Willi Woessmann

Allogeneic haematopoietic stem cell transplantation in relapsed or refractory anaplastic large cell lymphoma of children and adolescents – a Berlin–Frankfurt–Münster group report

Patients with refractory or early relapsed anaplastic large cell lymphoma (ALCL) have a poor chance of survival. We report 20 children and adolescents with high‐risk relapsed or refractory ALCL who underwent allogeneic haematopoietic stem cell transplantation (HSCT). We retrospectively analysed 20 patients who relapsed between December 1991 and April 2003 during (six patients) or soon after first‐line Berlin–Frankfurt–Münster‐type chemotherapy (14 patients) and underwent allogeneic HSCT. Nine patients received allogeneic HSCT after the first relapse and 11 after multiple relapses. Eight patients received their transplants from matched sibling donors, eight from unrelated donors and four from haploidentical family donors. The conditioning regimen was based on total body irradiation in 15 patients. Two patients relapsed after allogeneic HSCT and died. Three patients died of transplant‐related toxicity. Event‐free survival at 3 years after allogeneic transplant was 75 ± 10%. There was no influence of donor type or conditioning regimen on outcome. Two of six patients with progressive disease during frontline therapy survived compared with 13/14 patients with a first relapse after frontline therapy. Two of three patients who were transplanted with active lymphoma and all five patients who received allogeneic HSCT for relapse following autologous HSCT survived disease‐free. Allogeneic HSCT is effective and has acceptable toxicity as rescue therapy for high‐risk ALCL relapse. It even offers cure for patients refractory to chemotherapy, suggesting a graft‐versus‐ALCL effect.

Relapsed or Refractory Anaplastic Large-Cell Lymphoma in Children and Adolescents After Berlin-Frankfurt-Muenster (BFM)–Type First-Line Therapy: A BFM-Group Study

PURPOSE To evaluate risk factors for outcome in children and adolescents with relapse of anaplastic large-cell lymphoma (ALCL) after comparable first-line therapy. PATIENTS AND METHODS We analyzed a population-based cohort of 74 children with relapsed ALCL after Berlin-Frankfurt-Muenster-type first-line therapy between April 1990 and December 2003. The recommended salvage strategy was reinduction chemotherapy followed by autologous hematopoietic stem-cell transplantation (SCT). RESULTS With a median follow-up time of 8.4 years (range, 4.5 to 16.4 years), the 5-year overall survival (OS) rate after first relapse was 57% ± 6%. Survival correlated with time of relapse and clinically advanced dissemination. Five-year OS of 16 patients who experienced progression during first-line therapy was 25% ± 11% compared with 66% ± 6% for 58 patients with a later relapse (P = .002). Five-year OS of 11 patients with bone marrow or CNS involvement was 27% ± 13% compared with 62% ± 6% for 63 patients without involvement (P = .001). Five-year event-free survival (EFS) and OS of 39 children who received the recommended autologous SCT were 59% ± 8% and 77% ± 7%, respectively. EFS after autologous SCT was significantly associated with time to relapse (progression: n = 3; EFS, 0; later relapse: n = 36; EFS, 64% ± 8%; P = .014) and CD3 expression (CD3 negative: n = 25; EFS, 72% ± 9%; CD3 positive: n = 11; EFS, 18% ± 12%; P < .001), but not with site of relapse, conditioning regimen, or graft manipulation. No relapses occurred among 10 patients with relapsed CD3-positive ALCL treated with allogeneic SCT. CONCLUSION Reinduction chemotherapy followed by autologous SCT proved feasible and efficacious for patients with a first relapse of CD3-negative ALCL after first-line therapy. Patients with progression during first-line therapy or relapsed CD3-positive ALCL may benefit from allogeneic SCT.

Distribution of NPM1‐ALK and X‐ALK fusion transcripts in paediatric anaplastic large cell lymphoma: a molecular–histological correlation

Anaplastic large cell lymphomas (ALCL) in children express anaplastic lymphoma kinase (ALK) fusion genes, most commonly NPM1‐ALK. The distribution of X‐ALK among 66 childhood ALCLs was analysed. One ALCL was ALK‐negative. Reverse transcription polymerase chain reaction detected NPM1‐ALK in 58 tumours, all showing nuclear and cytoplasmic ALK staining. The remaining seven ALCL stained for ALK in the cytoplasm only: two expressed TPM3‐ALK, one ATIC‐ALK, one MYH9‐ALK; three no TPM3‐, TFG‐, ATIC‐, CLTC‐ or MYH9‐ALK. Almost 90% of paediatric ALK‐positive ALCLs express NPM1‐ALK. There was complete concordance between ALK staining pattern and the presence of a typical/variant ALK fusion partner.

ERK signaling pathway is differentially involved in erythroid differentiation of K562 cells depending on time and the inducing agent

K562 cells can be induced to differentiate along the erythroid lineage by a variety of chemical compounds, including hemin, butyrate, cisplatin and ara‐C. Differential signaling through MAP kinases has been suggested to be involved in this differentiation process. We have investigated the involvement of ERK activation/inhibition in hemin‐, butyrate‐, cisplatin‐ and ara‐C‐induced erythroid differentiation using the K562 cell line. ERK activity decreased for 2–4 h after administration of either inducing agent. ERK was then activated by hemin and cisplatin, while ERK phosphorylation remained decreased during incubation with butyrate and ara‐C. There was no activation of JNK or p38. The MEK‐1 inhibitors UO126 or PD98059 induced erythroid differentiation in K562 cells and acted additively with butyrate. Inhibition of MEK‐1 reduced the hemoglobin accumulation by hemin and cisplatin; erythroid differentiation by ara‐C was unchanged. The results suggest that inhibition of signaling through ERK in K562 cells may be needed to enter the erythroid differentiation process, while after initiation both activation and inhibition of signaling through ERK enhance erythroid differentiation, which, however, is dependent on the inducing compound.

Flow cytometric detection of circulating tumour cells in nucleophosmin/anaplastic lymphoma kinase-positive anaplastic large cell lymphoma: comparison with quantitative polymerase chain reaction.

Quantification of occult circulating tumour cells in blood or bone marrow (BM) enables the identification of patients with a high risk for relapse in nucleophosmin/anaplastic lymphoma kinase (NPM‐ALK)‐positive anaplastic large cell lymphoma (ALCL). We have developed a flow cytometric (FCM) assay to quantify the rare ALK‐ and CD30‐positive ALCL cells. When ALCL cells were admixed with normal peripheral blood or BM, ALK‐ and CD30‐positive cells could be detected above background level at an added concentration of 10−5 for all three cell lines tested. Sensitivity and costs of the assay were compared with quantitative real‐time polymerase chain reaction (PCR) for NPM‐ALK. The results of the FCM assay and quantitative PCR for NPM‐ALK correlated. The sensitivity of the PCR exceeded that of the FCM by at least one log. Quantitative PCR was more time‐consuming and expensive than FCM. Both methods were compared on BM or blood samples from 11 ALCL patients. FCM using antibodies against ALK and CD30 can sensitively and specifically detect the circulating ALCL cells in BM or blood. This method needs to be tested in a larger cohort of patients to determine whether it has sufficient sensitivity to be used as a substitute for quantitative PCR.

Mini buffy coat photopheresis for children and critically ill patients with extracorporeal photopheresis contraindications

BACKGROUND: Conventional extracorporeal photopheresis (ECP) has proven efficacy for the treatment of several diseases but is limited to patients with sufficient body weight. A novel simplified mini buffy coat ECP technique that allows treatment of small children and patients with apheresis contraindications has been developed.

Non‐anaplastic peripheral T‐cell lymphoma in children and adolescents – a retrospective analysis of the NHL‐BFM study group

Mature (peripheral) T‐cell lymphoma (PTCL) other than anaplastic large cell lymphoma is a heterogeneous group of diseases and exceedingly rare in children and adolescents. Survival rates range between 46% and 85%. This study reports the disease characteristics, treatment and outcome of all patients with the diagnosis of mature TCL registered in the Berlin‐Frankfurt‐Munster non‐Hodgkin lymphoma database between 1986 and 2012. All diagnoses were centrally reviewed and revised by clinico‐pathological correlation according to the criteria of the current World Health Organization classification. Of the 69 patients originally registered as having PTCL, the diagnosis was confirmed in 38 of them. Most patients were treated with an anaplastic large cell lymphoma (ALCL)‐like therapy regimen. Patients with PTCL‐not otherwise specified comprised the largest group and showed a 5‐year event‐free survival rate of 61 ± 11%. Patients suffering from Natural Killer/T‐cell‐ and hepatosplenic TCL had the poorest outcome. Our results suggest that the outcomes of children with mature TCL other than ALCL depend on the subtype and are worse than in all other paediatric lymphomas. The clinical experience presented in this largest study on paediatric mature TCL may serve as basis for future collaborative international prospective clinical trials.

Subcutaneous panniculitis-like T-cell lymphoma in children: a detailed clinicopathological description of 11 multifocal cases with a high frequency of haemophagocytic syndrome

DEAR EDITOR, Subcutaneous panniculitis-like T-cell lymphoma (SPLTCL) is defined as a/b T-cell-receptor-positive T-cell lymphoma of CD8-positive cytotoxic T cells involving exclusively the subcutaneous tissue. SPLTCL is rare but has been shown to affect all age groups including children. The clinical course of this lymphoma depends on the presence or absence of a haemophagocytic syndrome (HPS), which has been reported to develop secondarily in approximately 20% of cases of SPLTCL, usually associated with an unfavourable outcome. HPS can be regarded as a systemic hyperinflammatory reaction with fever, cytopenia and hepatosplenomegaly. According to the consensus criteria the diagnosis is based on further parameters such as the morphological detection of haemophagocytosis and specific laboratory features. We report here a multicentre collection of 11 paediatric cases of SPLTCL, and put a specific focus on the presence of HPS, treatment options and outcome. Our data indicate that HPS occurs in a substantial number of such patients, but was