Sézary syndrome (SS) is a rare disorder that accounts for approximately 3% of all cutaneous T-cell lymphomas. It is considered to be an aggressive variant characterized by the presence of erythroderma and circulating atypical T cells (Sézary cells), with or without lymphadenopathy.1 SS is classified as T4, N0-3, M0-1, B2 according to the International Society for Cutaneous Lymphomas (Table 1).1–3 Pruritus is the main symptom and can have a marked impact on quality of life.

The prognosis is poor, with a 5-year survival of 24%; few lasting responses or remissions have been reported after treatment.4

Systemic therapies are necessary for treatment, as those that exclusively target the skin are insufficient. The therapeutic choice is determined by the spread of the disease, the impact on quality of life, and the patient's age and comorbid conditions. Although several treatments are available for SS (Table 2),3 few efficacy studies have been published.

New therapies for SS, including biological therapies, have appeared in recent years. Alemtuzumab is a humanized monoclonal antibody that targets the CD52 glycoprotein expressed on the surface of T and B cells, natural killer cells, monocytes, and macrophages, leading to a depletion of those cells in the peripheral blood.3,5 It is thought to act by direct cell lysis mediated by neutrophils, complement, and antibody-dependent cytotoxicity and apoptosis.3–6 In 2001, alemtuzumab was approved for the treatment of B-cell chronic lymphocytic leukemia, although some authors have used it in cases of refractory SS and advanced mycosis fungoides (MF).

We present 5 patients (3 women and 2 men) diagnosed with stage IVA1 SS (T4, N0, M0, B2) who were treated with alemtuzumab between 2008 and 2012. Four patients had undergone previous treatments (phototherapy, prednisone, methotrexate, gemcitabine, and bexarotene).

Data were gathered on the following variables to assess the treatment with alemtuzumab (Table 3): duration, type of response, time until onset of the response, duration of the response after the interruption of treatment, and peripheral blood Sézary cells. In addition, we analyzed the clinical course, follow-up period, and complications associated with alemtuzumab.

The type of response was classified as follows: complete response (CR), partial response (PR), or disease progression (DP), in accordance with the study by Olsen et al.2 (Figure 1).

Figure 1.

A, Erythematous lesions on the abdomen of a patient with SS before starting treatment with alemtuzumab (case3). B, In the same patient, resolution of the erythema 4 weeks after starting treatment with alemtuzumab.

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The regimen used was the subcutaneous administration of an initial dose of 3mg, followed by doses of 10mg 3 times per week.

The 5 patients received oral prophylaxis with sulfamethoxazole-trimethoprim, aciclovir, and fluconazole for Pneumocystis jiroveci, herpesvirus, and Candida. For cytomegalovirus (CMV) prophylaxis, we performed weekly measurement of the viral load and administered anticipatory treatment with oral valganciclovir in the event of reactivation.

A response was achieved in 4 of the 5 patients (overall response rate, 80%); there were 2 PR (40%) and 2 CR (40%). The median duration of treatment was 8 weeks (range, 4-13 weeks) and the median duration of the response after the interruption of treatment was 13 months (range, 5-66 months).

Complications included pneumococcal pneumonia in 1 patient, a cytokine release syndrome in 3, and subclinical CMV reactivation in 2. There were no hematological complications.

The median follow-up was 27 months (range, 23-67 months) after the initiation of treatment. One patient died at 24 months due to transformation to a high-grade nonHodgkin lymphoma. At the time of writing, 3 patients are in progression and one continues in complete remission 67 months after completing the treatment.

Alemtuzumab has been used in both refractory, advanced-stage MF and in SS. The first description is from 1998 in 8 patients with MF.7 In 2003, the usefulness of alemtuzumab was demonstrated in a phase ii study of 22 patients with MF or SS.8 A number of small series and case reports have been published since that time. In the literature reviewed, we found a total of 13 series4,6–17 (detailed in Table 4) and 6 case reports of MF and SS.

The overall responses to treatment in the 2 largest studies—of 22 and 39 patients—were 55% and 51%, respectively.8,9 The median duration of the response was 12 months, although this varied between series.4,6–17 In the series of 39 cases, lasting remissions (more than 2 years) were observed in 5 patients with SS but in only 1 patient with MF.9

The treatment regimen has changed over the years. The drug was administered intravenously in the initial studies: sequential initial doses of 3mg, 10mg, and 30mg were administered, followed by 30mg 3 times a week.7,8,10–13 It was subsequently observed that alemtuzumab could be equally effective administered subcutaneously at low doses.4,14

Treatment-related complications include infection and hematologic toxicity. The regimen of 10mg subcutaneously has been shown to be associated with a lower incidence of these side effects.4,14,15 The most common opportunistic infection is CMV reactivation, although other types of infection have also been reported.4 Myelosuppression is the most common hematologic toxicity.4

Cytokine release syndrome is the most common complication during treatment.7,8,10,11 Its frequency can be reduced by progressive dose escalation. Lenihan et al.13 published 4 cases of cardiac toxicity during the treatment of previously healthy patients. As this has not been observed in any other study, the possibility of a causal relationship remains under debate. A case of cutaneous hemophagocytosis at the site of injection of alemtuzumab was recently reported in a patient without Epstein-Barr virus reactivation.18

In the literature reviewed, alemtuzumab has been used indistinctly for MF and for SS, and advanced-stage SS and MF are grouped together in most studies. Erythrodermic MF is now considered to be progression of MF with absent or minimal blood involvement, in contrast to the situation with SS, which arises de novo and shows significant blood involvement.1 In 2012, Clark et al.6 reported that alemtuzumab may only be effective when blood involvement is present (in SS and in cases of erythrodermic MF with blood involvement). Those authors suggested that the 2 diseases arose from distinct types of memory T cells: the malignant lymphocytes in patients with SS have a CCR7+/L-selectin+ central memory cell phenotype (migratory cells that are found in peripheral blood, in the skin, and in lymph nodes), whereas the malignant lymphocytes of MF arise from nonmigratory cells resident in the skin and that are not found in the peripheral blood. Alemtuzumab depletes all T lymphocytes in the blood, but the population of cells resident in the skin will escape from the effect of the antibody and persist after treatment. In addition, alemtuzumab requires the presence of neutrophils and natural killer cells (both of which are present in blood but not in skin) to achieve lymphocyte depletion, and hence it only eliminates cells in the peripheral blood. The main candidates for this treatment are therefore patients with SS.

Unfortunately, authorization for the indication of this drug in B-cell chronic lymphocytic leukemic and other hematological diseases was withdrawn in August 2012, and it is currently only available for multiple sclerosis. For the treatment of patients with SS, alemtuzumab can only be obtained by individualized access via protocol.

We have presented 5 cases of SS treated with alemtuzumab, achieving an 80% response rate. The regimen of 10mg administered subcutaneously was well tolerated and the median duration of the response was 13 months. Alemtuzumab can be a useful drug in cases of SS refractory to other treatments, achieving a rapid clinical response and improvement in quality of life, with a reduction or remission of the pruritus.

The authors declare that they have no conflicts of interest.