Chemoimmunotherapy with fludarabine, cytoxan and rituximab regimen: to use, not to use, or give it as “FCR-LITE”?

Over the past two decades we have witnessed major advances in the management of indolent lymphoproliferative disorders (LPDs), including chronic lymphocytic leukemia (CLL). Purine analogs, particularly fludarabine (F) [1], have been successfully introduced and used extensively in combination regimens with cytoxan (C) or mitoxantrone [2–4]. Monoclonal antibodies such as rituximab (R) are now also routinely incorporated into chemoimmunotherapy combination regimens, and impressively impact clinical responses in patients with indolent lymphomas and CLL who are in need of therapy [5].

The FCR regimen, is currently the gold standard combination for primary therapy for fit untreated patients with CLL, and is also considered a prime regimen for other indolent lymphomas. This combination regimen was used extensively with much success by Keating and colleagues [6] and later on by the German CLL Study Group, led by Hallek and associates [7], and was shown to be significantly superior to the FC combination or F alone in CLL. Despite the development of novel agents and newer monoclonal antibodies, FCR still remains the combination chemoimmunotherapy of choice for fit patients with CLL, yielding the highest complete response (CR) rate, the longest durations of remission and the best survival rates of all frontline regimens given as treatment for CLL [7].

The obvious disadvantages of F and FCR relate to toxicity in terms of myelosuppression, particularly neutropenia, varying degrees of cytopenia, and immune-suppression. Furthermore, problems relating to infections due to leukopenia during therapy and the late development of secondary hematopoietic malignancies began to influence and eventually limit the continuing routine use of this combination [8], especially in younger individuals with CLL and LPDs. This is particularly the case since other impressive newer agents, and effective combinations of these agents, have been proposed and used with success [9].

Elderly patients with both CLL and other indolent LPDs are often less fit and have associated comorbidities. In an attempt to reduce toxicity, conventional dosages employed in the FCR regimen have been modified: an attenuated schedule with lower doses of oral or intravenous (IV) FC has been shown to be very effective. The group from Siena first described the use of lower dose FC without rituximab, and this regimen was shown to have efficacy for indolent lymphoid malignancies, including CLL [10–12]. Likewise, in 2009, Foon and colleagues successfully used a “lighter” regimen of FC containing higher doses of R (FCR-LITE) [13], adding R as maintenance therapy. Results were impressive, with very high CR rates, an overall response rate (ORR) of 100% and less neutropenia. An update of this study was published last year, reporting a median progression-free survival of 5.8 years, while median overall survival had not yet been reached [14].

In this issue of Leukemia and Lymphoma, Fabbri et al. [15] report the results of a phase II study of elderly patients with non-Hodgkin lymphoma (NHL), treated upfront with attenuated oral doses of FC, combined with IV R. In this study, involving patients with a median age of 76 years, not only were the dosages of FC reduced, but also the number of cycles administered was limited to four. Using this short and FCR-LITE regimen, they were able to achieve an ORR of 92% and CR of 48%, and with only mild toxicity. Admittedly, and as the authors acknowledge, the trial used ultrasound rather than standard computed tomography (CT) monitoring for response assessment [16], so the reported response rates may not be precisely comparable to other reports in the literature. Nonetheless, this study is yet another achievement for Fabbri and colleagues from the Siena group, who have consistently reported the use of attenuated doses of this regimen since 2004 [10–12].

Recent literature clearly shows that we have entered a new era in CLL and LPDs, striving to go beyond just controlling the disease, with the aim of achieving minimal residual disease status, and maximal eradication of the malignancy, searching for “cure” [9,17]. Can we best do this with established regimens such as FCR, or with newer and potentially more effective drugs currently available and/or on the horizon? Which patients should be treated, with potential cure as a goal? Today's options include agents such as bendamustine and lenalidomide [9], which have made an impressive entry into this field. Soon we may have agents that target the B-cell receptor pathway, such as the novel Bruton kinase inhibitor, ibrutinib, which looks so promising for patients with CLL [17,18]. But have we already crossed the line into the era of abandoning the FCR regimen? Until now, none of the above novel drugs have long enough follow-up periods, or progression-free survival data equivalent to those described for FCR, so only time will tell. However, for many patients with CLL and LPDs the future certainly seems brighter than the not so distant past.

Potential conflict of interest

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