Long-term treatment with rituximab is feasible in selected patients with B-CLL: response-adjusted low-dose maintenance treatment with rituximab in patients with relapsed B-CLL, who achieved a partial or minimal response to prior rituximab therapy.

The feasibility and efficacy of flexible, response-adjusted rituximab maintenance therapy in B-cell chronic lymphocytic leukemia (B-CLL) was investigated in 12 patients with an at least minor response to four weekly cycles of 375 mg/m(2) of rituximab induction therapy. Rituximab maintenance therapy consisted of infusions of 100 mg rituximab every 4 weeks. If disease progression occurred, either the rituximab dose was increased or the time between infusions was shortened. Treatment-related side effects led to discontinuation of rituximab maintenance therapy in three cases. Maintenance therapy was successfully conducted for > or =6 months in seven cases; three of these individuals have been on maintenance therapy for >1 year to 3.5 years so far. Long-term toxicity, as determined based on hematological and immunological parameters, was mild.

Acquired immunodeficiency syndrome-related lymphoma: simultaneous treatment with combined cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy and highly active antiretroviral therapy is safe and improves survival--results of the German Multicenter Trial.

BACKGROUND: Highly active antiretroviral therapy (HAART) has improved the survival of patients with acquired immunodeficiency syndrome-related lymphoma (ARL). The German ARL Study Group investigated whether HAART administered concomitantly with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy compromised the course of immune parameters during and after chemotherapy and exerted a positive effect on remission and survival. METHODS: From 1997 to 2001, 72 patients with ARL were stratified prospectively into a standard-risk group (n = 48 patients) and a high-risk group (n = 24 patients) with either 0-1 or 2-3 of the following risk factors: CD4 < 50/microL, prior opportunistic infection, and/or a World Health Organization performance status > or = 3. Patients in the high-risk group received > or =75% of the CHOP regimen. RESULTS: In the standard-risk group (CD4 = 223/muL; age-adjusted International Prognostic Index [aaIPI], 38% > or = 2), the complete remission (CR) rate was 79%, and median survival was not reached after a median 47 months of follow-up. CD4 counts did not change from baseline to 4 weeks after the end of chemotherapy (206/microL). In the high-risk group (CD4 = 34/muL; aaIPI, 88% > or = 2), the CR rate was 29%, and the median survival was 7.2 months (3 patients survived for > 3 yrs). Toxicity was moderate: Leukopenia Grade 3 or 4 occurred in 100 of 249 chemotherapy cycles (40%) in the standard-risk group and in 70 of 102 cycles (69%) in the high-risk group. CONCLUSIONS: Based on the aaIPI, the survival of patients in the standard-risk group was very similar to that achieved by nonhuman immunodeficiency virus-infected patients who had aggressive lymphomas. Concurrent CHOP plus HAART can be administered in an outpatient setting. Thus, the authors recommend using this modality as first-line therapy for patients with ARL.

Imatinib in Philadelphia chromosome-positive chronic phase CML patients: molecular and cytogenetic response rates and prediction of clinical outcome.

Previous clinical trials with the tyrosine kinase inhibitor imatinib in chronic-phase Philadelphia chromosome-positive chronic myelogenous leukemia (CML) resulted in 95% of hematologic and 60% major cytogenetic remissions in patients who failed a previous interferon-alpha-containing regimen. In an identical clinical trial setting with 39 chronic-phase CML patients we achieved comparable cytogenetic response rates after a median follow up of 30.1 weeks, with an almost identical toxicity profile. In order to identify predictive markers for the therapeutical use of imatinib, we monitored apart from standard hematology parameters bcr/abl fusion transcripts by quantitative real-time fluorescence RT-PCR. As previous investigations demonstrated that the plasma protein alpha-1 acid glycoprotein might inactivate circulating levels of free imatinib by protein binding with high affinity, we assessed plasma alpha-1 acid glycoprotein concentrations in our study cohort as well. Median bcr/abl fusion transcripts declined gradually over the entire treatment period and became significantly lowered at month 3 after initiation of imatinib therapy. Further, we observed elevated pretreatment levels of alpha-1 acid glycoprotein in patients who relapsed with leukemia, whereas initial bcr/abl mRNA copy numbers were not of predictive value. In addition, we provide data showing molecular response to this therapy in the vast majority of patients. Finally, our results support the hypothesis, that initially elevated plasma levels of alpha-1 acid glycoprotein might serve as a predictive marker for the clinical outcome of treatment with imatinib.

Treatment options of AIDS-related lymphoma.

Recently, the median survival of patients with AIDS-related lymphoma has changed significantly. This effect is mainly because of changes in the use of antiviral (highly active antiretroviral therapy; HAART) or chemotherapy regimens. Several novel treatment options have been explored in patients with lymphoma. It is hoped that innovative strategies will lead to a survival benefit in these patients. In this review, we present an update of current strategies for the treatment of AIDS-related lymphoma.

New directions in the diagnosis and treatment of chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia of adults in Western countries. It is a systemic haematological malignancy that originates from B cells (B-CLL) in 95% of patients, while only a minority are derived through malignant transformation of T cells (T-CLL). Although B-CLL is classified as a non-Hodgkin's lymphoma, several issues make this leukaemia a unique entity among malignant lymphoma. Inhibition of the programmed cell death (apoptosis) and upregulation of the anti-apoptotic protein Bcl-2 are key elements of the pathophysiology of B-CLL cells and define clinical prognosis. Furthermore, B-CLL cells are arrested in G0/G1 phase of the cell cycle. Dysfunctional apoptosis and cell cycle are the main reasons for the clinical enigma, that CLL can not yet be cured with conventional chemotherapy. However, the molecular pathways that are responsible for this characteristic feature of the B-CLL cells still need further definition.Recently, considerable progress has been made in defining the molecular basis for the pathogenesis of CLL and in finding new therapeutic options. Recent studies indicate that B-CLL cells may be delineated from two main groups of normal B cells, i.e. pre- and postgerminal B cells, and can be distinguished through lack of or existence of mutations of the V heavy chain gene. This differential mutational status of the Ig V gene has significant impact on patient survival. Modern cytogenetic methods such as fluorescence in situ hybridisation (FISH) have opened a new era in the molecular analysis of CLL cells. Determining the chromosomal aberration of the leukaemic cells has become a standard scientific programme for each clinical trial. The cytogenetic profile may soon help to define a clinical risk profile and guide the various treatment strategies. Further progress has been made in the therapy of CLL. Purine analogues such as fludarabine were able to induce significant improvement in remission rates; however, they did not lead to improved survival. Chimera of murine or rat monoclonal antibodies and human antibodies were designed to treat CLL. Antibodies such as rituximab and alemtuzumab (Campath-1H), directed against CD20 and CD52, respectively, appear as attractive alternatives to conventional chemotherapy because of their lack of significant myelotoxicity. Studies using myeloablative chemotherapy followed by autologous or allogeneic stem cell transplantation were initiated with the hope of finding a cure for CLL. In contrast to autologous stem cell transplantation, allogeneic transplants appear to display a plateau of relapse rates. In conclusion, for many years CLL was considered as a chronic haematological malignancy that required only few diagnostic tools and for whom no hope of cure could be offered. The current review focuses on recent improvements in diagnosis and treatment of CLL that have opened a new era in the management of patients with this systemic malignancy.

Phase 2 study of a combined immunochemotherapy using rituximab and fludarabine in patients with chronic lymphocytic leukemia.

This multicenter phase 2 trial investigated safety and efficacy of a new immunochemotherapeutic regimen combining rituximab (R) and fludarabine (F) in patients with fludarabine- and anthracycline-naive chronic lymphocytic leukemia (CLL). The rationale for using R + F includes single-agent efficacy of both drugs, in vitro synergism of R and F, and no apparent overlapping toxicity. Of 31 eligible patients with B-CLL enrolled, 20 were previously untreated and 11 relapsed. Treatment consisted of fludarabine administered at standard doses (25 mg/m(2)/d; days 1-5, 29-33, 57-61, and 85-89) and rituximab (375 mg/m(2)/d) given on days 57, 85, 113, and 151. Side effects such as fever, chills, and exanthema were generally mild (National Cancer Institute Common Toxicity Criteria [NCI-CTC] grade 1/2 in 48% and grade 3 and/or 4 in 3% of patients). Fever and chills were mainly associated with the first rituximab infusion. Hematologic toxicity included neutropenia (grade 1 and/or 2 in 26%, grade 3 and/or 4 in 42%) and thrombocytopenia (grade 1 and/or 2 in 19%, grade 3 and/or 4 in 9%). One patient died of cerebral bleeding during prolonged thrombocytopenia after the second cycle of fludarabine. There were a total of 32 infections in 16 patients, none of which was fatal. The overall response rate (complete remission [CR] and partial remission [PR]) was 87% (27 of 31 evaluable patients). In 20 previously untreated patients, 17 (85%) responded. Ten of 31 patients achieved CR (5 of 20 untreated; 5 of 11 pretreated; 9 of 21 Binet stage B, 1 of 10 Binet stage C). The median duration of response was 75 weeks. We conclude that the combination of rituximab and fludarabine is feasible and effective in patients with B-CLL.

The combination of fludarabine and cyclophosphamide results in a high remission rate with moderate toxicity in low-grade non-Hodgkin's lymphomas.

We undertook a prospective study to evaluate the role of the combination of fludarabine and cyclophosphamide in patients with low-grade non-Hodgkin's lymphoma. Twenty-seven patients with low-grade non-Hodgkin's lymphoma were treated with i.v. fludarabine (30 mg/m ) and cyclophosphamide (250 mg/m ) on days 1-3. Cycles were given at 4-week intervals for a maximum of six courses. Fourteen patients (52%) were previously untreated, 13 patients (48%) had been treated with at least one chemotherapy regimen before. Of the 27 patients, 11 (41%) obtained a complete and 13 (48%) a partial remission, thus the overall response rate was 89%. The remission rate in untreated patients was slightly higher than in pretreated patients (93 versus 85%). The toxicity was mild, no treatment-related mortality occurred. Neutropenia was the most common side effect, grade 4 neutropenia of rather short duration was observed in less than 7% of the cycles. At the end of the treatment, the mean CD4 count was 155/ l and the mean CD8 count 204/ l. Severe infections did not occur. These results show that the combination of fludarabine and cyclophosphamide in the doses used in this study is an effective regimen with manageable toxicity in low-grade non-Hodgkin's lymphoma.