G. Henze

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.

Between April 1985 and March 1987 130 children and adolescents up to 18 years of age with first relapse of acute lymphoblastic leukemia (ALL) were registered on the stratified and randomized multicentric trial ALL-REZ BFM 85 designed for patients pretreated with intensive front-line therapies. Stratification criteria were time and site of relapse: bone marrow (BM) relapse on or up to 6 months after stopping front-line therapy (group A), BM relapse beyond 6 months after therapy (group B), and isolated extramedullary relapse at any time (group C). Treatment consisted of alternating courses of polychemotherapy including randomly administered high- or intermediate-dose methotrexate (HDMTX:12 g/m2 as 4-hour infusion; IDMTX: 1 g/m2 as 36-hour infusion). During maintenance therapy the patients received daily oral thioguanine and biweekly intravenous (IV) MTX. The overall second complete remission (CR) rate was 92% (groups A, B, and C: 88%, 92%, and 100%), and the probability of event-free survival (EFS) at 6 years is 0.31 +/- 0.04 (groups A, B, and C: 0.18 +/- 0.05, 0.30 +/- 0.07, and 0.72 +/- 0.11). HDMTX did not prove to be superior to IDMTX, which led to premature stopping of randomization. Risk factor analyses showed early relapse, particularly BM relapse within 18 months, and T-cell phenotype to be independent predictors of poor outcome. The incidence of central nervous system (CNS) relapses following BM relapse was 19%, indicating that reprophylaxis to the CNS with IV/intrathecal (IT) MTX was insufficient. For 17 children who received bone marrow transplantation in second CR from HLA-compatible siblings the EFS was 0.53 +/- 0.12 at 5 years. Their outcome was not influenced by the above-mentioned risk factors. With the proposed treatment regimen long-lasting second remissions can be achieved in about one third of patients even after intensive front-line treatment.

Cellular drug resistance is thought to be an important cause of the poor prognosis for children with relapsed or refractory acute lymphoblastic leukemia (ALL), but it is unknown when, to which drugs, and to what extent resistance is present. We determined in vitro resistance to 13 drugs with the MTT assay. Compared with 141 children with initial ALL, cells from 137 children with relapsed ALL were significantly more resistant to glucocorticoids, L-asparaginase, anthracyclines, and thiopurines, but not to vinca-alkaloids, cytarabine, ifosfamide, and epipodophyllotoxins. Relapsed ALL cells expressed the highest level of resistance to glucocorticoids, with a median level 357- and >24-fold more resistant to prednisolone and dexamethasone, respectively, than initial ALL cells, whereas the resistance ratios for the other drugs differed from 0.8- to 1.9-fold, intraindividual comparisons between initial and relapsed samples from 16 children with ALL showed that both de novo and acquired drug resistance were involved. Specific in vitro drug-resistance profiles were associated with high-risk relapsed ALL groups. In vitro drug resistance was also related to the clinical response to chemotherapy in relapsed/refractory childhood ALL. We conclude that drug resistance may explain the poor prognosis for children with relapsed/refractory ALL. These day may be helpful to design alternative treatment regimens for relapsed childhood ALL.

The methotrexate (MTX) rescue agent carboxypeptidase G2 (CPDG2) rapidly hydrolyses MTX to the inactive metabolite DAMPA (4-[[2,4-diamino-6-(pteridinyl)methyl]-methylamino]-benzoic acid) and glutamate in patients with MTX-induced renal failure and delayed MTX excretion. DAMPA is thought to be an inactive metabolite of MTX because it is not an effective inhibitor of the MTX target enzyme dihydrofolate reductase. DAMPA is eliminated more rapidly than MTX in these patients, which suggests a nonrenal route of elimination. In a phase II study (May 1997-March 2002), CPDG2 was administered intravenously to 82 patients at a median dose of 50 U kg(-1) (range 33-60 U kg(-1)). Eligible patients for this study had serum MTX concentrations of >10 microM at 36 h or >5 microM at 42 h after start of MTX infusion and documented renal failure (serum creatinine > or =1.5 times the upper limit of normal). Immediately before CPDG2 administration, a median MTX serum level of 11.93 microM (range 0.52-901 microM) was documented. Carboxypeptidase G2 was given at a median of 52 h (range 25-178 h) following the start of an MTX infusion of 1-12 g m(-2) 4-36 h(-1) and resulted in a rapid 97% (range 73-99%) reduction of the MTX serum level. Toxicity related to CPDG2 was not observed. Toxicity related to MTX was documented in about half the patients; four patients died despite CPDG2 administration due to severe myelosuppression and septic complications. In conclusion, administration of CPDG2 is a well-tolerated, safe and a very effective way of MTX elimination in delayed excretion due to renal failure.