Alemtuzumab therapy for leukemic CTCL: Diffuse erythema as a positive predictor of complete remission

To the editor

Low dose alemtuzumab (LDA) is a highly effective and generally well tolerated therapy for refractory cutaneous T cell lymphoma (CTCL) patients with peripheral blood disease.¹ LDA is effective in patients with blood involvement (leukemic disease) but ineffective in MF, reflecting the fact that these lymphomas derive from distinct T-cell subsets. Malignant T cells in patients with blood disease have the phenotype of CCR7⁺/L-selectin⁺ central memory cells (T_CM), migratory cells that recirculate between skin, blood and lymph nodes whereas MF T cells are derived from non-migratory skin resident memory T cells (T_RM).² Because the mechanism of T cell depletion with LDA requires neutrophils and/or NK cells, cells frequent in blood but rare in skin, LDA kills T cells in blood but not in skin.¹ In patients with blood disease, LDA depletes all circulating T cells and purges the skin over time of recirculating malignant T cells, leading to complete and often durable remissions in 50% of patients while sparing benign T cells in skin.¹ We present here our findings that clinical appearance can be used to discriminate patients likely to experience a complete remission following LDA from those that will have persistent and/or worsening skin disease.

Methods

Work was performed as per the Declaration of Helsinki and approved by the Dana-Farber Cancer Institute IRB. T cells isolated from skin³ or blood were stained with directly-conjugated monoclonal antibodies and analyzed on a Becton-Dickinson FACSCanto using FACSDiva software (V5.1).

Results

Diffuse cutaneous erythema without discrete plaques and/or tumors is associated with complete remission after LDA

23 patients with peripheral blood disease ( Supplemental Table 1) were treated with LDA (10mg subcutaneously, three times a week). Of these, 17 patients presented with diffuse erythema without superimposed plaques or tumors (Figure 1A). 13 experienced complete remissions following LDA and the remaining four had residual or emergent skin disease controllable by skin-directed therapy alone (Supplemental Table 1). In contrast, of six patients presenting with discrete patches, plaques or tumors with or without background diffuse erythema (Figure 1B), none experienced full remissions after LDA; one responded fully to subsequent electron beam therapy and five had recurrent and/or progressive disease including two patients who developed large cell transformation.

Figure 1. Diffuse cutaneous erythema and a lack of discrete plaques and/or tumors is associated with excellent clinical responses to LDA.

(A) The clinical presentation of three patients who achieved complete remissions after LDA therapy are shown. (B) Discrete patches, plaques or tumors on presentation are associated with incomplete responses to LDA. Appearance at presentation of two patients who had clearance of blood disease but incomplete clearing or worsening of skin disease after LDA are shown.

Circulating malignant T cells with a T_CM phenotype correlate with LDA responsiveness

In19 patients, we measured the proportion of malignant T cells with T_CM markers (CCR7⁺/L-selectin⁺). Of 10 patients with >80% T_CM, eight experienced full remission with LDA alone (Figure 2A) and two after subsequent skin directed therapies (Supplemental Table 1). Of 9 patients with <80% T_CM, three cleared after LDA alone and six had persistent and/or progressive disease (Figure 2B). The proportion of malignant T_CM in skin could be measured in 12 patients; 4/6 patients with >80% T_CM in skin cleared with LDA alone, 1/6 cleared with LDA plus skin directed therapy and 1/6 progressed. Two patients with different clones in the blood and skin did not clear completely with LDA but experienced full remission after additional skin-based therapies (Supplemental Table 1). In two patients with worsening skin disease during or after LDA, biopsies showed large numbers of non-clonal, activated IFNγ-producing CD8 T cells, suggesting inflammation was mediated by benign T cells (Figure 2C).

Figure 2. Patients who have circulating malignant T cells with a T_CM phenotype have better responses to LDA therapy.

(A) Clinical presentation and the T cell phenotype of a representative patient with >80% T_CM malignant T cells are shown. Malignant T cells (shown in red) were identified by their expression of a clonal TCRVβ subunit and the percentage of malignant CCR7⁺/L-selectin⁺ T_CM was determined by flow cytometry. This patient achieved a complete remission on LDA. (B) Clinical presentation and phenotype of a representative resistant patient with <80% T_CM circulating malignant T cells are shown. Only 16% of circulating malignant T cells had a T_CM phenotype. Clinically, diffuse erythema cleared in this patient after alemtuzumab but discrete lesions remained. (C) In two patients, diffuse erythema cleared after alemtuzumab but localized skin lesions clinically worsened despite reduction of the malignant clone in skin. Skin biopsy demonstrated that the malignant clone had been reduced by alemtuzumab therapy, from 50% before therapy to 9% after. Worsening skin lesions were infiltrated by highly activated IFNγ-producing non-clonal CD8 T cells, suggesting inflammation was mediated by activation of benign reactive T cells. Histograms on the right are gated to show only CD8 T cells.

Discussion

All patients treated with LDA had clearance of peripheral blood disease but only patients presenting with diffuse erythema without superimposed plaques or tumors also had complete and long-lasting clearance of skin disease. Initial clinical presentation was more predictive of response than complex cellular phenotyping of T cells from blood and skin. In other words, the eyes of a well-trained dermatologist were more powerful than a comprehensive translational program in identifying complete responders to LDA. On a scientific level, diffuse erythema is likely caused by migrating T cells and only T cells that migrate into blood that are cleared by LDA. Fixed skin lesions are more likely to be caused by T_RM, cells that escape LDA clearance by remaining long-term in skin. Based on our clinical and scientific findings, we recommend the use of LDA with or without adjuvant skin directed therapy in patients with diffuse cutaneous erythema but we caution against its use in patients with pre-existing plaques and/or tumors.