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Depending on stage and risk factor profile, more than 80% of patients with Hodgkin disease (HD) will be cured with modern treatment strategies. In early-stage, favorable HD, extended field irradiation has been the standard treatment resulting in cure rates of greater than 90%. However, due to the recognition of fatal long-term effects, especially the high rates of second solid tumors, extended field irradiation therapy is now being abandoned by most study groups. Instead, mild chemotherapy for control of occult disease is combined with involved field irradiation. In early-stage, unfavorable (intermediate) HD, for which combined modality treatment is already the treatment of choice, extended field irradiation is replaced by involved field irradiation for the same reasons. A different situation is found in advanced HD. In this case, standard therapy consists of eight cycles of polychemotherapy. Until recently, modifications of the standard chemotherapy regimens had not changed the poor outcome of advanced-stage patients. The development of a new dose-intensified regimen (BEACOPP) now for the first time has significantly improved the prognosis of these patients. Patients who relapse following radiation therapy alone for early stage HD have satisfactory results with combination chemotherapy and are not considered candidates for high-dose chemotherapy with autologous stem cell transplantation. For patients with relapsed HD after combination chemotherapy, the current data support the use of high-dose chemotherapy with autologous stem cell transplantation.
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PURPOSE: To explore the use of gemcitabine for the treatment of patients with relapsing or refractory Hodgkin's disease. PATIENTS AND METHODS: Eligible patients had measurable disease and more than one previous chemotherapy regimen. Patients previously treated with high-dose chemotherapy with autologous bone marrow or peripheral stem-cell support were not included. Gemcitabine, 1,250 mg/m(2), was administered as a 30-minute intravenous infusion on days 1, 8, and 15 of each 28-day cycle of therapy. The dosing schedule remained fixed, and any dose of gemcitabine that could not be given on time was omitted. Patients who had not experienced any hematologic or nonhematologic toxicity after one complete cycle of therapy were permitted to have subsequent doses increased by 20%: that is, from 1, 250 mg/m(2) to 1,500 mg/m(2). RESULTS: Of the 23 enrolled patients, 22 were assessable for response; all 23 patients were included in the efficacy analysis. Disease status for two patients (9%) reached a state of complete remission, and seven patients (30%) achieved a partial response, for an overall response rate of 39% (95% confidence interval, 19.7% to 61.5%). The likelihood of achieving a response was not influenced by a patients' main pretreatment characteristics or by their response to their last prior chemotherapy. The median duration of response was 6.7 months (range, 2 to 33+ months), and the median overall survival time was 10.7 months (range, 4 to 34.7+ months). In general, toxicities were mild; no treatment-related deaths occurred, and only one life-threatening adverse event was reported for this study. CONCLUSION: Gemcitabine was shown to be active in heavily pretreated patients with Hodgkin's disease, producing a response rate of 39%. Additionally, drug-related toxicities were mild, which thus suggests the possible inclusion of gemcitabine in an earlier phase of treatment.
PURPOSE: To determine differences in prognosis between primary progressive Hodgkin's disease (HD) and aggressive non-Hodgkin's lymphoma (NHL), we retrospectively analyzed patients with progressive lymphoma who were treated with different salvage chemotherapy regimens including high-dose chemotherapy (HDCT) followed by autologous stem-cell support (ASCT). PATIENTS AND METHODS: One hundred thirty-one patients with primary progressive lymphoma (HD, n = 67; NHL, n = 64) were enrolled. Primary progressive disease was defined as disease progression during first-line chemotherapy or only transient response (complete or partial response lasting </= 90 days) after induction treatment. Patients 60 years or younger with progressive lymphoma were eligible to receive HDCT with ASCT. RESULTS: The overall response rate after salvage chemotherapy for patients with primary progressive HD and NHL was 33% and 15%, respectively. Twenty-five HD patients (37%) received HDCT. Most patients with NHL had progressive disease under salvage treatment, with only six patients (10%) receiving HDCT. Of those, only two patients were alive and in continuous complete remission 3 and 12 months after HDCT. No patient with NHL survived longer than 26 months after first diagnosis. Actuarial OS after 5 years was 19% for all HD patients; 53% for HD patients receiving HDCT, and 0% for patients who did not receive HDCT. In HD patients, multivariate regression analysis identified chemosensitive disease on salvage treatment (P =.0001) and HDCT (P =.031) as significant prognostic factors for freedom from treatment failure. Significant prognostic factors for OS are chemosensitive disease (P =.0005), HDCT (P =.039), and B symptoms at the time of progress (P =.046). CONCLUSION: There are striking differences in the prognosis of patients with progressive HD and aggressive NHL. The prognosis of progressive NHL patients is dismal. Most patients have rapidly progressive disease after salvage treatment and are, therefore, excluded from HDCT programs. In contrast, progressive HD patients can achieve long-term survival after HDCT.
We performed a retrospective clinicopathologic study on sequential biopsy specimens from 90 patients with Philadelphia chromosome-positive chronic myelogenous leukemia to study therapy-specific effects of busulfan (28 patients), hydroxyurea (32 patients), and interferon-alfa (IFN-alfa; 30 patients). Bone marrow specimens were evaluated by morphometry after silver impregnation and staining with monoclonal antibodies to identify reticulin fibers, nucleated erythroid precursors, megakaryocytes, and macrophages. To compute dynamics of histopathology implicating corresponding changes in time, relevant indices were calculated. Quantification of megakaryocytopoiesis and its precursor cell population showed a significant increase in the IFN-alfa and busulfan groups compared with the hydroxyurea group. These changes were associated with a development of myelofibrosis during therapy. Although a significant increase in fiber density was detectable in the busulfan group, the progression index proved to be twice as high after IFN-alfa therapy. In contrast, a considerable number of patients displayed a regression of myelofibrosis after hydroxyurea treatment. The general association of the megakaryocyte lineage with myelofibrosis was in line with experimental findings. The mature macrophage population and its activated subfraction revealed a marked proliferation (IFN-alfa group) during treatment. Growth and activation of macrophages may be compatible with their putative function during erythrocytopoietic regeneration and with stimulation of their phagocytic properties.
We performed a phase II study to determine the efficacy of maximal cytoreductive therapy with up to five cycles of Dexa-BEAM (dexamethasone, carmustine [BCNU], etoposide, cytarabine, and melphalan) followed by high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) for patients with advanced relapsed or refractory indolent lymphoma. Thirty-two patients with primary refractory or relapsed indolent lymphoma were treated with the Dexa-BEAM regimen. Thirteen patients had primary refractory disease, 4 patients partial remission, and 15 patients first or subsequent relapse. Patients achieving PR or CR received HDCT with ASCT. The conditioning regimen used was BEAM (carmustine [BCNU], etoposide, cytarabine, and melphalan). Twenty-two patients responded to Dexa-BEAM resulting in a response rate of 78%. Maximum response was observed after 3.2 (range 2-5) courses. One patient with progressive disease died in septic shock during neutropenia. Nineteen patients with partial or complete remission after Dexa-BEAM received HDCT. Hematopoietic stem cells (HSC) were collected after two cycles of Dexa-BEAM. The median number of CD34+ HSC reinfused was 3.1 x 10(6)/kg (range 1.6-8.2 x 10(6)/kg). There was no transplantation-related death. All patients receiving HDCT achieved complete remission. Overall survival (OS) and freedom from treatment failure (FFTF) for all patients are estimated to be 68% and 65% at two years, respectively. With a mean follow-up of 20 months (range 8-42 months), 16/19 patients receiving HDCT are in continuous complete remission. The Dexa-BEAM regimen is effective in overcoming drug resistance in patients with indolent lymphoma who failed to respond to conventional treatment or who relapsed. The CR rate of 100% of those patients receiving HDCT and ASCT after maximal cytoreductive treatment with Dexa-BEAM suggests the use of HDCT at the time of maximal response.
Mantle-cell lymphoma (MCL) is not a curable disease using conventional chemotherapy. Patients with MCL have the shortest median time to progression and the shortest median survival of all lymphoma subtypes after first-line treatment. In the present study we determined the efficacy of maximal cytoreductive therapy with up to four cycles of Dexa-BEAM (dexamethasone, carmustine [BCNU], etoposide, cytarabine, and melphalan) followed by high-dose chemotherapy (HDCT) and autologous hematopoietic stem cell support (ASCT) for patients with advanced relapsed or refractory MCL. Nine consecutive patients with relapsed or refractory MCL were included. Three patients had partial remission (PR), three patients progressive disease (PD) upon first line tretment, and three patients first or subsequent relapse. After 2 to four cycles of Dexa-BEAM eight patients achieved complete remission (CR), resulting in a response rate of 88%. Six of 8 patients responding to Dexa-BEAM received high-dose chemotherapy HDCT (BEAM) and autologous hematopoietic stem cell transplantation (ASCT). With a median follow up of 24 months six patients are alive. Five of those six patients are still in contiuous CR (range 13-54 months).
We present a 46-year-old patient with Ph-chromosome negative, bcr-negative chronic myeloid leukaemia (CML) in accelerated phase with a clonal trisomy 21 in the leukaemic blast cells. A rapid progress of disease with appearance of monocytosis is described, showing similar features to chronic myelomonocytic leukaemia (CMML). Heterogeneous characteristics and possible distinction of these two entities are discussed.
A multicenter, immunohistochemical and morphometric study was performed on diagnostic pretreatment bone marrow biopsies in 614 adult patients with Ph1+ chronic myeloid leukemia (CML) to compare histological features with clinical findings. For identification of megakaryopoiesis we used the monoclonal antibody CD61 and additionally the PAS reaction to determine the subfraction of atypical micromegakaryocytes and precursors. Labelling of erythroid precursors was carried out by a monoclonal antibody directed against glycophorin C. In order to selectively stain macrophages and their activated subset we applied CD68 and the GSA-I lectin. Density of argyrophilic fibers (reticulin plus collagen) was measured following Gomori's silver impregnation method. In accordance with laboratory data morphological variables revealed a comparable amount of congruence in the various groups of CML patients derived from different sources. In about 26% of patients early (reticulin) to advanced (collagen) fibrosis was detectable. Significant correlations were calculated between the extent of myelofibrosis with splenomegaly, anemia and increasing numbers of erythroblasts and myeloblasts in the peripheral blood count. These features were assumed to indicate more advanced stages of the disease process with ensuing transition into myeloid metaplasia and consequently were associated with an unfavorable prognosis. Significant relationships were revealed between the number of CD61+ megakaryocytes and more important, also their precursor fraction with the degree of fibrosis. This result extends previous experimental findings regarding the impact of immature elements of this cell lineage for the generation of myelofibrosis. The significant association of erythroid precursors with the number of mature (resident) macrophages including their activated GSA-I subset may shed some light on their functional involvement in iron turnover and hemoglobin synthesis. A modified histological classification of predominant bone marrow features is introduced. This simplified synthesis staging system (Cologne Classification) is not only associated with certain sets of laboratory data, but also with different survival patterns.
BACKGROUND: Treatment strategies in Hodgkin's disease (HD) are changing fundamentally over the last decades. Both radiotherapy and combination chemotherapy are effective treatment modalities. However, the optimal choice of treatment or combinations of treatment is still debated for different prognostic groups. PATIENTS AND METHODS: The German Hodgkin's Lymphoma Study Group (GHSG) initiated randomized clinical trials since 1978. Over the past 20 years, more than 6000 patients with HD in all stages were randomized, treated and followed by the GHSG. Patients are now being recruited from more than 300 clinical centers. RESULTS: As a consequence of different clinical trials, it is now the policy of the GHSG to tailor treatment to the individual risk of patients, giving favorable patients less intensive and less toxic therapy than unfavorable patients. The treatment for early and intermediate stage HD becomes quite similar with few cycles of polychemotherapy followed by involved field irradiation. In advanced stage HD, the introduction of dose intensified chemotherapy (BEACOPP), has improved treatment results and thus will substitute the MOPP or ABVD regimens. CONCLUSIONS: Although most of the patients with HD will be cured by modern treatment strategies, several questions are still subjects of ongoing clinical trials: 1) which chemotherapy regimen in which quantity will be the best with respect to efficacy and toxicity and 2) which dose and field size of radiotherapy is adequate within the combined modality.
There is overwhelming evidence that at least a substantial number of cases, if not all, of Hodgkin's disease (HD) represent monoclonal B-cell disorders. The treatment of HD is changing strikingly. In early stages of disease, extended field irradiation has been the standard resulting in excellent cure rates. Due to the recognition of fatal long-term effects, however, especially the high rates of second solid tumors, extended field radiotherapy is now being abandoned by most study groups. Instead, mild chemotherapy for control of occult disease is combined with involved field irradiation. In intermediate stage HD, where combined modality treatment is the treatment of choice, extended field irradiation is substituted by involved field irradiation for the same reasons. In advanced stage HD, 8 cycles of polychemotherapy (plus additional radiotherapy for large tumor masses and residual lymphomas) for decades has cured only 50% to 60% of patients. The development of a new dose-intensified regimen (BEACOPP) for the first time has significantly improved that prognosis. In relapsed HD, recently published phase III studies suggest an improvement of relapse-free survival of patients using high-dose chemotherapy followed by autologous stem cell transplantation (ASCT).
BACKGROUND AND OBJECTIVES: Diagnosis of essential thrombocythemia (ET) remains a challenging problem and has been predominantly established by exclusion of other thrombocythemic disorders. In this context the updated diagnostic criteria of the Polycythemia Vera Study Group (PVSG) are generally accepted, although histopathologic features of the bone marrow were only marginally considered. DESIGN AND METHODS: A retrospective evaluation was performed of 168 patients presenting with ET in accordance with the criteria of the PVSG. Analysis was focused on the discriminating impact of bone marrow morphology. RESULTS: Histopathology revealed that our cohort of patients could be divided into three distinct groups (true ET, questionable ET and false ET). These groups were characterized by certain diagnostic constellations of clinical data on admission. True ET was found in 53 patients presenting with no or a borderline splenomegaly and no relevant anemia or leuko-erythroblastic blood picture. The other patients showed clinical signs and symptoms which were more compatible with initial-prefibrotic (52 patients) or early (68 patients) idiopathic-primary myelofibrosis (IMF) with severe thrombocythemia. In true ET no significant hypercellularity of the bone marrow including myeloid precursors or an increase in reticulin fibers was detectable. Most prominent were changes of megakaryopoiesis which revealed large to giant-sized cells lacking a definite maturation defect. Their appearance in true ET contrasted with the clusters of abnormally differentiated, often bizarre elements of this lineage in patients with initial and early IMF (questionable or false ET). Calculation of survival disclosed a relevant disparity with a non-significant loss in life expectancy of 10.9% in true ET compared to 29.6% in questionable and 51.3% in false ET. Follow-up studies and repeated bone marrow biopsies revealed no transition into myelofibrosis in true ET, whereas this did occur in 22 of 27 patients with questionable and false ET. In the latter cohort bone marrow changes were accompanied by increasing anemia, splenomegaly, tear-drop poikilocytosis and reduction of the platelet count consistent with IMF. INTERPRETATION AND CONCLUSIONS: A detailed evaluation of bone marrow features, in particular megakaryopoiesis is recommended to establish positive criteria for the diagnosis of ET and thus to accomplish a significant improvement of the PVSG postulates. In this context ongoing clinical trials on ET must regard pretreatment bone marrow biopsies as a major clue to diagnosis.
Patients receiving chemotherapy for Hodgkin's disease can potentially be treated in the out-patient department. In spite of this the proportion of patients receiving the chemotherapy on in-patient departments is 54% per chemotherapy cycle in average in the HD6 trial for advanced Hodgkin's disease of the German Hodgkin Study Group (GHSG). The aim of this retrospective analysis is to identify the set of parameters which influence the decision of in- or out-patient treatment for the patients in the HD6 trial. Parameters tested in the univariate analysis are the patient characteristics, the type of chemotherapy, toxicity and the type of treatment institution. The significant parameters are included in a logistic regression model. From this multivariate analysis the type of treatment institution turned out to be the most important factor in the decision of treatment setting. Restricting the analysis to university clinics, the treatment setting of the first two cycles is more influencial than patient dependent parameters.
The article present an evaluation (02/1999) of the study of primary treatment of Hodgkin's disease (HD) according to the third generation of the German Hodgkin's Disease Study Group (GHSG), and our experience with this treatment strategy. HD7 study of early stages HD showed better results (fewer relapses) for combined chemo and radiotherapy than for radiotherapy alone (2x ABVD + extended field radiotherapy compared to extended field radiotherapy alone). HD8 study of intermediate stage HD did not show any difference between chemotherapy 2x (COPP + ABVD) combined with radiotherapy extended field, or involved field. Due to the long-term consequences (especially secondary neoplasm), in the current (fourth) generation protocol extended field radiotherapy in early and intermediate stage HD has been replaced by a combination of lesser toxic chemotherapy and involved field radiotherapy. HD9 study of advanced HD. The standard treatment at present of COPP/ABVD (A) was compared with the new chemotherapeutic regimen, BEACOPP baseline (B) and escalated (C). The first evaluation of this study (1996) showed better results in the case of BEACOPP. The latest evaluation showed significantly better results for the escalated version. This is best illustrated by the low percentage of disease progression (C 2%, B 8%, A 12%, p < 0.05). Therefore, DHSG is considered to be the new standard for treatment of advanced stage HD. OUR RESULTS: Between 1995-1998, 54 patients with primary HD were treated at the FN Královaké Vinohrady, Prague according to the third generation GHSG protocol. Of these, 5 patients (9%) according to HD7, 14 (26%) according to HD8 and 35 patients (65%) according to HD9. Our results correspond to those of the whole GHSG, but they can not be statistically evaluated because of the small number of patients involved.
OBJECTIVES: To analyze virological and clinical efficacy of protease inhibitor based antiretroviral regimens in a cohort of unselected HIV-infected patients. METHODS: Prospective analysis of all HIV-infected patients started on protease inhibitor therapy until August 31, 1997 in two outpatient clinics. Partial viral suppression was defined as reduction of HIV-RNA at least 1log(10) below baseline and complete viral suppression as reduction below the limit of detection. Risk factors for clinical and virological failure were analyzed by a Cox proportional hazard model. RESULTS: 387 patients (median observation time 381 days) were analyzed. In 312 patients (81%) partial and in 265 (68%) complete viral suppression was observed. Secondary failure occurred in 75 patients and could be reversed in 11/75. The probability of virological failure at one year was 51% for complete and 47% for partial suppression. CD4-cells increased by a median of 101/microl overall and 39/microl for patients without partial virologic suppression. 57 clinical events or deaths occurred in 44 pts. Risk factors for virological failure were AIDS at baseline (RR 1.6) and use of Saquinavir vs. Indinavir or Ritonavir (RR 1.7), for clinical failure AIDS at baseline (RR 4. 9), CD4-cell count (0.74 for increase of 50/microl), degree of viral suppression (RR 0.1 for complete suppression) and PI used (Saquinavir vs. Indinavir or Ritonavir, RR 2.7). CONCLUSIONS: Virological failure of PI based combination therapy is common and associated with advanced HIV-infection. Clinical failure is associated with advanced HIV-infection and failure to suppress viral replication.
BACKGROUND: The overall mortality due to metastatic cancer has not or only minimally been reduced in spite of intensive research and many innovations in the field of conventional antineoplastic therapy in the past decade. In the last years it has become a fact that tumor growth is angiogenesis-dependent. Therefore, inhibitors of angiogenesis are a new class of antineoplastic substances with a novel mechanism of action that might be a powerful complement to conventional cytostatic therapy. SUBSTANCES AND CLINICAL TRIALS: Inhibitors of tumor-angiogenesis which have entered clinical trials, with their results published until December 1998 are discussed here. Most results originate from phase-I or phase-II clinical trials. They are discussed and compared in respect to toxicity and response. Also some substances with high therapeutic potential which are still in preclinical testing are discussed. RESULTS: Many of the investigated angiogenesis inhibitors demonstrated anti-tumor effects in phase-I or phase-II clinical trials. The commonest manifestation was stable disease, followed by partial remissions. In a few cases, complete remissions were observed. The toxicities of these substances differ both in type and degree of side effects. CONCLUSION: Some antiangiogenic drugs appear to be promising candidates for a clinical use in the therapy of solid tumors. Further conclusions can only be drawn after evaluation of the results of ongoing phase-III clinical trials.
Eleven patients with relapsed fludarabine-resistant B-cell chronic lymphocytic leukemia (CLL) or leukemic variants of low-grade B-cell non-Hodgkin's lymphoma (NHL) were treated with the chimeric monoclonal anti-CD20 antibody rituximab (IDEC-C2B8). Peripheral lymphocyte counts at baseline varied from 0.2 to 294.3 x 10(9)/L. During the first rituximab infusion, patients with lymphocyte counts exceeding 50.0 x 10(9)/L experienced a severe cytokine-release syndrome. Ninety minutes after onset of the infusion, serum levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) peaked in all patients. Elevated cytokine levels during treatment were associated with clinical symptoms, including fever, chills, nausea, vomiting, hypotension, and dyspnea. Lymphocyte and platelet counts dropped to 50% to 75% of baseline values within 12 hours after the onset of the infusion. Simultaneously, there was a 5-fold to 10-fold increase of liver enzymes, d-dimers, and lactate dehydrogenase (LDH), as well as a prolongation of the prothrombin time. Frequency and severity of first-dose adverse events were dependent on the number of circulating tumor cells at baseline: patients with lymphocyte counts greater than 50.0 x 10(9)/L experienced significantly more adverse events of National Cancer Institute (NCI) grade III/IV toxicity than patients with less than 50.0 x 10(9)/L peripheral tumor cells (P = .0017). Due to massive side effects in the first patient treated with 375 mg/m(2) in 1 day, a fractionated dosing schedule was used in all subsequent patients with application of 50 mg rituximab on day 1, 150 mg on day 2, and the rest of the 375 mg/m(2) dose on day 3. While the patient with the leukemic variant of the mantle-cell NHL achieved a complete remission (9 months+) after treatment with 4 x 375 mg/m(2) rituximab, efficacy in patients with relapsed fludarabine-resistant B-CLL was poor: 1 partial remission, 7 cases of stable disease, and 1 progressive disease were observed in 9 evaluable patients with CLL. On the basis of these data, different infusion schedules and/or combination regimens with chemotherapeutic drugs to reduce tumor burden before treatment with rituximab will have to be evaluated.