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3824 Potential Impact of Treatment with Inotuzumab Ozogamicin on Chimeric Antigen Receptor T-Cell Therapy in Children with Relapsed or Refractory Acute Lymphoblastic LeukemiaClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 704. Cellular Immunotherapies: Clinical: Poster III
Hematology Disease Topics & Pathways:
Lymphoid Leukemias, ALL, Biological, Antibody Therapy, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Diseases, Pediatric, Therapies, Lymphoid Malignancies, Young Adults, Study Population
Monday, December 13, 2021, 6:00 PM-8:00 PM

Valeria Ceolin1,2*, Erica Brivio, MD2,3*, Susan R. Rheingold4, Allison Barz Leahy, MD5*, Britta Julia Vormoor6*, Maureen M. O'Brien, MD7, Jeremy Rubinstein8*, Krzysztof Kalwak9*, Barbara De Moerloose10*, Elad Jacoby11, Peter Bader12, José L. Fuster13*, Franco Locatelli, MD, PhD14, Peter Hoogerbrugge2, Friso Calkoen2* and Christian M. Zwaan2,3

1Department of Pediatric Oncology/Hematology, Regina Margherita Children's Hospital, University of Turin, Turin, Italy
2Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
3Erasmus University MC-Sophia Children’s Hospital, Rotterdam, Netherlands
4Division of Pediatric Oncology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
5Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA
6Princess Maxima Center for Paediatric Oncology, Utrecht, Netherlands
7Cincinnati Children's Hospital Medical Center, Cincinnati, OH
8Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati School of Medicine, Cincinnati, OH
9Department of Pediatric Hematology, Oncology and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland
10Department of Pediatric Oncology/Hematology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
11Division of Pediatric Hematology, Oncology and BMT, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center and Sackler Faculty of Medicine, Tel Aviv, Israel
12Department of Pediatric Oncology/Hematology, Clinic for Children and Youth Medicine, University Hospital Frankfurt, Goethe University, Frankfurt, Germany
13Pediatric Hematology Unit, Hematology Department, Hospital de Valdecilla, Santander, Spain
14Department of Hematology/Oncology and Cell and Gene Therapy, Bambino Gesù Children’s Hospital, Sapienza, University of Rome, Rome, Italy

Background: Chimeric Antigen Receptor T-cells targeting CD19 (CART-19) have shown promising efficacy for relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The ELIANA trial leading to market authorization of tisagenlecleucel excluded prior therapy with monoclonal antibodies. Blinatumomab prior to CART-19 seems associated with a higher risk of early failure (Pillai, Blood Advances 2019). Inotuzumab ozogamicin (InO) is an anti-CD22 antibody conjugated to calicheamicin. InO as bridging therapy to CART-19 (n=11) was associated with a shorter overall survival (OS) (Dourthe, Leukemia 2021). InO given prior to leukapheresis might impact on the quality of T-cells collected and, when used as bridging, could result in insufficient CD19 positive (CD19+) antigen load and affect CAR T-cell expansion.

We report on a cohort of children and young adults with R/R BCP-ALL treated with InO prior to CART-19 infusion.

Methods: Data of patients (pts) treated with CART-19 after InO given at any time before and/or after apheresis, irrespective of other anti-leukemic treatments, were collected using a standardized Case Report Form. The study was approved by the ethics committee of the UMC Utrecht (MvdL/is/21/500393)

Results: Thirty-nine pts were treated in 10 centers and received CART-19 between July 2016 and April 2021. Thirty-four received commercial tisagenlecleucel and 5 academic products. Median age was 13 years (range 1–23); 25 were male. Four pts (10.3%) had received a prior CART-19 infusion and 15 (38%) blinatumomab, 18 (46%) had been previously transplanted.

All pts received at least two doses of InO (range 2-12); 12 before apheresis only (median time 48 days (range 13-560) between last InO dose and apheresis); 27 as bridging therapy (median time 52 days (range 16-257) from last InO dose to CART-19 infusion), including 5 who had also received InO before apheresis. At time of the infusion, 22 pts were in complete remission (CR) (<5% marrow blasts) including 10 with negative minimal residual disease (MRD; <0.01% by flow or <10-4 by PCR). In all pts receiving InO prior to apheresis viable CART products were manufactured. One product was out-of-specification due to insufficient interferon-γ, but a subsequent production fulfilled release criteria.

At day 28 (d28) post infusion 35/39 were in CR (89.7%), of whom 31 (88.6%) were also MRD negative. Four pts (10.3%) did not achieve CR: 3/4 were not in CR at the time of the infusion; all of them received InO as bridging within 2 months before the infusion.

With a median follow-up of 12.5 months (range 1–50) after CART-19 infusion, 12-month event free survival (EFS) was 59% (95% confidence interval (CI) [42.0-76.0]) and OS was 79.5% (95% CI [64.6-94.4]). There was no significant difference in OS/EFS between pts who received blinatumomab and InO prior to CART-19 infusion (n=15) and those who received InO only (n=24) (p=0.61 and p=0.37, respectively). Sixteen pts (45.7%) relapsed at median 163 days (range 28–655) after CART-19 infusion; 7/16 (43.8%) had a CD19+ relapse (median 287 days; range 28–655), 8/16 (50.0%) had a CD19 negative (CD19-) relapse (median 163 days; range 136–273) (1 status unknown).

There was no significant difference in 12-month OS/EFS between pts who received InO before apheresis or as bridging (OS 83.3% vs 77.8%, p=0.50; EFS 58.3% vs 59.3%, p=0.62); and no difference in d28 MRD response (p=0.57) or incidence of CD19+ or CD19- relapses (p=0.48) between the 2 groups.

Twelve of the 35 pts in CR at d28 (34.2%) lost BCA, median 92 days after CART-19 infusion (range 29−294) (1 data not available); 7/12 relapsed, 5/7 with CD19+ relapse. Among the 35 responders, 5/12 pts who received InO before harvesting lost BCA (1 data not available) vs 7/23 pts who received InO as bridging. There was no significant difference in 12-month EFS between pts who received CART-19 with low CD19 burden at start of lymphodepletion chemotherapy (MRD <10-4 and BCA, n=6) compared to the rest of the population (p=0.30).

Conclusion: InO as a bridging strategy to CAR T-19 does not seem to result in inferior response when EFS/OS are compared to published data (Maude, NEJM 2018; Pasquini, Blood Adv, 2020). The ITCC/IntReALL-059 study will treat very high risk first relapsed BCP-ALL pts (very early relapse or presence of TP53 mutation and/or deletion, hypodiploidy, t(1;19)/t(17;19), KTM2A/AF4) with InO reinduction followed by CART, given the poor prognosis with current strategies.

Disclosures: O'Brien: Jazz: Honoraria; Pfizer: Honoraria, Research Funding. Jacoby: NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Locatelli: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharamceutical: Speakers Bureau; Takeda: Speakers Bureau. Zwaan: SANOFI: Consultancy; NOVARTIS: Consultancy; ROCHE: Consultancy; INCYTE: Consultancy; PFIZER: Consultancy, Research Funding; JAZZ: Other: travel funding, Research Funding; BMS: Research Funding; Abbvie: Research Funding.

*signifies non-member of ASH