Prognostic significance of circulating tumor cells in bone marrow or peripheral blood as detected by qualitative and quantitative PCR in pediatric NPM-ALK–positive anaplastic large-cell lymphoma

Damm‐Welk, Christine; Busch, Kerstin; Burkhardt, Birgit; Schieferstein, Jutta; Viehmann, Susanne; Oschlies, Ilske; Klapper, Wolfram; Zimmermann, Martin; Harbott, Jochen; Reiter, Alfred; Woessmann, Willi

doi:10.1182/blood-2007-02-066852

Cited by 118 publications

(126 citation statements)

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“…8,9 Minimal disseminated disease, as detected by polymerase chain reaction analysis for NPM-ALK in blood or bone marrow, serum antibody titers against ALK and the morphological subtype are strong predictors of clinical outcome. [10][11][12][13][14] The main morphological subtypes are: (i) the common type, which is composed of large tumor cells with pleomorphic nuclei; (ii) the small cell variant with ALK proteinexpressing tumor cells that do not differ in size from reactive T-cells; (iii) the lymphohistiocytic variant with abundant histiocytes admixed with the lymphoma cells which are as small as in the small cell variant; and (iv) other rare subtypes. Especially in the non-common type of ALCL (small cell and lymphohistiocytic variant) the tumor cells are admixed with a large number of reactive, non-neoplastic bystander cells, predominantly T cells, which can account for more than 90% of the neoplastic infiltrate.…”

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confidence: 99%

Expression of CD8 is associated with non-common type morphology and outcome in pediatric anaplastic lymphoma kinase-positive anaplastic large cell lymphoma

et al. 2013

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Anaplastic lymphoma kinase-positive anaplastic large T-cell lymphoma is characterized by morphological variability. Morphological variants (non-common subtype) are associated with a poor outcome. They display abundant reactive bystander cells admixed with the lymphoma cells. So far, the difficulty in distinguishing lymphoma cells from bystander cells by visual inspection has prevented detailed and reliable immunophenotypic analysis using conventional immunohistochemistry. To overcome these limitations, we analyzed 124 cases of pediatric anaplastic lymphoma kinase-positive anaplastic large cell lymphoma treated within clinical trials using immunofluorescence multi-staining and digital image analysis combining antibodies against anaplastic lymphoma kinase to specifically identify lymphoma cells with antibodies against CD30, CD3, CD5, CD8, Ki67 and phosphorylated STAT3. Non-common type anaplastic lymphoma kinase-positive anaplastic large cell lymphomas express CD8 more frequently than common type anaplastic lymphoma kinase-positive anaplastic large cell lymphomas (35.4% and 5.6%, respectively; P=0.0002). CD8 expression was associated with a poorer outcome. Importantly, in a multivariate analysis including clinical risk factors, histological subtype and CD8 expression, CD8-positivity proved to be an independent prognostic predictor of worse outcome (hazard ratio for survival 3.38, P=0.042).

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Section: Introductionmentioning

confidence: 99%

Expression of CD8 is associated with non-common type morphology and outcome in pediatric anaplastic lymphoma kinase-positive anaplastic large cell lymphoma

et al. 2013

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“…3 In addition, Damm-Welk et al 4 showed that patients with more than 10 normalized copy numbers (NCNs) NPM-ALK in BM had a cumulative incidence of relapse (CI-R) of 71±14% compared with CI-R of 18±6% for patients with 10 or fewer NCNs (Po0.001) and that quantitative PCR for NPM-ALK in BM and peripheral blood (PB) is highly concordant.…”

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confidence: 99%

“…The NCNs were expressed as copy number of the NPM-ALK per 10 4 copies ABL. 4 A total of 28 children affected by de novo ALCL (median age 9.9 years; median follow-up 3 years) were enrolled in this study between September 2001 and June 2007. The study was approved by the local ethics committees and informed consent was obtained for all of the patients.…”

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confidence: 99%

“…Although in our relatively small cohort of patients it did not reach statistical significance, the relationship between MRD and event is in line with the results of Damm-Welk et al who reported that patients with more than 10 NCNs NPM-ALK in BM and/or PB have a significantly worse prognosis. 4 Subsequently, we examined whether the level of minimal disseminated disease (MDD) in PB and the level of antibody titer could identify, with higher sensitivity, a group of patients at greater risk of relapse. Interestingly, we found that MDD positivity with more than 10 NCNs NPM-ALK in PB and antibody titer p1/2250 was significantly associated in univariate analysis with the risk of relapse, as 62.5% of patients with these two characteristics relapsed compared with only 15% of the remaining patients (Fisher's exact test, P ¼ 0.02) (Figure 2).…”

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confidence: 99%

“…By binding to the DNA minor groove in a sequencespecific manner, calicheamicin causes DNA double-strand breaks and cell killing. 4 Thus, the binding of GO to cell-surface CD33 and subsequent internalization is critical for its antileukemic effect.…”

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confidence: 99%

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Kinetics of humoral response to ALK and its relationship with minimal residual disease in pediatric ALCL

et al. 2008

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naplastic large-cell lymphoma (ALCL) makes up approximately 15% of pediatric non-Hodgkin's lymphoma (NHL) and the vast majority of them is associated with the t(2;5) translocation that results in the expression of a hybrid oncogenic tyrosine kinase. It consists of the amino terminus of the nuclear protein nucleophosmin (NPM) fused to the intracytoplasmic region of the anaplastic lymphoma kinase (ALK) that impacts many cellular responses including proliferation, growth and apoptosis.1 In addition to its direct effects of ALK on signal transduction pathways, ALK overexpression may also induce a host immune reaction, giving rise to autologous anti-ALK antibodies in patients with ALK-positive ALCL. Circulating antibodies against NPM-ALK were originally reported in 11 ALK-positive ALCL patients using an immunocytochemical approach.2 In that study, no conclusions concerning the clinical significance of anti-NPM-ALK antibodies could be drawn, due to the small number of patients; however, a tendency to higher antibody levels in pretreatment blood samples was observed. Recently, we demonstrated that minimal bone marrow (BM) involvement at diagnosis is a common event in pediatric ALCL and that minimal BM disease monitoring can identify patients at risk of relapse.3 In addition, Damm-Welk et al.4 showed that patients with more than 10 normalized copy numbers (NCNs) NPM-ALK in BM had a cumulative incidence of relapse (CI-R) of 71plusminus14% compared with CI-R of 18plusminus6% for patients with 10 or fewer NCNs (P<0.001) and that quantitative PCR for NPM-ALK in BM and peripheral blood (PB) is highly concordant. In this study, we assessed the levels of anti-NPM-ALK antibodies at diagnosis and at stop therapy in plasma of children with ALCL treated according to the ALCL-99 protocol5 and evaluated the possible correlation with minimal residual disease (MRD) status during chemotherap

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Observation of Alectinib‐ and Crizotinib‐ included chemotherapy in children with ALK‐positive anaplastic large cell lymphoma: A single institutional experience

Pei

Zhang

et al. 2022

Cancer Medicine

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Approximately one‐third children with anaplastic large cell lymphoma (ALCL) relapse after completion of chemotherapy, particularly for those high‐risk patients. The introduction of novel therapeutic modalities is much needed for these sub‐group patients. Two groups ( n = 3, n = 4) of ALCL patients were treated with crizotinib‐ and alectinib‐included ALCL‐99 therapy, respectively, achieving complete remission rates of 66.7% and 100%. Two patients of crizotinib group relapsed, while none relapsed among the alectinib‐treated patients. Adding alectinib instead of crizotinib sufficiently suppressed and maintained the deep NPM ‐ ALK molecular response. ALK inhibitors were well tolerated with only grade 1 adverse events in both groups. Though a relatively small case number, this study raised the possibility that alectinib‐included therapeutic regimens may benefit the early response, in‐depth molecular remission, and persistent remission to some extent. Further studies are warranted to validate our preliminary findings.

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Prognostic significance of circulating tumor cells in bone marrow or peripheral blood as detected by qualitative and quantitative PCR in pediatric NPM-ALK–positive anaplastic large-cell lymphoma

Cited by 118 publications

References 34 publications

Expression of CD8 is associated with non-common type morphology and outcome in pediatric anaplastic lymphoma kinase-positive anaplastic large cell lymphoma

Expression of CD8 is associated with non-common type morphology and outcome in pediatric anaplastic lymphoma kinase-positive anaplastic large cell lymphoma

Kinetics of humoral response to ALK and its relationship with minimal residual disease in pediatric ALCL

Observation of Alectinib‐ and Crizotinib‐ included chemotherapy in children with ALK‐positive anaplastic large cell lymphoma: A single institutional experience

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