Paris S. Mitrou

Bendamustine Plus Rituximab Is Effective and Has a Favorable Toxicity Profile in the Treatment of Mantle Cell and Low-Grade Non-Hodgkin's Lymphoma

PURPOSE The aim of this multicenter-study was to evaluate the progression-free survival, response rate and toxicity of the combination of bendamustine and rituximab (BR) in patients with mantle cell or low-grade lymphomas in first to third relapse or refractory to previous treatment. PATIENTS AND METHODS A total of 245 courses (median, four courses per patient) were administered to 63 patients. Bendamustine was given at a dose of 90 mg/m2 as a 30-minute infusion on days 1 and 2, combined with 375 mg/m2 rituximab on day 1, for a maximum of four cycles every 4 weeks. Histologies were 24 follicular, 16 mantle cell, 17 lymphoplasmacytoid, and six marginal zone lymphoma. RESULTS Fifty-seven of 63 patients responded to BR, corresponding to an overall response rate of 90% (95% CI, 80% to 96%) with a complete remission rate (CR) of 60% (95% CI, 47% to 72%). The median time of progression-free survival was 24 months (range, 5 to 44+ months), and the median duration of overall survival has not yet been reached. In mantle cell lymphomas, BR showed a considerable activity, achieving a response rate of 75% (95% CI, 48% to 93%) with a CR rate of 50%. Myelosuppression was the major toxicity, with 16% grade 3 and 4 leukocytopenia. Thrombocytopenia was rare, with only 3% grade 3 and 4. CONCLUSION These results demonstrate that the BR combination is a highly active regimen in the treatment of low-grade lymphomas and mantle cell lymphomas.

GM-CSF in a Double-Blind Randomized Placebo-Controlled Trial in Therapy of Adult Patients with De Novo Acute Myeloid Leukemia

We investigated whether GM-CSF given concomitantly with chemotherapy (CT) and thereafter, improves the outcome of adults with de novo AML by increasing the efficacy of CT and reducing infections. CT included Ara-C, daunorubicin and etoposide (DAV) for induction and early consolidation therapy and one cycle with high-dose (patients aged < or = 50 years) or intermediate dose Ara-C (patients aged > 50 years)/daunorubicin for late consolidation therapy. Eight patients were randomized after DAVI to receive either GM-CSF (E. coli, 250 micrograms/m2/day, s.c.) or placebo starting 48 h prior to DAVII and the subsequent courses and given throughout CT until the absolute neutrophil count had recovered to > 500/microliters. The CR rate was 81% in the GM-CSF and 79% in the placebo group (p = 0.57; Fishers exact test). The probability of relapse-free survival at 41 months after a median follow-up of 35 months was 42% in the GM-CSF and 41% in the placebo group (p = 0.89; log rank test). GM-CSF did not shorten the period of neutropenia < or = 500/microliters, while it prolonged the duration of thrombocytopenia < or = 25,000/microliters. The incidence and severity of infections as well as the non-hematological toxicity were similar in both groups. In summary, in this randomized trial GM-CSF as an adjunct to AML therapy was feasible. For the present GM-CSF does not have a significant effect on treatment outcome.

Positron Emission Tomography (PET) for Staging and Evaluation of Response to Treatment in Patients with Hodgkin's Disease

Forty two examinations utilizing F-18 FDG-PET were performed in 23 patients with Hodgkins disease to study for involved lymphoma regions and compared to conventional staging procedures. Twenty stagings were performed at diagnosis of untreated Hodgkins disease or at first relapse, and 22 restagings during and after chemoradiotherapy. At diagnosis in 5 of 20 patients PET and other procedures revealed different extranodal manifestations and in 3 patients established different clinical staging. PET seemed to be accurate in the assessment of lymphoma involvement in nodal sites. During follow up, in 10 out of 22 investigations different results and discrepancy were recorded, mostly due to the different extent of F-18-FDG metabolism in residual masses in lymphatic tissues compared to CT, X-ray or ultrasonography. The results indicate that PET may have advantages in the assessment of remissions in nodal sites. Less conclusive results were observed with regard to extranodal involvement or inflammatory disease. In conclusion PET may be sufficient for the staging of the majority of patients with Hodgkins disease and particularly for assessing remission status in nodal sites, but PET may have disadvantages in the evaluation of extranodal lymphoma and inflammatory disease.

Lactate dehydrogenase-release assay: A reliable, nonradioactive technique for analysis of cytotoxic lymphocyte-mediated lytic activity against blasts from acute myelocytic leukemia

Treatment of patients in remission of acute myelocytic leukemia using immunotherapy with interleukin 2 is a new approach to prolonging remission duration in this disease. As an important mechanism for the pathophysiology of eradication of residual myelocytic blast populations, activation of cytotoxic effector lymphocytes has frequently been discussed. However, the associated immunological research has been complicated to some extent, because in conventional chromium 51-release assays, blast cells frequently fail to incorporate sufficient amounts of51Cr and/or spontaneously release high amounts of51Cr. Recently, we established a culture system which promotes the out-growth of cytotoxic T lymphocytes in bone marrow-derived mononuclear cells cultured in IL-2. To study cytotoxicity and the responsible mechanisms of the obtained T-cell lines and clones, we modified a previously described cytotoxicity assay, based on the release of lactate dehydrogenase (LDH-release assay) for use in cryopreserved blasts obtained from the bone marrow of patients with acute myelocytic leukemia. Using this assay, we were able to detect cytotoxicity of IL-2-activated peripheral blood lymphocytes from three healthy controls against a number of blast samples obtained from the bone marrow of patients with AML (up to more than 40% lysis at an effector target cell ratio of 20∶1). However, a minority of AML blasts seem to be resistant to lysis by IL-2-activated lymphocytes. In bone marrow-derived T-cell lines from patients with AML we detected lytic activity against autologous blasts in three of seven cases tested by LDH release, ranging from 29 to 63% at an effector target ratio of 10∶1. Additionally, T-cell clones with different phenotypes were established which were able to mediate cytotoxicity against autologous blast cells. Thus, cytotoxicity against freshly isolated blasts from patients with acute myelocytic leukemia can be analyzed reliably, reproducibly, and without the use of isotopes by the LDH-release assay.

In vitro studies with bendamustine: Enhanced activity in combination with rituximab

Studies in vitro have shown that bendamustine, given as a monotherapy or in combination, can induce apoptosis in many cell types, including B-cell chronic lymphocytic leukemia and low-grade lymphoma cells. Evidence is accumulating to suggest that bendamustine may also have synergistic effects in combination therapies. Rituximab is a promising new agent for the treatment of hematologic malignancies and has been shown to have synergistic actions with other chemotherapeutic agents. The actions of the combination of bendamustine and rituximab on ex vivo B-cell chronic lymphocytic leukemia cells and the DOHH-2 cell line, derived from CD20-positive lymphoma cells, are discussed in this article.

Changing incidence and prognostic factors of survival in AIDS-related non-Hodgkin's lymphoma in the era of highly active antiretroviral therapy (HAART).

Non-Hodgkins lymphoma is an AIDS-defining disease. The impact of HAART on the epidemiology and prognosis is debated controversially. A retrospective analysis has been performed in order to determine the influence of HAART. We collected data of 214 cases of AIDS-related Lymphoma (ARL) treated at our centre from January 1984 until May 2003 and analysed them using the Kaplan-Meier-, log rank- and Cox proportional hazard-model. The incidence of ARL increased between 1991 and 1994 up to a peak of 14.83 per 1000 patient years. In the subsequent periods from 1995 onwards however, it decreased to 3.7 in 1000 patient years. The incidence of AIDS-related primary CNS lymphomas (PCNSL) took a comparable, yet more pronounced development. Using the univariate Kaplan-Meier analysis prolonged survival was significantly associated with the achievement of a complete remission as well as with a favourable virological response to HAART. No significant differences could be shown for the use of protease inhibitors as well as for virological response being achieved before the diagnosis of NHL. When using the Cox model, complete remission overrides viral response and thus remained the only independent prognostic factor. Classical prognostic factors (CD4 count, prior Kaposi Sarcoma, extranodal manifestation, staging and histological subtype of NHL) were no longer significant for HAART patients in the multivariate analysis. These results illustrate the requirement for new prospective studies in order to determine the best options and ideal timing of coadministering chemotherapy and the type of HAART. Furthermore this study demonstrates that HAART decreases the incidence of ARL, and that achievement of a complete remission in patients suffering from ARL is--according to the multivariate analysis--the single most important prognostically relevant factor with respect to the time of survival.

Clinical Experience with Fludarabine and its Immunosuppressive Effects in Pretreated Chronic Lymphocytic Leukemias and Low-Grade Lymphomas

Fludarabine monophosphate (FAMP) is a new adenine nucleoside analogue with a promising efficacy in B-cell chronic lymphocytic leukemia (B-CLL) and low-grade non-Hodgkin lymphomas (NHLs). Here, the clinical experience and side effects with FAMP are reported in 77 patients with pretreated CLL (59 B-CLL, 2 T-CLL) and low-grade NHLs (9 immunocytic lymphomas including 5 Waldenströms macroglobulinaemia, 2 centrocytic (cc) and 5 centroblastic-centrocytic (cb-cc) NHLs). 70/77 patients are evaluable for response. All except 8 patients were pretreated with one to four different regimens and had progressive disease. FAMP was administered at a dosage of 25 mg/m2 daily for 5 days as 30 minute infusion every fifth week. Partial (PR) or complete remission (CR) was achieved in 38/56 (68%) and 3/56 (5%) of evaluable patients with CLL, respectively. In 7/8 (1 x CR, 6 x PR) evaluable patients with immunocytic lymphoma and in 3/6 (3 x PR) patients with cc or cb-cc lymphoma remissions were obtained. The probability of progression-free survival was 66% and the event-free survival was 25% and 22% at 12 and 18 months. The median progression-free survival until relapse or death, however, was only 7 months (2-20+). Major toxic effects included infections in 22 patients (grade 3 and 4 WHO), granulocytopenia (mainly grade 3) and nausea in 8 patients (mainly grade 1). 19/22 patients were in PR at the time of occurrence of infectious complications. Meanwhile, 14 patients died due to septicaemia, pneumonia or other infections. Nine patients developed severe septicaemia, 4 patients had pneumocystis carinii or aspergillus pneumonias. The high infection rate may not only be due to hypogammaglobulinaemia and granulocytopenia induced by FAMP but also to a remarkable decrease of CD4+ cells from a median of 2479 to 241 CD4+ cells/microliters after 6 cycles of FAMP. In one case a tumor lysis syndrome was observed. No CNS toxicity was noted. It is concluded that FAMP is effective even in patients with advanced CLL and low-grade NHLs refractory to multiple chemotherapy regimens. However, FAMP has a marked suppressive effect on granulocytes and T-lymphocytes, predominantly CD4+ lymphocytes.

Positron emission tomography for the staging of Hodgkin's lymphoma: Increasing the body of evidence in favor of the method

The staging of Hodgkins lymphoma (HL) is crucial for an optimal therapy, and fluorine-18-deoxyglucose-positron emission tomography (FDG-PET) is increasingly used in this regard. However, there is still a scarcity of available data on the staging of HL. Twenty-eight consecutive patients with newly diagnosed HL were included in this study. PET results were compared with conventional staging, including clinical workup, computerized tomography (CT) and sonography. Evaluation was focused on the description of involved lymph node (LN) regions or organs rather than on a lesion-by-lesion analysis. In supradiaphragmal LN, the results of PET and CT scans were positive in 26% and negative in 68% of cases. Furthermore, PET was positive in 5% (CT negative), and CT showed enlarged LN in 1% of cases (PET negative). In infradiaphragmal LN, PET/CT results were positive in 10% and negative in 88% of cases. In 2% of cases, PET showed additional foci, while in 1% the CT was positive. PET changed the staging in 21% of cases (4 up-stagings, 2 down-stagings) and this was confirmed during follow-up. PET should therefore be routinely used for staging HL until larger clinical studies can demonstrate patients who may not require this additional investigation or those patients who are reliably staged on the basis of PET alone.

Fludarabine and epirubicin in the treatment of chronic lymphocytic leukaemia: A German multicenter phase II study

PURPOSE Fludarabine has been reported to be the most effective single-agent in previously treated chronic lymphocytic leukaemia (CLL). Based on the in vitro synergism of fludarabine with anthracyclines and on results showing a higher efficacy of CHOP against COP we attempted to improve treatment results with a combination of fludarabine and an anthracycline. PATIENTS AND METHODS The aim of the multicenter study was to evaluate the rate and duration of remissions and investigate the toxic and immunosuppressive effects of fludarabine and epirubicin in the treatment of CLL in Binet stages B and C as first-line therapy or in first relapse. Thirty-eight patients were treated with fludarabine 25 mg/m2 on days 1-5 and epirubicin 25 mg/m2 on days 4 and 5. RESULTS The overall response rate (OR) was 82% (95% confidence interval (95% CI): 66%-92%) with a CR rate of 32% (95% CI: 18%-49%). For the 25 previously untreated patients the OR was 92% (95% CI: 74%-99%) including 40% CRs (95% CI: 21%-61%). Granulocytopenia grade 3 occurred in 23% of all evaluable cycles, and grade 4 in 17%. The median remission duration was 19 months (range 6-37 months). CONCLUSION The results show that the combination of fludarabine and epirubicin is tolerable and highly effective in the treatment of CLL. With the addition of epirubicin to fludarabine, it appears possible to achieve a higher response rate and a more rapid response, especially of nodal manifestations. This regimen can be administered in an outpatient facility except for the first cycle because of the risk of a tumour lysis. The possible benefit of the combination presented here in the treatment of CLL in comparison to single-agent fludarabine treatment is presently under study in a prospective randomized multicenter study.

Interleukin-2 Bolus Infusion as Late Consolidation Therapy in 2nd Remission of Acute Myeloblastic Leukemia

The activation of autologous cytotoxic cells by interleukin-2 (IL-2) may be a promising tool for elimination of minimal residual blast populations in patients with acute myelocytic leukemia (AML) to prolong disease-free survival. Here, we report the results of a phase II study using IL-2 for consolidation therapy in patients with second remission of de novo AML. All patients in 1st relapse of AML received a uniform induction therapy consisting of intermediate high-dose AraC (iHDAraC) 2 x 600 mg/m2 d1-4 and VP-16 100 mg/m2 d1-7. Patients achieving 2nd remission were treated with 4 cycles recombinant IL-2 (rIL-2) 9 x 10(6) IU/m2 administered on d1-5 and 8-12/cycle as 1h infusion every six weeks. In 37/66 (56%) evaluable patients, complete remission (CR) was achieved. So far, 21/37 patients (4 after additional autologous bone marrow transplantation (ABMT) received rIL-2 consolidation. Three patients are too early for evaluation, 4 received allogeneic BMT, 6 relapsed before IL-2 was scheduled and 4 refused treatment with rIL-2. The median disease-free survival (DFS) was 11 (4-49+) months. Up to now, in 5/21 (24%) patients the duration of 2nd remission exceeded that of 1st remission 7/21 (33%) are in ongoing 2nd remission (7+ to 49+ months). The side effects of rIL-2 were generally moderate and manageable. Only in two patients, previously treated with ABMT, severe side effects occurred; septicaemia and pneumonia in one patient and desquamative erythrodermia in the second one. In accordance with other studies rebound lymphocytosis with a marked increase of CD56(+)-cells and release of secondary cytokines such as TNF-alpha, IFN-gamma and IL-6 was observed. The schedule is feasible and the data suggest a possible benefit for DFS, which, however has to be confirmed by randomized trials.