Risk of secondary leukemia after treatment with etoposide (VP-16) for Langerhans' cell histiocytosis in Italian and Austrian-German populations.

To estimate the risk of secondary leukemias after treatment with etoposide (VP-16), we evaluated subjects treated for Langerhans' cell histiocytosis (LCH) according to cooperative protocols in Italy or in Austria, Germany, Holland and Switzerland (AGDS). For each subject, information was collected on the cumulative dosages of chemotherapy and radiotherapy received, vital status and occurrence of secondary leukemia. The expected number of leukemias was estimated using age-specific incidence rates from the cancer registries in Italy and Germany. Standardized incidence ratios (SIR) were used to measure the risk of secondary leukemia among LCH patients. Five leukemias occurred among the 241 Italian study patients (SIR 520), whereas no cases were reported among the 363 AGDS patients. Interestingly, and in contrast to previous descriptions of epipodophyllotoxin-related leukemias which are mostly FAB M4 or M5, these leukemias showed typical FAB M3 features, and received a dose of VP-16 > 4,000 mg/m2. Among the AGDS cohort, very few subjects were exposed to high doses of VP-16. The risk of secondary acute non-lymphoblastic leukemia (s-ANLL) among the Italian subjects exposed to VP-16 was more than 1,000 times greater than expected. The study suggests that high doses of VP-16 appear to increase the risk of s-ANLL in LCH patients. The fact that all the leukemias described in the Italian LCH cohort were promyelocytic, and evidence of a higher incidence of promyelocytic leukemias among Italians and Latinos, suggest that high doses of etoposide in subjects of Latino origin may lead to aberrations on chromosomes 15 and 17.

Increased risk of secondary leukemia after single-agent treatment with etoposide for Langerhans' cell histiocytosis.

The study evaluated 139 patients diagnosed with Langerhans' cell histiocytosis (LCH) and enrolled in any protocol of the Italian Association of Pediatric Hematology/Oncology since 1982. Treatment was etoposide (VP-16) only in 50 patients, VP-16 and other drugs with an already established leukemogenic effect in 17 patients, only drugs with leukemogenic effect in 6 patients, other drugs in 35 patients, and surgery only in 31 patients. Median length of follow-up after diagnosis was 65 months (range, 1 to 126 months) for a total of 742.5 person-years at risk (PYRs). Three cases of acute myelogenous leukemia (AML) were reported; only 0.0044 case was expected. The standard incidence ratio (SIR) of AML in this cohort was 680.5 [95% confidence interval (CI), 140.2-1988.5], and the incidence rate per 1000 PYRs was 4.0 (95% CI, 0.8-11.8). For the subgroup treated with single-agent VP-16, the SIR after treatment was 2270.0 (95% CI, 275-8199), and the incidence rate after treatment was 14.7 (95% CI, 1.8-42.8). The study confirms a higher risk of leukemia after LCH and supports the hypothesis of an association between treatment-related acute nonlymphocytic leukemia and single-agent treatment with VP-16.

Lactate dehydrogenase isoenzyme patterns in blood cells from histiocytosis X children.

To find a clinical assay for histiocytosis X (HX) diagnosis, measurements were made of both activity and isoenzyme distribution of lactate dehydrogenase (LDH; EC 1.1.1.27) from the blood cells of 6 acute phase and 9 remission patients. A significant increase in the LDH activity measured in the monocytes and lymphocytes isolated from the blood of the acute phase patients was found. The increased activity was due to an enhancement of the normal pattern of LDH isoenzymes in these cells and not to a change in isoenzyme distribution. No increase was found in monocyte LDH isoenzymes from the patients in remission.

Langerhans cell histiocytosis in childhood: results from the Italian Cooperative AIEOP-CNR-H.X '83 study.

Ninety patients with biopsy-proven Langerhans cell histiocytosis (LCH) were enrolled from June, 1983, to December, 1988, in the multicenter AIEOP-CNR-H.X. '83 study. They were divided into two groups: poor prognosis (PP), comprising 11 children with organ dysfunction (OD), and good prognosis (GP), made up of 79 patients without OD. Eighty-four patients were evaluable for treatment results. Among GP patients, 16 with a single lesion received only local treatment, while 59 entered a clinical trial of immunotherapy and/or monochemotherapy with vinblastine (VBL). Nonresponders, sequentially received doxorubicin (ADM) and then etoposide (VP16). PP patients were treated with 4 week cycles of vincristine, ADM, cyclophosphamide, and prednisone for nine courses. The overall survival was 92.8% (100% for GP patients and 45.5% for PP patients) at 48 months. The complete response (CR) rates for immunotherapy, VBL, ADM, and VP16 were 10%, 62.9%, 42.8%, and 88.2%, respectively. Two of the 11 PP patients had a CR (18.2%), while six died and three are still alive with recurrent disease. The overall incidence of disease-related disabilities was 47.7%, while that of diabetes insipidus was 20%. Monochemotherapy is probably adequate in GP patients, while more effective treatments are needed for PP patients.

Angioimmunoblastic lymphadenopathy with dysproteinemia: report of a case in infancy with review of literature.

A case of angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) in infancy is reported. The disease had a mild onset with generalized lymphadenopathy, hepatosplenomegaly, thrombocytopenia, polyclonal hypergammaglobulinemia, and T-cell deficiency. The AILD course lasted more than 100 months, alternating clinical remission to recurrent relapses. Hepatitis B viral infection suddenly evolving to hepatic failure was the cause of death. From a rapid survey of the present knowledge, the nosology, immunological features, and therapy of AILD are discussed and a possible presumptive pathogenetic pathway is proposed.

Etoposide in recurrent childhood Langerhans' cell histiocytosis: an Italian cooperative study.

Eighteen evaluable children with recurrent Langerhans' cell histiocytosis (LCH) which was resistant to standard therapy, were treated with etoposide (VP 16-213), 200 mg/m2/day for 3 days every 3 weeks, to study the efficacy and toxicity of this drug. Complete and partial responses were demonstrated in 15 patients (83.3%). Only one of the 12 children achieving a complete remission has relapsed. No dose-limiting major toxicities were registered. Although etoposide might be an effective treatment in recurrent LCH which needs a chemotherapeutic approach, it is emphasized that this drug must be used carefully.

[Massive therapy and transplant of autologous bone marrow in childhood lymphomas and solid tumors. State of the art and perspectives]. / Terapia massiva e trapianto di midollo autologo nei linfomi e tumori solidi pediatrici. Stato dell'arte e prospettive.

The role of massive therapy followed by autologous bone marrow transplantation (ABMT) in pediatric tumours is reviewed. The rationale of such an approach based on dose-response relationship in clinical oncology, the usefulness of total body irradiation (TBI) as a part of conditioning regimens, and phase I and II trials with high dose drug combinations are discussed. The results of ABMT in lymphomas, sarcomas, neuroblastomas and other tumours are critically analyzed with special emphasis on prognostic factors, differences among conditioning regimens, intensive therapy morbidity and marrow purging procedures. Finally future perspectives and questions still unsolved are briefly summarized.

Heterogeneity of immunological patterns in Langerhan's histiocytosis and response to crude calf thymic extract in 11 patients.

Response to treatment with daily intramuscularly administered crude calf thymic extract (Suppressin) in 11 patients with Langerhan's histiocytosis (L.H.) is reported. In ten patients, T-lymphocytic subsets were studied before starting immunotherapy: OKT3 positive and OKT4 positive cells were reduced in four patients; OKT8 positive cells were reduced in two patients; three patients were normal. After immunotherapy, one patient entered complete remission, four patients had stationary disease, and six had marked clinical progression. Subsequently eight patients underwent conventional chemotherapy, and only three entered complete remission. This study has demonstrated the heterogeneity of immunological patterns in L.H. and justifies the necessity for investigations on the immunoregulatory mechanism of L.H.