A, Clinical images of 3 patients who achieved complete remission after LDA therapy. B, Clinical images at presentation of 2 patients who achieved clearance of blood disease but incomplete clearing or worsening of skin disease after LDA treatment. Discrete patches, plaques, or tumors on presentation were associated with incomplete response to LDA therapy.
In all histograms, numbers in the corners specify the percentage represented by the given quadrant. A, Clinical presentation before therapy and the T-cell phenotype of a representative treatment-responsive patient with greater than 80% TCM malignant T cells. In the graphs, the black dots represent nonclonal T cells. Malignant T cells (shown in red) were identified by their expression of a clonal T-cell receptor (TCR) Vβ subunit; the percentage of malignant CCR7+/L-selectin+ TCM was determined by flow cytometry. This patient achieved a complete remission on LDA. B, Clinical presentations before and after treatment and the phenotype of a representative treatment-resistant patient with less than 80% TCM circulating malignant T cells. In the graphs, the black dots represent nonclonal T cells. Only 16% of circulating malignant T cells (shown in red) had a TCM phenotype. Clinically, diffuse erythema cleared in this patient after LDA therapy, but discrete lesions remained. C, In 2 patients, diffuse erythema cleared after LDA therapy, but localized skin lesions clinically worsened despite reduction of the malignant clone in the skin. In the graphs, the black dots represent nonclonal T cells; malignant T cells are shown in red. Skin biopsies demonstrated that the malignant clone had been reduced from 50% before LDA therapy to 9% afterwards. Worsening skin lesions were infiltrated by highly activated interferon-γ (IFNγ)-producing nonclonal CD8+ T cells, suggesting that inflammation was mediated by activation of benign reactive T cells. Histograms on the right are gated to show only CD8+ T cells.
eTable 1. Patient Characteristics
Watanabe R, Teague JE, Fisher DC, Kupper TS, Clark RA. Alemtuzumab Therapy for Leukemic Cutaneous T-Cell LymphomaDiffuse Erythema as a Positive Predictor of Complete Remission. JAMA Dermatol. 2014;150(7):776-779. doi:10.1001/jamadermatol.2013.10099
Low-dose alemtuzumab (LDA) therapy is highly effective and generally well tolerated for refractory cutaneous T-cell lymphoma (CTCL) with peripheral blood disease.1 Treatment with LDA is effective in patients with blood involvement (leukemic disease) but ineffective in mycosis fungoides (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 (TCM) (migratory cells that recirculate between skin, blood, and lymph nodes), while MF T cells are derived from nonmigratory skin resident memory T cells (TRM).2 Because the mechanism of T-cell depletion with LDA requires neutrophils and/or natural killer cells (cells common 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 herein our findings that clinical appearance can be used to differentiate patients likely to experience a complete remission following LDA from those who will have persistent and/or worsening skin disease.
Work was performed according to the ethical principles set out in the Declaration of Helsinki and was approved by the Dana-Farber Cancer Institute institutional review board. All patients provided written informed consent. T cells isolated from skin3 or blood were stained with directly conjugated monoclonal antibodies and analyzed on a Becton-Dickinson FACSCanto using FACSDiva software (version 5.1).
Twenty-three patients with peripheral blood disease (eTable 1 in the Supplement) were treated with LDA (10 mg subcutaneously, 3 times a week). Of these, 17 patients presented with diffuse erythema without superimposed plaques or tumors (Figure 1A). Thirteen patients experienced complete remission following LDA treatment, and the remaining 4 had residual or emergent skin disease controllable by skin-directed therapy alone (eTable 1 in the Supplement). In contrast, of 6 patients presenting with discrete patches, plaques, or tumors with or without background diffuse erythema (Figure 1B), none experienced full remission after LDA; 1 responded fully to subsequent electron beam therapy, and 5 had recurrent and/or progressive disease, including 2 patients who developed large cell transformation.
In 19 patients, we measured the proportion of malignant T cells with TCM markers (CCR7+/L-selectin+). Of 10 patients with greater than 80% TCM, 8 experienced full remission with LDA alone (Figure 2A), and 2 after subsequent skin-directed therapies (eTable 1 in the Supplement). Of 9 patients with less than 80% TCM, 3 cleared after LDA therapy alone, and 6 had persistent and/or progressive disease (Figure 2B). The proportion of malignant TCM in skin could be measured in 12 patients; in 4 of 6 patients with greater than 80% TCM in skin, disease cleared with LDA therapy alone; in 1 of 6 it cleared with LDA plus skin-directed therapy; and in 1 of 6, the disease progressed. Two patients with different clones in the blood and skin did not experience complete clearance with LDA therapy alone but experienced full remission after additional skin-based therapies (eTable 1 in the Supplement). In 2 patients with worsening skin disease during or after LDA therapy, biopsies showed large numbers of nonclonal, activated, interferon-γ–producing CD8+ T cells, suggesting that inflammation was mediated by benign T cells (Figure 2C).
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 was 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 research program in identifying complete responders to LDA therapy. On a scientific level, diffuse erythema is likely caused by migrating T cells, and only T cells that migrate into blood are cleared by LDA. Fixed skin lesions are more likely to be caused by TRM, 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 preexisting plaques and/or tumors.
Corresponding Author: Rachael A. Clark, MD, PhD, Department of Dermatology, Brigham and Women’s Hospital, 221 Longwood Ave, Room 505A, Boston, MA 02115 (firstname.lastname@example.org).
Accepted for Publication: December 3, 2013.
Published Online: April 23, 2014. doi:10.1001/jamadermatol.2013.10099.
Author Contributions: Dr Clark had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Watanabe, Fisher, Kupper, Clark.
Acquisition of data: Watanabe, Teague, Fisher, Kupper.
Analysis and interpretation of data: Watanabe, Teague, Kupper, Clark.
Drafting of the manuscript: Clark.
Critical revision of the manuscript for important intellectual content: Watanabe, Teague, Fisher, Kupper, Clark.
Statistical analysis: Kupper.
Obtained funding: Kupper, Clark.
Administrative, technical, or material support: Teague, Fisher, Kupper.
Study supervision: Fisher, Clark.
Conflict of Interest Disclosures: Drs Kupper and Clark previously had an equity interest in TremRX, a start-up company that seeks as a long-term business plan to improve vaccine formulation and delivery. During the period Drs Kupper and Clark held the equity, the interest was deemed to create a financial conflict of interest (as defined by the specific Public Health Service regulations) with the research discussed in this article. To resolve this matter, Drs Kupper and Clark divested themselves of the equity interest in this company, so this financial conflict of interest no longer exists. Dr Clark has served as a Scientific Advisor for Novartis and Stiefel Laboratories and received honoraria for these services. No other disclosures are reported.
Funding/Support: This study was supported in part by a Special Fellow Award from the Leukemia & Lymphoma Society (Dr Watanabe); SPORE in Skin Cancer grant P50 CA9368305 from the National Institutes of Health (NIH)/National Cancer Institute (Dr Kupper); NIH/National Institute of Allergy and Infectious Diseases grant R01 A1025082 (Dr Kupper); NIH grant R01 AI097128 (Drs Kupper and Clark); a generous charitable contribution from Edward P. Lawrence, Esq; a Damon Runyon Cancer Research Foundation Clinical Investigator Award (Dr Clark); NIH/National Institute of Arthritis, Musculoskeletal, and Skin Diseases (NIAMS) grants R01 AR056720 and R01 AR063962 (Dr Clark); and NIH/National Institute of Mental Health (NIMH) grant R03 MH095529 (Dr Clark).
Role of the Sponsor: None of the funders had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We are indebted to the patients who made this work possible, both for entrusting us with their clinical care and for donating skin and blood samples.