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

Abstract

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 fl udarabine (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]. Th e FCR regimen, is currently the gold standard combination for primary therapy for fi t untreated patients with CLL, and is also considered a prime regimen for other indolent lymphomas. Th is 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 signifi cantly 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 fi t 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 immunesuppression. 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 fi t and have associated comorbidities. In an attempt to reduce toxicity, conventional dosages employed in the FCR regimen have been modifi ed: an attenuated schedule with lower doses of oral or intravenous (IV) FC has been shown to be very eff ective. Th e group from Siena fi rst described the use of lower dose FC without rituximab, and this regimen was shown to have effi cacy 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,