Blinatumomab for paediatric mixed phenotype acute leukaemia

Bartram, Jack; Balasch-Carulla, Milena; Bhojaraja, Shashank; Adams, Stuart; Cheng, Danny; Inglott, Sarah; Kulkarni, Nimish; Mahendrayogam, Arunthethy; O’Connor, Olya; Pavasovic, Vesna; Vora, Ajay

doi:10.1111/bjh.17707

Cited by 8 publications

(5 citation statements)

References 14 publications

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“…For example, it is now known that the use of blinatumomab or CAR-T cells can cause lineage switch, in particular, through selection of pre-existing myeloid leukemic subpopulation [ 24 ]. This possibility directly affects the choice of chemotherapy elements used together with immunotherapy [ 25 ]. Therefore, a clear distinction between MPAL and ALL cases is clinically important, and the combination of flow cytometry, flow cell sorting and molecular studies can provide valuable data.…”

Section: Discussionmentioning

confidence: 99%

Recognizing Minor Leukemic Populations with Monocytic Features in Mixed-Phenotype Acute Leukemia by Flow Cell Sorting Followed by Cytogenetic and Molecular Studies: Report of Five Exemplary Cases

Semchenkova

Zerkalenkova

Demina

et al. 2023

IJMS

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Mixed-phenotype acute leukemia (MPAL), a rare and heterogeneous category of acute leukemia, is characterized by cross-lineage antigen expression. Leukemic blasts in MPAL can be represented either by one population with multiple markers of different lineages or by several single-lineage populations. In some cases, a major blast population may coexist with a smaller population that has minor immunophenotypic abnormalities and may be missed even by an experienced pathologist. To avoid misdiagnosis, we suggest sorting doubtful populations and leukemic blasts and searching for similar genetic aberrations. Using this approach, we examined questionable monocytic populations in five patients with dominant leukemic populations of B-lymphoblastic origin. Cell populations were isolated either for fluorescence in situ hybridization or for clonality assessment by multiplex PCR or next-generation sequencing. In all cases, monocytic cells shared the same gene rearrangements with dominant leukemic populations, unequivocally confirming the same leukemic origin. This approach is able to identify implicit cases of MPAL and therefore leads to the necessary clinical management for patients.

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Section: Discussionmentioning

confidence: 99%

Recognizing Minor Leukemic Populations with Monocytic Features in Mixed-Phenotype Acute Leukemia by Flow Cell Sorting Followed by Cytogenetic and Molecular Studies: Report of Five Exemplary Cases

Semchenkova

Zerkalenkova

Demina

et al. 2023

IJMS

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“…Indeed, one can classify such cases as MPAL due to presence of cells with immunophenotypic features of both lymphoid and myeloid lineages. Nevertheless, small visible (on the MRD level) myeloid tumor population on the background of huge BM infiltration by B-lineage blasts is never considered as the obstacle for the blinatumomab application [ 34 , 35 , 36 ]. Such selection of pre-existing myeloid tumor population is also considered as the lineage switch [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

“…Such selection of pre-existing myeloid tumor population is also considered as the lineage switch [ 37 ]. Moreover, even for B/Myeloid MPAL, targeting of CD19 does not always lead to the selection of myeloid population [ 34 , 35 , 36 ], especially if myeloid-type therapy is used [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

“…Despite detailed description of immunophenotypic and molecular changes, it is still difficult to make a definitive conclusion of the prognostic value of lineage conversion. Of course, cases of resistance to blinatumomab via lineage switch have grim prognosis, although for patients for whom completion of CD19-targeting did not result in immediate switch, subsequent myeloid-style treatment could be the way for relapse prevention even for children with pre-existing myeloid tumor subpopulation [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

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Lineage Conversion in Pediatric B-Cell Precursor Acute Leukemia under Blinatumomab Therapy

Semchenkova

Mikhailova

Komkov

et al. 2022

IJMS

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We report incidence and deep molecular characteristics of lineage switch in 182 pediatric patients affected by B-cell precursor acute lymphoblastic leukemia (BCP-ALL), who were treated with blinatumomab. We documented six cases of lineage switch that occurred after or during blinatumomab exposure. Therefore, lineage conversion was found in 17.4% of all resistance cases (4/27) and 3.2% of relapses (2/63). Half of patients switched completely from BCP-ALL to CD19-negative acute myeloid leukemia, others retained CD19-positive B-blasts and acquired an additional CD19-negative blast population: myeloid or unclassifiable. Five patients had KMT2A gene rearrangements; one had TCF3::ZNF384 translocation. The presented cases showed consistency of gene rearrangements and fusion transcripts across initially diagnosed leukemia and lineage switch. In two of six patients, the clonal architecture assessed by IG/TR gene rearrangements was stable, while in others, loss of clones or gain of new clones was noted. KMT2A-r patients demonstrated very few additional mutations, while in the TCF3::ZNF384 case, lineage switch was accompanied by a large set of additional mutations. The immunophenotype of an existing leukemia sometimes changes via different mechanisms and with different additional molecular changes. Careful investigation of all BM compartments together with all molecular –minimal residual disease studies can lead to reliable identification of lineage switch.

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“…Retrospective data support preferred treatment of B/myeloid MPAL with a B-lymphoblastic leukemia chemotherapy regimen, rather than an AML regimen, [7][8][9][10] and recent reports including a series from our institution describe the use of blinatumomab in relapsed or refractory CD19 + MPAL with promising clinical response. [11][12][13][14][15] The phenomenon of lineage switch has been reported in the context of treatment of acute leukemias, 16 including recently in cases of MPAL and cases treated with blinatumomab, 15,17,18 although it is debatable whether the current case would constitute a lineage switch given the sequence of clinical events and lack of a true relapse. 19 CONCLUSION CD19 assessment on blast population(s) is critically important in the evaluation of acute leukemia.…”

Section: Discussionmentioning

confidence: 99%

When Flow Is Turbulent: CD19 Intensity Is a Pitfall in Acute Leukemia Classification

Kallen¹,

Emadi

Duong

et al. 2022

AJSP: Reviews and Reports

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Mixed phenotype acute leukemias (MPALs) are a rare category of acute leukemia with biologic and genetic heterogeneity and a prognosis generally inferior to those of single lineage leukemias. The diagnosis depends on immunophenotypic assessment with a comprehensive panel of monoclonal antibodies by multiparameter flow cytometry and lineage assignment by the World Health Organization criteria. CD19 assessment is required for establishing a B-cell component in MPALs, as is determination of its intensity of expression, and assessment of the additional B-cell markers CD79a, cytoplasmic CD22, and CD10. We report the case of an MPAL, initially classified as an acute myeloid leukemia with weak CD19 expression and later reclassified upon clear demonstration of a B-cell component; such cases highlight a pitfall in classification of acute leukemias, particularly given heterogeneous antigen expression between fluorochromes and subjectivity in judgment of intensity. Practical take-away points include the need for hypervigilance in marker performance patterns in flow cytometry, both between fluorochromes and over time, the benefits of repeat sampling and blast assessment between laboratories, and the potential quality improvements unlocked by expanded flow cytometry panels in diagnostic hematopathology.

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Blinatumomab for paediatric mixed phenotype acute leukaemia

Cited by 8 publications

References 14 publications

Recognizing Minor Leukemic Populations with Monocytic Features in Mixed-Phenotype Acute Leukemia by Flow Cell Sorting Followed by Cytogenetic and Molecular Studies: Report of Five Exemplary Cases

Recognizing Minor Leukemic Populations with Monocytic Features in Mixed-Phenotype Acute Leukemia by Flow Cell Sorting Followed by Cytogenetic and Molecular Studies: Report of Five Exemplary Cases

Lineage Conversion in Pediatric B-Cell Precursor Acute Leukemia under Blinatumomab Therapy

When Flow Is Turbulent: CD19 Intensity Is a Pitfall in Acute Leukemia Classification

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