Minimal residual disease (MRD) status prior to allogeneic stem cell transplantation is a powerful predictor for post-transplant outcome in children with ALL

Bader, Peter; Hancock, Jeremy; Kreyenberg, Hermann; Goulden, Nick; Niethammer, D.; Oakhill, A.; Steward, Colin G.; Handgretinger, Rupert; Beck, James F.; Klingebiel, Thomas

doi:10.1038/sj.leu.2402552

Cited by 172 publications

(144 citation statements)

References 15 publications

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“…All of the patients selected for this study were MRD negative or low positive before the transplant, which has been shown to denote a low risk of post transplant relapse in several studies. [5][6][7][8]17 Moreover, 11 of 16 positive samples coming from patients with fusion genes were negative in simultaneous fusion transcript detection. We employed two non-self-specific RQ-PCR assays and observed a substantial percentage of false-positive amplifications in our cohort of samples.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4] Several groups, including ours, reported the unfavorable prognostic significance of high MRD levels before transplant in children with high-risk ALL. [5][6][7][8] Studies exploring the significance of post transplant MRD were based on the detection of mixed chimerism, 9,10 flow cytometry (FC), 11 the fusion gene PCR in case of Ph þ ALL, 12 PCR using clone-specific Ig or TCR V-(D)-J sequences [13][14][15][16] and, most recently, real-time quantitative PCR (RQ-PCR) detection of clonal Ig/TCR rearrangements. 17 Consistently, all studies showed that detectable MRD at any time after SCT represents a substantial risk of post transplant relapse, both in children and in adults.…”

Section: Introductionmentioning

confidence: 99%

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B-cell reconstitution after allogeneic SCT impairs minimal residual disease monitoring in children with ALL

Froňková

Mužíková

Mejstříková

et al. 2008

Bone Marrow Transplant

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Minimal residual disease (MRD) detection using quantification of clone-specific Ig or TCR rearrangements before and after transplantation in children with high-risk ALL is an important predictor of outcome. The method and guidelines for its interpretation are very precise to avoid both false-negative and -positive results. In a group of 21 patients following transplantation, we observed detectable MRD positivities in Ig/TCR-based real-time quantitative PCR (RQ-PCR) leading to no further progression of the disease (11 of 100 (11%) total samples). We hypothesized that these positivities were mostly the result of nonspecific amplification despite the application of strict internationally agreed-upon measures. We applied two non-self-specific Ig heavy chain assays and received a similar number of positivities (20 and 15%). Nonspecific products amplified in these RQ-PCR systems differed from specific products in length and sequence. Statistical analysis proved that there was an excellent correlation of this phenomenon with B-cell regeneration in BM as measured by flow cytometry and Ig light chain-j excision circle quantification. We conclude that although Ig/TCR quantification is a reliable method for post transplant MRD detection, isolated positivities in Ig-based RQ-PCR systems at the time of intense B-cell regeneration must be viewed with caution to avoid the wrong indication of treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

B-cell reconstitution after allogeneic SCT impairs minimal residual disease monitoring in children with ALL

Froňková

Mužíková

Mejstříková

et al. 2008

Bone Marrow Transplant

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“…[1][2][3][4][5][6][7][8][9][10][11] Many contemporary treatment protocols are testing the clinical utility of monitoring MRD and others have already incorporated MRD studies to aid the selection of postremission induction therapies. 12,13 MRD assays have also shown utility for patients undergoing hematopoietic stem cell transplantation, [14][15][16][17] and provide a novel parameter to assess the efficacy of emerging novel antileukemic agents. 18 Among the available methods for MRD detection in ALL, flow cytometric analysis of abnormal immunophenotypes and polymerase chain reaction (PCR) amplification of antigen-receptor genes are the most widely used.…”

Section: Introductionmentioning

confidence: 99%

Comparative analysis of flow cytometry and polymerase chain reaction for the detection of minimal residual disease in childhood acute lymphoblastic leukemia

et al. 2004

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Minimal residual disease (MRD) is an independent prognostic factor in childhood acute lymphoblastic leukemia (ALL). The most widely applied MRD assays in ALL are flow cytometric identification of leukemia immunophenotypes and polymerase chain reaction (PCR) amplification of antigen-receptor genes. We measured MRD by both assays in 227 patients with childhood B-lineage ALL. Of 1375 samples (736 bone marrow and 639 peripheral blood) examined, MRD was o0.01% in 1200, and X0.01% in 129 by both assays; MRD levels measured by the two methods correlated well. Of the remaining 46 samples, 28 had MRD X0.01% by flow cytometry but o0.01% by PCR. However, PCR (which had a consistent sensitivity of 0.001%) detected leukemic gene rearrangements in 26 of these 28 samples. Conversely, in 18 samples, MRD was X0.01% by PCR but o0.01% by flow cytometry. In nine of these samples, flow cytometry had a sensitivity of 0.001%, and detected aberrant immunophenotypes in eight samples. Therefore, the two most widely used methods for MRD detection in ALL yield concordant results in the vast majority of cases, although the estimated levels of MRD may vary in some. The use of the two methods in tandem ensures MRD monitoring in all patients.

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“…However, outcome of patients with ALL is also poor when allogeneic SCT is performed in a non-remission status or in a status with high levels of minimal residual disease. 8 Misawa et al describe a patient with refractory RMS for which an allogeneic SCT was performed after a myeloablative regimen. The patient reached a PR.…”

mentioning

confidence: 99%

Metastatic rhabdomyosarcoma cured after chemotherapy and allogeneic SCT

Donker

Hoogerbrugge

Mavinkurve‐Groothuis

et al. 2008

Bone Marrow Transplant

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Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents. Successful treatment of children with RMS requires multimodal therapy. However, despite advances in combined chemotherapy, radiation therapy and surgery, children with stage IV RMS have a uniformly poor outcome. 1 In case of nonembryonal histology in combination with metastatic involvement in three or more organ systems, the prognosis is dismal (3-year survival 5%). 2 Other unfavourable risk factors include the age at diagnosis of more than 10 years, bone or BM metastases and RMS of the extremities. Patients with more than two of these risk factors have a 5-year survival of 9%. 3 Most patients achieve a remission after conventional therapy, but relapse is frequent, indicating persistence of minimal residual disease. 4 Although RMS is a chemosensitive disease, the benefits of high-dose chemotherapy followed by autologous haematopoietic stem cell rescue for children with stage IV or relapsed RMS are not clear because randomized trials comparing this treatment with standard chemotherapy are lacking. In a meta-analysis of 389 patients identified from 22 publications, there was no significant survival advantage of high-dose chemotherapy followed by autologous haematopoietic stem cell rescue for patients with relapsed or metastatic RMS as compared with standard chemotherapy. 5 GVL effect is well documented after allogeneic SCT for haematological malignancies. Recently, the evidence of graft-versus-tumour effect has also been described in patients with a variety of solid tumours. 6 Only sporadic cases have been reported of allogeneic SCT in high-risk RMS patients. Wiegel et al. 7 report on two children with relapsed stage IV RMS who received allogeneic SCT after a myeloablative regimen in a non-remission status. Both patients died of disease progression. However, outcome of patients with ALL is also poor when allogeneic SCT is performed in a non-remission status or in a status with high levels of minimal residual disease. 8 Misawa et al. describe a patient with refractory RMS for which an allogeneic SCT was performed after a myeloablative regimen. The patient reached a PR. As tumour regression occurred after the reduction of immunosuppressants on day þ 30, the authors suggest the existence of a graft-versus-tumour effect. However, 80 days after transplantation, disease progression occurred. On day 165, the patient died of progressive disease in the final stage accompanied by fungal pneumonia. 9 In this letter we report, a patient with stage IV RMS who achieved CR and is in ongoing remission for 4 years after combined therapy followed by allogeneic SCT.An 8-year-old Caucasian girl was diagnosed with an alveolar RMS of the right gastrocnemical muscle (Figure 1). PAX-3 and PAX-7 fusion genes, which are specific for alveolar RMS were detected by reverse-transcription PCR. Staging revealed stage IV with extensive local, abdominal and thoracic lymph node metastases in combination with skeletal metastases (Figure 2). Bilateral crystal b...

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Minimal residual disease (MRD) status prior to allogeneic stem cell transplantation is a powerful predictor for post-transplant outcome in children with ALL

Cited by 172 publications

References 15 publications

B-cell reconstitution after allogeneic SCT impairs minimal residual disease monitoring in children with ALL

B-cell reconstitution after allogeneic SCT impairs minimal residual disease monitoring in children with ALL

Comparative analysis of flow cytometry and polymerase chain reaction for the detection of minimal residual disease in childhood acute lymphoblastic leukemia

Metastatic rhabdomyosarcoma cured after chemotherapy and allogeneic SCT

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