Wolfgang Dörffel

Late valvular and other cardiac diseases after different doses of mediastinal radiotherapy for hodgkin disease in children and adolescents: Report from the longitudinal GPOH follow‐up project of the German–Austrian DAL‐HD studies

To analyze the impact of mediastinal irradiation on the incidence of cardiac late effects in long‐term survivors of pediatric Hodgkin disease (HD).

Response-adapted radiotherapy in the treatment of pediatric Hodgkin’s disease: an interim report at 5 years of the German GPOH-HD 95 trial ☆

PURPOSE A multinational trial on pediatric Hodgkins disease (HD) with the aim to reduce the risk of long-term toxicity of combined modality treatment by restricting dose and volume of radiation therapy (RT) while maintaining the excellent treatment results of previous German multicenter trials (DAL-HD82-90). METHODS AND MATERIALS Patients were treated according to stage of disease (CS) and defined risk factors in three treatment groups (TG) with 2, 4, or 6 cycles of combination chemotherapy. When a complete remission (CR) had been achieved, treatment was terminated without RT independent of initial stage or tumor bulk. Patients with a partial remission (PR) of >75% tumor regression were irradiated with 20 Gy using modified involved fields; in the case of PR <75% RT dose was 30 Gy, residual masses >50 mL received 35 Gy. RESULTS From August 1995 to July 2000 a total of 956 patients have been registered, 830 as trial patients, 39% in TG1, 27% in TG2, 34% in TG3. 827 patients were evaluable by June 2001 with a median follow-up of 38 months. Chemotherapy (CTx) resulted in CR in 22%, PR >75% in 62%, PR <75% in 12%. Event-free survival (EFS) for the entire group is 90% (SD 0.01), for TG1 94%, TG2 91%, and TG3 84%; the overall survival is 97% in Kaplan-Meier-analysis. Relapse-free survival (RFS) is superior for patients with RT after PR (93%) than for those without RT after CR (89%); the difference is significant (p = 0.01) for advanced stages, however not in TG1. Seventy-two events were observed by June 2001: 28 progressions during the initial therapy or within the first 3 months, 38 relapses, 3 second malignancies, three fatal accidents or infections; 18 patients have died. CONCLUSION Treatment results of the GPOH-HD 95 trial are excellent thus far. The reduction of RT dose and volume in PR has not caused a significant impairment of overall and event-free survival in comparison to the previous German trials; however, failure rates are higher in advanced stages when RT is omitted after achieving a CR. It is too early to tell whether the HD 95 protocol will be successful in reducing late toxicity.

Resection Alone in 58 Children With Limited Stage, Lymphocyte-predominant Hodgkin Lymphoma-Experience From the European Network Group on Pediatric Hodgkin Lymphoma

Lymphocyte‐predominant Hodgkin lymphoma (LPHL) is a rare, CD20‐positive, good prognostic lymphoma in children. Patients with early‐stage LPHL who underwent successful surgical lymph node resection alone have been reported. To clarify the optimum treatment strategy in children, European study groups were asked to report their experience of surgery alone used in the treatment of pediatric LPHL.

Treatment of Children and Adolescents With Hodgkin Lymphoma Without Radiotherapy for Patients in Complete Remission After Chemotherapy: Final Results of the Multinational Trial GPOH-HD95

UNLABELLED PURPOSE To minimize the risk of late effects in pediatric Hodgkin lymphoma (HL) by omitting radiotherapy (RT) in patients in complete remission (CR) after chemotherapy and reducing the standard radiation dose to 20 Gy in patients in incomplete remission. PATIENTS AND METHODS Between 1995 and 2001, 925 patients with classical HL (cHL) were registered from seven European countries in German Society of Pediatric Oncology and Hematology Hodgkin Lymphoma Trial 95. Patients in treatment group 1 (TG1; early stages) received two cycles of vincristine, prednisone, procarbazine, and doxorubicin or vincristine, prednisone, etoposide, and doxorubicin chemotherapy; additional two or four cycles of cyclophosphamide, vincristine, prednisone, and procarbazine were added in TG2 (intermediate stages) or TG3 (advanced stages), respectively. Patients in CR (assessed by computed tomography or magnetic resonance imaging) did not undergo RT. Those with tumor volume reduction more than 75% received reduced involved-field RT with 20 Gy and an additional 10- or 15-Gy boost only for larger residuals. RESULTS Rates of overall survival, progression-free survival (PFS), and event-free survival at 10 years were (± SE) 96.3% ± 0.6%, 88.2% ± 1.1%, and 85.4% ± 1.3%, respectively. PFS for TG1 patients without or with RT was 97.0% ± 2.1% versus 92.2% ± 1.7% (P = .214) but was unsatisfactory for nonirradiated patients in TG2 (68.5% ± 7.4% v 91.4% ± 1.9%; P < .0001), with similar but not significant results in TG3 (82.6% ± 5.4% v 88.7% ± 2.0%, P = .259). Reduction of the standard radiation dose from 25 to 20 Gy did not increase failure rate. CONCLUSION RT can be omitted in early stage HL in so defined CR following this chemotherapy. RT with 20(-35) Gy proved to be sufficient in patients with incomplete remission following chemotherapy.

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.

Impact of Latent Epstein-Barr Virus Infection on Outcome in Children and Adolescents With Hodgkin's Lymphoma

PURPOSE The prognostic significance of latent Epstein-Barr virus (EBV) infection in Hodgkins lymphoma (HL) is debated controversially. Especially in the pediatric age group, no conclusive data are available. PATIENTS AND METHODS Eight hundred forty-two children and adolescents (median age, 13.7 years) from pediatric multicenter treatment studies HD-90 and HD-95 were studied for latent EBV infection in Hodgkins and Reed-Sternberg cells by immunostaining against latent membrane protein 1 (LMP-1). Results were compared with established risk factors. RESULTS Two hundred sixty-three patients (31%) were LMP positive. EBV infection correlated with sex (39% male v 23% female; P < .001), histologic subtype (69% mixed cellularity v 22% nodular sclerosis v 6% lymphocyte predominance; P < .001) and young age. With a median follow-up of 4.9 years, 820 patients (97%) are alive. Probability of overall survival at 10 years (+/- standard deviation) for EBV-negative and -positive patients was 98.1% +/- 0.6% and 95.1% +/- 1.4%, respectively (P = .017 by log-rank test). A negative effect of EBV infection became evident for patients with nodular sclerosis subtype Bennett II (P = .02), and those treated for advanced stages (P = .003). In multivariate analysis, LMP positivity was an independent factor for adverse outcome (RR = 3.08). Probability of failure-free survival (FFS) in LMP positive and negative patients was 89.1% +/- 2.3% and 84.1% +/- 3.9%, respectively (P = .86). CONCLUSION With effective combined treatment modalities in pediatric HL, latent EBV infection has no influence on FFS but is associated with an inferior overall survival in crucial subgroups.

Relapse of TEL-AML1–Positive Acute Lymphoblastic Leukemia in Childhood: A Matched-Pair Analysis

PURPOSE The aim of this study was to investigate whether, in relapsed childhood acute lymphoblastic leukemia (ALL), the frequent genetic feature of TEL-AML1 fusion resulting from the cryptic chromosomal translocation t(12;21)(p13;q22) is an independent risk factor. PATIENTS AND METHODS A matched-pair analysis was performed within a homogeneous group of children with first relapse of BCR-ABL-negative B-cell precursor (BPC) ALL treated according to relapse trials ALL-Rezidiv (REZ) of the Berlin-Frankfurt-Münster Study Group. A total of 249 patients were eligible for this study: 53 (21%) were positive for TEL-AML1, and 196 (79%) were negative. Positive patients were matched for established most-significant prognostic determinants at relapse, time point, and site of relapse, as well as age and peripheral blast cell count at relapse. RESULTS Fifty pairs matching the aforementioned criteria could be determined. The probabilities with SE of event-free survival and survival at 5 years for matched TEL-AML1 positives and negatives are 0.63 +/- 0.10 versus 0.38 +/- 0.10 (P =.09) and 0.82 +/- 0.09 versus 0.42 +/- 0.19 (P =.10), respectively. These results were confirmed by multivariate analysis, revealing an independent prognostic significance of time point and site of relapse (both P <.001) but not of TEL-AML1 expression (P =.09). CONCLUSION TEL-AML1 expression does not constitute an independent risk factor in relapsed childhood BCP-ALL after matching for relevant prognostic parameters. It undoubtedly characterizes genetically an ALL entity associated with established favorable prognostic parameters. High-risk therapeutic procedures such as allogeneic SCT should be considered restrictively.

Breast Cancer in Young Women After Treatment for Hodgkin’s Disease During Childhood or Adolescence: An Observational Study With up to 33-Year Follow-up

BACKGROUND The treatment of Hodgkins disease (HD; also called Hodgkins lymphoma) in children and adolescents with radiotherapy and chemotherapy leads to high survival rates but has a number of late effects. The most serious one is the development of a secondary malignant tumor, usually in the field that was irradiated. In women, breast cancer can arise in this way. METHOD Data on the occurrence of secondary breast cancer (sBC) were collected from 590 women who were treated in five consecutive pediatric HD treatment studies in the years 1978-1995 and then re-evaluated in a late follow-up study after a median interval of 17.8 years (maximum, 33.7 years). Information was obtained from 1999 onward by written inquiry to the participants and their treating physicians. The cumulative incidence of sBC was calculated by the Gooley method. RESULTS By July 2012, sBC had been diagnosed in 26 of 590 female HD patients; the breast cancer was in the irradiated field in 25 of these 26 patients. Their age at the time of treatment for HD was 9.9 to 16.2 years (the pubertal phase), and sBC was discovered with a median latency of 20.7 years after HD treatment (shortest latency, 14.3 years) and at a median age of 35.3 years (youngest age, 26.8 years). The radiation dose to the supradiaphragmatic fields ranged from 20 to 45 Gy. The cumulative incidence for sBC 30 years after treatment for HD was 19% (95% confidence interval, 12% to 29%). For women aged 25 to 45 in this series, the frequency of breast cancer was 24 times as high as in the corresponding normal population. CONCLUSION Women who were treated for HD in childhood or adolescence have an increased risk of developing breast cancer as young adults. The risk is associated with prior radiotherapy and with the age at which it was administered (the pubertal phase). Because of these findings, a structured breast cancer screening project for this high-risk group has been initiated in collaboration with the German Consortium for Hereditary Breast and Ovarian Cancer (Deutsches Konsortium für familiären Brust- und Eierstockkrebs).

Characterization and Expression of CT45 in Hodgkin's Lymphoma

Purpose: The monoclonal antibody Ki-A10 (IgG1) generated after immunization of mice with Hodgkins lymphoma cell line L428 detects a nuclear antigen in human tissues with a restricted distribution pattern similar to cancer/testis antigens. The aim of this study was to characterize the antigen and to determine the expression profile in Hodgkins lymphoma. Experimental Design: The half-life and phosphorylation of the antigen were determined by radiolabeling. The antigen was characterized by immunopurification and sequencing. Demethylation of genes is used to induce cancer/testis antigens. Ki-A10-negative cells were treated with 5-aza-2′-deoxycytidine. The Ki-A10 expression in paraffin-embedded tumors was determined immunohistochemically. Results: Immunopurification of the 25/22-kDa antigen and sequencing revealed a peptide of 14 amino acids corresponding to the gene product of the newly described gene family MGC27005, located on chromosome Xq26.3, now termed CT45. CT45 is significantly phosphorylated and down-regulated during mitosis. Demethylation of CT45-negative HeLa cells and stimulated peripheral blood lymphocytes induced CT45 expression. Except testis, immunohistochemical stainings of normal tissues, reactive lymphoid lesions, and most malignant tumors were negative. In comparison, 54 of 99 (55%) samples from pediatric and adolescent Hodgkins lymphoma patients enrolled in the multicenter trial HD-95 stained Ki-A10 positive. Ki-A10 expression correlated with histologic subtypes (nodular sclerosis Hodgkins lymphoma 68% versus mixed cellularity Hodgkins lymphoma 40% versus nodular lymphocyte predominant Hodgkins lymphoma 9%; P < 0.001). Conclusions: Ki-A10 is the first monoclonal antibody that detects CT45. As benign lymphoid lesions did not express CT45, the use of Ki-A10 antibody will facilitate the discrimination of Hodgkins lymphoma from reactive lymphadenopathies.

Secondary Malignancies Following Treatment for Hodgkin's Lymphoma in Childhood and Adolescence

BACKGROUND About 155 persons under age 18 develop Hodgkins lymphoma (HL) in Germany every year. More than 90% survive at least 20 years. They may, however, suffer from late sequelae of treatment, including secondary malignant neoplasia (SMN). METHODS 2548 patients from the German, Austrian, and Swiss pediatric Hodgkins lymphoma studies that were conducted over the period 1978-2002 were asked every 2-3 years about possible late sequelae of treatment, either directly or through their physicians. The documented cases of SMN were analyzed for cumulative incidence, standardized incidence rates (SIR), and absolute excess risk (AER). RESULTS 147 cases of SMN were diagnosed in 138 of the 2548 patients, including 47 cases of thyroid cancer, 37 of breast cancer, and 15 of hematopoietic neoplasia. The cumulative incidence of SMN at 20, 25, and 30 years was 7% , 11.2% , and 18.7% , respectively. These percentages are rather low compared to other international studies. For all types of SMN, the SIR was 9.1 and the AER was 16.8. Among the 123 patients with secondary solid tumors, 105 (85% ) had a tumor in the irradiated region. CONCLUSION Survivors of pediatric HL must be informed about the risk of late sequelae of treatment for HL, including SMN in the irradiated region, and that they will need regular follow-up examinations. In the future, radiotherapy for children and adolescents should be further reduced or entirely avoided.