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. 2016 Dec 1;8(3):99–105. doi: 10.1177/2040620716681749

The role of combined fludarabine, cyclophosphamide and rituximab chemoimmunotherapy in chronic lymphocytic leukemia: current evidence and controversies

Alan P Skarbnik 1,✉, Stefan Faderl 2
PMCID: PMC5305006  PMID: 28246553

Abstract

Chemoimmunotherapy (CIT) has become a cornerstone in the treatment of patients with chronic lymphocytic leukemia (CLL). The combination of fludarabine, cyclophosphamide and rituximab (FCR) has emerged as the standard of care for therapy of previously untreated patients with CLL who are younger than 65 years and have no significant comorbidities. In this article, we review the role of FCR in the current treatment paradigm for CLL.

Keywords: chemoimmunotherapy, CLL, FCR, fludarabine, rituximab

Introduction

It is estimated that over 15,000 new patients will be diagnosed with chronic lymphocytic leukemia (CLL) and approximately 5000 will die from this disease in the United States in 2016 [Surveillance, Epidemiology, and End Results Program, 2015]. CLL is a disease more commonly diagnosed in elderly (median age 72 years), male (2:1 male to female ratio), and white populations.

CLL is an extremely heterogeneous disease, with some patients living decades without needing treatment, while others, such as those harboring high-risk mutations, present with a rapidly progressive disease. Since >70% of patients with CLL are >65 years of age, aggressive treatment is challenging. Although new therapies with B-cell antigen receptor signaling pathways inhibitors (e.g. ibrutinib or idelalisib) and the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax have demonstrated favorable results across all risk group subsets [Byrd et al. 2013; Furman et al. 2014; Roberts et al. 2016], only ibrutinib is available as frontline therapy, based on results from the RESONATE-2 trial [Burger et al. 2015]. Furthermore, the long-term safety record is not always established as a recent safety warning regarding increase mortality of patients treated with idelalisib has demonstrated. Hence, there is still a role for chemoimmunotherapy (CIT) in the treatment of CLL. Multiple clinical trials for the treatment of CLL are ongoing, and for those patients who are eligible and willing, enrollment in clinical trials should be the preferred approach. However, for those patients who are unwilling or are unable to be enrolled in a clinical trial, and can tolerate it, CIT remains a standard treatment for CLL. The combination of fludarabine, cyclophosphamide and rituximab (FCR) is a widely used CIT regimen for CLL. Here, we will review its current role in the treatment paradigm for CLL.

Development of the FCR regimen

Before the advent of modern CIT combinations, treatment for CLL consisted in using single alkylating agents, such as chlorambucil. Alkylating agents, with or without steroids, provided response rates of 40–77% in patients with previously untreated CLL [Knospe et al. 1974; Montserrat et al. 1985]. In fact, addition of steroids in these trials did not significantly improve efficacy, while increasing toxicity from the treatment. The addition of other cytotoxic agents, such as vinca alkaloids, anthracyclines, cytarabine or even combinations of alkylating agents failed to improve outcomes in this patient population [Keating et al. 1988; Kempin et al. 1982; Liepman and Votaw, 1978].

Fludarabine, a fluorinated purine nucleoside analogue that is resistant to deamination by adenosine deaminase, was initially studied as a single agent in patients with relapsed/refractory (R/R) CLL, yielding responses of 33–57% [Grever et al. 1988; Keating et al. 1989]. In previously untreated patients, overall response rates (ORRs) of single agent fludarabine were as high as 70% [Keating et al. 1991].

A large randomized trial compared fludarabine versus chlorambucil versus fludarabine plus chlorambucil in patients with previously untreated CLL [Rai et al. 2000]. ORRs were 63%, 31% and 61% for fludarabine, chlorambucil, and fludarabine plus chlorambucil, respectively. Overall survival (OS) was 66 months, 56 months and 55 months for fludarabine, chlorambucil, and fludarabine plus chlorambucil, respectively, without a statistically significant difference.

In an attempt to improve response rates with fludarabine alone and based on in vitro evidence of synergistic activity between fludarabine and cyclophosphamide [Yamauchi et al. 2001], a regimen combining these two agents (FC) was tested as a therapy for CLL, including patients who were previously exposed to fludarabine as a single agent [O’Brien et al. 2001]. A total of 128 patients with CLL were treated with different FC schedules. Patients not refractory to fludarabine or alkylating agents at the time of entry onto the study had an overall response rate of ⩾80%. The synergy between these two agents was further evidenced by the fact that patients who were refractory to fludarabine when entering the study still achieved a 38% response rate following the FC combination. However, complete response (CR) rates remained low, at 35% for previously untreated patients.

Rituximab, a chimeric, monoclonal antibody targeting CD20, was shown to increase cytotoxicity of both fludarabine and cyclophosphamide in lymphoma cell lines [Demidem et al. 1997; Alas et al. 2000]. This provided the rationale to combine rituximab with the FC regimen (FCR). The FCR regimen was initially evaluated in a phase II trial by the MD Anderson group, in patients with R/R CLL [Wierda et al. 2005]. The regimen consisted of rituximab 375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycles 2–6; fludarabine 25 mg/m2/day and cyclophosphamide 250 mg/m2/day were administered for 3 days each cycle. According to the final updated report for this trial [Badoux et al. 2011], among the 280 patients evaluable for response, 30% achieved CR, 14% achieved nodular partial remission (nPR) and 30% achieved partial remission (PR) for an ORR of 74%. Patients who had ⩽3 prior therapies achieved significantly higher CR and PR rates when compared with those who had four or more prior therapies (CR/nPR = 52% versus 4%, p < 0.0001). Prior exposure to rituximab or fludarabine, without combination with an alkylating agent, did not affect response rates negatively (CR/nPR 62% and ORR 84%); however, patients who received prior combinations of fludarabine and an alkylating agent presented intermediate response rates (CR/nPR 42% and ORR 73%), with patients who had fludarabine refractoriness presenting significantly worse response rates when compared with those with previous response to fludarabine-containing regimens (CR/nPR = 8% versus 46%, p = 0.023). Median progression-free survival (PFS) for patients achieving CR was 60 months, 38 months for those in nPR (p = 0.076) and 15 months for those achieving PR (p < 0.001). PFS was also lower for those patients who presented high-risk cytogenetic abnormalities (del 17p, del 11q, 3 or more cytogenetic abnormalities).

The regimen of FCR was then evaluated in patients with previously untreated CLL in a phase II trial [Keating et al. 2005]. For the 224 patients in this trial, CR was 70% and ORR was 95%. Pretreatment characteristics significantly associated with a lower probability of achieving CR (p < 0.05) were advanced Rai and Binet stages, older age, higher white blood cell counts, lower platelet counts, higher serum β2-microglobulin level, bone marrow biopsy cellularity >50%, and splenomegaly >5 cm below the left costal margin. A total of 207 patients had bone marrow aspirates evaluated by flow cytometry for residual disease, with 67% of those patients presenting <1% CD5- and CD19-coexpressing cells, considered a ‘flow cytometry CR’. The more common complications with this regimen were myelosuppression and infections. An update on the results of this trial revealed 6-year OS and failure-free survival of 77% and 51%, respectively, with a median time to progression of 80 months [Tam et al. 2008].

The CLL8 phase III trial was the first major randomized trial which was designed to compare FC with FCR in treatment-naïve CLL patients [Hallek et al. 2010; Fischer et al. 2016]. In an open-label fashion, 817 patients were randomized to receive one of these regimens. The recently published update to this trial showed that, with a median follow up of 5.9 years, the PFS for FCR versus FC was 56.8 versus 32.9 months (hazard ratio (HR), 0.59; 95% confidence interval (CI), 0.50–0.69, p < 0.001). Furthermore, there was a significant OS advantage: not reached for the FCR group versus 86 months for the FC group (HR, 0.68; 95% CI, 0.54–0.89, p = 0.001). Major toxicities associated with this therapy were myelosuppression (which could be prolonged) and infectious complications.

Pitfalls of the FCR regimen

Although FCR is the regimen that, to date, provides the best outcomes in terms of CR rates, PFS and OS in patients with treatment-naïve CLL, several issues have to be considered when choosing this treatment.

First, in clinical practice there is a significant number of patients who do not tolerate receiving the planned 6 cycles of therapy, usually due to significant myelosuppression or neutropenic fever. It is customary to support patients with growth factors (i.e. G-CSF) through every cycle of therapy. Prophylaxis against Pneumocystis jirovecii pneumonia and viral infections should be strongly considered. We usually recommend using sulfamethoxazole trimethoprim and acyclovir for patients undergoing FCR.

Poor tolerance to FCR is especially common in older (>65 years old) patients. The CLL10 study compared FCR with bendamustine and rituximab (BR) for physically fit patients with treatment-naïve CLL [Eichhorst et al. 2016]. A total of 561patients were included in the intent-to-treat analysis. The investigators selected healthy patients for this study, using the Cumulative Illness Rating Scale, where patients needed a score of six or less, and adequate renal function (creatinine clearance ⩾70 ml/min) as inclusion criteria. Patients with del (17p) were excluded. There were imbalances in the distribution of certain patient characteristics between both groups. There was a higher proportion of patients with an unmutated immunoglobulin heavy chain variable gene (IGHV) status as well as patients >70 years old in the BR group; whereas there were more patients with del (11q) in the FCR group. In the FCR group 29% of patients received less than the planned 6 cycles of therapy, compared with 19% in the BR group. For patients >65 years of age, 43% did not receive the full planned treatment course in the FCR group, compared with 24% in the BR group (p = 0.013). PFS was significantly shorter in the BR group (41.7 months versus 55.2 months, HR 1.643, p = 0.0003). In younger (⩽ 65 years old) patients, PFS with FCR was significantly longer than with BR (53.6 months versus 38.5 months; p = 0.0004), however, in the elderly (>65 years old) patient population there was no difference in PFS between the two treatment groups. For patients with unmutated IGHV status, there was significantly longer time to progression for those receiving FCR (42.7 months versus 33.6 months with BR; p = 0.017). PFS was also substantially longer with FCR for patients carrying del (11q) (37.8 months versus 25.3 months with BR; p = 0.0002). When comparing the rates of negative minimal residual disease (MRD) status in FCR versus BR, the triple therapy combination provided better results both in blood (49% versus 38%; p = 0.041) and bone marrow (27% versus 11%, p < 0.0001). No difference in OS was observed between treatment groups. Severe neutropenia was more often observed in the FCR arm (85% versus 59%, p < 0.001) Severe infections occurred significantly more frequently (40% versus 26%, p = 0.001) in the FCR arm during treatment phase until 6 months follow up, especially in older patients (46% versus 26%; p = 0.001). Treatment-related mortality was 5% (FCR) and 2% (BR), respectively.

Another trial evaluated a reduced-dose FCR regimen (FCR-lite) for treatment-naïve patients, with the intent of reducing grade 3/4 neutropenia [Foon et al. 2009, 2012]. The regimen was changed to fludarabine 20 mg/m2 and cyclophosphamide 150 mg/m2 for 3 consecutive days, with rituximab 500 mg/m2 every other week for six 28-days cycles, followed by rituximab 500 mg/m2 every 3 months until relapse. The OR and CR rates were 93% and 73% respectively, and grade 3/4 neutropenia was noted in 11% of the cycles of therapy. Of those patients who discontinued therapy due to neutropenia (10%), 80% were >65 years of age. Median OS had not been reached and median PFS was 5.8 years.

Second, FCR is not equally effective across all subgroups of CLL patients. A retrospective observational analysis of 404 patients who were treated with standard FCR as first-line for CLL revealed that different genetic/chromosomal combinations predict the success rate of this therapy [Rossi et al. 2015]. In univariate and multivariate analyses, patients with a mutated IGHV gene had a 5-year PFS of 58% versus 36% for those with an unmutated gene (p = 0.0005). For patients harboring 11q chromosomal deletion the 5-year PFS was 18% versus 49% for patients without this deletion and for patients with 17p chromosomal deletion the 5-year PFS was 11% versus 48% for those with an intact chromosome 17. The investigators were able to define three distinct patient groups: low risk (IGHV-mutated and no 11q or 17p deletion), intermediate risk (IGHV-unmutated or 11q deletion) and high risk (17p deletion). With a median follow up of 70 months, the median PFS and 5-year OS for the low-risk group were not reached and 91% respectively, for the intermediate-risk group they were 52 months and 83% respectively and for the high-risk group they were 22 months and 55% respectively. Several other publications found similar outcomes [Lin et al. 2009; Fink et al. 2013; Stilgenbauer et al. 2014]. A recent publication evaluating patients from the original phase II FCR trials identified that, at 12.8 years, the PFS for patients with a mutated IGHV gene was 53.9%; whereas for those with an unmutated gene it was 8.7% [Thompson et al. 2016]. Approximately 50% of patients with a mutated IGHV achieved MRD-negative status following treatment. For this population, the 12.8 years PFS was 79.8%. A plateau was seen on the PFS curve in patients with mutated IGHV, with no relapses beyond 10.4 years in 42 patients.

A prospective study evaluated pretreatment characteristics and treatment response, including bone marrow MRD status, in patients who received FCR as frontline treatment for CLL [Strati et al. 2014]. Bone marrow MRD was quantified by flow cytometry in samples after cycle 3 and 2 months after the last FCR cycle. MRD-negative status was achieved in 17% of 194 patients evaluated after cycle 3 and in 43% of 161 patients at final response assessment. Pretreatment factors associated with MRD-negative status after completion of treatment in univariate analysis were β2-microglobulin (B2M) <4 mg/l (p = 0.03), mutated IGHV gene (p = 0.02), trisomy 12 (p = 0.004), and absence of deletion 17p (p = 0.04), and in multivariate analysis only trisomy 12 and mutated IGHV gene were associated with MRD-negative status. Factors not significantly associated (p > 0.05) with MRD-negative status in univariate analysis included age >65 years, Rai stage III–IV, absolute lymphocyte count >75 K/μl; CD38 ⩾ 30%; ZAP70 positivity; del (13q) and del (11q); and receiving more than three courses of FCR. Pretreatment characteristics associated with MRD-negative status after cycle 3, in multivariate analysis, were mutated IGHV gene (OR, 2.7; 95% CI, 1.1–6.3; p = 0.02) and trisomy 12 (OR, 2.7; 95% CI, 1.1–7.2;p = 0.05). MRD-negative status was also independently associated with prolonged PFS and OS in multivariate analysis (PFS: HR 0.1; 95% CI, 0.01–0.8; p = 0.03); (OS: HR 0.6; 95% CI, 0.4–0.9; p = 0.02); however, when analyzing only patients who achieved a CR, MRD-negative status did not correlate with either increased PFS or OS. Most interestingly in this study was the finding that, for those patients achieving MRD-negative status after 3 cycles of FCR, there did not seem to be any advantage, in terms of PFS, in continuing treatment beyond those cycles.

Third, treatment with alkylating agents has a potential to lead to secondary myeloid malignancies. In a retrospective study, 4.5% of patients who were treated with frontline FCR for CLL developed myeloid malignancies [Zhou et al. 2012]. Most cases were myelodysplastic syndromes (MDSs), although acute myelogenous leukemia was also reported. The overall latency for development of treatment-related myeloid malignancies was 35 months. Abnormal cytogenetics was present in 96% of patients, with frequent chromosomes 5 and 7 abnormalities. Treatment with fludarabine also may lead to secondary myeloid malignancies, especially when combined with DNA-damaging agents such as cyclophosphamide. In a retrospective study of 137 patients who received fludarabine-based combination chemotherapy for CLL or indolent non-Hodgkin lymphoma, with a median follow up of 40 months after completion of therapy, the rate of secondary MDS/AML was 2.5% for patients who received fludarabine-based therapy as first-line and 9.3% for those who received fludarabine-based therapy as second-line or further [Tam et al. 2006].

FCR in the current treatment landscape for CLL

Currently, the use of FCR as frontline therapy for CLL is controversial

When feasible, we recommend that all patients who require therapy should be enrolled in a clinical trial. Otherwise, based on the data presented above, our recommendation is to use FCR in younger (⩽65 years old) CLL patients who present with mutated IGHV and no high-risk cytogenetics (17p deletion, 11q deletion, three or more cytogenetic abnormalities or p53 mutations) as in this particular patient population, there is significant potential for long-term PFS when using FCR and a low risk of relapses after 10 years. For all other cases, we would recommend alternative therapies. There is a need for additional head-to-head trials between FCR and novel therapies to support this recommendation, however, given the potential risks associated with the use of FCR in older patients, and the poorer outcomes of FCR in patients with unmutated IGHV or deletion 11q or 17p we recommend carefully selecting other options for this patient population.

Additionally, for patients being treated with FCR, we recommend checking MRD status after three cycles and if in CR and MRD-negative status, early termination of therapy should be considered.

For those patients who relapse after receiving previous FCR treatment, and had a remission lasting at least 3 years, it is acceptable to retreat with FCR, while being cautious about the risk of developing secondary malignancies. Treatment with BR following relapse after FCR may carry similar risks. It may be advisable to evaluate bone marrow samples for potential abnormalities associated with MDS or AML (such as an increase in blasts, dysplastic features and cytogenetic abnormalities) before re-treating with FCR or BR following relapse. In this scenario, one should also consider alternative options such as B-cell receptor pathway inhibitors or clinical trials.

Evaluation of FCR as a backbone for novel combinations, in particular B-cell receptor pathway inhibitors, is warranted, especially for the high-risk population. Given recent reports of increased rate of severe infections in trials including idelalisib plus chemotherapy, appropriate infection surveillance should be considered in trials combining novel agents with chemotherapy, including FCR. Table 1 provides a list of ongoing trials.

Table 1.

Ongoing clinical trials including FCR-like regimens as backbone.

ClinicalTrials.gov identifier Patient population Intervention
NCT00868413 R/R CLL Navitoclax (BCL-2 inhibitor) + FCR versus navitoclax + BR
NCT02158091 Frontline CLL, age ⩽ 65 Duvelisib + FCR
NCT02251548 Frontline CLL, age ⩽ 65 Ibrutinib + FCR
NCT02048813 Frontline CLL, age ⩽ 70 Ibrutinib + rituximab versus FCR
NCT02629809 Frontline CLL with mutated IGHV Ibrutinib + fludarabine, cyclophosphamide and obinutuzumab
NCT01762202 Frontline CLL, age ⩽ 65 Fludarabine + cyclophosphamide + ofatumumab
NCT01096992 Frontline CLL Fludarabine + bendamustine + Rituximab
NCT00918723 Frontline CLL FCR + vorinostat
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BCL-2, B-cell lymphoma 2; BR, bendamustine and rituximab; CLL, chronic lymphocytic leukemia; FCR, fludarabine, cyclophosphamide and rituximab; IGHV, immunoglobulin heavy chain variable gene; R/R, relapsed/refractory.

Footnotes

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement: Alan P Skarbnik: Speakers’ Bureau for Gilead Sciences (Foster City, CA, USA) and Genentech (San Francisco, CA, USA), Advisory Board for Abbvie (Chicago, IL, USA) and Pharmacyclics (Sunnyvale, CA, USA).

Contributor Information

Alan P. Skarbnik, Division of Lymphoma, John Theurer Cancer Center, Blood and Marrow Transplantation Program, John Theurer Cancer Center at Hackensack University Medical Center, 92 Second Street, Hackensack, NJ 07624, USA.

Stefan Faderl, Division of Leukemia, John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ, USA.

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Articles from Therapeutic Advances in Hematology are provided here courtesy of SAGE Publications

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