Prognostic Role of Minimal Residual Disease in Mature B-Cell Acute Lymphoblastic Leukemia of Childhood

Mussolin, Lara; Pillon, Marta; Conter, Valentino; Piglione, Matilde; Nigro, Luca Lo; Pierani, Paolo; Micalizzi, Concetta; Buffardi, Salvatore; Basso, Giuseppe; Zanesco, Luigi; Rosolen, Angelo

doi:10.1200/jco.2007.11.3159

Cited by 37 publications

(31 citation statements)

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“…32 Future progress might be achieved by such diagnostic measures as the detection of residual disease in Burkitt lymphoma by positron emission tomography, which could not be implemented in this study starting in 2002 for all of the participating centers. The evaluation of minimal residual disease in Burkitt leukemia in patients with initial bone marrow involvement, as pioneered in children, 33 may identify early vs late responders. New therapeutic options could include the intensification of rituximab, newer anti-CD20 antibodies, or the application of other monoclonal antibodies targeting CD19, an antigen highly expressed in Burkitt lymphoma.…”

Section: Discussionmentioning

confidence: 99%

Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial

Hoelzer

Walewski

Döhner

et al. 2014

Blood

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Key Points• Largest prospective trial for adult Burkitt lymphoma/ leukemia patients. • Substantial cure rates and high treatment-realization rates in all age groups.This largest prospective multicenter trial for adult patients with Burkitt lymphoma/ leukemia aimed to prove the efficacy and feasibility of short-intensive chemotherapy combined with the anti-CD20 antibody rituximab. From 2002 to 2011, 363 patients 16 to 85 years old were recruited in 98 centers. Treatment consisted of 6 5-day chemotherapy cycles with high-dose methotrexate, high-dose cytosine arabinoside, cyclophosphamide, etoposide, ifosphamide, corticosteroids, and triple intrathecal therapy. Patients >55 years old received a reduced regimen. Rituximab was given before each cycle and twice as maintenance, for a total of 8 doses. The rate of complete remission was 88% (319/363); overall survival (OS) at 5 years, 80%; and progression-free survival, 71%; with significant difference between adolescents, adults, and elderly patients (OS rate of 90%, 84%, and 62%, respectively). Full treatment could be applied in 86% of the patients. The most important prognostic factors were International Prognostic Index (IPI) score (0-2 vs 3-5; P 5 .0005), age-adjusted IPI score (0-1 vs 2-3; P 5 .0001), and gender (male vs female; P 5 .004). The high cure rate in this prospective trial with a substantial number of participating hospitals demonstrates the efficacy and feasibility of chemoimmunotherapy, even in elderly patients. This trial was registered at www.clinicaltrials.gov as #NCT00199082. (Blood. 2014;124(26):3870-3879)

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Section: Discussionmentioning

confidence: 99%

Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial

Hoelzer

Walewski

Döhner

et al. 2014

Blood

249

201

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“…[1][2][3][4] MRD evaluation is included in most treatment regimens for newly diagnosed ALL in which it yields an important risk group stratification parameter. [5][6][7][8][9] Multiple studies evaluating MRD continue to demonstrate the prognostic value in newly diagnosed pediatric ALL patients, [10][11][12] and there is increasing evidence that MRD is also of prognostic importance in relapsed ALL. [13][14][15][16][17][18] Initial reports on a relatively small numbers of relapsed patients [13][14][15] have been confirmed in a representative number of relapsed intermediate-risk ALL patients in the ALL-REZ P95/96 trial.…”

Section: Introductionmentioning

confidence: 99%

Minimal residual disease analysis by eight-color flow cytometry in relapsed childhood acute lymphoblastic leukemia

et al. 2015

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ABSTRACTleukemic cells from normal B-lineage subpopulations in bone marrow during treatment. While this can be more easily accomplished during times of continued chemotherapy and cytopenia, it is decisively more challenging in periods of hematopoietic regeneration. The performance of the FCM-MRD method depends, therefore, on the time points of application within a given treatment protocol, and the results of the FCM-MRD evaluation obtained within one study cannot be extrapolated directly to another trial if different treatment protocols are used.In the front-line ALL protocols, extensive analyses of FCM-MRD and comparisons with PCR-MRD have been performed. 12,14,25,26,[34][35][36][37][38] However, given considerable differences between front-line and relapsed ALL treatment regimens, the FCM-MRD in relapsed ALL and its relationship to PCR-MRD requires an independent comprehensive investigation. Moreover, FCM-MRD, being largely the methodology of detection of rare cells, is a technically challenging and rapidly developing field of flow cytometry. 25,27 While the majority of FCM-MRD studies have been performed using three-and four-color techniques, the recent reports on MRD data within front-line AIEOP-BFM ALL 2000 and DCOG-ALL10 protocols demonstrated improvement of the MRD analysis using six-and sevencolor FCM. 35,39 In the present study we addressed FCM-MRD in the ALL-REZ BFM 2002 relapse trial for childhood ALL using eight-color FCM and compared it with PCR-MRD in a prospective blinded study. We analyzed MRD levels by both methods in a total of 263 follow-up bone marrow samples from 122 patients with B-cell precursor (BCP)-ALL. During the study, we tested various antibody combinations, defined the protocol-adjusted antibody panel, and evaluated qualitative and quantitative concordance between FCM-MRD and PCR-MRD. Methods Patients and treatmentPatients in the presented study cohort had a first BCP-ALL relapse and were enrolled in the international trial ALL-REZ BFM 2002. Patients' samples were obtained in accordance with the informed consent guidelines of the local medical ethics committees. The research protocol for the assessment of MRD and the treatment protocol were approved by the local medical ethics committees. The clinical characteristics of the study cohort are presented in Online Supplementary Table S1. Standard-, intermediate-and high-risk groups and their treatment strategies are defined in the Online Supplementary Material and Methods and Online Supplementary Table S2. Minimal residual disease assessment by polymerase chain reaction and flow cytometryIn order to analyze and optimize the FCM-MRD methodology, 263 follow-up bone marrow samples from 122 patients were assessed by FCM in parallel to PCR analysis at multiple time points during the treatment. Samples were collected and initially prepared uniformly as described in the Online Supplementary Material and Methods. PCR-MRD measurements were performed as described previously. 15,19,40 FCM-MRD was assessed on the basis of standard protocols describ...

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“…Lymphoblasts are characterized by surface expression of B-cell markers, particularly CD19, CD20 and immunoglobulin (Ig) M (Mussolin et al, 2011). The t(8;14)(q24;q32) chromosomal translocation is observed in about 75% of BL/B-AL cases, and can thus be used as a marker to study minimal BM infiltration (Mussolin et al, 2003(Mussolin et al, , 2007Lovisa et al, 2009). The outcome of BL and B-AL has greatly improved with intensive, short duration, pulse polychemotherapy courses, adapted to stage (Reiter et al, 1999;Patte et al, 2001Patte et al, , 2007Patte, 2003;Woessmann et al, 2005;Cairo et al, 2007;Gerrard et al, 2008;Minard-Colin et al, 2015;Sandlund, 2015).…”

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Detection of prognostic factors in children and adolescents with Burkitt and Diffuse Large B‐Cell Lymphoma treated with theAIEOP LNH‐97 protocol

et al. 2016

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SummaryBurkitt lymphoma (BL) and Diffuse Large B-Cell Lymphoma (DLBCL) account for most cases of non-Hodgkin lymphoma (NHL) in childhood. We report the clinical characteristics, outcome and prognostic factors in children with BL or DLBCL treated according to the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) LNH-97 protocol. Patients aged up to 18 years that were newly diagnosed with BL/DLBCL were included in the study. Therapy consisted of pre-phase followed by 2-6 high-dose chemotherapy courses tailored according to lactate dehydrogenase (LDH) value and disease stage. A total of 442 patients (379 BL, 63 DLBCL) were enrolled between 1997 and 2014, of whom 18 failed to achieve remission, 6 experienced treatment-related death, 2 developed second malignancy and 20 relapsed. At a median follow-up time of 5 years, overall survival was 93% (AE1%) and event-free survival was 90% (AE1%). LDH value above the median value had an independently negative prognostic value (P < 0Á0001). However, in the subgroup of 128 patients in which minimal disseminated disease (MDD) was analysed, MDD-positivity became the only unfavourable prognostic factor for progression-free survival. Tailored chemotherapy could be extremely effective with limited toxicity. Identification of MDD as a hallmark of a higher risk of treatment failure may provide a target population for treatment intensification by anti-CD20.

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Prognostic Role of Minimal Residual Disease in Mature B-Cell Acute Lymphoblastic Leukemia of Childhood

Abstract: Our study demonstrated that MRD carries a negative prognostic impact in B-ALL patients and suggests that a better risk-adapted therapy, possibly including the use of anti-CD20 monoclonal antibody, should be considered in selected patients.

Cited by 37 publications

References 21 publications

Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial

Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial

Minimal residual disease analysis by eight-color flow cytometry in relapsed childhood acute lymphoblastic leukemia

Detection of prognostic factors in children and adolescents with Burkitt and Diffuse Large B‐Cell Lymphoma treated with theAIEOP LNH‐97 protocol

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