A comparison of the efficacy and safety of oral and intravenous fludarabine in chronic lymphocytic leukemia in the LRF CLL4 trial

Abstract

BACKGROUND: An oral formulation of fludarabine was introduced for use in chronic lymphocytic leukemia in 2001 following studies demonstrating the bioequivalence of a 40 mg/m2 oral dose with a 25 mg/m2 intravenous dose. We assessed retrospectively the efficacy of these two routes of administration in the LRF CLL4 trial. METHODS: A total of 777 patients were randomized from 1999‐2004 to receive fludarabine, alone or with cyclophosphamide, or chlorambucil. In 2001, a protocol amendment allowed the oral formulation. There were 117 assessable patients who received fludarabine intravenously and 252 who received it orally. A total of 387 patients given chlorambucil acted as a control group. RESULTS: Patients given oral fludarabine were less likely to receive the full dose (P = .0004) and experienced more, predominantly gastrointestinal, toxicity. Progression‐free survival (PFS) and overall survival were not affected by the route of administration (PFS hazard ratio, 1.10; 95% confidence interval, 0.87‐1.40), but the overall rate of response to treatment appeared to be lower with the oral formulation (P = .003). However, patients recruited since 2001 were older (P = .03) and were more likely to have TP53 deletion, and response rates after 2001 were also lower in the chlorambucil group. After excluding patients with TP53 deletion, no significant difference in outcome was attributable to the route of administration. CONCLUSIONS: Although the LRF CLL4 data suggest no important difference in the effectiveness of oral compared with intravenous fludarabine, randomized trials are needed to reliably evaluate this comparison, particularly in combination with rituximab. Meanwhile, it is important to monitor compliance and gastrointestinal side effects with the oral route and to switch to intravenous therapy if a reduced dose is being received. Cancer 2011. © 2010 American Cancer Society.

Impact of dose intensity on outcome of fludarabine, cyclophosphamide, and rituximab regimen given in the first-line therapy for chronic lymphocytic leukemia

“…Patients were followed up for one year in order to detect late toxicities such as prolonged cytopenia (<50x10 9 /L platelets or <1x10 9 /L neutrophils). Progression-free survival (PFS) was calculated from the first day of the last FCR cycle until relapse (>5x10 9 /L lymphocytes and/or palpable spleen, liver or lymph nodes), treatment-free survival (TFS) and overall survival (OS) were calculated after any second-line therapy and death from any cause, respectively. Survival status was confirmed by phone to the referring physicians, or was based on the database of our hospital outpatients' clinic.…”

“…From all these studies, it seems that toxicity is more related to the dose rather than to the route of administration. 9 However, the influence of the dose on clinical benefit remains uncertain.…”

Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL

“…FC given orally is at least as effective as when given IV. 36,37 Our high efficacy of FC was achieved despite dose reductions, but compared with the CLL8 study, 5 the median cumulative doses of F and C (F corrected for the different route of administration) did not differ.…”

A Case of Mucosa-Associated Lymphoid Tissue Lymphoma in Nasopharynx and Thyroid Gland

“…153 Cases of PML have been reported with rituximab treatment (usually in combination with chemotherapy regimens) in patients with CLL/SLL or other types of NHL. [154][155][156][157][158][159][160][161][162][163][164] Patients with low CD4+ T-cells prior to or during anti-tumor treatment with rituximab-containing regimens may be particularly susceptible to PML. 152,154,155 Patients with NHL receiving treatment with another anti-CD20 monoclonal antibody ofatumumab, 165 or the anti-CD30 antibody-drug conjugate brentuximab vedotin, may also be at potential risk for PML.…”

“…Although the oral formulation of fludarabine has been investigated [160][161][162] and is approved by the FDA for the treatment of CLL (in patients who have not responded to or have progressed after treatment with at least one alkylating agent), its use in combination regimens for CLL has not yet been established. Moreover, no prospective randomized trials have evaluated the activity and safety of the oral formulation …”