Page 74 - Haematologica Vol. 107 - September 2022

ARTICLE - High tumor burden and response to blinatumomab A. Cabannes-Hamy et al.
30% of patients with Ph-negative BCP-ALL relapse, re- gardless of their age, with only 50% of second CR, and a poor long-term survival of around 10-20% at 5 years after relapse.8
Blinatumomab is a bispecific T-cell engager that recruits T cells on CD19-positive blast cells and induces anti-leu- kemic cytotoxicity. In a phase III study in patients with re- lapsed/refractory (R/R) BCP-ALL, blinatumomab showed a benefit over standard of care in terms of overall re- sponse rate and OS.9 In a phase II study including MRD- postive (MRD+) patients, blinatumomab resulted in complete MRD response in 78% of patients after one cycle, and was associated with significantly longer re- lapse-free survival (RFS) and OS than MRD non-re- sponders.10 Among relapsed/TKI-refractory Ph+ BCP-ALL, blinatumomab showed anti-leukemia activity, with 36% of CR/CRh during the first two cycles, and 88% of complete MRD response among CR/CRh responders.11
Predictors of the response to blinatumomab were poorly investigated.12 Recent studies suggested some BCP-ALL subgroups including CRLF2-rearranged ALL may be more sensitive to blinatumomab.13 Whereas the absolute lym- phocyte count is not correlated to the response, a high rate of regulator T cells may inhibit the cytoxicity redi- rected by blinatumomab.14 Finally, the expression of spe- cific CD19 isoforms lacking the epitope recognized by blinatumomab may also lead to primary resistance to this bispecific antibody.13 As for other immunotherapies, the effector/target ratio is supposed to play a critical role in the efficacy of blinatumomab. However, the prognostic im- pact of leukemic tumor burden on the response to blina- tumomab remains a matter of debate and confounding results emerged from comparisons treated at different disease stages.
The present study aimed to explore the role of pre-blina- tumomab tumor load on patient outcome in a real-life co- hort of patients treated between 2012 and 2016 for R/R or MRD+ adult BCP-ALL. The prognostic impact of prethera- peutic leukemic burden was investigated.
Methods
Study design
The present study is a retrospective, multicenter, case series study evaluating the efficacy and the tolerance of blinatumomab in adult patients treated for a BCP-ALL in the French compassionate use program. The study fo- cuses on the impact of pre-blinatumomab tumor burden on patient outcome.
Inclusion criteria were: i) patients aged 15 years or more, ii) patients treated in the GRAALL network, iii) patients with Ph-negative or Ph+ BCP-ALL, in R/R to salvage ther- apy (R/R cohort) or in first or second remission with MRD+
(MRD+ cohort), iv) patients treated with blinatumomab in the French compassionate use (ATU: Autorisation Tempo- raire d’Utilisation) program. The study was registered as clinicaltrials gov. Identifier: NCT03751072 and was ap- proved by an independent Ethic Committee, in accordance with the Declaration of Helsinki.
Response and safety assessment
Hematological CR was defined as <5% blasts in the bone marrow (BM) aspirates, with full hematologic recovery in the peripheral blood (neutrophil count >1×109/L and pla- telet count >100×109/L). Complete remission with incom- plete hematologic recovery (CRi) was defined as <5% BM blasts with neutrophil count <1×109/L or platelet count <100×109/L. Complete MRD response was defined by the absence of detectable MRD, either by molecular immuno- globulin/T-cell receptor quantification, by flow cytometry (with sensitivity of 0.01%), or by BCR-ABL1 quantification in Ph+ ALL patients.
Statistical analysis
OS was defined as the time between blinatumomab first infusion and death, censoring patients alive at last follow- up. RFS was defined as the time between first blinatumo- mab infusion for MRD+ patients or the time of post-blinatumomab CR/CRi for relapsed patients and either death or relapse, censoring patients at last follow- up. In some analysis, OS and RFS were also censored at the time of HSCT. Univariate and multivariate analyses as- sessing the impact of pre-blinatumomab tumor burden were performed with a Cox model. Proportional hazards assumptions were graphically checked. MRD+ and relapse cohorts were analyzed separately. Statistical analysis was performed with the statistical software STATA/SE (Version 16.1, StataCorp LLC, College Station, Texas, USA).
Results
Patient’s characteristics
Among the 80 patients who received blinatumomab in the French compassionate ATU program, 73 were included in this study from 11 GRAALL network centers (Figure 1). Thirty-five patients were in first complete remission (CR1) with persistent MRD (MRD+ cohort), and 38 were in first or subsequent relapse (relapse cohort). Patient in first CR1 were mostly treated according to GRAALL frontline pro- tocols for Ph+ and Ph- BCP-ALL.3,15 The choice of salvage therapy was left to the discretion of the treating clinician and many different schedules were used including weekly dosing of alkaloids and steroids, second-line ITK, hyper- CVAD, or pediatric-inspired regimen.
Patient’s characteristics are summarized in Table 1.
The median age of the MRD+ cohort was 32 years (range,
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