Outcome of First Salvage Therapy in Patients With Chronic Lymphocytic Leukemia Relapsing After First-line Fludarabine,Cyclophosphamide, and Rituximab

Patients receiving salvage therapy for relapsed CLL following first-line FCR have overall response rates of 60% and median survival of 38 months. We describe pre-treatment characteristics predicting for outcome after salvage therapies. Patients receiving chemoimmunotherapy had better response rates and duration compared to antibody therapy alone.Brief AbstractChemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) is an effective initial therapy with an estimated 40% relapse rate at 6 years. There is no consensus salvage therapy for relapsed patients. All patients with chronic lymphocytic leukemia (CLL) who relapsed or were refractory following first-line FCR administered between July 1999 and December 2003 were included for analysis. Patients with Richter's transformation were excluded. We analyzed the impact of pre-treatment characteristics (Table 1) and response duration following FCR on responses and survival after salvage therapy. Response outcomes were analyzed using 1996 National Cancer Institute response criteria. Overall survival (OS) and time to treatment failure (TTF) were calculated using the method of Kaplan and Meier. Of 300 patients treated with first-line FCR, 111 patients (37%) have required salvage therapy. Median age at relapse was 61 years, and 36% of patients had Rai stage III or IV disease (Table 1). The salvage regimen included antibody alone, chemoimmunotherapy, or novel therapeutic approaches including lenalidomide. Responses included 17% CR, 12% nodular PR, and 32% PR with an overall response (OR) of 60%. Median OS was 38 months, and median TTF was 9 months. Rai stage III/IV disease, β2M > 4 mg/L, deletion of 17p by fluorescence in situ hybridization and TTF < 12 months following FCR were associated with significantly shorter TTF and OS following first salvage. Patients treated with single-antibody therapy had low response rates (CR/nPR, 9%; OR, 44%) and short TTF (6 months). Combination of alemtuzumab and rituximab improved responses (CR/nPR, 50%; OR, 75%) but did not improve TTF (8 months). Patients treated with FCR or CFAR (cyclophosphamide/fludarabine/alemtuzumab/rituximab) demonstrated good responses (CR/nPR, 50%; OR, 83%) with improved TTF (20 months) but no significant improvement in OS (44 months) compared to patients receiving antibody only (OS, 41 months). Patients who relapse after FCR can be successfully retreated with a similar chemoimmunotherapy regimen (FCR, CFAR) with reasonable response rates and remission duration; however, chemoimmunotherapy does not appear to improve OS over antibody therapy alone in first salvage.     

Combined fludarabine and rituximab for low grade lymphoma and chronic lymphocytic leukemia

As both fludarabine and rituximab are active against indolent lymphoproliferative disorders, we have studied the combination of fludarabine and rituximab in patients with low-grade lymphoma and chronic lymphocytic leukemia (CLL) in phase I/II fashion. Of 33 patients enrolled, 21(63.6%) had low-grade lymphoma and 12 (36.4%) had CLL. They received fludarabine 30 mg/m 2 on days 1-4 and rituximab 125, 250 or 375 mg/m 2 on day 5 at intervals of 28 days to a maximum of 8 cycles. Three patients were removed from the study because of rituximab-associated anaphylaxis and four because of prolonged hematopoietic toxicity. Toxicity and responsiveness did not differ at the different dose levels of rituximab. For 29 evaluable patients, responses were seen in 82.8% and complete responses in 34.5%. Of 7 responding patients not referred for stem cell transplantation, 6 remain in complete remission at a median follow-up of 16 months (range 4-30 months). Of 13 previously untreated patients, all responded and 46.2% had a complete response. Of 16 previously treated patients, 68.5% responded and 25% had a complete response. The combination of fludarabine and rituximab has major activity and acceptable toxicity in patients with low-grade lymphoma and CLL.     

What is the optimal initial treatment for chronic lymphocytic leukemia?

For decades, initial therapy for chronic lymphocytic leukemia (CLL) consisted of alkylators such as chlorambucil (Leukeran). The introduction of nucleoside analogs such as fludarabine and monoclonal antibodies such as rituximab (Rituxan) markedly changed the initial therapy of CLL, particularly in the United States. Fludarabine and combination regimens such as fludarabine/cyclophosphamide (FC) have achieved higher complete response (CR) rates and progression-free survival (PFS) than chlorambucil in previously untreated CLL, but long-term overall survival has not improved, due to concurrent improvement in salvage therapy of relapsed CLL patients. Upfront chemoimmunotherapy regimens such as fludarabine/rituximab (FR) and fludarabine/cyclophosphamide/rituximab (FCR) have similarly improved CR rates and PFS in previously untreated CLL patients, but it is unclear whether overall survival is improved. Advances in cytogenetic analysis and other biologic prognostic factors have greatly enhanced clinicians' ability to risk-stratify newly diagnosed CLL patients, and knowledge of such prognostic factors is necessary to properly interpret results of clinical treatment studies. The choice of initial therapy for an individual patient should depend upon the patient's age and medical condition, cytogenetic and other prognostic factors, and whether the goal of therapy is maximization of CR and PFS or palliation of symptoms with minimal toxicity.     

Long-Term Results of Chemoimmunotherapy With Fludarabine,Cyclophosphamide, and Rituximab for Patients With Relapsed and Refractory Chronic Lymphocytic Leukemia

IntroductionThe majority of patients with progressive chronic lymphocytic leukemia (CLL) will relapse after front-line treatment and will require salvage therapy. The addition of rituximab (R) to fludarabine (F) and cyclophosphamide (C) is associated with improved responses and relapse-free survival in untreated patients with CLL (Hallek et al, 2009) and patients with CLL in first relapse (Robak et al, 2008). We present an update of FCR in patients with relapsed or refractory CLL.Patients and MethodsWe administered FCR between November 1999 and 2008 to 284 patients with relapsed CLL. Patients received a combination of fludarabine 25 mg/m² day 1-3, cyclophosphamide 250 mg/m² day 1-3, and rituximab on day 1 at 375mg/m² for cycle 1, and 500 mg/m² for cycles 2 to 6. Patients were assessed for response by 1996 National Cancer Institute (NCI) Working Group response criteria and for time to failure of therapy (TTF) and overall survival (OS). We assessed standard pretreatment characteristics including response to prior therapy.ResultsPatients entered into the study had a median age of 60 years (31-84 years). Median number of prior treatments was 2 (range, 1-10). Responses included 86 patients with CR (31%), 41 nPR (15%), and 84 PR (30%); OR was 75%. Median OS is 46 months (95% CI, 41-54 months), and median TTF is 21 months (95% CI, 19-27 months). On multivariate analysis, the variables independently associated with longer TTF were younger age, higher platelets, lower lactate dehydrogenase (LDH) or serum creatinine, lower number of prior treatment, fludarabine sensitivity, and absence of chromosome 17 abnormalities on karyotype. Six full dose cycles of FCR were administered to 104 patients (36%). The most common hematologic toxicity was grade 3 and 4 neutropenia complicating 22% and 34% of treatment courses. Forty-six patients (16%) experienced one or more episodes of pneumonia or sepsis during or following treatment.ConclusionFCR is an effective regimen in patients with relapsed CLL. FCR should be considered as salvage therapy for patients in third relapse or less, not refractory to fludarabine or without chromosome 17 abnormalities or complex karyotype. Elderly patients (> 70 years) experienced more treatment-related toxicity and should be assessed for comorbidities prior to therapy.     

Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia.

PURPOSE: To assess the efficacy of combination therapy with fludarabine and cyclophosphamide in patients with chronic lymphocytic leukemia (CLL) based on data suggesting in vitro synergistic activity of the two agents. PATIENTS AND METHODS: A total of 128 patients with CLL were treated with fludarabine 30 mg/m(2) intravenously daily for 3 days and cyclophosphamide at either 500 mg/m(2) daily for 3 days (n = 11), 350 mg/m(2)/d for 3 days (n = 26), or 300 mg/m(2) daily for 3 days (n = 91). The cyclophosphamide dose was decreased because of myelosuppression in the early part of the study. Patients were divided into four groups based on the expectation for response to single-agent fludarabine, including previously untreated patients, patients previously treated with alkylating agents, patients successfully treated with alkylating agents and fludarabine but relapsing, and patients refractory to fludarabine with or without alkylating agents. RESULTS: Fludarabine and cyclophosphamide produced > or = 80% response rates in all patients not refractory to fludarabine at the start of therapy as well as a 38% response rate in patients who were refractory to fludarabine. The complete remission (CR) rate was 35% in previously untreated patients, which was not significantly different from the CR rate in historical control patients treated with single-agent fludarabine. However, residual disease assessed by flow cytometry occurred in only 8% of previously untreated patients achieving CR, and median time to progression has not been reached after a median follow-up of 41 months. The main complication of therapy was related to myelosuppression and infection. Neutropenia to less than 500 x 10(9)/L was noted in 48% of patients who received cyclophosphamide 300 mg/m(2). Pneumonia or sepsis occurred in 25% of patients, and fever of unknown origin occurred in another 25%. Pneumonia or sepsis were significantly more frequent in patients who were refractory to fludarabine at the start of combination chemotherapy. CONCLUSION: Fludarabine and cyclophosphamide seem to have a significant advantage over single-agent fludarabine in the salvage setting. Although the CR rate was not increased in previously untreated patients, residual disease detected by flow cytometry was rare and remission durations seemed to be prolonged in this subset. Myelosuppression and infection remain the most significant complications of therapy in CLL.     

Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia.

PURPOSE: Fludarabine and cyclophosphamide (FC), which are active in treatment of chronic lymphocytic leukemia (CLL), are synergistic with the monoclonal antibody rituximab in vitro in lymphoma cell lines. A chemoimmunotherapy program consisting of fludarabine, cyclophosphamide, and rituximab (FCR) was developed with the goal of increasing the complete remission (CR) rate in previously untreated CLL patients to >/= 50%. PATIENTS AND METHODS: We conducted a single-arm study of FCR as initial therapy in 224 patients with progressive or advanced CLL. Flow cytometry was used to measure residual disease. Results and safety were compared with a previous regimen using FC. RESULTS: The median age was 58 years; 75 patients (33%) had Rai stage III to IV disease. The CR rate was 70% (95% CI, 63% to 76%), the nodular partial remission rate was 10%, and the partial remission rate was 15%, for an overall response rate of 95% (95% CI, 92% to 98%). Two thirds of patients evaluated with flow cytometry had less than 1% CD5- and CD19-coexpressing cells in bone marrow after therapy. Grade 3 to 4 neutropenia occurred during 52% of courses; major and minor infections were seen in 2.6% and 10% of courses, respectively. One third of the 224 patients had >/= one episode of infection, and 10% had a fever of unknown origin. CONCLUSION: FCR produced a high CR rate in previously untreated CLL. Most patients had no detectable disease on flow cytometry at the end of therapy. Time to treatment failure analysis showed that 69% of patients were projected to be failure free at 4 years (95% CI, 57% to 81%).     

Consolidation therapy with high-dose cyclophosphamide improves the quality of response in patients with chronic lymphocytic leukemia treated with fludarabine as induction therapy.

Fludarabine is the most active agent in the treatment of chronic lymphocytic leukemia (CLL). Despite this activity only a minority of patients treated with fludarabine achieve a complete response. We evaluated a new treatment program of sequential therapy with fludarabine followed by high-dose cyclophosphamide in previously untreated patients with CLL. This report details the results in 25 patients with previously untreated CLL. Patients received fludarabine (25 mg/m2/day x 5 days every 4 weeks for six cycles) as induction followed by consolidation with high-dose cyclophosphamide at one of three dose levels 1.5 g/m2, 2.25 g/m2, or 3 g/m2 administered every 2 weeks for three doses. High-dose cyclophosphamide was given with G-CSF support (5 microg/kg/day days 3-12). Complete response (CR) required a normal physical examination, normal CBC, a normal bone marrow evaluation including no residual lymphoid nodules on biopsy. A nodular response was defined as a complete response with the exception of an occasional residual nodule seen on bone marrow biopsy. Flow cytometric analysis for CD5:CD19 dual staining and kappa/lambda clonal excess was performed in all patients as a sensitive measure of minimal residual disease (MRD). Selected patients had patient/tumor-specific oligonucleotides generated that were subsequently used in a polymerase chain reaction as an extremely sensitive measure of MRD. There were no treatment-related deaths and no patient encountered unacceptable toxicity. After completion of this sequential regimen 76% (95% confidence interval: 59-93%) of patients had a major response: eight (32%) achieved a CR, four (16%) a nodular response, seven (28%) a PR, and six patients (24%) failed. Four patients withdrew from study during induction with fludarabine and did not receive at least one cycle of cyclophosphamide. Of the 21 patients who received consolidation with cyclophosphamide 10 (48%) had an improved quality of response when compared to that achieved with fludarabine. Two patients (8%) had no disease detectable by flow cytometry ('flow cytometric' CR) after six cycles of fludarabine. This improved to nine patients (36%) after high-dose cyclophosphamide. Following consolidation with high-dose cyclophosphamide three patients (12%) tested negative by PCR. All of these patients had morphologic evidence of residual disease after six cycles of fludarabine. Consolidation with high-dose cyclophosphamide increased the fraction of patients achieving a nodular response or CR three-fold (16% to 48%). This appears to be clinically relevant because with a median follow-up of 52 (range 34-78) months the projected 6-year survival for patients achieving a CR or NR is 91% compared to 41% for all others (P = 0.012). We conclude that sequential therapy with fludarabine followed by high-dose cyclophosphamide in previously untreated patients with CLL is safe and can improve the quality of response in a large proportion of patients compared to therapy with fludarabine alone.     

Fludarabine, cyclophosphamide, and rituximab in patients with advanced, untreated, indolent B-cell nonfollicular lymphomas: phase 2 study of the Italian Lymphoma Foundation

BACKGROUND:

Indolent nonfollicular non‐Hodgkin B‐cell lymphomas (INFLs) are clonal mature B‐cell proliferations for which treatment has not been defined to date.

METHODS:

In this phase 2 study of patients with advanced INFL, the authors evaluated the efficacy and safety of first‐line rituximab, fludarabine, and cyclophosphamide (FCR) as induction immunochemotherapy (rituximab 375 mg/m² intravenously on day 1 of each cycle and on days 1 and 14 of cycles 4 and 5; fludarabine 25 mg/m² intravenously on days 2‐4, cyclophosphamide 250 mg/m² intravenously on Days 2‐4) every 28 days for 6 cycles followed by a maintenance phase with 4 infusions of rituximab (375 mg/m² intravenously on day 1) every 2 months for responders.

RESULTS:

Forty‐seven patients were enrolled. Among 46 evaluable patients (28 men; median age, 59 years), 19 were diagnosed with lymphoplasmacytic lymphoma, 21 were diagnosed with small lymphocytic lymphoma, and 6 were diagnosed with nodal marginal zone lymphoma. The overall response rate after maintenance was 89.1% with a 67.4% complete remission (CR) rate (CR/unconfirmed CR) and a 21.7% partial response rate. After a median follow‐up of 40.9 months, the failure‐free survival and progression‐free survival rates both were 90.1%, and the overall survival rate was 97.4%. The main toxicity was hematologic, and related grade 3 and 4 neutropenia was observed in 55.3% of patients.

CONCLUSIONS:

FCR induction therapy followed by a short maintenance phase is a highly effective regimen with acceptable toxicity. Cancer 2012. © 2011 American Cancer Society.     

Treatment of fludarabine‐refractory chronic lymphocytic leukemia

The development of resistance to purine analogs defines a poor‐risk subset of patients with chronic lymphocytic leukemia (CLL). Although in recent years chemoimmunotherapeutic combinations such as fludarabine, cyclophosphamide, and rituximab have induced response rates of 95% in previously untreated patients and increased the rates of failure‐free survival, CLL remains incurable for many patients because of a lack of disease response or the development of refractoriness to fludarabine. Fludarabine‐refractory disease is defined as CLL that does not respond to fludarabine or that recurs within 6 months of treatment with a fludarabine‐containing regimen. The natural course of the disease is associated with poor survival. Salvage therapeutic strategies include alemtuzumab‐containing regimens, targeted agents, and allogeneic stem cell transplantation. Single‐agent alemtuzumab induces response in up to 40% of patients with fludarabine‐refractory CLL, but responses are not durable, and the median survival is approximately 1 to 2 years. Alemtuzumab is also combined with fludarabine, cyclophosphamide, and/or rituximab, and other agents such as lenalidomide and flavopiridol, as well as targeted agents, and used in fludarabine‐refractory CLL. Cumulative evidence suggests that allogeneic stem cell transplantation is an efficacious therapeutic strategy for patients who do not respond to fludarabine or who develop disease recurrence within 12 months after purine analog treatment. In conclusion, chemoimmunotherapy regimens that include alemtuzumab and/or rituximab and allogeneic stem cell transplantation improve the prognosis of this disease, but there is a continued need for novel, more effective therapies. Cancer 2009. © 2009 American Cancer Society.     

Phase I-II Clinical Trial of Oxaliplatin,Fludarabine, Cytarabine,and Rituximab Therapy in Aggressive Relapsed/Refractory Chronic Lymphocytic Leukemia or Richter Syndrome

BackgroundTo improve outcomes of patients with Richter syndrome (RS) and relapsed/refractory chronic lymphocytic leukemia (CLL), we modified the OFAR1 regimen (oxaliplatin and cytarabine doses of the oxaliplatin, fludarabine, cytarabine, and rituximab) for this phase I-II study (OFAR2).Patients and MethodsOFAR2 consisted of oxaliplatin at 30 mg/m² on days 1 to 4, fludarabine at 30 mg/m², cytarabine at 0.5 g/m², rituximab at 375 mg/m² on day 3, and pegfilgrastim at 6 mg on day 6. Fludarabine and cytarabine were given on days 2 and 3 (cohort 1), days 2 to 4 (cohort 2), or days 2 to 5 (cohort 3) every 4 weeks. Phase II followed the “3 + 3” design of phase I.ResultsThe 102 patients (CLL, 67; RS, 35) treated had heavily pretreated high-risk disease. Twelve patients were treated in phase I; cohort 2 was the phase II recommended dose. The most common toxicities were hematologic. Response rates (phase II) were 38.7% for RS (complete response [CR], 6.5%) and 50.8% for relapsed/refractory CLL (CR, 4.6%). The median survival durations were 6.6 (RS) and 20.6 (CLL) months. Among 9 patients who underwent allogeneic stem cell transplantation (SCT) as post-remission therapy, none has died (median follow-up, 15.9 months).ConclusionOFAR2 had significant antileukemic activity in RS and relapsed/refractory CLL. Patients undergoing SCT as post-remission therapy had favorable outcomes.     

Phase I study of bryostatin 1 and fludarabine in patients with chronic lymphocytic leukemia and indolent (non-Hodgkin's) lymphoma.

PURPOSE: Preclinical studies suggested that bryostatin 1 might potentiate the therapeutic effects of fludarabine in the treatment of hematologic malignancies. We undertook a phase I study to identify appropriate schedules and doses of bryostatin 1 and fludarabine to be used in phase II studies. EXPERIMENTAL DESIGN: Patients with chronic lymphocytic leukemia (CLL) or indolent lymphoma received fludarabine daily for 5 days and a single dose of bryostatin 1 via a 24-hour continuous infusion either before or after the fludarabine course. Doses were escalated in successive patients until recommended phase II doses for each sequence were identified on the basis of dose-limiting toxic events. RESULTS: Bryostatin 1 can be administered safely and tolerably with full dose fludarabine (25 mg/m(2)/d x 5). The recommended bryostatin 1 phase II dose is 50 microg/m(2) for both sequences, bryostatin 1 --> fludarabine and fludarabine --> bryostatin 1. The combination is active against both CLL and indolent lymphomas with responses seen in patients who had been previously treated with fludarabine. Correlative studies do not support the hypothesis that bryostatin 1 potentiates fludarabine activity through down-regulation of protein kinase C in target cells. CONCLUSIONS: Bryostatin 1 can be administered with full dose fludarabine, and the combination is moderately active in patients with persistent disease following prior treatment. In view of the activity of monoclonal antibodies such as the anti-CD20 monoclonal antibody rituximab in the treatment of CLL and indolent lymphomas, the concept of combining bryostatin 1 and fludarabine with rituximab warrants future consideration.     

Fludarabine and cyclophosphamide using an attenuated dose schedule is a highly effective regimen for patients with indolent lymphoid malignancies

BACKGROUND: Preclinical data have supported the use of fludarabine and cyclophosphamide (FC) in combination for the treatment of indolent lymphoid malignancies. Previously reported schedules were highly effective, but were complicated by significant myelotoxicity and infectious complications. In the current study, the authors analyzed their experience with an attenuated dose regimen to determine whether equivalent efficacy could be achieved with reduced toxicity. METHODS: Sixty-four patients with indolent lymphoid malignancies were treated with intravenous fludarabine at a dose of 25 mg/m(2) and cyclophosphamide at a dose of 250 mg/m(2), each given on Days 1-3 for a median of 4 cycles. The median age of the patients was 60 years. Nineteen percent of the patients were previously untreated, and 45% had refractory disease; the patients had received a median of 2 prior therapies. With regard to histology, 41% of the patients had chronic lymphocytic leukemia or its variants, whereas the remainder of patients had low-grade non-Hodgkin lymphoma, predominantly follicule center cell lymphoma. RESULTS: A total of 237 cycles were delivered. The principal toxicities reported were neutropenia (NCI CTC Grade 4 in 17% of cycles) and infection (Grade >/= 3 in 6% of cycles). The overall response rate and complete response rate were 86% and 29%, respectively. No significant difference could be discerned with regard to response rates for patients with untreated, recurrent, or refractory disease. CONCLUSIONS: The FC schedule used in the current study was found to be highly effective in patients with indolent lymphoid malignancies. Toxicity was lower compared with higher dose schedules, whereas efficacy appeared to be equivalent.     

Durable complete responses from therapy with combined epratuzumab and rituximab: final results from an international multicenter, phase 2 study in recurrent, indolent, non-Hodgkin lymphoma

BACKGROUND: In this international, multicenter trial, the authors evaluated rituximab (anti-CD20) plus epratuzumab (anti-CD22) in patients with postchemotherapy relapsed/refractory, indolent non-Hodgkin lymphoma (NHL), including long-term efficacy. METHODS: Forty-nine patients with follicular NHL (FL) (N = 41) or small lymphocytic lymphoma (SLL) (N = 7) received intravenous epratuzumab 360 mg/m2 and then intravenous rituximab 375 mg/m2 weekly x4. The regimen was tolerated well. RESULTS: Twenty-two of 41 patients with FL (54%) had an objective response (OR), including 10 (24%) complete responses (CR) (CR/unconfirmed CR [CRu]), whereas 4 of 7 patients with SLL (57%) had ORs, including 3 (43%) with CR/CRu. Rituximab-naive patients (N = 34) had an OR rate of 50% (26% CR/CRu rate), whereas patients who previously responded to rituximab (N = 14) had an OR rate of 64% (29% CR/CRu rate). An OR rate of 85% was observed in patients with FL who had Follicular Lymphoma International Prognostic Index (FLIPI) risk scores of 0 or 1 (N = 13), whereas 28 patients with intermediate or high-risk FLIPI scores (> or =2) had an OR rate of 39% (18% CR/CRu rate). In patients with FL, the median response duration was 13.4 months, and that duration increased to 29.1 months for 10 patients who had a CR/CRu, including 4 patients who had durable responses with remissions that continued for >4 years. In patients with SLL, the median response duration was 20 months, including 1 patient who had a response that continued for >3 years. CONCLUSIONS: The combination of epratuzumab and rituximab induced durable responses in patients with recurrent, indolent NHL.     

Recent progress in the management of chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a clonal disease characterized by proliferation and accumulation of small CD5-positive B cells. More than 50% of patients are asymptomatic at diagnosis and usually require no treatment. However, treatment is needed in the advanced and progressive disease. Chlorambucil with or without steroids has been the drug of choice for many years in previously untreated patients with CLL. The purine nucleoside analogs (PNAs), fludarabine (FA), cladribine (2-CdA-chlorodeoxyadenosine) and pentostatin (DCF, 2'-deoxycoformycin) also have been introduced for treatment of CLL. Significantly higher overall response (OR) and complete response (CR) and longer progression free survival (PFS) in patients with CLL treated with FA or 2-CdA have been confirmed in randomized, multicenter trials and more recently in meta-analysis. However, the median survival time did not differ between patients treated with PNA and alkylating agents. Combination therapies with PNAs and cyclophosphamide and especially with cyclophosphamide and rituximab are more active than monotherapy in terms of OR, CR and PFS. Several reports have shown significant activity of alemtuzumab in previously untreated and pretreated patients even when refractory to FA. Alemtuzumab also can be used in CLL as a preparative regimen before stem cell transplantation (SCT) and to eliminate minimal residual disease (MRD). Recently, several new agents have shown promise in treating CLL, including new monoclonal antibodies, agents targeting bcl-2 family of proteins, antisense oligonucleotides and other agents. Moreover, autologous and allogenic hematopoietic cell transplantations are increasingly considered for treatment of patients with CLL. In this review current therapeutic strategies in CLL are presented.     

Chemoimmunotherapy with oral low-dose fludarabine,cyclophosphamide and rituximab (old-FCR) as treatment for elderly patients with chronic lymphocytic leukaemia

Median age at diagnosis for chronic lymphocytic leukaemia (CLL) patients is now 72 years, thus a consistent number of patients may not tolerate standard doses i.v. of fludarabine, cyclophosphamide and rituximab (FCR), the best available therapy, due to unacceptable myelotoxicity and risk of severe infections. We studied safety and efficacy of the addition of rituximab to the oral low-dose FC regimen (old-FCR) in a selected population of 30 elderly (median age 75, 15 untreated, 15 treated with 1 prior therapy) CLL patients. Complete remission (CR) rate was 80% in the untreated patients (overall response rate, ORR 93%), and 30% in pretreated patients (ORR 74%). Progression free survivals (PFS) were 45 months and 30 months in the untreated and treated patients, respectively. In patients achieving CR, old-FCR led to PFS of 67 months. Moreover, haematological toxicity was mild (grade 3–4: 15%) and patients were treated mostly in outpatient clinic. Old-FCR could be a good therapy option for elderly CLL patients outside clinical trials, larger studies are needed to confirm our findings.     

CHOP with high dose cyclophosphamide consolidation versus CHOP alone as initial therapy for advanced stage,indolent non-Hodgkin's lymphomas

The role of high dose therapy, including autologous stem cell transplantation (ASCT) in indolent non-Hodgkin's lymphomas remains controversial. We evaluated a dose intense regimen of CHOP induction followed by high dose cyclophosphamide consolidation (CHOP-HC) versus CHOP alone in a prospective comparison to assess intensified therapy without ASCT. Twenty-five patients with previously untreated advanced stage indolent NHL were enrolled: follicular lymphoma, grade 1 (11 patients) and grade 2 (8 patients); small lymphocytic lymphoma (5 patients); and lymphoplasmacytic lymphoma (1 patient). All patients were treated as clinically indicated. The median age was 47 years (21-70). There were 15 males, and 10 females. Three patients had intra-abdominal stage II, 2 patients with stage III, and 20 patients with stage IV disease. All patients received induction with CHOP for 4 cycles (weeks 1,4,7,10): cyclophosphamide 750 mg/m 2 IV, doxorubicin 50 mg/m 2 IV, vincristine 1.4 mg/m 2 IV (2 mg capped dose) and prednisone 100 mg PO ×5 days. Following induction, responding patients were given consolidation with either high dose cyclophosphamide @ 3 gm/m 2 IV for 3 doses with G-CSF (weeks 13,15,17) or 2 additional cycles of CHOP (weeks 13,16), stratified by stage and bulk of disease. The overall response rate to CHOP was 92% (3 CR, 8 PR) and to CHOP-HC was 93% (4 CR, 8 PR). The overall response, complete response and partial response rates were comparable in both arms. Median progression free survival for CHOP was 15.9 and 23.0 months for CHOP-HC. At 74.3 months median follow-up, all patients in the CHOP arm have recurred; 3 patients in the CHOP-HC arm (3 CR) have not recurred. The median overall survival has not been reached (at 5 years, 77% OS for CHOP-HC versus 83% OS for CHOP alone]. Greater hematologic toxicity was observed with CHOP-HC resulting in an increased number of hospitalizations for sepsis. There were no treatment-related deaths. No myelodysplasia or acute leukemia has been seen to date. With no obvious improvement in CR and with greater hematologic toxicity than CHOP, CHOP-HC is not recommended for treatment of indolent non-Hodgkin's lymphomas.     

Rituximab purging and maintenance therapy combined with autologous stem cell transplantation in patients with diffuse large B-cell lymphoma

The aim of this prospective, single-arm study was to test the efficacy and tolerability of autologous stem cell transplantation (auto-SCT) combined with in vivo rituximab purging and post-transplant rituximab maintenance therapy in patients with diffuse large B-cell lymphoma (DLBCL). This study included 12 DLBCL patients aged 18-65 years with an International Prognostic Index ≥2. The patients received 4-6 cycles of induction therapy consisting of rituximab plus cyclophosphamide, adriamycin, vincristine and prednisone followed by salvage therapy prior to stem cell mobilization. This regimen was followed by rituximab maintenance therapy (375 mg/m(2) every three months for two years). Prior to auto-SCT, six patients (50%) achieved complete remission (CR) and six (50%) achieved unconfirmed complete remission (CRu). Three months after transplantation, 11 patients (91.7%) achieved CR and one achieved CRu. After two cycles of rituximab maintenance therapy, all 12 patients achieved CR. Long-term CR was achieved by 10 patients, while two experienced relapse at 14 and 20 months after the end of rituximab maintenance therapy. The median follow-up period was 44 months (range 35-61). Disease-free survival was noted in 10 patients, while two experienced relapse. The three-year overall survival (OS) and progression-free survival (PFS) were 100 and 83%, respectively. Prolonged hypogammaglobulinemia occurred in two patients, although no increase in major infections was observed. Hepatitis B surface antigen was continuously negative in all 12 patients. Our results demonstrated that auto-SCT combined with in vivo rituximab purging and post-transplant rituximab maintenance is safe and effective, and may extend OS and PFS in younger high-risk DLBCL patients.     

Fludarabine combination therapy for the treatment of chronic lymphocytic leukemia

Fludarabine combination therapies have attained an increased popularity in the treatment of chronic lymphocytic leukemia (CLL). Among them, the combination of fludarabine/cyclophosphamide (FC) is by far the best regimen studied. Patients receiving FC at relapse show response rates (RRs) of 70%-94% with 11%-34% complete remission (CR) rates. In previously untreated patients with CLL, RRs of 64%-88% with 21%-46% CR rates were observed. The main side effects of FC are myelotoxicity and infections; most complications are reported as fever of unknown origin, infections of the upper respiratory tract, or herpes virus infection. There is probably a correlation between the higher dose of cyclophosphamide (> 750 mg/m2 per treatment course) and an increase in the number of severe infectious complications. Similar results were reported regarding the RRs and side effects of the combination of fludarabine/epirubicin. The triple combination of fludarabine/cyclophosphamide/mitoxantrone and fludarabine combinations with anti-CD20 (rituximab) or anti-CD52 (Campath-1H) antibody, might be even be more promising, since a relevant number of complete molecular remissions are achieved with these drugs. The precise role of fludarabine combinations within the overall treatment strategy remains to be determined. Our current recommendation is to use these combinations at relapse, while their use in first-line therapy should be investigated in clinical protocols. It remains to be shown whether patients with CLL achieve improved overall survival with these combination chemotherapies.     

Immunochemotherapy with rituximab, vincristine and 5-day cyclophosphamide for heavily pretreated follicular lymphoma

PURPOSE: Therapeutic options for relapsed or refractory follicular lymphoma include combination chemotherapy, immunotherapy and, for selected patients, autotransplant. Because of the different mechanisms of action and non-overlapping toxicities, combination of rituximab with chemotherapy is a rational approach. METHODS: 30 patients with follicular non-Hodgkin's lymphoma with advanced-stage disease were treated with four cycles of immunochemotherapy with rituximab 375 mg/m2 on day 1, vincristine 2 mg i.v. on day 2 and cyclophosphamide 400 mg/m2 i.v. from days 2 to 6, repeated at 3-week intervals. All patients had received multiple lines of therapy (median 3); 9 (30%) had relapses (2 after high-dose therapy with autologous transplant), and 21 (70%) were in relapse and refractory to salvage treatment (with an anthracycline-containing regimen in 19). RESULTS: Of 29 patients evaluable for response, 16 (55 %) obtained a complete response (CR) and 3 (10%) a partial response (PR), with an overall response rate of 65% (19/29); 10 patients (35%) achieved less than PR. The median event-free survival was 16.1 months for all patients, being 22.8 months for responders. After a median follow-up of 2 years from the start of therapy (range 6 months to 3.8 years), of 16 patients who achieved CR, 10 remain free of disease. CONCLUSION: The combination of rituximab with vincristine and 5-day cyclophosphamide is able to produce CR in patients with advanced follicular lymphoma, even in patients resistant to third-generation regimens. The regimen designed on the basis of pharmacokinetics of the chimeric antibody seemed important for the clinical efficacy of the combination.     

Role of CD20 Monoclonal Antibodies in Previously Untreated Chronic Lymphocytic Leukemia

Monoclonal antibodies (MoAbs) directed against the CD20 antigen on B cells have dramatically altered the treatment landscape for patients with chronic lymphocytic leukemia (CLL). Rituximab, a chimeric mouse/human MoAb, was the first antibody to be approved for the treatment of indolent B-cell lymphomas. Although single-agent, standard-dose rituximab has limited activity as first-line therapy for patients with CLL, it has synergistic therapeutic activity when combined with chemotherapy. Indeed, chemoimmunotherapy with combined fludarabine (F), cyclophosphamide (C), and rituximab was shown to improve both progression-free and overall survival in a randomized phase III clinical trial compared with FC in previously untreated patients with CLL. In this article, we review important clinical trials that have incorporated rituximab with other agents for treatment-naive patients with CLL. We also highlight second- and third-generation CD20 MoAbs approved or in development for the treatment of CLL.