Immunochemotherapy with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Versus Fludarabine and Cyclophosphamide (FC) Improves Response Rates and Progression-Free Survival (PFS) of Previously Untreated Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL)

Abstract

Introduction: Previous phase II studies have suggested that a combination of FCR may increase the outcome of both untreated and relapsed CLL pts. In order to validate this concept the German CLL study group (GCLLSG) initiated a multicentre, multinational phase III trial, CLL8, to evaluate the efficacy and tolerability of FCR versus FC for the first-line treatment of pts with advanced CLL. Methods and Patients: 817 pts with good physical fitness as defined by a cumulative illness rating scale (CIRS) score (Extermann et al., JCO 1998) of up to 6 and a creatinine clearance (cr cl) □d 70 ml/min were enrolled between July 2003 and March 2006. Pts were randomly assigned to receive 6 courses of either FC (N=409; F 25mg/m2 i.v. d1–3 and C 250 mg/m2 i.v. d1–3; q 28 days) or FC plus R (N=408; 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent cycles; q 28 days). Both treatment arms were well balanced with regard to age, stage, genomic aberrations and VH status. 64% were Binet B, 32% Binet C and 5% Binet A. The median age was 61 years (range 30 to 81), the median CIRS score was 1 (range 0–8). The overall incidences of trisomy 12 and abnormalities of 13q, 11q23, and 17p13 detected by FISH were 12%, 57%, 25%, and 8%, respectively, with no statistically significant differences between treatment arms. A mean number of 5.2 courses was given in the FCR arm versus 4.8 courses in the FC arm (p=0.006). 74% (FCR) and 67% (FC) of pts received 6 cycles. Dose was reduced by more than 10% in at least one treatment course in 43% (FCR) and 30% (FC) of pts, and in 21% (FCR) and 17% (FC) of all treatment courses given. 17 pts did not receive any study medication, 10 due to violation of enrolment criteria (4 decreased renal function, 2 active secondary malignancies, 2 active infections, 1 autoimmune thrombocytopenia, 1 pt not requiring treatment), 3 due to withdrawal of consent, 2 due to worsened concomitant diseases. 2 pts were lost before start of treatment. 56 pts were not evaluable for response: 17 did not receive any study medication, 16 withdrew consent before interim staging, 7 due to violation of enrolment criteria, 4 discontinued treatment due to toxicity and 12 due to early death (caused by toxicity, progression or secondary malignancy). Prophylactic use of antibiotics or growth factors was not generally recommended in the protocol. Results: At the time of analysis, June 2008, the median observation time was 25.5 months (mo). 761 pts (FCR 390; FC 371) were evaluable for response, 787 pts (FCR 400; FC 387) for PFS and all for OS. The overall response rate (ORR) was significantly higher in the FCR arm (95%; 370/390) compared to FC (88%; 328/371 (p=0.001). The complete response rate of the FCR arm was 52% as compared to 27.0% in the FC arm (p<0.0001). PFS was 76.6% at 2 years in the FCR arm and 62.3% in the FC arm (p<0.0001). There was a trend for an increased OS rate in the FCR arm (91% vs 88% at 2 years p=0.18). Hazard Ratio for PFS was 0.59, for OS 0.76. The largest benefit for FCR was observed in Binet stage A and B with regard to CR, ORR and PFS (A: p=0.01, B: p<0.0001). FCR treatment was more frequently associated with CTC grade 3 and 4 adverse events (47% of FC vs 62% of FCR treated pts). Severe hematologic toxicity occurred in 55% (FCR) versus 39% (FC) of all patients. Significant differences were observed for neutropenia (FCR 33,6%; FC 20,9% p=0.0001) and leukocytopenia (FCR 24%; FC 12,1% p<0.0001) but not for thrombocytopenia (FCR 7,4%; FC 10,8% p=0.09) and anemia (FCR: 5,4% FC 6,8% p=0.42). The incidence of CTC grade 3 or 4 infections was not significantly increased in the FCR arm (18,8% versus 14,8% in the FC arm, p=0.68). Tumor lysis syndrome (FCR 0,2% FC 0,5%) and cytokine release syndrome (FCR 0,2% FC 0,0%) were rarely observed in both arms. Treatment related mortality occurred in 2.0% in the FCR and 1.5% in the FC arm. Multivariate analyses were performed to evaluate factors predicting outcome. Amongst these variables age, sex, Binet stage, CIRS score, renal function (cr cl < 70 ml/min) were independent prognostic factors predicting OS or PFS. Conclusion: Treatment with FCR chemoimmunotherapy improves response rates and PFS when compared to the FC chemotherapy. FCR caused more neutropenia/leukopenia without increasing the incidence of severe infections. These results suggest that FCR chemoimmunotherapy might become the new standard first-line treatment for physically fit CLL patients.

Alemtuzumab by continuous intravenous infusion followed by subcutaneous injection plus rituximab in the treatment of patients with chronic lymphocytic leukemia recurrence

“…Two recent, large randomized trials have demonstrated that chemoimmunotherapy results in superior response rates and progression-free survival over chemotherapy alone. 7,8 Alemtuzumab, a humanized immunoglobulin (Ig)G1 monoclonal antibody targeting the human CD52 antigen, has been approved for use in patients with CLL based on 2 clinical studies in patients with refractory disease and frontline patients, respectively. 9,10 Monoclonal antibodies directed against other target antigens have also demonstrated activity, most notably the anti-CD20-specific monoclonal antibody rituximab.…”

Enhancing the Action of Rituximab in Chronic Lymphocytic Leukemia by Adding Fresh Frozen Plasma

“…30 An important multicenter phase III trial demonstrating a significant advantage of progression-free survival achieved by adding RTX to the initial chemotherapy reg-imen in treatment-naive CLL patients found no significant benefit for RTX in the group of advanced-disease patients (Binnet stage C). 31 This recent observation suggests that hitherto poorly understood factors (possibly complement abnormalities common in advancedstage CLL) 17 may be responsible for this lack of clinical effect. If proven efficacious in a larger group of CLL patients, adding FFP may represent an additional, nontoxic and cost-effective way of increasing the efficacy of RTX, thus facilitating its use in patients with malignant B-cell diseases in combination with chemotherapy as well as in nonmalignant autoimmune diseases, such as cryoglobulinemia, 32 Sjogren's syndrome, 33 and other conditions.…”

Hematologist/oncologist disease‐specific expertise and survival: Lessons from chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)

“…Alemtuzumab, 15 bendamustine, 16 ofatumumab, 17 and rituximab have all received US Food and Drug Administration (FDA) approval for treatment of CLL in the last decade, which has also seen better definition of the role of allogeneic transplant for selected patients. 18 Multidrug regimens combining chemotherapeutic agents with monoclonal antibodies have dramatically improved response rates, progression free survival, [19][20][21] and overall survival (OS). 22 There have also been considerable improvements in the understanding and management of complications of CLL including autoimmune hemolytic anemia (AIHA), immune thrombocytopenic purpura (ITP), pure red blood cell aplasia (PRBCA), hypogammaglobulinemia, and infectious complications.…”