The natural history of fludarabine-refractory chronic lymphocytic leukemia patients who fail alemtuzumab or have bulky lymphadenopathy

Abstract

The natural history and outcome of salvage treatment for patients with fludarabine-refractory chronic lymphocytic leukemia who are either refractory to alemtuzumab ("double-refractory") or ineligible for alemtuzumab due to bulky lymphadenopathy ("bulky fludarabine-refractory") have not been described. We present the outcomes of 99 such patients (double-refractory n = 58, bulky fludarabine-refractory n = 41) undergoing their first salvage treatment at our center. Patients received a variety of salvage regimens including monoclonal antibodies (n = 15), single-agent cytotoxic drugs (n = 14), purine analogue combination regimens (n = 21), intensive combination chemotherapy (n = 36), allogeneic stem cell transplantation (SCT; n = 4), or other therapies (n = 9). Overall response to first salvage therapy other than SCT was 23%, with no complete responses. All four patients who underwent SCT as first salvage achieved complete remission. Early death (within 8 weeks of commencing first salvage) occurred in 13% of patients, and 54% of patients experienced a major infection during therapy. Overall survival was 9 months, with hemoglobin < 11 g/dL (hazard ratio 2.3), hepatomegaly (hazard ratio 2.4), and performance status > or = 2 (hazard ratio 1.9) being significant independent predictors of inferior survival.

The Prognostic Value of TP53 Mutations in Chronic Lymphocytic Leukemia Is Independent of Del17p13: Implications for Overall Survival and Chemorefractoriness

“…Clonal evolution leading to acquisition of TP53 mutations or deletion may be a mechanism of chemorefractoriness in CLL otherwise devoid of TP53 abnormalities at diagnosis (6,25,26). Sequential samples were available for 14 CLL who had no TP53 abnormalities at diagnosis and who later developed chemorefractoriness.…”

Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study

“…The prognosis for patients with fludarabine-refractory CLL was poor, with low response rates and short progression-free survival (PFS) and OS. 9,10 Outcomes were worse for patients also refractory to alemtuzumab, the CD52 mAb approved for fludarabine-refractory CLL. 9,10 Ofatumumab is a human CD20 mAb with single-agent activity in refractory CLL.…”

“…9,10 Outcomes were worse for patients also refractory to alemtuzumab, the CD52 mAb approved for fludarabine-refractory CLL. 9,10 Ofatumumab is a human CD20 mAb with single-agent activity in refractory CLL. In the interim analysis of the pivotal international trial in patients with fludarabine-and alemtuzumab-refractory (FA-ref; n ϭ 59) CLL or fludarabine-refractory CLL with bulky (Ͼ 5 cm lymph nodes) lymphadenopathy (BF-ref; n ϭ 79), the overall response rate (ORR) with ofatumumab was 58% and 47% in the FA- 12,13 Ofatumumab binds to a distinct epitope composed of the small and large loop domains of CD20, with more effective in vitro complement-dependent cytotoxicity [14][15][16] in cell lines and primary CLL cells with low CD20 expression.…”

“…9,10 Outcomes were worse for patients also refractory to alemtuzumab, the CD52 mAb approved for fludarabine-refractory CLL. 9,10 …”

Assessment of the efficacy of ofatumumab in patients with chronic lymphocytic leukaemia treated in the Department of Haematooncology and Bone Marrow Transplantation of the Medical University in Lublin – Prelimary results

“…The response rate was only 23%, while the risk of infectious complications was high for 54% of the patients. Monotherapy with rituximab was one of the available options, but it proved to be disappointing due to the lack of response and median OS of only 6 months [5].…”