Sequential chemoimmunotherapy of fludarabine, mitoxantrone, and cyclophosphamide induction followed by alemtuzumab consolidation is effective in T‐cell prolymphocytic leukemia

Abstract

BACKGROUND Scarce systematic trial data have prevented uniform therapeutic guidelines for T‐cell prolymphocytic leukemia (T‐PLL). A central need in this historically refractory tumor is the controlled evaluation of multiagent chemotherapy and its combination with the currently most active single agent, alemtuzumab. METHODS This prospective multicenter phase 2 trial assessed response, survival, and toxicity of a novel regimen in previously treated (n = 9) and treatment‐naive (n = 16) patients with T‐PLL. Induction by fludarabine, mitoxantrone, and cyclophosphamide (FMC), for up to 4 cycles, was followed by alemtuzumab (A) consolidation, up to 12 weeks. RESULTS Of the 25 patients treated with FMC, 21 subsequently received alemtuzumab. Overall response rate to FMC was 68%, comprising 6 complete remissions (all bone‐marrow confirmed) and 11 partial remissions. Alemtuzumab consolidation increased the intent‐to‐treat overall response rate to 92% (12 complete remissions; 11 partial remissions). Median overall survival after FMC‐A was 17.1 months and median progression‐free survival was 11.9 months. Progression‐free survival tended to be shorter for patients with high‐level T‐cell leukemia 1 oncoprotein expression. Hematologic toxicities were the most frequent grade 3/4 side effects under FMC‐A. Exclusively in the 21 alemtuzumab‐consolidated patients, 13 cytomegalovirus reactivations were observed; 9 of these 13 represented a clinically relevant infection. CONCLUSIONS FMC‐A is a safe and efficient protocol in T‐PLL, which compares favorably to published data. Cancer 2013;119:2258–2267. © 2013 American Cancer Society.

Trial Watch

“…In particular, cyclophosphamide has been tested as a possible alternative to standard therapeutic approaches in patients affected by (1) T-cell promyelocytic leukemia, as part of an induction chemotherapeutic cocktail including fludarabine and mitoxantrone; 55 (2) melanoma, according to a metronomic schedule in combination with low-dose IL-2; 56 (3) non-small cell lung carcinoma (NSCLC), as part of a therapeutic regimen encompassing a mucin 1-targeting vaccine; 57 or (4) various solid tumors, including colorectal carcinoma, in combination with low-dose IL-2 and/or tyrosine kinase receptor inhibitors such as sorafenib and imatinib 58 - 62 . Altogether, the results of these studies suggest that metronomic cyclophosphamide can be safely combined with conventional chemotherapeutic as well as with targeted anticancer agents and often results in immunological responses that may be therapeutically significant, at least in some patients.…”

Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia

“…1,2 Patients typically present with elevated white blood cell counts, hepatosplenomegaly, generalized lymphadenopathy, anemia, and/or thrombocytopenia as abnormal T cells infiltrate the peripheral blood, bone marrow, lymph nodes, spleen, and occasionally pleural fluid and skin. Previously, few therapeutic options existed for T-PLL patients.…”

T-cell prolymphocytic leukemia in an adolescent with ataxia-telangiectasia: novel approach with a JAK3 inhibitor (tofacitinib)

“…Despite responses to chemo/immunotherapy (alemtuzamab 11,12 with/without pentostatin, 13 hematopoietic cell transplantation, 14 fludarabine/mitoxantrone/cyclophosphamide, 15 or methylpredinisolone 16 and other alkylators), 17 the median progression-free survival (8-12 months) and overall survival (20-24 months) in T-PLL remain dismal. 18 Longer survival is seen with hematopoietic cell transplantation; however, 33% to 47% of patients relapse within 36 months and treatment-related mortality is almost as high.…”