Considerations for monitoring minimal residual disease using immunoglobulin clonality in patients with precursor B-cell lymphoblastic leukemia

Jo, Irene; Chung, Nack‐Gyun; Lee, Seok; Kwon, Ah Reum; Kim, Jiyeon; Choi, Hayoung; Jang, Woori; Kim, Seongkoo; Lee, Jae Woo; Yoon, Jae‐Ho; Cho, Bin; Han, Kyungja; Kim, Yonggoo; Kim, Myungshin

doi:10.1016/j.cca.2018.10.037

Cited by 8 publications

(6 citation statements)

References 23 publications

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“…A total of 89% of cases were successfully characterized using FR1 primer sets, similar to the results of previous studies in B-cell neoplasia ( 4 , 5 ). The frequency of common V-J rearrangements was also in line with our previous study ( 10 ). Unnormalized and normalized MRD values showed good correlation, which was predicted because both values were calculated based on clonal Ig read count.…”

Section: Discussionsupporting

confidence: 92%

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Clinical implication of minimal residual disease assessment by next-generation sequencing-based immunoglobulin clonality assay in pediatric B-acute lymphoblastic leukemia

Lee

Kim²,

Ahn³

et al. 2022

Front. Oncol.

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Measuring minimal residual disease (MRD) during treatment is valuable to identify acute lymphoblastic leukemia (ALL) patients who require intensified treatment to avert relapse. We performed the next-generation sequencing (NGS)-based immunoglobulin gene (Ig) clonality assay and evaluated its clinical implication in pediatric B-ALL patients to assess MRD. Fifty-five patients who were diagnosed and treated with de novo (n = 44) or relapsed/refractory B-ALL (n = 11) were enrolled. MRD assessment was performed using the LymphoTrack ® Dx IGH and IGK assay panels. The percentage of the clonal sequences per total read count was calculated as MRD (% of B cells). The data were normalized as the proportion of total nucleated cells (TNC) by LymphoQuant™ Internal control or the B-cell p r o p o r t i o n i n e a c h s a m p l e e s t i m a t e d b y fl o w c y t o m e t r y o r immunohistochemistry. Clonal Ig rearrangement was identified in all patients. The normalized MRD value was significantly lower than the unnormalized MRD value (p < 0.001). When categorizing patients, 27 of 50 patients (54%) achieved normalized MRD <0.01%, while 6 of them did not achieve MRD <0.01% when applying the unnormalized value. The normalized post-induction MRD value of 0.01% proved to be a significant threshold value for both 3-year event-free survival (100% for MRD <0.01% vs. 60.9% ± 10.2% for MRD ≥0.01%, p = 0.007) and 3-year overall survival (100% for MRD <0.01% vs. 78.3% ± 8.6% for MRD ≥0.01%, p = 0.011). However, unnormalized MRD was not a significant factor for outcome in this cohort. Our study demonstrated that MRD assessment by NGS-based Ig clonality assay could be applied in most pediatric B-ALL patients. Normalized post-induction MRD <0.01% was a significant prognostic indicator.

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Section: Discussionsupporting

confidence: 92%

“…All experiments were performed according to the manufacturer’s guidelines, which were previously reported ( 10 ). Briefly, amplification by PCR was performed using 240 ng of gDNA per sample, and master mixes contain primers designed with barcoded sequence adaptors.…”

Section: Methodsmentioning

confidence: 99%

Clinical implication of minimal residual disease assessment by next-generation sequencing-based immunoglobulin clonality assay in pediatric B-acute lymphoblastic leukemia

Lee

Kim²,

Ahn³

et al. 2022

Front. Oncol.

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“…Because MRD for Ph-negative ALL was only assessed beginning in 2019, just a part of patients had available MRD data, which made it difficult to analyze in detail. 32 …”

Section: Methodsmentioning

confidence: 99%

Superior survival outcome of blinatumomab compared with conventional chemotherapy for adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia: a propensity score–matched cohort analysis

Yoon

Kwag

Lee

et al. 2023

Therapeutic Advances in Hematology

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Background: Blinatumomab showed a higher complete remission (CR) rate and a safe bridging to allogeneic hematopoietic cell transplantation (allo-HCT) in adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (R/R BCP-ALL). Objectives: We tried to analyze the outcome of blinatumomab compared with the real-world historical data. We expected superior outcome of blinatumomab compared with historical conventional chemotherapy. Design: We conducted a retrospective study using real-world data in the Catholic Hematology Hospital. Methods: Total 197 consecutive cases of R/R BCP-ALL were treated with conventional chemotherapy ( n = 113) or blinatumomab, which was available since late 2016 ( n = 84). Patients who achieved CR underwent allo-HCT if donor was available. We conducted a propensity score–matched cohort analysis using 5 criteria of age, CR duration, cytogenetics, previous allo-HCT, and salvage lines between historical group and blinatumomab. Results: Each cohort consisted of 52 patients. In blinatumomab group, CR rate was higher (80.8% versus 53.8%, p = 0.006) and more patients proceeded to allo-HCT (80.8% versus 46.2%, p < 0.001). Among the CR patients with available minimal residual disease (MRD) results, 68.6% in blinatumomab group and 40.0% in conventional chemotherapy group were MRD-negative. Regimen-related mortality during the chemotherapy cycles was significantly higher in the conventional chemotherapy group (40.4% versus 1.9%, p < 0.001). Estimated 3-year overall survival (OS) was 33.2% (median, 26.3 months) after blinatumomab, and 15.4% (median, 8.2 months) after conventional chemotherapy ( p < 0.001). Estimated 3-year non-relapse mortality were 30.3% and 51.9% ( p = 0.004), respectively. In multivariate analysis, CR duration < 12 months showed more relapses and poor OS, and conventional chemotherapy showed higher non-relapse mortality and poor OS. Conclusions: Matched cohort analysis showed superior outcomes of blinatumomab compared with conventional chemotherapy. However, large numbers of relapses and non-relapse mortalities continue to occur even after blinatumomab followed by allo-HCT. Novel therapeutic strategies are still needed for R/R BCP-ALL.

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“…CR was defined as ≤5% bone marrow (BM) blasts, absolute neutrophil count >1×10 9 /L, and platelets >100×10 9 /L. Minimal residual disease (MRD) negativity was defined as no detectable blasts using a high‐throughput sequencing method for clonal rearrangements of immunoglobulin gene (assay sensitivity, <10 ‐5 ), as previously described . Clonal immunoglobulin rearrangement was assessed by the LymphoTrack® IGH FR1/2/3 assay panel (InVivoScribe Technologies) from a BM sample.…”

Section: Methodsmentioning

confidence: 99%

Feasible outcome of blinatumomab followed by allogeneic hematopoietic cell transplantation for adults with Philadelphia chromosome‐negative acute lymphoblastic leukemia in first salvage

et al. 2019

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In adult patients with relapsed or refractory (R/R) Philadelphia chromosome‐negative (Ph‐negative) B‐cell presursor acute lymphoblastic leukemia (BCP‐ALL), complete remission (CR) and overall survival (OS) rates are poor. We analyzed treatment outcomes and prognostic factors for 32 adult patients with R/R Ph‐negative BCP‐ALL who received blinatumomab at first salvage. Patients who achieved CR proceeded to allogeneic hematopoietic cell transplantation (allo‐HCT). At the time of blinatumomab treatment, 11 patients (34.3%) were primary refractory, 10 (31.4%) had relapsed with first CR duration (CRD1) ≥12 months, and 11 (34.3%) had relapsed with CRD1 <12 months. After the first blinatumomab cycle, 22 (68.8%) achieved CR. At the end of the second cycle, 20 of the 22 patients remained in persistent CR, and 1 patient achieved new CR. The overall minimal residual disease negativity rate was 75% among evaluable patients with persistent CR. Patients with CRD1 <12 months were associated with poorer response to blinatumomab. Twenty (62.5%) of 32 patients underwent allo‐HCT in blinatumomab‐induced CR. After a median follow‐up of 15.2 months, the 1‐year OS rates for all patients and patients receiving allo‐HCT in CR were 55.5% (median OS, 18.2 months) and 70.7%, respectively. Patients with CRD1 <12 months, extramedullary disease (EMD), and high peripheral blood blasts were associated with poorer OS. Blinatumomab is effective for achieving good quality CR and bridging to allo‐HCT for adult patients with R/R Ph‐negative BCP‐ALL in first salvage. The role of blinatumomab in patients with CRD1 <12 months, EMD, or high tumor burden should be evaluated in future trials.

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Considerations for monitoring minimal residual disease using immunoglobulin clonality in patients with precursor B-cell lymphoblastic leukemia

Cited by 8 publications

References 23 publications

Clinical implication of minimal residual disease assessment by next-generation sequencing-based immunoglobulin clonality assay in pediatric B-acute lymphoblastic leukemia

Clinical implication of minimal residual disease assessment by next-generation sequencing-based immunoglobulin clonality assay in pediatric B-acute lymphoblastic leukemia

Superior survival outcome of blinatumomab compared with conventional chemotherapy for adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia: a propensity score–matched cohort analysis

Feasible outcome of blinatumomab followed by allogeneic hematopoietic cell transplantation for adults with Philadelphia chromosome‐negative acute lymphoblastic leukemia in first salvage

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