Martin Schrappe

Non-Hodgkin's lymphomas of childhood and adolescence: results of a treatment stratified for biologic subtypes and stage--a report of the Berlin-Frankfurt-Münster Group.

PURPOSE To prove the efficacy of a treatment stratified according to histology for children with non-Hodgkins lymphoma (NHL), including acute B-cell leukemia (B-ALL). PATIENTS AND METHODS From October 1986 to March 1990, 302 assessable patients, 0.6 to 17.8 years of age, with newly diagnosed NHL were enrolled onto study ALL/NHL-BFM 86. Fifty percent of patients had Burkitt-type lymphomas, including B-ALL; 24% had lymphoblastic lymphoma; 18% had diffuse large-cell lymphoma; and 8% had an NHL not further classified. Therapy group B included Burkitts-type lymphomas, B-ALL, and most large-cell lymphomas including Ki-1 anaplastic large-cell lymphoma. Patients with stage I and II disease resected received three, while all others received six, 5-day therapy courses (dexamethasone, methotrexate [MTX] 0.5 g/m2 [5 g/m2 for stage IV and B-ALL], and intrathecal [IT] therapy in each course, plus ifosfamide, cytarabine, and etoposide alternating with cyclophosphamide and doxorubicin). Therapy for group non-B patients (lymphoblastic lymphoma and pleomorphic T-cell lymphoma [PTCL]) consisted of a Berlin-Frankfurt-Münster (BFM) acute lymphoblastic leukemia protocol, including cranial irradiation for advanced stage. Local therapy was restricted to patients with incomplete tumor regression. RESULTS The probabilities of event-free survival (pEFS) at 7 years were 80% +/- 2% for the whole group, 81% +/- 3% for group B (n = 225), and 78% +/- 5% for group non-B (n = 77) with a follow-up duration of 3.6 to 7 years (median 5 years). Treatment results were comparable between NHL subtypes, except for PTCL, in which three of four patients suffered from relapse. Local disease manifestations were the most frequent site of failure. CONCLUSION This therapy strategy provided patients of all NHL subtypes with an equally high chance to survive event-free, except patients with PTCL. With reduced systemic failure, local tumor control may become more important.

Osteonecrosis: A treatment related toxicity in childhood acute lymphoblastic leukemia (ALL)—experiences from trial ALL‐BFM 95

Osteonecrosis (ON) as a complication during treatment of acute lymphoblastic leukemia (ALL) has gained rising attention over the past decade. Corticosteroids, representing an essential element of antileukemic therapy, are known to induce ON, which in turn may cause significant morbidity. Due to spontaneous reporting of affected patients with ON, a group‐wide evaluation was performed to determine incidence, risk factors, and morbidity for ON.

Identification of germline susceptibility loci in ETV6-RUNX1-rearranged childhood acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is a malignant disease of the white blood cells. The etiology of ALL is believed to be multifactorial and likely to involve an interplay of environmental and genetic variables. We performed a genome-wide association study of 355 750 single-nucleotide polymorphisms (SNPs) in 474 controls and 419 childhood ALL cases characterized by a t(12;21)(p13;q22) — the most common chromosomal translocation observed in childhood ALL — which leads to an ETV6–RUNX1 gene fusion. The eight most strongly associated SNPs were followed-up in 951 ETV6-RUNX1-positive cases and 3061 controls from Germany/Austria and Italy, respectively. We identified a novel, genome-wide significant risk locus at 3q28 (TP63, rs17505102, PCMH=8.94 × 10−9, OR=0.65). The separate analysis of the combined German/Austrian sample only, revealed additional genome-wide significant associations at 11q11 (OR8U8, rs1945213, P=9.14 × 10−11, OR=0.69) and 8p21.3 (near INTS10, rs920590, P=6.12 × 10−9, OR=1.36). These associations and another association at 11p11.2 (PTPRJ, rs3942852, P=4.95 × 10−7, OR=0.72) remained significant in the German/Austrian replication panel after correction for multiple testing. Our findings demonstrate that germline genetic variation can specifically contribute to the risk of ETV6–RUNX1-positive childhood ALL. The identification of TP63 and PTPRJ as susceptibility genes emphasize the role of the TP53 gene family and the importance of proteins regulating cellular processes in connection with tumorigenesis.

Expression and structural analysis of glucocorticoid receptor isoform gamma in human leukaemia cells using an isoform-specific real-time polymerase chain reaction approach

Summary. Glucocorticoids are broadly used for chemotherapy in childhood acute lymphoblastic leukaemia (ALL). The intracellular effects of glucocorticoids are mediated through the glucocorticoid receptor. The human glucocorticoid receptor gamma isoform (hGR‐gamma) differs from the main isoform (hGR‐alpha) by an additional amino acid within the DNA binding domain of the receptor protein. This may decrease hGR‐alpha‐mediated transcriptional activation. The importance of hGR‐gamma expression in childhood ALL is unknown. To evaluate hGR‐gamma mRNA expression levels, a real‐time polymerase chain reaction (PCR)‐based approach, allowing the selective amplification of hGR‐gamma, was developed and optimized. We were able to demonstrate target selectivity of hGR‐gamma amplification using sequence‐specific primers. Studying the structure of the 3′ end of hGR‐gamma, a combination of this isoform with other hGR isoforms could be demonstrated. Using analysis of hGR‐gamma‐specific amplification in comparison with the expression of hGR‐total (all isoforms) in leukaemic blasts from patients with either a good response to prednisone (PGR) or poor‐prednisone response (PPR) in vivo, relative hGR‐gamma expression was observed to be lower in cells from patients with PGR compared with PPR, in particular after 10 h of dexamethasone stimulation. These data were correlated with cell survival, demonstrating a more pronounced induction of apoptosis in cells from patients with PGR as compared with PPR.

Therapy Results in Five ALL-BFM Studies Since 1970: Implications of Risk Factors for Prognosis

Prognosis in childhood acute lymphoblastic leukemia (ALL) after risk-adapted therapy is first of all dependent on the quality of therapy. Conventional risk factors such as WBC, age, sex, organ involvement, and other features certainly have lost their prognostic significance in varying degrees during the evolution of risk-adapted and necessarily intensive therapy. Still, the tumor burden and other ill-defined or unknown factors are responsible for therapy failure. Obviously, the patient group with therapy failure must be the target of future efforts.

Role of cranial radiotherapy for childhood T-cell acute lymphoblastic leukemia with high WBC count and good response to prednisone. Associazione Italiana Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Münster groups.

PURPOSE The ALL-BFM 90 and AIEOP-ALL 91 studies share the same treatment backbone and have 5-year event-free survival (EFS) rates close to 75%. This study evaluated the impact of differing presymptomatic CNS therapies in T-cell acute lymphoblastic leukemia (T-ALL) patients with a good response to prednisone (PGR) according to WBC count and Berlin-Frankfurt-Münster (BFM) risk factor (RF). PATIENTS A total of 192 patients (141 boys; median age, 7.5 years) with T-ALL, PGR, RF less than 1.7, and no CNS leukemia diagnosed between 1990 and 1995 were enrolled onto the ALL-BFM 90 (n = 123) or AIEOP-ALL 91 (n = 69) study. Presymptomatic CNS therapy consisted of cranial radiation (CRT) and intrathecal methotrexate (I.T. MTX) (11 doses) in the BFM study and of extended triple intrathecal therapy (T.I.T.) (17 doses) in the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) study. Patients were divided into a low-WBC group (WBC count < 100,000/microL) and a high-WBC group (WBC count > 100,000/microL). EFS was compared using the log-rank test. RESULTS For patients treated with CRT and I.T. MTX (BFM group), the 3-year EFS rate was 89.8% (SE = 3.5) for 99 patients in the low-WBC group versus 81.9% (SE = 8.2) in the high-WBC group (difference not significant). Conversely, for patients treated with T.I.T. alone (AIEOP group), the EFS rate was 80.6% (SE = 5.6) in 55 patients with a low WBC count versus 17.9% (SE = 11.0) in 14 patients with a high WBC count (P < .001). CONCLUSION These data suggest that CRT may not be necessary in PGR T-ALL patients with a WBC count less than 100,000/microL; on the contrary, in patients with a high count, extended T.I.T. may be inferior to CRT and I.T. MTX.

Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and susceptibility to pediatric acute lymphoblastic leukemia in a German study population

BackgroundMethylenetetrahydrofolate reductase (MTHFR) has a major impact on the regulation of the folic acid pathway due to conversion of 5,10-methylenetetrahydrofolate (methylene-THF) to 5-methyl-THF. Two common polymorphisms (677C>T and 1298A>C) in the gene coding for MTHFR have been shown to reduce MTHFR enzyme activity and were associated with the susceptibility to different disorders, including vascular disease, neural tube defects and lymphoid malignancies. Studies on the role of these polymorphisms in the susceptibility to acute lymphoblastic leukemia (ALL) led to discrepant results.MethodsWe retrospectively evaluated the association of the MTHFR 677C>T and 1298A>C polymorphisms with pediatric ALL by genotyping a study sample of 443 ALL patients consecutively enrolled onto the German multicenter trial ALL-BFM 2000 and 379 healthy controls. We calculated odds ratios of MTHFR genotypes based on the MTHFR 677C>T and 1298A>C polymorphisms to examine if one or both of these polymorphisms are associated with pediatric ALL.ResultsNo significant associations between specific MTHFR variants or combinations of variants and risk of ALL were observed neither in the total patient group nor in analyses stratified by gender, age at diagnosis, DNA index, immunophenotype, or TEL/AML1 rearrangement.ConclusionOur findings suggest that the MTHFR 677C>T and 1298A>C gene variants do not have a major influence on the susceptibility to pediatric ALL in the German population.

Primary Mediastinal Large B-Cell Lymphoma With Sclerosis in Pediatric and Adolescent Patients: Treatment and Results From Three Therapeutic Studies of the Berlin-Frankfurt-Münster Group

PURPOSE Primary mediastinal large B-cell lymphoma with sclerosis (PMLBL) is a rare entity of non-Hodgkins lymphoma (NHL) arising from thymic mature B cells. Optimal treatment strategies remain to be established, especially in pediatric patients. PATIENTS AND METHODS This study analyzes clinical characteristics and treatment outcome of 30 pediatric patients with PMLBL, diagnosed in multicenter therapy NHL-Berlin-Frankfurt-Münster Group (BFM) trials. Treatment was stratified by stage and serum lactate dehydrogenase (LDH) and consisted of four to six 5-day courses of chemotherapy using steroids, oxazaphosphorine alkylating agents, methotrexate, cytarabine, etoposide, and doxorubicin. Radiation was not part of the protocol. RESULTS From April 1986 to August 1999, 1,650 patients with newly diagnosed NHL were enrolled in the NHL-BFM trials; 30 patients (1.8%) had PMLBL. Median age was 14.3 years (range, 1.4 to 16.7 years); 15 patients were male and 15 patients were female. With a median observation time of 5 years (range, 1 to 12 years), probability of event-free survival (pEFS) at 5 years was 0.70 (SE, 0.08). Two patients erroneously diagnosed as T-cell NHL received non-B-cell therapy and died from progress of disease. Events in 28 patients receiving B-cell therapy included early progress during therapy (n = 1) and relapse (n = 6). Residual mediastinal masses were present in 23 patients after two courses of therapy and in 15 patients after the end of therapy. LDH > or = 500 U/L was associated with increased risk of failure in multivariate analysis. CONCLUSION PMLBL mainly is found in adolescents. Dose-intense chemotherapy including high-dose methotrexate yields a pEFS at 5 years of 0.70 (SE, 0.08). LDH is of prognostic value in pediatric patients with PMLBL.

GSTP1 and MDR1 genotypes and central nervous system relapse in childhood acute lymphoblastic leukemia

The probability of event-free survival of childhood acute lymphoblastic leukemia (ALL) approaches 80% or more with the use of modern multiagent chemotherapeutic regimens. One major contribution to this success has been reduction of the rate of central nervous system (CNS) relapses to less than 5%. However, heterogeneity is observed with regard to the incidence of CNS relapse in homogenously treated patient populations. One potential explanation for this heterogeneity is variation in the genetic background of these populations. Glutathione S-transferase P1 and P-glycoprotein are implicated in resistance to a variety of chemotherapeutic agents and have been localized to the blood-brain barrier. In a matched case-control study, we investigated the associations between CNS relapse in childhood ALL and the presence of phenotypically relevant single nucleotide polymorphisms within the GSTP1 (codon 105 and 114) and MDR1 genes (ABCB1; coding for Pgp; exon 26, C3435T). Significant reductions in risk of CNS relapse were observed for patients homozygous for the GSTP1 Val105 allele as well as for patients with the MDR1 3435T/T or C/T genotype. For both genotypes, the effect was restricted to patients at intermediate or high risk of treatment failure.These results suggested a modulating role for host genetic variation in the development of CNS relapse in childhood ALL treated according to Berlin-Frankfurt-Münster protocols.

Non-Hodgkin's lymphoma in adolescents: experiences in 378 adolescent NHL patients treated according to pediatric NHL-BFM protocols

Age-related differences in the distribution, biology and treatment response of non-Hodgkins lymphoma (NHL) in adolescents remain to be elucidated. The current analyses present clinical parameters and outcomes of adolescents treated in pediatric NHL-BFM trials. Patients were stratified by histological subtype: lymphoblastic lymphoma (LBL); mature B-NHL, including Burkitts lymphoma/leukemia (BL/B-AL), diffuse B-cell lymphoma (DLBCL-CB) and mediastinal B-cell lymphoma (PMLBL); and anaplastic large cell lymphoma (ALCL). Between October 1986 and December 2007, 2915 patients were registered, including 378 (13%) adolescents (15–18 years) with BL/B-AL (n=101), ALCL (n=74), DLBCL-CB (n=55), T-LBL (n=45), PMLBL (n=24), pB-LBL (n=13) and rare or not-specified NHL subtypes (n=66). The 5-year event-free survival (EFS) was 79±2% for adolescents compared with 85±1% for patients aged <15 years (P=0.014). EFS was 83±7% for adolescents with T-LBL, 82±4% with BL/B-AL, 85±5% with DLBCL-CB, 57±10% with PMLBL and 70±6% with ALCL. According to sex, the 5-year EFS in females versus males, respectively, was 70±5 versus 83±2% overall (P=0.004), 57±17 versus 92±6% (P=0.0036) for T-LBL patients and 71±9 versus 97±3% (P=0.0067) for DLBCL-CB patients. Adolescents with NHL treated according to pediatric NHL-BFM protocols had an EFS of 79±2%, which is marginally inferior to that of children. In adolescents with T-LBL and DLBCL-CB, female sex was associated with a worse prognosis.