Alemtuzumab in Combination with Interferon-α or Gemcitabine in Aggressive and Advanced Cutaneous T-Cell Lymphomas: Report of Preliminary Results
Authors: Rupoli Serena , Goteri Gaia , Picardi Paola , Pulini Stefano , Costagliola Antonello , Canafoglia Lucia , Mulattieri Simonetta , Stronati Andrea , Scortechini Anna Rita , Ottaviani Marco , Nicolini Massimiliano , Serresi Stefano , Cellini Andreina , Offidani Anna Maria , Leoni Pietro 
Published: April 2020

Abstract
Combination therapy is commonly used in the treatment of advanced and aggressive cutaneous T-cell lymphomas (CTCL), like Mycosis Fungoides (MF) and Sézary Syndrome (SS). Alemtuzumab, the humanized anti-CD52 antibody primarily developed for the treatment of B-CLL, has been also administered effectively in patients with CTCL as monotherapy, but it might be an ideal candidate for combination therapy either with a biological immune response modifier like interferon (IFN)-α, or with a drug known to be particularly active in CTCL like gemcitabine. No data on the activity of combination schemes including alemtuzumab in CTCL seem to be available. The aim of this study was to explore the clinical activity of alemtuzumab in two combination modalities, including either IFN-α or gemcitabine. We enrolled 5 patients, 4 males and 1 female, affected by SS/erythrodermic MF, with a median age of 57 yrs (43–74) and a median disease history of 21 mo.s (9–95). Two patients were treated with both combination schemes. Before starting therapy, all patients except one had a rapidly progressive disease, relapsed or refractory to previous treatments, and had previously received three or more systemic chemotherapy regimens. Most patients had reduced performance status and all had severe itching. Four patients received alemtuzumab in combination with IFN-α: subcutaneous alemtuzumab was administered at 3 mg on day 1, 10 mg on day 3, followed by 15 mg on alternating days for 7 total doses; after a further 3 months of treatment with IFN-α (3 MU three times weekly) the patients received reinduction with alemtuzumab (10 mg weekly for another month). Three patients received alemtuzumab in combination with gemcitabine: subcutaneous alemtuzumab was given at 10 mg on days 1, 8 and 15 of a 28-day schedule in combination with gemcitabine at a dose of 1200 mg/m2 intravenously (median number of cycles=4). Trimethoprim/sulphamethoxazole (twice daily 2 times per week) and valacyclovir (500 mg twice daily) were administered from day 2 until at least 2 months after alemtuzumab discontinuation. The response (complete/CR, partial/PR, stable disease/SD) was assessed in skin, lymph nodes and peripheral blood, by using the SWAT criteria and by comparing the absolute number of circulating Sezary cells (SC) detected by flow-cytometry before and after treatment. The overall response (OR) was determined as the worse result obtained in the different sites. The OR rate was 57.1% (4 PR vs 3 SD), higher in the group treated with alemtuzumab and gemcitabine (66.7%: 2 PR vs 1 SD) than in the group treated with alemtuzumab and IFN-α(50%, 2 PR and 2 SD). The better response rate obtained in the group treated with gemcitabine was due to the higher activity in the skin (2 CR, 1 SD vs 2 PR, 2 SD) and in the lymph nodes (3 PR vs 3 PR, 1 SD). The circulating SC count was low at the end of therapy (median, 164, range, 24–530), with a lower median value in the group treated with gemcitabine (131), than in the group treated with IFN-α (303). Itching, self-assessed on a 0 to 10 visual analog scale, was significantly reduced from a median score of 9 before treatment, to 1 at the end of therapy. Both combination treatments were well tolerated. Infusion-related adverse events were not reported. Grade 3–4 hematologic toxicity was observed only in one case treated by alemtuzumab and gemcitabine (grade 3 leukopenia). One patient from the group treated with alemtuzumab and IFN-α had infectious complications (CMV pneumonitis and pulmonary aspergillosis). Two patients treated with gemcitabine showed CMV detectable viral load in peripheral blood without any occurrence of complications. All patients treated with alemtuzumab and IFN-α experienced a progressive disease, respectively at 5, 9, 11, 12 months, whereas the 3 patients treated with alemtuzumab and gemcitabine are still in PR at 4, 10, 12 months (median overall PFS: 9 mo.s). At last follow-up, 3 patients are still alive with disease, while two had died, one for unrelated causes and the other for progressive disease. Although the present series is small, our observations point towards a potential role of alemtuzumab in combination schemes in heavily pretreated CTCL patients, as the response rate (57%) appears better than that reported in the literature for alemtuzumab alone (OR 33%), and the toxicity profile of both combination seems to be fairly acceptable. Moreover, gemcitabine might be a better candidate than IFN-α for combination therapy with alemtuzumab, since the progression-free survival seems to be prolonged.