Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90.

Anaplastic large-cell lymphoma (ALCL) accounts for approximately 10% of pediatric non-Hodgkin lymphoma (NHL). Previous experience from NHL-Berlin-Frankfurt-Münster (BFM) trials indicated that the short-pulse B-NHL-type treatment strategy may also be efficacious for ALCL. The purpose of this study was to test the efficacy of this protocol for treatment of childhood ALCL in a large prospective multicenter trial and to define risk factors. From April 1990 to March 1995, 89 patients younger than 18 years of age with newly diagnosed ALCL were enrolled in trial NHL-BFM 90. Immunophenotype was T-cell in 40 patients, B-cell in 5, null in 31, and not determined in 13. Stages were as follows: I, n = 8; II, n = 20; III, n = 55; IV, n = 6. Extranodal manifestations were as follows: mediastinum, n = 28; lung, n = 13; skin, n = 16; soft tissue, n = 13; bone, n = 14; central nervous system, n = 1; bone marrow, n = 5. After a cytoreductive prephase, treatment was stratified into 3 branches: patients in K1 (stage I and II resected) received three 5-day courses (methotrexate [MTX] 0.5 g/m(2), dexamethasone, oxazaphorins, etoposide, cytarabine, doxorubicin, and intrathecal therapy); patients in K2 (stage II nonresected and stage III) received 6 courses; patients in K3 (stage IV or multifocal bone disease) received 6 intensified courses including MTX 5 g/m(2), high-dose cytarabine/etoposide. The Kaplan-Meier estimate for a 5-year event-free survival was 76% +/- 5% (median follow-up, 5.6 years) for all patients and 100%, 73% +/- 6%, and 79% +/- 11% for K1, K2, and K3, respectively. Events were as follows: progression during therapy, n = 2; progression or relapse after therapy, n = 20; second malignancy, n = 1. It was concluded that short-pulse chemotherapy, stratified according to stage, is effective treatment for pediatric ALCL. B symptoms were associated with increased risk of failure. (Blood. 2001;97:3699-3706)

Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: A report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90.

In study NHL-BFM 90, we investigated whether the serum lactate dehydrogenase (LDH) concentration and early response are useful markers for stratification of therapy for childhood B-cell neoplasms in addition to stage, if the outcome of patients with abdominal stage III and LDH >/=500 U/L can be improved by high-dose (HD) methotrexate (MTX) at 5 g/m(2) instead of intermediate-dose (ID) MTX at 500 mg/m(2) in the preceding study 86; whether 2 therapy courses are enough for patients with complete resection; and whether combined systemic and intraventricular chemotherapy is efficacious for central nervous system-positive (CNS(+)) patients. After a cytoreductive prephase, treatment was stratified into 3 risk groups: patients in R1 (completely resected) received 2 5-day courses (ID-MTX, dexamethasone, oxazaphorins, etoposide, cytarabine, doxorubicin, and intrathecal therapy), patients in R2 (extra-abdominal primary only or abdominal tumor and LDH <500 U/L) received 4 courses containing HD-MTX, and patients in R3 (abdominal primary and LDH >/=500 U/L or bone marrow/CNS/multilocal bone disease) received 6 courses. Incomplete responders after 2 courses received an intensification containing HD-cytarabine/etoposide. Patients with no or necrotic tumor thereafter received 3 more courses; 6 patients with viable tumor received autologous bone marrow transplantation. From April 1990 through March 1995, 413 evaluable patients were enrolled (R1, 17%; R2, 40%; and R3, 43%). The 6-year event-free survival (pEFS) was 89% +/- 2% for all and 100%, 96% +/-2%, and 78% +/- 3% in R1, R2, and R3, respectively. The pEFS of patients with abdominal stage III and LDH >/=500 U/L was 81% +/- 4% as compared with 43% +/- 10% in study 86. Of 26 CNS(+) patients, 5 died early, but only 3 relapsed.

Impaired renal function and tumor lysis syndrome in pediatric patients with non-Hodgkin's lymphoma and B-ALL. Observations from the BFM-trials.

OBJECTIVE: Tumor lysis syndrome and renal failure remain important complications early in the course of therapy for pediatric Non-Hodgkin's lymphoma (NHL), frequently leading to therapeutic alterations. In the presented series, children with NHL and tumor lysis syndrome are retrospectively analysed regarding clinical features of acute renal failure and its implications on therapy. PATIENTS AND METHODS: From 4/1990 to 10/1997, 1192 patients diagnosed of any form of NHL have been registered in the NHL-BFM trials. 63 of these patients were reported to have suffered from impaired renal function and/or tumor lysis syndrome before or during initial treatment. Clinical data of these patients were analysed regarding diagnosis, stage, tumor mass, therapy and complications. RESULTS: 62 of 63 patients with impaired renal function and/or tumor lysis syndrome were diagnosed of Burkitt's lymphoma or B-ALL; 58 (92%) of these patients had advanced stages of disease and high LDH-levels (> 500 U/l). 43 of 63 patients had already signs of impaired renal function at admission. Hyperuricemia was the commonest cause of impaired renal function. Renal infiltration or enlargement was observed in 27 of 63 patients. 6 patients were diagnosed of urinary tract obstruction. 25 patients required hemodialysis. Despite improved renal function before administration of MTX, 21 of 63 patients suffered from protracted MTX-elimination during the first course of therapy. 7 of 63 patients (11%) with tumor lysis syndrome died of sepsis after the first course of therapy, another two patients died within 48 hours of therapy due to electrolyte imbalances. CONCLUSIONS: In pediatric NHL-patients, Burkitt's lymphoma and B-ALL appear to be the commonest cause of metabolic complications early in chemotherapy. Patients with advanced stages and large tumor mass are at high risk for renal failure. Impaired renal function predisposes patients to further complications and toxic death. Prophylactic use of urate-oxidase in all patients with advanced stage NHL might limit the incidence of tumor lysis syndrome. Prospective studies on renal function prior to and during therapy are required in order to develop a clinical profile reliably detecting patients at risk for developing renal failure and subsequent complications.

High incidence of significant bone loss in patients with severe congenital neutropenia (Kostmann's syndrome).

OBJECTIVE: Clinical observation of bone pain, unusual fractures in two patients, and diffuse osteopenia/osteoporosis led us to assess bone mineral content and density in 30 patients with severe congenital neutropenia who were treated with recombinant-methionyl-human granulocyte colony-stimulating factor (r-metHuG-CSF). STUDY DESIGN: We reviewed roentgenograms in 29 of these 30 patients to evaluate bone loss before and during treatment. In addition, in 17 of the 30 patients, bone mineral status could be assessed by both quantitative computed tomography (Q-CT; n = 16) and dual energy x-ray absorptiometry (DXA; n = 1). In one patient, Q-CT was not possible because of severe vertebral fractures. RESULTS: Of the 30 patients investigated, 15 had evidence of osteopenia/osteoporosis observed on spine radiographs (n = 5), on Q-CT/DXA (n = 1/n = 1), or on radiographs and Q-CT (n = 8). In 13 of the 30 patients, only a lateral radiograph of the lumbar spine was available, 5 of 13 showing either increased kyphosis and wedging of the vertebrae or compression fractures of the vertebral bodies, indicating severe established osteoporosis. In eight patients, the findings of the spinal radiographs were normal. In nine patients, spinal radiographs were taken before r-metHuG-CSF treatment. Osteoporotic vertebral deformation (n = 3) or reduced bone mass (n = 3) was seen in six of these nine patients. The levels of serum biochemical markers of bone metabolism were all within normal ranges except for mild elevation of the serum alkaline phosphatase level. The degree of spinal bone mineral loss did not correlate with dose and duration of r-metHuG-CSF treatment or with the age or sex of the patients. CONCLUSIONS: These data indicate a high incidence of bone mineral loss in children with severe congenital neutropenia. The underlying pathogenesis of bone demineralization is not clear. It is more likely that the bone loss was caused by the pathophysiologic features of the underlying disease, but it is possible that r-metHuG-CSF accelerates bone mineral loss.

Absence of G-CSF receptors and absent response to G-CSF in childhood Burkitt's lymphoma and B-ALL cells.

The expression of the granulocyte colony-stimulating factor (G-CSF) receptor in childhood Burkitt's lymphoma (BL) cells, and the mitogenic effect of G-CSF on these cells, was studied in a panel of 13 Epstein-Barr virus (EBV) positive and negative BL cell lines derived from nine children. G-CSF receptor mRNA expression was investigated by Northern blot analysis and reverse transcriptase polymerase chain reaction (RT-PCR). Binding of G-CSF to BL cell lines was measured by chemical crosslinking of 125I-G-CSF, and proliferation by thymidine incorporation. Inducibility of the G-CSF receptor was studied by stimulation with interleukin-1 beta, tumour necrosis factor-alpha, Staphylococcus aureus Cowan A, anti-human IgM, phorbol myristate acetate, calcium ionophore A23187, and by infection in vitro by immortalizing and non-immortalizing strains of EBV. BL cell lines, unstimulated or stimulated by biological reagents or EBV infection, did not bind radioionated G-CSF in crosslinking experiments. No stimulation by recombinant human G-CSF was observed in 3H-thymidine incorporation assays. No G-CSF receptor mRNA was detected by Northern blot analysis or RT-PCR in BL cell lines. It is concluded that G-CSF plays no direct stimulatory role in the growth of these malignant B-cells, making a deleterious influence of G-CSF in the clinical treatment situation unlikely.

[NHL-BFM 90 therapy study in treatment of malignant non-Hodgkin's lymphomas in children and adolescents. Part 1: Classification and allocation to strategic therapy groups. BIF study group]. / Therapiestudie NHL-BFM 90 zur Behandlung maligner Non-Hodgkin-Lymphome bei Kindern und Jugendlichen. Teil 1: Klassifikation und Einteilung in strategische Therapiegruppen. BIF Studiengruppe.

One of the goals of the study NHL-BFM 90 was to investigate the distribution and prognosis of the different subtypes of Non-Hodgkin's Lymphoma (NHL) in children and adolescents according to histological, cytomorphological and immunological characteristics. From 4/1990 to 12/1992, 346 patients (pts) (84 females, 262 males) were enrolled (median age: 9.1 years; range: 0.8-17.9 years). Histology was available from 290 pts (84%), cytomorphology from 155 (44%), and immunophenotyping from 245 (70%). Cases with L1 oder L2 cytomorphology according to the French-American-British Classification were classified as lymphoblastic lymphoma and those with L3 cytomorphology as Burkitt-Type lymphoma or acute B-cell leukemia (B-ALL) if a histological classification was not available. By means of the combined analysis of all three diagnostic criterias the classification of the NHL according to the updated Kiel-classification was possible in 312 cases: 49% were classified as Burkitt-type-lymphoma (incl. B-ALL), 22% als lymphoblastic lymphoma, 10% as large cell anaplastic lymphoma (LCAL), 6% as centroblastic lymphoma, only few cases were classified as NHL of other subtypes, 3 pts (1%) suffered from low grade malignant lymphomas, and in 34 pts (10%) the NHL was not further classified. Patients were stratified according to NHL-subentities in 3 branches (Non-B-NHL, B-NHL, LCAL) of different treatment modalities. The estimated probability of a 3-year event free survival (pEFS) was 88 +/- 2% for the whole group (follow up 7 to 40 months, median 23 months) while pEFS of different subtypes was: lymphoblastic lymphoma: 91 +/- 4%; Burkitt-type-lymphoma/B-ALL: 90 +/- 2%; centroblastic lymphoma: 94 +/- 6%, LCAL: 88 +/- 6%. We conclude that the stratification of treatment modalities in study NHL-BFM 90 according to biological entities provided patients of different NHL-subtypes an equal chance to survive event free. The efficacy of the treatment strategy for rare subtypes, however, is not evaluable yet.

[NHL-BFM 90 therapy study in treatment of malignant non-Hodgkin's lymphomas in children and adolescents. Part 2: An intermediate term analysis of the non-B-NHL therapy group. BFM Study group]. / Therapiestudie NHL-BFM 90 zur Behandlung maligner Non-Hodgkin-Lymphome bei Kindern und Jugendlichen. Teil 2: Eine Zwischenanalyse der Therapiegruppe Non-B-NHL. BFM Studiengruppe.

The goals of study NHL-BFM 90 for the therapy group Non-B NHL are to prospectively evaluate the dynamic of tumor regression and the persistence of a residual mass after induction therapy for its prognostic impact. Patients (pts) of stages I and II receive induction composed of prednisone, vincristine (VCR), daunorubicin, L-asparaginase (L-ASP), cyclophosphamide (CP), cytarabine (ARA-C), 6-mercaptopurine (6-MP) and intrathecally (i.th.) methotrexate (MTX), followed by consolidation (6-MP,MTX 5 g/m2 x 4, MTX i.th.), and maintenance up to 24 months. Pts of stages III and IV receive additionally reinduction (Dexamethasone, VCR, doxorubicin, L-ASP, CP, ARA-C, 6-thioguanine, MTX i.th.) and cranial irradiation. Pts with < 70% tumor regression at day 33 of induction receive an intensified chemotherapy. Pts with > 70% tumor regression at day 33 but a persistent mass at the end of induction have a surgical resection. Pts with a completely necrotic residual mass continue with consolidation therapy. Pts with active residual lymphoma receive an intensified chemotherapy. No local radiotherapy is given. From 4/1990 to 12/1992, 80 pts were registered; 71 pts are evaluable for response. The distribution of stages is as follows: 6, 1, 47, 17 pts of stage I, II, III, IV, respectively. The probability of event free survival at 3 years is 87 +/- 4% for the whole group (median observation time 21 months). 66 pts are evaluable for the dynamic of response.(ABSTRACT TRUNCATED AT 250 WORDS)

[NHL-BFM 90 therapy study in treatment of malignant non-Hodgkin's lymphoma in children and adolescents. Part 3: An intermediate term analysis of the B-NHL/B-ALL]. / Therapiestudie NHL-BFM 90 zur Behandlung maligner Non-Hodgkin-Lymphome bei Kindern und Jugendlichen. Teil 3: Eine Zwischenanalyse der Therapiegruppe B-NHL/B-ALL.

The aims of trial NHL-BFM 90 for patients (pts) suffering from B-cell neoplasms are to prove whether: 1. Treatment for pts with complete resection can be reduced from 3 to 2 therapy courses; 2. Results for pts of stage III with large abdominal tumors can be improved by high dose (HD) chemotherapy; 3. Survival for pts with incomplete initial response can be improved by therapy intensification; 4. Intraventricularly applied CNS chemotherapy can improve the outcome for CNS positive pts. Therapy is stratified into 3 branches. Branch 1: completely resected; branch 2: not resected, extra-abdominal localization only or abdominal localization and LDH < 500 U/l; branch 3: abdominal localization and LDH > or = 500 U/l, and all pts with BM or/and CNS involvement or multifocal bone disease. A 5-day prephase is followed by 2 (R1), 4 (R2), 6 (R3) therapy courses composed of dexamethasone (DEXA), methotrexate (MTX) 5 g/m2/24 h (in branch R1, 500 mg/m2), MTX/Cytarabine (ARA-C)/prednisolone (PRED) i.th., vincristine (not in branch R1), ifosfamide alternating with cyclophosphamide, ARA-C/etoposide (VP16) alternating with doxorubicin. CNS pos. pts receive MTX/ARA-C/PRED applied intraventricularly. Pts with incomplete response after 2 courses receive an intensification (DEXA, Vindesine, HD-ARA-C, VP16, and MTX/ARA-C/PRED i.th.). Pts with viable tumor after the intensified course receive mega-dose chemotherapy with autologous BM rescue (aBMT). From 4/1990 to 12/1992, 228 pts were registered; 212 pts are evaluable for response. The probability of event free survival (pEFS) at 3 years is 89 +/- 2% for the whole group, 97 +/- 3% for pts of branch R1 (n = 32), 99 +/- 1% for patients of branch R2 (n = 87), and 77 +/- 4% for patients of branch R3 (n = 94) (median observation time 21 months). 7 pts of branch R3 died early due to infections. 15 pts failed therapy (one pt each in branch R1, and R2, 13 pts in branch R3). pEFS for pts with stage III abdominal disease and LDH > or = 500 U/l is 80 +/- 6 as compared to 53 +/- 8% in the preceding studies (p < .02). Of 13 evaluable pts with CNS disease 3 died early of infection, however none suffered from relapse. Only 1 of 22 pts of branch R2 who had residual tumors after 2 therapy courses suffered from progress in contrast to 9 of 33 such pts of branch R3. Only 2 pts had viable tumor after the intensification course CC. They received aBMT, both are in CCR.(ABSTRACT TRUNCATED AT 400 WORDS)

Differential regulation of stem cell factor mRNA expression in human endothelial cells by bacterial pathogens: an in vitro model of inflammation.

Production of hematopoietic growth factors by endothelial cells plays a pivotal role during inflammatory processes. Stem cell factor (SCF) is known to be expressed constitutively in endothelial cells. To investigate the regulation of this cytokine expression by inflammatory stimuli, we cocultured human umbilical vein endothelial cells (HUVEC) with various gram-negative bacterial strains (Escherichia coli, Yersinia enterocolitica, Chlamydia trachomatis, and Neisseria meningitidis, respectively). Experiments were performed with bacterial concentrations ranging from 10(2) to 10(7) bacteria/mL for 3 hours. SCF-specific mRNA expression was studied using Northern blot analysis. Stimulation with the enteropathogenic bacterial strains Y enterocolitica and E coli resulted in a significant concentration-dependent increase of SCF mRNA expression. Similar results were obtained in coculture experiments with N meningitidis. As shown in experiments with E coli, the accumulation of SCF transcripts was also time-dependent. In contrast, coculture of HUVEC with the intracellular gram-negative strain C trachomatis had no effect on SCF mRNA expression. To elucidate the role of the gram-negative bacterial cell wall components, we stimulated HUVEC with bacterial lipopolysaccharide (LPS). LPS induced a maximal SCF mRNA accumulation within 2 hours followed by decrease of SCF-specific transcripts to the basal level after 24 hours. In addition, we exposed HUVEC to the classical inflammatory cytokine interleukin-1 alpha (IL-1 alpha). Kinetic experiments showed a similar pattern of regulation with an increase of SCF mRNA within 2 hours, persisting up to 12 hours, and a decrease to basal transcription after 24 hours. From these data, we conclude that SCF expression is regulated by inflammatory stimuli, such as IL-1 alpha and bacterial pathogens, suggesting an important role of SCF during inflammation.

Successful treatment strategy for Ki-1 anaplastic large-cell lymphoma of childhood: a prospective analysis of 62 patients enrolled in three consecutive Berlin-Frankfurt-Munster group studies.

PURPOSE: To prove prospectively the efficacy of a short-pulse chemotherapy for treatment of Ki-1 anaplastic large-cell lymphoma (ALCL) of childhood. PATIENTS AND METHODS: From October 1983 to December 1992, 62 patients (median age, 9.7 years) with newly diagnosed Ki-1 ALCL were enrolled onto Non-Hodgkin's Lymphoma-Berlin-Frankfurt-Munster (NHL-BFM) studies 83, 86, and 90. The most frequent immunophenotype was T cell. Ki-1 ALCL differed from other subsets of NHL of childhood by the more frequent involvement of bone, soft tissue, and skin, and by the lack of bone marrow (BM) disease. A 5-day prephase course (prednisone/cyclophosphamide) was followed by two different 5-day courses of chemotherapy: course A consisted of dexamethasone, methotrexate (MTX) 0.5 g/m2 (24-hour infusion), intrathecal chemotherapy, ifosfamide, cytarabine (Ara-C), and etoposide (VP-16); course B consisted of cyclophosphamide and doxorubicin instead of ifosfamide, and Ara-C/VP-16, respectively. Treatment was stratified into three branches. Branch 1 (stage I and stage II resected) received three courses; branch 2 (stage II not resected, stage III), six courses; and branch 3 (stage IV), six intensified courses containing MTX 5 g/m2, and Ara-C 2 g/m2. Local radiotherapy was not performed. RESULTS: Four patients failed to enter remission, and one died of infection. Seven patients relapsed within 9 months after diagnosis; two patients had isolated local relapses, but BM and CNS were never involved. Fifty patients have been in first continuous complete remission (CR) for 0.6 to 9.7 years (median, 2.5), and 56 are alive. The probabilities for survival and event-free survival (EFS) at 9 years are 83% +/- 7% (SE) and 81% +/- 5%. Skin involvement was the only negative prognostic parameter. CONCLUSION: Short-pulse chemotherapy over 2 to 5 months without local therapy modalities is effective in the treatment of Ki-1 ALCL.

[Long-term treatment with recombinant human granulocyte colony stimulating factor in patients with severe congenital neutropenia]. / Langzeitbehandlung mit rekombinantem humanen Granulozyten-Kolonien stimulierenden Faktor bei Patienten mit schwerer kongenitaler Neutropenie.

Severe congenital neutropenia is a disorder of myelopoiesis characterized by severe neutropenia secondary to either a maturational arrest of myelopoiesis at the level of promyelocytes (Kostmann-Syndrome; SCN) or regular cyclic fluctuations in the number of blood neutrophils with a median ANC below 500/microliter (cyclic neutropenia). We have treated 32 patients with SCN and 4 patients with cyclic neutropenia. Thirty of 32 patients with SCN and all 4 patients with SCN responded to r-met HuG-CSF treatment with an increase of the median ANC to above 1000/microliter. The doses needed to achieve and maintain the response varied between 0.8 and 120 micrograms/kg/d. Long-term treatment did not exhaust the myelopoiesis: The mean ANC remained stable up to 5 years of treatment. The increase in ANC was associated with dramatic clinical responses: significant reduction of severe bacterial infections, reduction of intravenous antibiotic treatment episodes, and reduction of hospitalizations. No severe bacterial infections occurred in any of the r-met HuG-CSF responders during long-term treatment. Severe adverse event, most likely associated with the underlying disease, included the development of MDS/Leukemia in two patients, and osteopenia/osteoporosis in 12 patients. These results demonstrate the beneficial effects of r-met HuG-CSF treatment in severe congenital neutropenia patients.

Effects of human stem cell factor (c-kit ligand) on proliferation of myeloid leukemia cells: heterogeneity in response and synergy with other hematopoietic growth factors.

A novel hematopoietic growth factor, the stem cell factor (SCF), for primitive hematopoietic progenitor cells has recently been purified and its gene has been cloned. In this study we tested the mitogenic activity of recombinant human SCF on myeloid leukemia cells as well as the expression of its receptor. We have investigated the proliferation of 31 myeloid leukemia cell lines as well as fresh myeloid leukemic blasts from 17 patients in a 72-hour 3H-thymidine uptake assay in the presence of various concentrations of recombinant human (rh) SCF alone or in combination with saturating concentrations of granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, M-CSF, interleukin-3 (IL-3), or erythropoietin (EPO). Only five of 31 lines, but fresh leukemic blasts from 12 of 17 patients with acute myeloid leukemia (AML), significantly responded to SCF. The responding cell lines were of the acute promyelocytic, chronic myeloid, megakaryoblastic, and erythroleukemia origin, the responding blast preparations of all French-American-British subtypes. Synergistic activities of SCF were found with G-CSF, GM-CSF, EPO, and IL-3. To determine the SCF binding sites on leukemic cells, we used 125I-radiolabeled SCF in Scatchard analysis and cross-linking studies. The leukemic cell lines responding to SCF expressed from 2,300 up to 29,000 binding sites per cell. The SCF receptor expression was downregulated in vitro by the presence of its ligand. Cross-linking studies demonstrated a 150-Kd SCF receptor on the surface of all responding myeloid leukemias. This study suggests that SCF may be an important factor for the growth of myeloid leukemia cells, either as a direct stimulus or as a synergistic factor for other cytokines. Furthermore, using polymerase chain reaction analysis of total RNA from the myeloid leukemia lines, we found expression of SCF-mRNA in 17 of 30 lines, suggesting autocrine mechanisms in the growth of a subgroup of leukemic cells by coexpression of SCF and its receptor.