One-point flow cytometric MRD measurement to identify children with excellent outcome after intermediate-risk BCP-ALL: results of the ALL-MB 2008 study

Popov, Alexander; Henze, Guenter; Roumiantseva, Julia; Budanov, Oleg; Belevtsev, Mikhail; Verzhbitskaya, Tatiana; Boyakova, Elena; Movchan, Liudmila; Tsaur, Grigory; Fadeeva, Maria; Lagoyko, Svetlana; Zharikova, Liudmila; Miakova, Natalia; Litvinov, Dmitry; Khlebnikova, Olga; Streneva, Olga; Stolyarova, Elena; Ponomareva, Natalia; Novichkova, Galina; Fechina, Larisa; Алейникова, О. В.; Karachunskiy, Alexander

doi:10.1007/s00432-022-04378-3

Cited by 12 publications

(17 citation statements)

References 46 publications

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“…In our opinion, children who respond slowly are not candidates for merely intensifying conventional chemotherapy, but for other forms of therapy, such as targeted therapies or immunotherapies. Different quantitative MFC–MRD thresholds proved to be the best discriminators: for the SR group (0.1% at EOI 39 ) and for the ImR group (0.01% at EOI 22 ). Even in the HR group, the MFC–MRD < 0.01% at EOI identified patients with an extremely low risk of recurrence 23 .…”

Section: Discussionmentioning

confidence: 97%

“…Quantitative (relative to quantitative thresholds) and kinetic (logarithmic reduction) assessments of MFC–MRD at both time points effectively separated patients into three groups with different risk of recurrence. We recently published the results obtained with just a single MFC–MRD measurement 22,23,39 . Patients were evaluated for whom the risk of recurrence was initially defined on the basis of clinical characteristics and who received low‐intensity (for the SR group) or medium‐intensive (for the ImR group) therapy from the outset 21,22,39 .…”

Section: Discussionmentioning

confidence: 99%

“…Although in this study the cohort was limited to patients in whom both time points were available, the prognostic significance of the proposed thresholds remained the same (Figure S4). Despite the early randomizations in the induction therapy of the ALL‐MB 2008 study, a single MFC–MRD measurement at the EOI proved effective in all randomization arms 21,22 . Early administration of PEG‐asparaginase on day 3 in the SR group in addition to or instead of daunorubicin reduced the number of MFC–MRD slow responders.…”

Section: Discussionmentioning

confidence: 99%

“…The treatment design is briefly shown in Figure S1. In detail, the treatment plan for all three risk groups has been presented previously 21–23 . Briefly, all patients in the SR and ImR groups received induction therapy, followed by three cycles of consolidation and maintenance therapy.…”

Section: Methodsmentioning

confidence: 99%

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A simple procedure to identify children with B‐lineage acute lymphoblastic leukemia who can be successfully treated with low or moderate intensity: Sequential versus single‐point minimal residual disease measurement

Popov

Henze

Roumiantseva

et al. 2023

Pediatric Blood & Cancer

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Sequential monitoring of minimal residual disease (MRD) by molecular techniques or multicolor flow cytometry (MFC) has emerged over the past two decades as the primary tool to optimize treatment in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The aim of our study was to compare the prognostic power of repeated MFC-MRD measurement with single-point MRD assessment in children with BCP-ALL treated with the reduced-intensity protocol ALL-MB 2008. Data from consecutive MFC-MRD at day 15 and day 36 (end of induction, EOI) were available for 507 children with Philadelphia-negative BCP-ALL. They were stratified into standard risk (SR, n = 265), intermediate risk (ImR, n = 211), and high risk (HR, n = 31) according to the initial clinical characteristics defined in the ALL-MB 2008 protocol. Quantitative (relative to quantitative thresholds) and kinetic (logarithmic reduction) assessments of MFC-MRD at both time points effectively separated patients into three groups with different risk of recurrence. On the other hand, starting with low (for the SR group) and moderate (for the ImR group) induction therapy, a single MFC-MRD measurement at EOI proved sufficient to unequivocally identify patients in whom this therapy is highly effective and distinguish them from those who cannot be successfully treated with such therapy. Therefore, initiating treatment with low or moderate treatment from the start, together with careful consideration of initial clinical risk factors and

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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A simple procedure to identify children with B‐lineage acute lymphoblastic leukemia who can be successfully treated with low or moderate intensity: Sequential versus single‐point minimal residual disease measurement

Popov

Henze

Roumiantseva

et al. 2023

Pediatric Blood & Cancer

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“…However, patients with KMT2A-g leukemia were also included because it was believed that they, too, might benefit from moderate-intensity therapy, as has been shown for older children. [19][20][21] In the present study, we summarize the diagnostic and outcome characteristics of infants with KMT2A-g BCP-ALL consistently treated with the moderate-intensity MLL-Baby protocol.…”

Section: Introductionmentioning

confidence: 99%

Genetic characteristics and treatment outcome in infants with KMT2A germline B‐cell precursor acute lymphoblastic leukemia: Results of MLL‐Baby protocol

Popov¹,

Tsaur

Permikin

et al. 2023

Pediatric Blood & Cancer

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The aim of this study was to present the diagnostic and outcome characteristics of infants with germline status of KMT2A gene (KMT2A‐g) B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL) treated consistently according to the MLL‐Baby protocol, a moderate‐intensity protocol. Of the 139 patients enrolled in the MLL‐Baby study, 100 (71.9%) carried different types of rearranged KMT2A (KMT2A‐r), while the remaining 39 infants (28.1%) had KMT2A‐g. KMT2A‐g patients were generally older (77% older than 6 months), less likely to have a very high white blood cell count (greater than 100 × 109/L), less likely to be central nervous system (CNS)‐positive, and more likely to be CD10‐positive. The 6‐year event‐free survival and overall survival rates for all 39 patients were 0.74 (standard error [SE] 0.07) and 0.80 (SE 0.07), respectively. Relapse was the most common adverse event (n = 5), with a cumulative incidence of relapse (CIR) of 0.13 (SE 0.06), while the incidence of a second malignancy (n = 1) and death in remission (n = 3) was 0.03 (SE 0.04) and 0.08 (SE 0.04), respectively. None of the initial parameters, including genetics and the presence of recently described fusions of NUTM1 and PAX5 genes, was able to distinguish patients with different outcomes. Only rapidity of response, measured as minimal residual disease (MRD) by flow cytometry, showed a statistically significant impact. Moderate‐intensity therapy, as used in the MLL‐Baby protocol in infants with KMT2A‐g BCP‐ALL, yields results comparable to other infant studies. Patients with a slow multicolor flow cytometry (MFC)‐MRD response should be subjected to advanced therapies, such as targeted or immunotherapies.

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Flow cytometric minimal residual disease measurement accounting for cytogenetics in children with non‐high‐risk acute lymphoblastic leukemia treated according to the ALL‐MB 2008 protocol

Popov,

Henze,

Tsaur

et al. 2024

Cancer Medicine

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BackgroundQuantitative measurement of minimal residual disease (MRD) is the “gold standard” for estimating the response to therapy in childhood B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL). Nevertheless, the speed of the MRD response differs for different cytogenetic subgroups. Here we present results of MRD measurement in children with BCP‐ALL, in terms of genetic subgroups with relation to clinically defined risk groups.MethodsA total of 485 children with non‐high‐risk BCP‐ALL with available cytogenetic data and MRD studied at the end‐of‐induction (EOI) by multicolor flow cytometry (MFC) were included. All patients were treated with standard‐risk (SR) of intermediate‐risk (ImR) regimens of “ALL‐MB 2008” reduced‐intensity protocol.Results and DiscussionAmong all study group patients, 203 were found to have low‐risk cytogenetics (ETV6::RUNX1 or high hyperdiploidy), while remaining 282 children were classified in intermediate cytogenetic risk group. For the patients with favorable and intermediate risk cytogenetics, the most significant thresholds for MFC‐MRD values were different: 0.03% and 0.04% respectively. Nevertheless, the most meaningful thresholds were different for clinically defined SR and ImR groups. For the SR group, irrespective to presence/absence of favorable genetic lesions, MFC‐MRD threshold of 0.1% was the most clinically valuable, although for ImR group the most informative thresholds were different in patients from low‐(0.03%) and intermediate (0.01%) cytogenetic risk groups.ConclusionOur data show that combining clinical risk factors with MFC‐MRD measurement is the most useful tool for risk group stratification of children with BCP‐ALL in the reduced‐intensity protocols. However, this algorithm can be supplemented with cytogenetic data for part of the ImR group.

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One-point flow cytometric MRD measurement to identify children with excellent outcome after intermediate-risk BCP-ALL: results of the ALL-MB 2008 study

Cited by 12 publications

References 46 publications

A simple procedure to identify children with B‐lineage acute lymphoblastic leukemia who can be successfully treated with low or moderate intensity: Sequential versus single‐point minimal residual disease measurement

A simple procedure to identify children with B‐lineage acute lymphoblastic leukemia who can be successfully treated with low or moderate intensity: Sequential versus single‐point minimal residual disease measurement

Genetic characteristics and treatment outcome in infants with KMT2A germline B‐cell precursor acute lymphoblastic leukemia: Results of MLL‐Baby protocol

Flow cytometric minimal residual disease measurement accounting for cytogenetics in children with non‐high‐risk acute lymphoblastic leukemia treated according to the ALL‐MB 2008 protocol

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