More than skin deep Free

In this issue of Blood, Scarisbrick et al¹ describe the “cutaneous lymphoma international prognostic index” (CLIPI), derived from an international, multicenter, prospective study of patients with advanced-stage mycosis fungoides (MF) and Sezary syndrome (SS). The CLIPI, comprising 4 prognostic factors (extensive nodal involvement, age >60 years, elevated lactate dehydrogenase, and the presence of large-cell transformation), effectively stratified patients into high- (3-4 risk factors), intermediate- (2 risk factors), and low-risk (0-1 risk factors) groups with 5-year overall survival rates of 18.3%, 44.7%, and 63.3%, respectively.

Risk stratification and therapeutic decision-making in primary cutaneous T-cell lymphomas are largely dependent on the extent of cutaneous and extracutaneous involvement. Although patients with limited-stage disease that is confined to the skin are largely managed with skin-directed therapies and may anticipate an overall survival measured in decades, those with advanced-stage disease that is more than skin deep benefit from palliative, systemic therapies. However, as the results of this study highlight, the outcomes in these patients are heterogeneous, and historically, risk stratification has been challenging.

The prospective and rigorous approach the authors adopted is the culmination of longstanding collaborative efforts. In 2010, the recently described International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging system was validated, and the extent of disease burden in any extracutaneous tissue compartment identified as relevant prognostic factors.² The 5-year overall survival for patients with extensive involvement of any tissue compartment (ie, T4, N3, M1, B2 disease) ranged from 17% to 41%. Data from this study was used to retrospectively develop a “first-generation CLIPI,” comprising male sex, age >60, and extensive blood, nodal, or visceral involvement as adverse risk factors.³ Upon completion of this previous work, performed at single centers in the United Kingdom and the United States, and perhaps recognizing that it takes a village to improve the understanding of rare hematologic malignancies like MF/SS, the Cutaneous Lymphoma International Consortium (CLIC) was formed. A prognostic index for advanced-stage MF/SS, comprising stage IV disease, age >60 years, large-cell transformation (LCT), and increased lactate dehydrogenase, was retrospectively developed and effectively stratified patients with 5-year overall survival rates ranging from 28% to 68%.⁴ Herein, the CLIC reports a prospective CLIPI (“PROCLIPI”), which effectively risk-stratified patients with advanced-stage MF/SS into risk groups with divergent outcomes. Compatible with previous studies, both extensive nodal involvement and LCT were associated with poor outcomes.

The identification of LCT as an adverse prognostic factor, although not surprising, is notable, because recent evidence highlights the extent to which LCT is transcriptionally and genetically distinct^5,6 and arguably an unmet need, yet, patients with LCT are excluded, underrepresented, or not reported in contemporary, practice-changing clinical trials.^7-10 Furthermore, patients with nodal effacement (N3 disease), another high-risk feature identified by PROCLIPI, are poorly responsive to these agents. Not surprisingly then, outcomes observed in the PROCLIPI are sobering, because outcomes have not substantially changed for high-risk patients, however defined, over the past few decades, thus highlighting the need for more effective therapeutic agents with activity that is more than skin deep. Consequently, clinical trial participation ought to be encouraged for these patients, particularly those that are high risk, including those with LCT.

Conflict-of-interest disclosure: The author declares no competing financial interests.