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Letters to the Editor
Immunophenotypic changes of leukemic blasts in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia who have been treat- ed with blinatumomab
Targeting the B-lineage surface antigen CD19 in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is one of the most successful examples of T-cell-based immunotherapies.1,2 The CD3/CD19 bispecific T-cell engager, blinatumomab, produces excellent responses in adult and pediatric patients with relapsed/refractory BCP-ALL.1-3 However, a significant proportion of patients do not respond to therapy or relapse.1,3 Acting as a strong selective factor, CD19-directed immunotherapy can drive the specific, but still not completely understood immune escape mechanism by the loss of CD19 expression on leukemic blasts, thereby leading to CD19-negative relapses.3,4 This loss of CD19 creates significant chal- lenges to the application of multicolor flow cytometry (MFC) for monitoring minimal residual disease (MRD). Moreover, the expression of other markers can also change, and the frequency of these changes is still unclear. As accurate detection of residual tumor cells has emerged as a key tool in evaluating efficacy and predict- ing failures after CD19-directed therapies,5 these obsta- cles to flow cytometry are highly significant. The current report briefly summarizes our data on MFC-MRD and
relapse detection in patients treated with blinatumomab with emphasis on changes in the expression of markers that are relevant for MFC-MRD investigations.
We carried out a retrospective review of 90 pediatric patients with relapsed/refractory ВCP-ALL who received blinatumomab between December 2015 and August 2020. The characteristics of the patients, including their cytogenetic data, are presented in Online Supplementary Table S1. All patients, except for two in whom treatment was interrupted because of disease progression, received at least one 28-day course of blinatumomab (median number of courses 1; range, 1-4). Blinatumomab was kindly provided by Amgen as part of a named-patient extended-access program. Blinatumomab treatment was administered to 67 of the 90 studied patients as a “bridge therapy” to allogeneic stem cell transplantation (Online Supplementary Table S1). Morphological examination and MFC-MRD detection in bone marrow aspirates were per- formed before and after each cycle of blinatumomab, while, for patients who underwent hematopoietic stem cell transplantation, MFC-MRD evaluation was carried out on days +30, +90, +120, +180, +360 after transplan- tation or in cases of suspected relapse.
All patients underwent routine diagnostic immunophe- notyping and MRD detection by eight- or ten-color flow cytometry according to the standard protocols of the Moscow-Berlin group.6,7 During the study period MFC was performed on FACS Canto II, FACS Celesta (both
Figure 1. Outcome after blinatumomab treatment in the studied patients (n=90) with emphasis on the expression of CD19. Patients who achieved complete multicolor flow cytometry (MFC)-minimal residual disease (MRD)-negative remission and those with bone marrow (BM) MFC-MRD-negativity, but with progression of extramedullary disease are grouped together and named “Lack of leukemic cells in BM”. Remaining cases (n=48) include resistant ones (n=8), relapses (21 CD19-positive, 6 CD19-negative and 3 switches to acute myeloid leukemia) and patients with blasts detected by MFC at MRD-level in bone marrow at least once (n=10).
haematologica | 2021; 106(7)
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