Role of peripheral blood minimum residual disease at day 8 of induction therapy in high-risk pediatric patients with acute lymphocytic leukemia

Salina, Thais Ditolvo Da Costa; Ferreira, Yvelise Antunes; Alves, Eliana Brasil; Ferreira, Cristina Motta; Paula, Erich Vinícius De; Mira, Marcelo Távora

doi:10.1038/srep31179

Cited by 6 publications

(6 citation statements)

References 20 publications

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“…Thus, currently, BM is preferred over PB for MRD assessment. However, detection of PB MRD has been shown to predict the risk stratification category determined by BM MRD (Salina et al, 2016;Volejnikova et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Over the past decades, multiparametric flow cytometry (MFC) has become a powerful tool in MRD detection. Although bone marrow (BM) is generally the preferred specimen type for MFC MRD assessment because of its higher sensitivity, the utility of peripheral blood (PB) MRD assessment is also being explored due to the ease of sample collection that allows for frequent sampling (Salina et al, 2016; Volejnikova et al, 2011). It may also add clinical and diagnostic value in early detection of relapsed extramedullary disease (Keegan et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Circulating CD22+/CD19−/CD24− progenitors and CD22+/CD19+/CD24− mature B cells: Diagnostic pitfalls for minimal residual disease detection in B‐lymphoblastic leukemia

Zhou

Karrs

et al. 2022

Cytometry Part B Clinical

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BackgroundMultiparametric flow cytometry (MFC) has become a powerful tool in minimal residual disease (MRD) detection in B‐lymphoblastic leukemia/lymphoma (B‐ALL). In the setting of targeted immunotherapy, B‐ALL MRD detection often relies on alterative gating strategies, such as the utilization of CD22 and CD24. It is important to depict the full diversity of normal cell populations included in the alternative B‐cell gating methods to avoid false‐positive results. We describe two CD22‐positive non‐neoplastic cell populations in the peripheral blood (PB), including one progenitor population of uncertain lineage and one mature B‐cell population, which are immunophenotypic mimics of B‐ALL.MethodsUsing MFC, we investigated the prevalence and phenotypic profiles of both CD22‐positive populations in 278 blood samples from 52 patients with B‐ALL; these were obtained pre‐ and post‐treatment with CD19 and/or CD22 CAR‐T therapies. We further assessed whether these two populations in the blood were exclusively associated with B‐ALL or recent anticancer therapies, by performing the same analysis on patients diagnosed with other hematological malignancies but in long‐term MRD remission.ResultsThe progenitor population and mature B‐cell population were detected at low levels in PB of 61.5% and 44.2% of B‐ALL patients, respectively. Both cell types showed distinctive and highly consistent antigen expression patterns that are reliably distinguishable from B‐ALL. Furthermore, their presence is not restricted solely to B‐ALL or recent therapy.ConclusionsOur findings aid in building a complete immunophenotypic profile of normal cell populations in PB, thereby preventing misdiagnosis of B‐ALL MRD and inappropriate management.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Circulating CD22+/CD19−/CD24− progenitors and CD22+/CD19+/CD24− mature B cells: Diagnostic pitfalls for minimal residual disease detection in B‐lymphoblastic leukemia

Zhou

Karrs

et al. 2022

Cytometry Part B Clinical

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“…Peripheral blood MRD ,1% by day 8 has been used as one of the prognostic factors in pediatric ALL studies. 26,27 Our study used both bortezomib and rituximab during induction, using the drug synergy in the initial phase of therapy to achieve early and deep responses. This end point was used as an indicator of the in vivo activity of this combination in the first 7 days of induction, as no drug other than prednisolone was administered during this period.…”

Section: Discussionmentioning

confidence: 99%

Bortezomib and rituximab in de novo adolescent/adult CD20-positive, Ph-negative pre-B-cell acute lymphoblastic leukemia

Jain¹,

Sengar²,

Goli³

et al. 2021

Blood Advances

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The expression of CD20 in precursor B-cell ALL is associated with poor outcomes. The addition of rituximab to intensive chemotherapy in CD-20 positive ALL has led to improved outcomes in several studies. However, there is no clear evidence regarding the optimal number of doses and its benefit without an allogeneic stem cell transplant. Achieving measurable residual disease (MRD) negative status post-induction would reduce the requirement for a transplant. Novel approaches are needed to induce a higher proportion of MRD negative complete responses in patients with high-risk ALL. Given bortezomib's activity in relapsed ALL and its synergism with rituximab in B-cell lymphomas, the addition of bortezomib to rituximab and chemotherapy may provide an incremental benefit in CD20-positive-precursor B-cell ALL. We conducted a phase II study to test the activity of bortezomib and rituximab in combination with a pediatric-inspired regimen during induction therapy in newly diagnosed adolescents and adults (>14 years of age) with CD20-positive, Philadelphia (Ph)-negative precursor B- ALL, with bone marrow MRD negativity at the end of induction (EOI) as the primary endpoint. From December 2017 through August 2019, a total of 35 patients were enrolled. EOI-MRD-negative status was achieved in 70.99% of patients, as opposed to 51.7% in the historical cohort treated with chemotherapy alone. MRD negative rates improved to 87.5% post-consolidation. At a median follow-up of 21 months, the event-free survival and overall survival were 78.8% [95% CI - 66%- 94%] and 78.7% [95% CI - 65.8%- 94%], respectively. There was no significant increase in toxicity with bortezomib and rituximab compared to the historical cohort. The incidence of neuropathy was 26% (all less than grade 3). The combination of bortezomib, rituximab, and a pediatric-inspired ALL regimen is active and well-tolerated in de-novo CD20-positive Ph-negative precursor B-ALL. This trial is registered with the Clinical Trials Registry-India, CTRI/2017/04/008393.

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“…Another study demonstrated the role of peripheral blood MRD at day 8 of the induction therapy. 28 The MRD measurement by the MFC is a feasible approach in our routine practice to refine the risk stratification of our patients. Our data suggest that the MRD at D15 has an influence on risk classification, being particularly useful for stratification of patients with a more favorable prognosis, as demonstrated in the literature.…”

Section: Discussionmentioning

confidence: 99%

Influence of minimal residual disease by multiparametric flow cytometry at day 15 of induction in risk stratification of children with B-cell acute lymphoblastic leukemia treated at a referral hospital in southern Brazil

Silva

Spagnol

Farias

et al. 2020

Hematology, Transfusion and Cell Therapy

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Background The minimal residual disease (MRD) is the most important prognostic factor for acute lymphoblastic leukemia (ALL) in children. This study aimed to investigate the influence of detecting the MRD by the multiparametric flow cytometry (MFC) at day 15 (D15) of the induction on the analysis of the risk group classifications of the different childhood ALL treatment protocols used in a referral hospital in southern Brazil. Method We retrospectively reviewed the medical records of patients with B-cell ALL, aged 1 to 18 years, treated at a hospital from January 2013 to April 2017. Main results Seventy-five patients were analyzed. Regarding the MRD by the MFC at D15, the analyses showed statistical significance when the MRD was grouped into three categories, < 0.1%, 0.1–10%, and > 10%, with the following distribution: 30.7%, 52.0%, and 17.3%, respectively. There was a significant association between D15 MRD-MFC < 0.1% and the likelihood of dying or relapsing and between D15 MRD-MFC > 10% and the likelihood of dying or relapsing. The cumulative hazard ratio for the relapse of patients with D15 MRD-MFC < 0.1%, 0.1–10%, and > 10% was 19.2%, 59.8%, and 80.1%, respectively. Conclusion Our analysis suggests D15 MRD-MFC < 0.1% as a cut-off point for patients with more favorable outcomes and that the MRD at D15 in risk classifications is particularly useful for the stratification of patients with a more favorable prognosis.

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Role of peripheral blood minimum residual disease at day 8 of induction therapy in high-risk pediatric patients with acute lymphocytic leukemia

Cited by 6 publications

References 20 publications

Circulating CD22+/CD19−/CD24− progenitors and CD22+/CD19+/CD24− mature B cells: Diagnostic pitfalls for minimal residual disease detection in B‐lymphoblastic leukemia

Circulating CD22+/CD19−/CD24− progenitors and CD22+/CD19+/CD24− mature B cells: Diagnostic pitfalls for minimal residual disease detection in B‐lymphoblastic leukemia

Bortezomib and rituximab in de novo adolescent/adult CD20-positive, Ph-negative pre-B-cell acute lymphoblastic leukemia

Influence of minimal residual disease by multiparametric flow cytometry at day 15 of induction in risk stratification of children with B-cell acute lymphoblastic leukemia treated at a referral hospital in southern Brazil

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