Potential Impact of Treatment with Inotuzumab Ozogamicin on Chimeric Antigen Receptor T-Cell Therapy in Children with Relapsed or Refractory Acute Lymphoblastic Leukemia
Authors: Ceolin Valeria , Brivio Erica , Rheingold Susan R. , Leahy Allison Barz , Vormoor Britta Julia , O'Brien Maureen M. , Rubinstein Jeremy , Kalwak Krzysztof , De Moerloose Barbara , Jacoby Elad , Bader Peter , Fuster José L. , Locatelli Franco , Hoogerbrugge Peter , Calkoen Friso , Zwaan Christian M. 
Published: November 2021

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) (&lt;5% marrow blasts) including 10 with negative minimal residual disease (MRD; &lt;0.01% by flow or &lt;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 &lt;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.