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-Hodgkin's 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 Burkitt's-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.

Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86.

PURPOSE: Cooperative Ewing's Sarcoma Study (CESS) 86 aimed at improving event-free survival (EFS) in patients with high-risk localized Ewing tumor of bone. PATIENTS AND METHODS: We analyzed 301 patients recruited from January 1986 to July 1991 (60% male; median age 15 years). Tumors of volume >100 mL and/or at central-axis sites qualified patients for "high risk" (HR, n = 241), and small extremity lesions for "standard risk" (SR, n = 52). Standard-risk patients received 12 courses of vincristine, cyclophosphamide, and doxorubicin alternating with actinomycin D (VACA); HR patients received ifosfamide instead of cyclophosphamide (VAIA). Tumor sites were pelvis (27%), other central axis (28%), femur (19%), or other extremity (26%). The initial tumor volume was <100 mL in 33% of cases and > or =100 mL in 67%. Local therapy was surgery (23%), surgery plus radiotherapy (49%), or radiotherapy alone (28%). Event-free survival rates were estimated by Kaplan-Meier analyses, comparisons were done by log-rank test, and risk factors were analyzed by Cox models. RESULTS: On May 1, 1999 (median time under study, 133 months), the 10-year EFS was 0.52. Event-free survival did not differ between SR-VACA (0.52) and HR-VAIA (0.51, P =.92). Tumor volume of >200 mL (EFS, 0.36 v 0.63 for smaller tumors; P =.0001) and poor histologic response (EFS, 0.38 v 0.64 for good responders; P =.0007) had negative impacts on EFS. In multivariate analyses, small tumor volumes of <200 mL, good histologic response, and VAIA chemotherapy augured for fair outcome. Six of 301 patients (2%) died under treatment, and four patients (1.3%) developed second malignancies. CONCLUSION: Fifty-two percent of CESS 86 patients survived after risk-adapted therapy. High-risk patients seem to have benefited from intensified treatment that incorporated ifosfamide.

Do patients with metastatic and recurrent rhabdomyosarcoma benefit from high-dose therapy with hematopoietic rescue? Report of the German/Austrian Pediatric Bone Marrow Transplantation Group.

Patients with primary metastatic or recurrent rhabdomyosarcoma (RMS) have a very poor prognosis. Since high-dose chemotherapy (HDC) +/- TBI was thought to improve survival, many centers performed this therapy using different types of hematopoietic rescue (auto BM or PBSC, allo BM). This is a retrospective, multi-center analysis of the results of treatment in 36 patients with primary metastatic or relapsed RMS who were given HDC +/- TBI and hematopoietic rescue between 1986 and 1994. The median age was 6 years (< 1-22 years). Primary therapy was given according to either one of the Cooperative German Soft Tissue Sarcoma Studies CWS-81, -86, -91 or the European Study for Stage IV Malignant Mesenchymal Tumors in Childhood. There were 22 alveolar RMS, 13 embryonal RMS and one undifferentiated sarcoma. The indication for HDC was primary metastatic disease (27 patients) or a relapse of a primary localized tumor (nine patients). Thirty-two patients were in 1st or 2nd CR when given HDC and four in VGPR. The median time from last event to HDC was 44 weeks (21-110). HDC consisted of fractionated melphalan ((4 x 30-45 mg/m2), VP16 40-60 mg/kg, carboplatin 3 x 400-500 mg/m2) in 26 patients, 10 of whom received additional FTBI. Seven patients were treated with melphalan alone or in combination with carboplatin. Two patients received cyclophosphamide/busulphan with TLI (total lymphoid irradiation) and one cyclophosphamide with FTBI. Thirty-one patients were given autologous BM or PBSC as hematopoietic rescue and five allogeneic bone marrow from HLA-identical siblings. Fourteen patients received GM-CSF or G-CSF after hematopoietic stem cell transfusion (HSCT). Ten patients received adjuvant IL-2. There was one toxic HDC-related death. Nine patients are alive and free of disease with a median observation time of 57 months (32-108). The median time from HDC to relapse was 4 months (1-17). The tumor recurred in the majority of patients at previously known sites; in three cases new metastatic sites were observed. Patients with primary localized tumors who had been treated with HDC because of relapse did slightly better (four of nine alive with NED) than patients with primary metastatic disease (five of 27 alive with NED). HDC is still of uncertain value in the therapy of poor-risk rhabdomyosarcoma and should be performed only as part of controlled clinical trials.

Diffusion-weighted magnetic resonance imaging of treatment-associated changes in recurrent and residual medulloblastoma: preliminary observations in three children.

PURPOSE: To emphasize a possible role of magnetic resonance (MR) diffusion-weighted imaging (DWI) for lesion conspicuity and detection of treatment effects in children with medulloblastoma. MATERIAL AND METHODS: Three children with medulloblastoma (two residual and one recurrent) were examined repetitively by MR diffusion-weighted imaging. Regional assessment of the apparent diffusion coefficient (ADC) was done for tumorous lesions and periventricular white matter appearing normal on standard MR images. RESULTS: All lesions were clearly visible on DWI. In the case of recurrent tumor, on one scan, DWI showed lesions that were not seen on contrast-enhanced MRI. Increase (41%) of ADC was seen in one lesion, which subsequently responded completely to treatment over 27 months' follow-up. Intermediate increases (23-26%) of ADC were found with partial therapy response in three lesions. In contrast, a decrease (-11%) of ADC in two lesions was seen with tumor progression. CONCLUSION: These observations may suggest a role for DWI in early detection of metastatic disease and treatment monitoring of medulloblastoma, warranting a formal study.

[Treatment strategies in malignant non-Hodgkin lymphomas in childhood]. / Behandlungsstrategien der malignen Non-Hodgkin-Lymphome im Kindesalter.

The prognosis of malignant non-Hodgkin lymphoma (NHL) in childhood has significantly improved due to stage-depending intensity and duration of treatment as well as the use of different therapeutic managements in non-B and B-lymphoma. According to the results of two consecutive BFM-studies (BFM-NHL 75/81, n = 116; BFM 81/83, n = 95) a curative rate of 70% may be reached with an acceptable therapeutic toxicity (under 2% deaths in the BFM-NHL-study 81/83). This result was already achieved in non-B-NHL in the study 75/81 by using an ALL therapy protocol. An improvement in the outcome of B-NHL was only achieved in the study 81/83 by introducing a new therapeutic concept including a combination of other agents and by reducing the duration of treatment to 8 weeks (stage I and II) and to 20 weeks (stage III and IV), respectively. In contrast to the non-B NHL, the prognosis of B-NHL distinctly varies according to the localized (I and II) and disseminated stage (III and IV). The probability of eventfree survival in the localized stage of B-NHL is excellent in both BFM-studies (86-100%). In the disseminated stage of B-NHL the result is not satisfying so far (61% in the study 81/83 vs. 38% in the study 75/81). The relapse cascade in non-B NHL proceeds similar to ALL in childhood. No relapses have been observed within 5 years after diagnosis. Recurrence in B-NHL only occurs within the first year after diagnosis which justifies the reduction of treatment duration.

[Childhood B-cell lymphomas and leukemias. Improvement of prognosis by a therapy developed for B-neoplasms by the BFM study group]. / Kindliche B-Zell-Lymphome und -Leukämien. Verbesserung der Prognose durch eine für B-Neoplasien konzipierte Therapie der BFM-Studiengruppe.

In two consecutive therapy studies, the BFM multicenter study group treated 55 children with B-NHL from 1975 until 1981 and another 55 children with B-NHL and 22 with B-ALL since 1981. In the 1975/81 study, a therapeutic regimen which produced excellent results in non-B-NHL and -ALL, emerged to be much less effective in disseminated B-NHL. With this regimen the probability of continuous complete remission (CCR) in advanced disease was 34% only after 7 years. Since 1981, a new therapeutic regimen of higher specificity for B-neoplasias improved the probability of CCR at the present time to 100% in localised B-NHL, to 63% in disseminated B-NHL and even in B-ALL to 49%.

Bacteriological and serological findings in a further case of transfusion-mediated Yersinia enterocolitica sepsis.

A 13-year-old patient developed severe shock due to administration of a Yersinia enterocolitica-contaminated red blood cell concentrate. Y. enterocolitica (serotype O:9, biotype II) was cultivated from the residual blood in the blood bag and from a stool sample of the blood donor. In the donor's plasma immunoglobulin M (IgM), IgA, and IgG antibodies against Yersinia outer proteins (YopM, -H, -D, and -E) were found. Since the donor remembered a short-lasting, mild diarrhea 14 days prior to blood donation, a transient attack of Yersinia enteritis may be associated with a longer than expected period of asymptomatic bacteremia that causes contamination of donor blood. Serological screening for IgM antibodies against Yersinia outer proteins might offer a way to reduce the risk of transfusion-associated Y. enterocolitica sepsis.

Myocardial high-energy phosphate metabolism is altered after treatment with anthracycline in childhood.

OBJECTIVES: We aimed to investigate whether changes in high-energy phosphate metabolism after treatment of children and young adults with anthracycline can be demonstrated non-invasively by 31P magnetic resonance spectroscopy. BACKGROUND: Abnormal myocardial energy metabolism has been suggested as a mechanism for anthracycline-induced cardiotoxicity. Deterioration in such has been shown in animal studies by resonance spectroscopy. METHODS: We studied 62 patients, with a mean age of 13.5+/-5 years, 3.7+/-4.3 years after a cumulative anthracycline dose of 270+/-137 mg/m2. Normal echocardiographic findings had been elicited in 54 patients. The control group consisted of 28 healthy subjects aged 20+/-7 years. Resonance spectrums of the anterior left ventricular myocardium were obtained at 1.5 Tesla using an image-selected in vivo spectroscopy localization technique. RESULTS: The ratio of phosphocreatine to adenosine triphosphate after blood correction was 1.09+/-0.43 for the patients, and 1.36+/-0.36 (mean+/-SD) for controls (p=0.005), with a significantly reduced mean ratio even in the subgroup of patients with normal echocardiographic results (1.11+/-0.44 versus 1.36+/-0.36, p=0.01). The ratio did not correlate with the cumulative dose of anthracycline. The ratio of phosphodiester to adenosine triphosphate was similar in patients and controls (0.90+/-0.56 versus 0.88+/-0.62). CONCLUSIONS: In patients treated with anthracyclines in childhood, myocardial high-energy phosphate metabolism may be impaired even in the absence of cardiomyopathy. Our data support the concept that anthracycline-induced cardiotoxicity is not clearly dose dependent.

MR diffusion imaging and 1H spectroscopy in a child with medulloblastoma. A case report.

We report on a child with a metastasising medulloblastoma which was assessed by MR diffusion imaging and 1H MR spectroscopy (MRS). Reduced mean apparent diffusion coefficients and a high amount of taurine could be demonstrated. This is the first reported case of high taurine in medulloblastoma in vivo and confirms earlier in vitro findings. It is suggested that the changes on diffusion imaging, possibly reflecting the small-cell histology of the tumour and high taurine in MRS, are indicative of medulloblastoma.

[The German Society of Pediatric Oncology Cooperative Ewing Sarcoma Studies CESS 81/86: report after 6 1/2 years]. / Die GPO cooperativen Ewing-Sarkom Studien CESS 81/86: Bericht nach 6 1/2 Jahren.

The GPO Cooperative Ewing's Sarcoma Study (CESS 81 with 10 months four-drug combination chemotherapy (vincristine, actinomycin D, cyclophosphamide, and adriamycin = VACA) and local control with surgery and/or radiation, following week 18, resulted in a Kaplan-Meier estimated disease-free survival of 51% after 6 1/2 years (51/93 patients disease-free). Tumor volume and histological response to primary chemotherapy were identified as most significant prognostic factors. As a consequence, the CESS 86 regimen was stratified according to risk of relapse. Standard risk patients (extremity tumors less than 100 ml tumor volume) were continued on VACA chemotherapy. In high risk patients (extremity tumors greater than 100 ml tumor volume, central tumors), cyclophosphamide in conventional dose (1200 mg/m2/course) was replaced by high doses of ifosfamide (6 g/m2/course) with mesna uroprotection (VAIA). Local control was obtained following week 9. Patients with radiation were randomised for conventional fractionation or accelerated split-course hyperfractionation. The study was piloted from February to December 1985: 27/37 patients were disease-free on October 1, 1987. The ongoing trial was started on January 1, 1986. On October 1, 1987. 63/66 patients were disease-free. In patients with large primaries, according to Kaplan-Meier life-table analysis, the disease-free survival was significantly better in patients receiving VAIA chemotherapy, compared to the previous VACA regimen. The toxicity of both combination chemotherapy regimens was comparable.

[BFM study 1981/83 of the treatment of highly malignant non-Hodgkin's lymphoma in children: results of therapy stratified according to histologic immunological type and clinical stage]. / BFM-Studie 1981/83 zur Behandlung hochmaligner Non-Hodgkin-Lymphome bei Kindern: Ergebnisse einer nach histologisch-immunologischem Typ und Ausbreitungsstadium stratefizierten Therapie.

99 children with non-Hodgkin's lymphoma entered the prospective, multicenter BFM study 81/83. They were treated with a four-fold stratified therapy according to clinical stage and origin of the lymphoma from B- or non-B-lymphocytes. In the BFM study 75/81, these criteria had been proven to be most relevant for prognosis. Therapy of non-B-NHL was very similar to the therapeutic concept as applied in acute lymphoblastic leukemias by the BFM group. For the NHL of B-type, a new therapeutic regimen was developed. Cytostatic drugs applied in this group were: medium dose methotrexate, cyclophosphamide in a fractionated manner of application, adriamycin, cytarabine, VM 26 and prednisone. The probability of disease-free survival was 80% after nearly 3 years for all patients. In non-B-NHL it was 89% in localized, and 79% in disseminated disease. All patients with localized B-NHL are surviving without relapse, while the probability of disease-free survival in patients with disseminated B-NHL was 67%. Thus, the therapy result in the latter group was doubled as compared to the result of the BFM study 75/81.

Favorable outcome of B-cell acute lymphoblastic leukemia in childhood: a report of three consecutive studies of the BFM group.

In 1981 the BFM group introduced a new treatment strategy for B-cell acute lymphoblastic leukemia (B-ALL). A cytoreductive prephase (prednisone/cyclophosphamide) was followed by eight 5-day courses of chemotherapy. Fractionated cyclophosphamide, methotrexate (MTX) 0.5 g/m2 (24-hour infusion), and MTX intrathecally were administered at each course and cytosine arabinoside (ARA-C)/teniposide (VM-26) was given alternately with doxorubicin. In study ALL-BFM-83, central nervous system (CNS) chemotherapy was intensified by adding dexamethasone, while MTX/ARA-C was administered intraventricularly. Therapy duration was reduced to six courses. In study ALL-BFM-86, MTX 0.5 g/m2 was replaced by high-dose (HD) MTX, 5 g/m2 (24-hour infusion), and MTX/ARA-C/prednisolone intrathecal therapy was introduced. Doses of ARA-C and VM-26 were increased and fractionated, cyclophosphamide was partially replaced by ifosfamide, and vincristine was added. CNS irradiation was 24 Gy for prevention and 30 Gy for overt disease in studies ALL-BFM-81 and -83, but was omitted in ALL-BFM-86. In all, 87 patients were enrolled, 22 (8 CNS-positive) in study All-BFM-81, 24 (7 CNS-positive) in study ALL-BFM-83, and 41 (0 CNS-positive) in study ALL-BFM-86. The estimated 5-year duration of event-free survival (EFS) was 43% in study ALL-BFM 81, 50% in study ALL-BFM-83, and 78% in study ALL-BFM-86 (minimal follow-up, 25 months). Nineteen of 24 relapses occurred while on therapy or shortly thereafter. In study ALL-BFM 81, the CNS was the most frequent site of failure. In ALL-BFM-83, there were no isolated CNS relapses, but more bone marrow (BM) relapses occurred. In ALL-BFM-86, localized manifestations were the predominant site of failure, no isolated BM relapses occurred, and only one CNS relapse was diagnosed. No single parameter exerted a consistent influence on outcome with one exception. The presence of residual disease after the first two courses was correlated with an increased risk of therapy failure. We conclude that an intensive, short-pulse therapy delivered within a 4-month period is highly effective in the treatment of B-ALL. In addition to fractionated cyclophosphamide/ifosfamide, a 24-hour infusion of HD MTX 5 g/m2 in conjunction with an i.th. therapy is an important component for prevention of both systemic and CNS relapses. CNS irradiation is not needed for CNS-negative patients.

[Treatment of soft tissue sarcomas in childhood and adolescence: results of the CWS-81 multicenter therapy study]. / Die Behandlung der Weichteilsarkome im Kindes- und Jugendalter: Ergebnisse der multizentrischen Therapiestudie CWS-81.

344 previously untreated patients, under 19 years of age, with soft tissue sarcoma (STS) entered the first German STS Study, CWS-81. 218 of them with chemosensitive STS (Group A: rhabdomyosarcoma [RMS], synovial sarcoma, extraosseous Ewing's sarcoma, undifferentiated sarcoma and malignant peripheral neuroectodermal tumor) were evaluable for this analysis after a minimum potential follow-up of 6 years. A staging system based on the extent of disease, defined post-surgically, was used. The chemotherapy for stages I-III (VACA cycle) consisted of vincristine, dactinomycin, cyclophosphamide and doxorubicin. Patients with metastatic disease as well as stage III patients who failed to respond to VACA, were given ifosfamide instead of cyclophosphamide. The definitive local tumor control procedure for patients in stages II-III depended upon the tumor status at second-look surgery after 16 weeks of chemotherapy (no irradiation, 40Gy or 50Gy). The DFS rate after 5 years for group A was 57 +/- 4% and for patients with non-metastatic tumors (Stages I-III), 69 +/- 4%. There was no difference in prognosis between stages I and II (DFS rate 88 +/- 5% and 88 +/- 6% respectively). The DFS rate for stage III was 54 +/- 5% and for stage IV, 11 +/- 5%. Lack of local tumor control was the main cause of therapy failure: 10% of patients with localized disease never achieved CR, 18% relapsed locally. The most important prognostic factors were tumor size (p = .0002) and the degree of tumor regression after primary chemotherapy (p = .02).(ABSTRACT TRUNCATED AT 250 WORDS)

[Current results of cooperative AML therapy studies in children: BFM-78 and 83]. / Aktuelle Ergebnisse der kooperativen AML-Therapiestudien bei Kindern: BFM-78 und -83.

271 children with AML entered the cooperative studies BFM-78 (151 pat.) and BFM-83 (120 pat.) since Dec. 1, 1978. In the second study BFM-83 the 8-10 week intensive induction/consolidation therapy of study BFM-78 was preceded by an 8-day intensive therapy consisting of cytosine arabinoside, daunorubicin and VP-16. 10 children died prior to starting the protocol therapy from hemorrhage and/or leukostasis. 80% of the 261 protocol patients achieved a complete remission. 7% were early deaths by hemorrhage and/or leukostasis 3% died of other complications. 10% were partial or nonresponders. 54 relapses, 11 with CNS involvement have occurred in study BFM-78 after a follow up of 2.10-6.7 years (median 4.10 yrs.). The life table probabilities for event free survival (EFS) and event free interval (EFI) after 6.7 years are 37% (SD 4%) and 47% (SD 5%) respectively. The results of study BFM-83 after a follow up of 0.3-2.8 years (median 1.8 yrs.) are: 23 relapses, EFS 40% (SD 10%) and EFI 48% (SD 12%). So far, the overall results of both studies are nearly identical. The analyses of the prognostic factors show that initial hyperleukocytosis (greater than or equal to 100 X 10(3)/mm3) represents a high risk for early fatal hemorrhage and/or leukostasis, for nonresponse and for the incidence of relapses. Initial deaths caused by hemorrhage and/or leukostasis occur also significantly more often in patients with M5-subtype and extramedullary organ involvement. Additional strategies for achieving a better prognosis in high risk patients are necessary.

The recurrence patterns of stages I, II and III neuroblastoma: experience with 77 relapsing patients.

BACKGROUND: Recurrences of neuroblastoma Evans' stage I-III are infrequent events and the types of its progression have rarely been reported. Therefore, we investigated the patterns of progression in a large series of patients with long follow-up. PATIENTS AND METHODS: The sites of relapse and time to progression and death of 381 consecutive patients in three cooperative trials (NB 79, 82, 85) with follow-up of 5-16 years were analysed. The Southern blot technique was used for N-myc investigation of tumor tissue. RESULTS: Of the 77 relapsing patients, 41 (53%) had local and 36 (47%) systemic recurrences. The relapses occurred in 9 of 76 stage I patients (6 local/3 systemic), in 4 of 82 stage II (1 local/3 systemic) and 64 of 223 stage III neuroblastoma (34 local/30 systemic) patients. The main sites of distant metastasis were bone marrow (41%), lymph nodes (39%) and bone (37%). The median transition time from localised to metastatic neuroblastoma was 13 months and the outcome as poor (overall survival 9 +/- 5%) as that of the primary metastatic disease (14 +/- 3%). Fifty-three children died of tumor progression and 15 patients of treatment-related complications or other non-tumor conditions. The median age at diagnosis was 43 months for the group with systemic relapse compared to 19 months with only local and 10 months without recurrences (p < 0.001). Elevated serum LDH levels at first diagnosis were seen in 81% with metastatic, in 55% with local and in 33% with no tumor progression (p < 0.001). N-myc amplification was found in 4/14 with local and in 6/12 with metastatic recurrences. CONCLUSION: The high incidence of systemic relapse and the long transition time suggest that transition from localised to metastatic neuroblastoma is not an uncommon pathway.

Pharmacokinetics of native Escherichia coli asparaginase (Asparaginase medac) and hypersensitivity reactions in ALL-BFM 95 reinduction treatment.

Repeated asparaginase treatment has been associated with hypersensitivity reactions against the bacterial macromolecule in a considerable number of patients. Immunological reactions may range from anaphylaxis without impairment of serum asparaginase activity to a very fast decline in enzyme activity without any clinical symptoms. Previous investigations on a limited number of patients have shown high interindividual variability of asparaginase activity time courses and hypersensitivity reactions in about 30% of patients during reinduction treatment. Therefore, monitoring of reinduction treatment was performed prospectively in 76 children with newly diagnosed acute lymphoblastic leukaemia (ALL). According to the ALL-Berlin-Frankfurt-Münster (BFM) 95 protocol, 10 000 U/m2 body surface area of native Escherichia coli asparaginase (Asparaginase medac) was given on d 8, 11, 15 and 18. In 45/76 children, trough and peak activities were determined with every dose, and also on d 4 and d 11 after the last administration. Data on asparaginase activity were not available from the remaining 31 patients, but information with regard to hypersensitivity reactions only was given. Eighteen out of 76 patients (24%) suffered a clinical hypersensitivity reaction; however, no silent inactivation was observed. Activity in the therapeutic range of greater than 100 U/l for at least 14 d was determined in 43 of the 45 patients who were analysed for enzyme activity.

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.