Bernd Lathan

Dexa-BEAM in patients with Hodgkin's disease refractory to multidrug chemotherapy regimens: a trial of the German Hodgkin's Disease Study Group.

PURPOSE A prospective phase II study was conducted to evaluate the efficacy of dexamethasone, carmustine, etoposide, cytarabine, and melphalan (Dexa-BEAM) as salvage chemotherapy for patients with Hodgkins disease. PATIENTS AND METHODS Fifty-five patients progressing on or relapsing after eight- or 10-drug chemotherapy (cyclophosphamide, vincristine, procarbazine, and prednisone plus doxorubicin, bleomycin, vinblastine, and dacarbazine [COPP+ABVD] or COPP+ABV+ifosfamide, methotrexate, etoposide, and prednisone [IMEP]) were treated with Dexa-BEAM. Patients who responded after two cycles of Dexa-BEAM either continued treatment for another two to three cycles or received high-dose chemotherapy/autologous bone marrow transplantation (HDCT/ABMT) with cyclophosphamide, etoposide, and carmustine (BCNU) (CVB) as conditioning regimen. RESULTS Seventeen patients (31%) achieved a complete remission and 16 (29%) a partial remission, resulting in a response rate of 60% (95% confidence interval, 46% to 73%). Progressive disease developed in 18 patients. Toxicity of Dexa-BEAM was acceptable with pronounced, but temporary World Health Organization (WHO) grade III/IV granulocytopenia and thrombocytopenia occurring in more than 90% of all courses. Two patients died of sepsis during granulocytopenia. Three prognostic subgroups could be distinguished: (1) patients progressing on initial chemotherapy, (2) patients relapsing within 12 months, and (3) patients with late relapses. The response rates for these groups were 52%, 60%, and 83%, and the median survival duration 12, 29, and 40+ months, respectively. In a nonrandomized comparison, the survival of patients who responded to two cycles of Dexa-BEAM and had additional cycles of Dexa-BEAM (n = 14) was not different from those responding patients who underwent HDCT/ABMT (n = 19). However, the power to detect a 20% survival difference was only 33% in this comparison. CONCLUSION Dexa-BEAM is an effective salvage treatment for patients with Hodgkins disease who fail to respond to multidrug chemotherapy. Efficacy and toxicity are comparable to HDCT/ABMT and underline the need for prospective randomized trials to define better the role of HDCT with and without ABMT in these patients.

Low-dose radiation is sufficient for the noninvolved extended-field treatment in favorable early-stage Hodgkin's disease: long-term results of a randomized trial of radiotherapy alone.

PURPOSE To show that radiotherapy (RT) dose to the noninvolved extended field (EF) can be reduced without loss of efficacy in patients with early-stage Hodgkins disease (HD). PATIENTS AND METHODS During 1988 to 1994, pathologically staged patients with stage I or II disease who were without risk factors (large mediastinal mass, extranodal lesions, massive splenic disease, elevated erythrocyte sedimentation rate, or three or more involved areas) were recruited from various centers. All patients received 40 Gy total fractionated dose to the involved field areas but were randomly assigned to receive either 40 Gy (arm A) or 30 Gy (arm B) total fractionated dose for the clinically noninvolved EF. No chemotherapy was given. RT films were prospectively reviewed for protocol violations and recurrences retrospectively related to the applied RT. RESULTS Of 382 recruited patients, 376 were eligible for randomized comparison, 190 in arm A and 186 in arm B. Complete remission was attained in 98% of patients in each arm. With a median follow-up of 86 months, 7-year relapse-free survival (RFS) rates were 78% (arm A) and 83% (arm B) (P =.093). The upper 95% confidence limit for the possible inferiority of arm B in RFS was 4%. Corresponding overall survival rates were 91% (arm A) and 96% (arm B) (P =.16). The most common causes of death (n = 27) were cardiorespiratory disease/pulmonary embolisms (seven), second malignancy (six), and HD (five). Protocol violation was associated with significantly poorer RFS. Nonirradiated nodes were involved in 42 of 52 reviewed relapses, infield areas in 18, marginal areas in 17, and extranodal sites in 16. CONCLUSION EF-RT alone attains good survival rates in favorable early-stage HD. The 30-Gy dose is adequate for clinically noninvolved areas. Protocol violation worsens the subsequent prognosis. Relapse patterns suggest that systemic therapy can reduce the 20% long-term relapse rate.

Rapidly alternating COPP/ABV/IMEP is not superior to conventional alternating COPP/ABVD in combination with extended-field radiotherapy in intermediate-stage Hodgkin's lymphoma: final results of the German Hodgkin's Lymphoma Study Group Trial HD5.

PURPOSE To investigate whether treatment results in intermediate-stage Hodgkins lymphoma can be improved by rapid application of non-cross-resistant drugs, the 10-drug regimen cyclophosphamide, vincristine, procarbazine, and prednisone (COPP), doxorubicin, bleomycin, and vinblastine (ABV), and ifosfamide, methotrexate, etoposide, and prednisone (IMEP), repeated every 6 weeks, was compared with conventional alternating COPP/doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) administered every 8 weeks. PATIENTS AND METHODS From January 1988 to January 1993, 996 patients in stage I or II Hodgkins lymphoma with at least one risk factor (massive mediastinal tumor, massive spleen involvement, extranodal disease, elevated ESR, or more than two lymph node areas involved) and all patients in stage IIIA Hodgkins lymphoma were randomized to receive two cycles of COPP/ABVD or COPP/ABV/IMEP followed by extended-field radiotherapy. RESULTS Both regimens produced similar rates for treatment responses (complete remission, 93% v 94%), freedom from treatment failure (80% v 79%), and overall survival (88% for both regimens) at a median follow-up time of 7 years. Most serious toxicities during chemotherapy were similar in both regimens. However, World Health Organization grade 3 and 4 leukocytopenia occurred significantly more frequently in the COPP/ABV/IMEP arm (53% v 44% of patients; P =.010). There were no differences in the number of serious infections and toxic deaths during therapy. The number of second malignancies was also the same in both arms (22 each). CONCLUSION Alternating COPP/ABVD and rapid alternating COPP/ABV/IMEP in combination with extended-field radiotherapy are equally effective in intermediate-stage Hodgkins lymphoma and produce excellent long-term treatment results.

Prognosis in adult AML is precisely predicted by the DISC-assay using the chemosensitivity-index Ci.

We prospectively investigated the correlation between DISC-assay results and clinical response and also survival in patients with AML using a new method of evaluation.

Cytotoxic activity of 9-β-d-arabinofuranosyl-2-fluoroadenine 5-monophosphate (fludarabine, NSC 312887) in a human tumor cloning system

A human tumor cloning system was utilized to screen for in vitro antitumor effects of the new purine antimetabolite 9-beta-D-arabinofuranosyl-2-fluoroadenine 5-monophosphate. Two hundred and thirty-one specimens were evaluable for drug sensitivity information (i.e. greater than or equal to 20 colonies on control plates). The overall in vitro response rates (defined as a less than or equal to 50% survival of tumor colony forming units) at two different concentrations of the new drug (0.1; 1.0 micrograms/ml) were between 21 and 24%. The new drug had significant antitumor activity (i.e. in more than 35% of specimens of those with at least five tested specimens) only against non-Hodgkins lymphoma and breast cancer.

Immunohistochemical detection of P-glycoprotein in normal and malignant tissues: a comparative study of three monoclonal antibodies, JSB-1, C 219 and 265/F4, against different epitopes using frozen and paraffin tissue sections.

In this study, the reactivity of three different monoclonal antibodies (MAbs) against the multiple-drug resistance (MDR)-related P-glycoprotein (P-170) were compared with each other using a collection of frozen and paraffin-embedded tumors, normal tissues and metastatic cells of malignant pleural and peritoneal effusions. The MAbs JSB-1, C 219 and 265/F4 were used in an indirect immunoperoxidase technique on frozen material. In addition, MAb C 219 was used on formalin-fixed, paraffin-embedded material from the same tumors, of which frozen sections were studied, and in a retrospective study C 219 was tested on paraffin blocks of the primary tumors that were responsible for the malignant effusions. The results show different staining patterns for all three MAbs to some extent. Results in frozen and paraffin sections obtained with MAb C 219 were comparable. MAb C 219 performs well both in frozen and formalin-fixed, paraffin-embedded material, making it a useful candidate for application in routine laboratory analysis. The retrospective analysis did not show consistency of P-170 expression in the same patients. This leads to the hypothesis that the actual status of P-170 expression in recurrent disease should be obtained before continuing or modifying chemotherapy. Clinical studies aimed at the correlation of immunohistochemistry with therapy response have to evaluate the relevance of P-170 expression in drug resistance of primary and metastatic tumors.

Therapy of Hodgkin’s Disease

Hodgkin’s disease is curable by radio- and/or chemotherapy. In limited stages most patients are treated with radiotherapy alone, which results in a high cure rate. In intermediate stages a combination

Myelodysplastic syndromes (MDS) in regular care in Germany – the oldest patients come to the fore

Hans Tilman Steinmetz, Ulrich Germing, Annette Sauer, Bernd Lathan, R€ udiger Liersch, Hans Tesch, J€ org Heßling, Enno Moorahrend, Jens Uhlig, Marcel Reiser, Roja Wahdat, Norbert Gattermann, Uwe Totzke and Stephan Schmitz Outpatient Clinics for Hematology and Oncology, Cologne, Germany; University Clinic for Hematology and Oncology, D€usseldorf, Germany; Outpatient Clinics for Hematology and Oncology, Potsdam, Germany; Outpatient Clinics for Hematology and Oncology, Dortmund, Germany; Outpatient Clinics for Hematology and Oncology, M€unster, Germany; Outpatient Clinics for Hematology and Oncology, Frankfurt/Main, Germany; Outpatient Clinics for Hematology and Oncology, Berlin, Germany; Outpatient Clinics for Hematology and Oncology, Porta Westfalica, Germany; Outpatient Clinic for Hematology and Oncology, Naunhof, Germany; TDS, Basel, Switzerland

Predictive Value of Pretherapeutic In-Vitro Chemosensitivity Testing in Adult AML

Individual prognosis in adult AML may still not be determined by known prognostic factors, e.g. age, cytogenetics. Short term in-vitro drug sensitivity tests such as the differential staining cytotoxicity (DISC) assay were developed to determine individual treatment outcome. We prospectively correlated DISC assay results and treatment outcome in patients (pts.) with AML using a new method of analysis. Pts. were treated according to the TAD-HAM regimen (thioguanine, Ara-C, daunorubicin-high dose Ara-C, mitoxantrone) in de-novo AML or the Ida-FLAG regimen (idarubicin, fludarabine, Ara-C, G-CSF) in relapsed or MDS-AML. The DISC assay was performed as described by Weisenthal et al. [1]. All drugs used for therapy were pretherapeutically tested at 5 different concentrations in primary cell cultures in triplicate samples of each patient. Assay results measured in % tumor cell survival (TCS) were transformed into a mathematical equation, which described the dose response relation. The area under the curve (AUC) and the calculated TCS at the middle test-concentration were then transformed into an index called chemosensitivity index Ci. If Ci was > 0.5 probability of clinical response to that drug was defined to be high, and if Ci was 0.5 of at least one drug used for therapy (TP=true positive correlation). 6/7 pts. were nonresponders and identified with Ci 0.5 was 672 days, median is not yet reached. Mean survival of the group with Ci 0.5) was 449 days, median 275 days. In conclusion, in-vitro chemosensitivity tests may provide a valuable tool for prediction of individual treatment outcome in pts. with AML. Prospective clinical trials using the DISC assay for treatment stratification and assay directed therapy strategies would be justified.

Prognostic Relevance of In-Vitro Drug Sensitivity Testing in Adult AML

The prognostic accuracy ofin-vitro drug sensitivity tests such as the differential staining cytotoxicity (DISC) assay must be assessed by correlation with response rates and also patient survival. We prospectively investigated the prognostic relevance of the DISC assay in adult patients (pts) with AML by using a new evaluation system called chemosensitivity index Ci.