Harnessing the Power of Existing Therapeutic Strategies to Treat Cutaneous T-cell Lymphomas

Harnessing the power of allo-HSCT in advanced CTCL

Mycosis fungoides (MF) and Sézary syndrome (SS) are rare cutaneous T-cell lymphomas (CTCL) with very poor prognosis in advanced stages and a high tendency to relapse.^1,2 Five-year survival rates decrease from 94% in early stages (stage 1A) to only 18% in advanced disease (stage 4B).³ Mainstay treatment strategies for early-stage CTCL include first-line topical therapies or oral agents, while systemic therapies are typically reserved for more advanced-stage disease.^4,5

My last editorial highlighted the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in high-risk patients with advanced MF or SS.⁶ According to the current recommendations of the European Organisation of Research and Treatment of Cancer (EORTC), allo-HSCT should be considered in patients with advanced MF and SS and poor prognosis but without significant comorbidity, with complete or near-complete remission achieved prior to transplantation.⁷ Previously, data presented at the 64th ASH Annual Meeting and Exposition in 2022 showed that allo-HSCT is a powerful therapeutic strategy in selected patients with advanced CTCL that might improve the prognosis of advanced-stage CTCLs. A retrospective analysis of allo-HSCT outcomes for 57 CTCL patients demonstrated 5-year overall survival (OS) and disease-free survival (DFS) rates of 57.6% and 37.9%, respectively, associated with low toxicity.^8,9 Now, additional data from the CUTALLO study demonstrates a survival advantage of allo-HSCT treatment in people with advanced-stage and poor prognostic CTCL.¹⁰

CUTALLO (ClinicalTrials.gov: NCT02520908) is an ongoing French prospective study investigating the effect of allo-HSCT compared with non-HSCT therapy on the outcome of individuals with advanced-stage CTCL.¹⁰ The study enrolled patients with advanced-stage MF or SZ and at least one poor prognostic criterion; participants who had disease progression shortly after enrollment were subsequently excluded. At a median follow-up of 12.6 months, de Masson et al. (2023) reported that patients with advanced CTCL receiving allo-HSCT had prolonged progression-free survival (PFS) (primary endpoint) versus matched patients receiving investigator-selected non-HSCT therapy.¹⁰ Median PFS was 9.0 months (95% confidence interval [CI]: 6.6–30.5 months) in the matched HSCT group versus 3.0 months (95% CI: 2.0–6.3 months) in the matched non-HSCT group (hazard ratio [HR]: 0.38 [95% CI: 0.21–0.69]; p<0.0001). Importantly, the authors of this study concluded that allo-HSCT should be made available for high-risk, advanced-stage MF or SS individuals who achieve pretransplant disease remission.¹⁰

Immunotherapy represents a promising avenue for CTCL management. The efficacy and safety of mogamulizumab, a monoclonal antibody targeting C-C chemokine receptor 4 (CCR4) was shown in a phase III MAVORIC trial¹¹ and confirmed in a recent retrospective, real-world OMEGA trial¹² in patients with advanced MF and SS. While the use of mogamulizumab before allo-HSCT may decrease disease burden, a higher risk of transplant complications including graft versus host disease (GVHD) has been reported in patients with adult T-cell lymphoma/leukemia who received mogamulizumab within a short time before HSCT, likely due to depletion of CCR4+ regulatory T cells.^13–15 These data suggest the need for maintenance of the recommended interval between mogamulizumab and allo-HSCT and close monitoring of patients for early signs of transplant-related complications.

Harnessing the power of topical calcineurin inhibitors in early CTCL

Topical calcineurin inhibitors (TCIs) such as tacrolimus and pimecrolimus are used widely as corticosteroid-sparing agents in the treatment of various cutaneous diseases such as atopic dermatitis and other skin diseases.¹⁶ Although a very small increase in the absolute risk of lymphoma has been reported with TCI use, no increased risk of skin cancers has been observed.^16,17 Moreover, evidence from the literature has reported that individuals with MF have mutations in the calcineurin pathway.¹⁸ A recent Spanish study reported by Ortiz-Romero et al. (2022) assessed the activity and safety of topical pimecrolimus (1% cream) in patients with early MF.¹⁹ PimTo-MF is the first clinical trial evaluating the treatment of CTCL with a calcineurin inhibitor.¹⁹ This phase II study was conducted across six medical centers in Spain in adults with histologically confirmed early MF. The median follow-up after baseline was 5.7 years.¹⁹ More than half of the study participants (56%) responded positively to pimecrolimus cream application (one complete response [CR], 21 partial responses [PR]), and it was well tolerated.¹⁹ These initial results suggest that topical pimecrolimus seems active and well tolerated in patients with early-stage MF.¹⁹

Despite recent advances in targeted treatment options for CTCLs, there remains an unmet need for effective therapies with good safety profiles for early- and late-stage CTCL. Harnessing the power of allo-HSCT, a potentially curative treatment for several hematological malignancies, shows promise for high-risk, advanced-stage MF or SS individuals. In addition, harnessing the power of existing atopic dermatitis treatments such as calcineurin inhibitors may be effective in early CTCLs but longer follow-up is required to confirm efficacy and safety.²⁰

Prof. Dr Emmanuella Guenova
Co-Editor-in-Chief
eic@healthbook.org

Conflict of interest

The author has declared that the manuscript was written in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

The author has declared that no financial support was received from any organization for the submitted work.

Author contributions

The author created and approved the final manuscript.