Serial evaluation of CD19 surface expression in pediatric B-cell malignancies following CD19-targeted therapy

Libert, Diane; Yuan, Constance; Masih, Katherine E.; Galera, Pallavi; Salem, Dalia; Shalabi, Haneen; Yates, Bonnie; Delbrook, Cindy; Shern, Jack F.; Fry, Terry J.; Khan, Javed; Stetler‐Stevenson, Maryalice; Shah, Nirali N.

doi:10.1038/s41375-020-0760-x

Cited by 37 publications

(41 citation statements)

References 16 publications

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“…7,14 However, leukaemic cells can show variable changes in CD19 expression during anti-CD19 therapy. 15 Polymerase chain reaction(PCR)-based MRD monitoring with patient-specific systems provides reliable results, regardless of the presence of CD19. 16,17 At the same time, genetic methods are unable to detect the expression of this surface antigen on cells.…”

Section: Introductionmentioning

confidence: 99%

“…18,19 With regard to CD19-directed therapy, the standard algorithm is limited by possible partial or complete elimination of the surface CD19. 15 Therefore, alternative pan-B-cell markers must be used for B-lineage compartment restriction, for example, CD22, CD24, 20 or intracellular (i)CD79a, which are generally detectable on blasts of B-lineage ALL. 21 However, CD19-directed therapy may influence the normal BM background as well.…”

Section: Introductionmentioning

confidence: 99%

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Relative expansion of CD19‐negative very‐early normal B‐cell precursors in children with acute lymphoblastic leukaemia after CD19 targeting by blinatumomab and CAR‐T cell therapy: implications for flow cytometric detection of minimal residual disease

et al. 2021

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CD19-directed treatment in B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) frequently leads to the downmodulation of targeted antigens. As multicolour flow cytometry (MFC) application for minimal/measurable residual disease (MRD) assessment in BCP-ALL is based on B-cell compartment study, CD19 loss could hamper MFC-MRD monitoring after blinatumomab or chimeric antigen receptor T-cell (CAR-T) therapy. The use of other antigens (CD22, CD10, CD79a, etc.) as B-lineage gating markers allows the identification of CD19-negative leukaemia, but it could also lead to misidentification of normal very-early CD19-negative BCPs as tumour blasts. In the current study, we summarized the results of the investigation of CD19-negative normal BCPs in 106 children with BCP-ALL who underwent CD19 targeting (blinatumomab, n = 64; CAR-T, n = 25; or both, n = 17). It was found that normal CD19-negative BCPs could be found in bone marrow after CD19-directed treatment more frequently than in healthy donors and children with BCP-ALL during chemotherapy or after stem cell transplantation. Analysis of the antigen expression profile revealed that normal CD19-negative BCPs could be mixed up with residual leukaemic blasts, even in bioinformatic analyses of MFC data. The results of our study should help to investigate MFC-MRD more accurately in patients who have undergone CD19-targeted therapy, even in cases with normal CD19-negative BCP expansion.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Relative expansion of CD19‐negative very‐early normal B‐cell precursors in children with acute lymphoblastic leukaemia after CD19 targeting by blinatumomab and CAR‐T cell therapy: implications for flow cytometric detection of minimal residual disease

et al. 2021

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“…Increasing the number of colors in a tube and the number of acquired events the sensitivity of FC can reach 2-in-10 6 (0.0002%) [33]. On the other hand, analysis and interpretation of FC data requires a well-trained, skilled, and experienced interpreter who not only knows the normal immunophenotype patterns of B-cell maturation in rest and marrow regeneration and can differentiate pathological populations from regenerating hematogones, but also holds and applies a knowledge of hematological diseases, their classification and therapy, as the nature of therapy may affect antigen expression, a phenomenon especially important to take into consideration when a patient is under a targeted therapy [34].…”

Section: Discussionmentioning

confidence: 99%

A Novel Method for the Evaluation of Bone Marrow Samples from Patients with Pediatric B-Cell Acute Lymphoblastic Leukemia—Multidimensional Flow Cytometry

Kárai

Tisza

Eperjesi

et al. 2021

Cancers

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Multicolor flow cytometry (FC) evaluation has a key role in the diagnosis and prognostic stratification of ALL. Our aim was to create new analyzing protocols using multidimensional dot-plots. Seventy-two pediatric patients with ALL were included in this single-center study. Data of a normal BM sample and three BM samples of patients with BCP-ALL were merged, then all B cell populations of the four samples were presented in a single radar dot-plot, and those parameters and locations were selected in which the normal and pathological cell populations differed from each other the most. The integrated profile of immunophenotype resulted in a simple, rapid, and accurate method. There were no significant differences between the percentages of lymphoblasts in the detection of minimal residual disease (MRD) by multidimensional or conventional FC method (p = 0.903 at Day 15 and p = 0.155 at Day 33). Furthermore, we found associations between the position and the number of clusters of blast cells in the radar plots and cytogenetic properties (p = 0.002 and p < 0.0001 by the position and p = 0.02 by the number of subclones). FC analysis based on multidimensional dot-plots is not only a rapid, easy-to-use method, but can also provide additional information to screen cases which require detailed genetic examination.

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“…Not only does blinatumomab therapy have inferior OS/EFS, particularly in those with high disease burden and EMD, it may decrease effectiveness of subsequent CD19 CAR T cells with modulation of both target and nontarget antigens. 43,44 Given that optimal CAR therapy is dependent on antigen density, prior BiTE therapy has the potential to diminish the efficacy and/or response durability of subsequent CD19 CAR T cells. 43,45 Beyond B-ALL…”

Section: Sequential Therapy: Considerationsmentioning

confidence: 99%

CAR T cells better than BiTEs

Molina

Shah

2021

Blood Advances

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This article has a companion Counterpoint by Subklewe. Despite significant advances in treatment regimens and outcomes in B-cell acute lymphoblastic leukemia (B-ALL), long-term survival remains poor for the 15% to 20% of pediatric patients and 50% of adults with relapsed or refractory (r/r) disease. 1-3 The emergence of immunotherapeutic strategies that use B-cell antigen-targeted single-chain variable fragments to direct T cells to specific surface antigens on BALL cells has revolutionized outcomes. These strategies include the US Food and Drug Administration (FDA)-approved bispecific T-cell engager (BiTE) blinatumomab and chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel. 4 Even though both therapies target CD19, outcomes vary significantly. We discuss considerations and potential benefits of the preferential use of CAR T-cell therapy over BiTE in r/r BALL , which can serve as a framework for evaluation of approaches with alternative antigen-targeting strategies. Efficacy of CAR vs BiTE: response rates, trafficking, and durability In the phase 2/3 trials leading to the FDA approval of blinatumomab in 2014, the objective response rate to blinatumomab in adult patients was 36% to 44%. Of those achieving a complete remission (CR), 63% to 88% had a minimal residual disease (MRD)-negative remission. 5-9 Importantly, of 70 pediatric patients evaluated, 39% achieved CR with only 14 (20%) being MRD negative. 10 Despite an improvement over responses with conventional salvage chemotherapy, as well as improved response rates for those with MRD-level disease, 11 results of the blinatumomab phase 2/3 and retrospective adult trials indicate that a significant portion of patients are resistant to blinatumomab (Table 1). 12

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Serial evaluation of CD19 surface expression in pediatric B-cell malignancies following CD19-targeted therapy

Cited by 37 publications

References 16 publications

Relative expansion of CD19‐negative very‐early normal B‐cell precursors in children with acute lymphoblastic leukaemia after CD19 targeting by blinatumomab and CAR‐T cell therapy: implications for flow cytometric detection of minimal residual disease

Relative expansion of CD19‐negative very‐early normal B‐cell precursors in children with acute lymphoblastic leukaemia after CD19 targeting by blinatumomab and CAR‐T cell therapy: implications for flow cytometric detection of minimal residual disease

A Novel Method for the Evaluation of Bone Marrow Samples from Patients with Pediatric B-Cell Acute Lymphoblastic Leukemia—Multidimensional Flow Cytometry

CAR T cells better than BiTEs

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