Therapy with Fludarabine, Cyclophosphamide and Rituximab (FCR) for Relapsed or Untreated Progressive Chronic Lymphocytic Leukemia (CLL): A Single Centre Experience

Reviewer: John P. Plastaras, MD, PhD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: March 21, 2007

Presenter: Pavlovsky, M A
Presenter's Affiliation: FUNDALEU, Argentina
Type of Session: Scientific

Background

Chronic lymphocytic leukemia (CLL) is an indolent neoplasm of B-cell origin, that is usually CD20+, CD5+, and CD23+. It is similar to small lymphocytic lymphoma (SLL) where the disease burden is predominantly in lymph nodes and the bone marrow is minimally involved.

Fludarabine is the most active single agent in CLL. Rituximab is an anti-CD20 antibody that has complementary activity with fludarabine with minimal toxicity.

The combination of fludarabine, cyclophophamide, and rituximab (FCR) has demonstrated superior rates of complete remission (CR), minimal residual disease (MRD) negativity, disease-free survival (DFS) and overall survival (OS) in previously treated and untreated patients with CLL, when compared with historical control groups using fludarabine alone or fludarabine and cyclophosphamide.

CD28 is a marker of worse prognosis in CLL

This study was undertaken to evaluate the efficacy of FCR in improving CR, DFS and OS rates in patients previously treated with chlorambucil-prednisone and untreated patients with CLL.

Materials and Methods
Phase II single institution, single-arm, prospective study in patients with either untreated or previously treated with chlorambucil-prednisone eligible for symptomatic treatment.

Patients:

45 CLL patients started treatment with FCR.
Median patient age was 63 years (range 34–88 years)
Binet’s stage:
- 8% stage A, 34% stage B, 58% stage C.
CD38 expression was positive (> 7% of cells) in 56% of patients and negative in 44%.
Untreated: 32 patients; Previously Treated: 8 patients

Treatment:
FCR chemotherapy: all agents were given intravenously every 4 weeks for 4–6 cycles

fludarabine (25 mg/m2/day x 3) and
cyclophosphamide (250 mg/m2/day x 3)
rituximab (375 mg/m2/day x 1)

Reponse Criteria:

CR was defined by CLL/NCI-WG criteria.
Minimal residual disease (MRD) negativity was < 1% of CD19 and CD5-positive cells in peripheral blood and bone marrow.

Results
41 patients completed treatment:

16 following previous relapse
25 previously untreated with progressive disease
The median number of cycles was 4.5 cycles

Response:

CR: 80% (of these, 97% were MRD negative)
Nodular Rartial Remission: 16% (of these, 100% were MRD negative)
Partial Remission: 8% of patients
Stable Disease: 2%

Remissions were more common in previously untreated patients:

Untreated: 87% (of these, 96% were MRD negative)
Previously Treated: 53% (of these, 87% were MRD negative)

Disease Free Survival was worse in previously-treated and CD38 positive patients:

Untreated: 91%; Previously Treated: 62% (p=0.02)
CD38 negative: 89%; CD38 positive: 66% (p=0.04)

Toxicity:

Grade 3–4 neutropenia: 33% of patients

Author's Conclusions

FCR induces a high CR and DFS rate and increases MRD negativity. Significantly higher DFS rates were observed in patients who were CD38 negative.

Clinical/Scientific Implications

The combination regimen of fludarabine, cyclophosphamide, and rituximab in patients that were either treatment naïve or previously treated was associated with excellent remission rates. It was generally well-tolerated except for frequent neutropenic fever (33%).

This study confirms that previously treated patients have lower remission rates. Also, the cell surface marker, CD38 is a negative prognostic marker in CLL with this treatment regimen.

Rituximab has been a major addition to the armamentarium against B-cell diseases. It is particularly appealing for indolent B-cell NHL as it has minimal toxicity and can be combined fairly easily with other treatments. The ideal schedule of incorporation of rituximab is an active area of investigation in number B-cell histologies.