the phase 2 arm, of which only one while on treatment with InO, and six after transplantation. Combining data from phase 1 (all dose levels) and 2 cohorts, SOS occurred in 26.1% of the patients transplanted post-InO, which is lower than reported by previous retrospective studies (52%, 11/21) but in line with data from the COG AALL1621 trial (28.6%, 6/21), all treating patients at 1.8 mg/m2 (1, 4). Pharmacodynamic analyses explored possible mechanisms of InO resistance, but did not find evidence for a relationship between response and CD22 expression, saturation or internalization, nor for CD22 splice variants. However, when accounting for all patients treated in Phase 1 and 2 with available data (n=10), in-vitro calicheamicin sensitivity seemed to influence response, despite our sample being too small to draw conclusions. Our findings might support the conduction of dedicated trials to investigate the role of CD22 expression as a possible predictor of response to InO, as well as the definition of an InO vitro calicheamicin sensitivity threshold. It is indeed relevant to stress that in our cohort only four patients had a CD22 expression <70%. 

 In conclusion, our study provides evidence of the high activity of InO as a single agent for re-inducing remission in relapsed/refractory pediatric BCP-ALL. Furthermore, InO was well tolerated, despite the risk of SOS should be carefully assessed and particularly for patients intended to proceed to HSCT. This justifies further investigation of InO in the setting of newly diagnosed and relapsed BCP-ALL such as the COG phase III trial AALL1732.  

  1. Bhojwani D, Sposto R, Shah NN, Rodriguez V, Yuan C, Stetler-Stevenson M, et al. Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. Leukemia. 2019 Apr 1;33(4):884–92.
  2. Calvo C, Cabannes-Hamy A, Adjaoud D, Bruno B, Blanc L, Boissel N, et al. Inotuzumab ozogamicin compassionate use for French paediatric patients with relapsed or refractory CD22-positive B-cell acute lymphoblastic leukaemia. Vol. 190, British Journal of Haematology. Blackwell Publishing Ltd; 2020. p. e53–6.
  3. Brivio E, Locatelli F, Lopez-Yurda M, Malone A, Diaz de Heredia C, Bielorai B, et al. A Phase I study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study). Blood. 2020 Oct 16.
  4. O’Brien MM, Ji L, Shah NN, Rheingold SR, Bhojwani D, Yuan CM, et al. Phase II Trial of Inotuzumab Ozogamicin in Children and Adolescents With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia: Children’s Oncology Group Protocol AALL1621. J Clin Oncol. 2022 Jan 10.

Edoardo Pennesi

MD, Prinses Maxima Centrum