Among pediatric patients (pts) with acute lymphoblastic leukemia (ALL), 10-15% relapse. Inotuzumab Ozogamicin (InO) is an anti-CD22 drug-conjugated antibody approved for adults with relapsed/refractory (R/R) B-cell precursor (BCP)-ALL CD22+. The primary objective of this phase IB trial (EudraCT: 2016-000227-71) was to determine the recommended phase 2 dose (RP2D) of InO in combination with a modified UKALL-R3 regimen in pediatric BCP-ALL CD22+ pts. Results from the InO single-agent (SA) phase IA and II of the same trial were published previously (Brivio et al., 2021; Pennesi et al., 2022). The study was sponsored by Erasmus MC and financed by Pfizer.

Subjects with M2 or M3 bone marrow (BM) and either ≥ 2nd relapse, or 1st relapse after allogeneic hematopoietic stem cell transplantation (HSCT), or with refractory disease were enrolled, using a rolling-6 design. Dose-Limiting Toxicities (DLTs) were assessed during cycle 1, and defined as delay in hematological recovery after day 42 in responding pts, and/or grade (Gr) ≥3 non- hematological toxicities lasting >48 hours, or >7 days for liver tests. InO (fractionated in 3 doses/cycle, days 1, 8, 15) was combined with vincristine 1.5 mg/m2 (days 3, 10, 17, 24), two blocks (days 1-5 and 15-19) of dexamethasone 20 mg/m2 (in 2 daily doses), and intrathecal (IT) therapy (methotrexate ± steroids and cytarabine as per local practice; days 1 and 8). After cycle 1, pts could arbitrarily receive additional combination therapy or SA InO.

Overall, 37 pts were screened, 30 were treated, 29 were evaluable for DLTs (1 received wrong dose) and 30 for response. See table 1 for patient characteristics. The initial dose level (DL) of InO tested was 1.1 mg/m2/cycle. Among 4 pts treated, 2 had a DLT: Gr 3 transaminase elevation >7 days and Gr 3 sinusoidal obstruction syndrome (SOS). InO was de-escalated to 0.8 mg/m2/cycle(n=6) without DLTs while awaiting a protocol amendment to reduce dexamethasone to 10 mg/m2/day, with the aim to reduce liver toxicity. Post amendment, InO was re-escalated to 1.1 mg/m2/cycle(n=6, 1 DLT: Gr 3 transaminase elevation >7 days); then to 1.4 mg/m2/cycle(n=3, no DLTs), and finally to 1.8 mg/m2/cycle (n=7; 1 DLT: absolute neutrophil count <0.5 x 109/L >D42), the same dose as per SA cohorts and as capped per protocol. Three additional pts were treated in an expansion cohort with 1.8 mg/m2/cycle. Median cumulative dose of InO per patient was 1.8 mg/m2 (range 0.5-3.3). Only 3/30 pts received 2 combination cycles, 1 received a combination cycle and 2 SA InO cycles; all other pts received 1 combination and 1 SA InO cycle.

The most common non-hematological adverse event (AE) was increased alanine aminotransferase (n=22, 73.3%), 13 (43.3%) events at Gr 3/4. Six (20%) pts had hyperbilirubinemia, none at Gr ≥ 3. Five (16.6%) pts developed SOS (1 Gr 4; 4 Gr 3) 1 during InO treatment and 4 after subsequent HSCT. Four (13.3%) pts experienced sepsis, 9 (30%) febrile neutropenia, 3 (10%) other Gr 3 infections. The most common hematological AE was thrombocytopenia (n=21, 70%), with 19 (63.3%) cases at Gr 3/4. No toxic deaths related to InO were observed.

The Overall Response Rate (ORR; BM M1 ± hematological recovery) was 76.7 % (n=23/30, 95%CI: 57.7 to 90.1%), and 73.3% (n=22/30, 95%CI: 54.1 to 87.7%) responded after cycle 1; 15 responders (65.2%) were minimal residual disease (MRD) negative (< 10-4) by end of study treatment; 12 (52.2%) after cycle 1. Among 11 subjects who received combination therapy at the RP2D (one due to wrong dosage), 9 (81.8%) achieved response, 7 (63.6%) also achieved MRD negativity. The estimated overall survival probability at 6 and 12 months was 73.9% (95%CI 58.8-92.9%) and 58.1% (95%CI 40.5-83.4%) respectively, with a median follow-up of 11.7 months (range 1.3-23.7). Post study therapy data were available for 22 responders; 14 proceeded directly to HSCT and 6 to CAR-T-cell therapy; 1 received blinatumomab and 1 proceeded to maintenance chemotherapy.

The RP2D of InO in combination with 1.5 mg/m2 of vincristine (days 3, 10, 17, 24) and 10 mg/m2 of dexamethasone (two 5-day blocks) was declared at 1.8 mg/m2/cycle (1.5 mg/m2/cycle once in remission). Liver toxicities remain the most relevant AE. The ORR seems comparable to the SA cohorts, but the sample size is small. SA InO is randomized against UKALL R3 in the upcoming trial B1931036 for high-risk first relapsed ALL; a phase 2 study in very-high-risk first relapsed ALL is ongoing (ITCC-059).

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van der Velden:Cytognos: Other: laboratory services agreement ; Agilent: Other: laboratory services agreement ; Euroflow: Patents & Royalties; BD biosciences: Other: laboratory services agreement . Sleight:Pfizer Inc: Current Employment. Rives:Amgen: Other: Advisory Board; Novartis: Other: Advisory Board. Díaz de Heredia Rubio:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: meeting and travel expenses ; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: meeting and travel expenses ; Biotest: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: meeting and travel expenses ; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: meeting and travel expenses . Bautista Sirvent:Roche: Other: Consulting Fees; Amgen: Other: Consulting Fees; Bayer: Other: Consulting Fees. Rizzari:Servier: Honoraria; Agmen: Honoraria; Jazz: Honoraria. Rossig:novartis: Other: consulting fees; Roche: Other: Consulting Fees; Pfizer Inc: Other: consulting fee; Amgen: Other: Consulting Fees. Locatelli:SOBI: Speakers Bureau; BlueBird bio: Speakers Bureau; Miltenyi: Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Neovii: Speakers Bureau; Jazz Pharmaceuticals: Honoraria; Medac: Speakers Bureau; Amgen: Speakers Bureau. Zwaan:Pfizer Inc: Honoraria; JAZZ: Honoraria; Abbvie: Honoraria; Abbvie: Honoraria; Novartis: Honoraria.

Author notes

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Asterisk with author names denotes non-ASH members.

© 2022 by The American Society of Hematology
2022
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