Pralatrexate Is Effective in Cytotoxic Cutaneous T-Cell Lymphomas
Authors: Poh Christina , Voutsinas Jenna M. , Huang Ivan , Warren Edus H. , Crimp Caitlin A. , Shadman Mazyar , Lynch Ryan C. , Till Brian G. , Ujjani Chaitra S. , Di Mengyang , Raghunathan Vikram , Smith Stephen D. , Wu Qian Vicky , Shinohara Michi M. , Gopal Ajay K. 
Published: December 2024

Introduction
Cytotoxic cutaneous T-cell lymphomas (CTCL), defined as T-cell lymphoproliferative disorders which express one or more cytotoxic markers such as perforin, granzyme B or TIA1, are generally aggressive and associated with poor prognosis. Because of their rarity, treatment options for these lymphomas are limited and derived from small retrospective studies with no standard of care. Multi-agent chemotherapy treatment is often utilized with disappointing results. Pralatrexate, a folate analog metabolic inhibitor approved for the treatment of relapsed or refractory peripheral T-cell lymphoma, has been shown to be active in non-cytotoxic CTCL histologies such as mycosis fungoides, Sézary syndrome and primary cutaneous anaplastic large cell lymphoma (Horwitz, et al. Blood 2012). However, there is a paucity of data for pralatrexate in cytotoxic CTCL. We conducted a retrospective analysis to evaluate the efficacy of pralatrexate in this patient population.
Methods
We identified patients with a diagnosis of primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma (CD8+ PCAETL), primary cutaneous gamma-delta T-cell lymphoma (PCGDTL) and subcutaneous panniculitis-like T-cell lymphoma (SPTCL) who were treated with at least one dose of pralatrexate between 2015 and 2024 from the University of Washington/Fred Hutchinson Cancer Center T-cell lymphoma database. The primary endpoint was overall response rate (ORR). Secondary efficacy endpoints included complete response (CR) rate, progression-free (PFS) and overall survival (OS).
Results
Sixteen patients meeting criteria were identified. Males comprised 56% of patients. Median age at diagnosis was 58.5 (range 20-76) years. Half of the patients (50%) were non-Hispanic whites, with Asians/Pacific Islanders, African Americans and Alaskan Natives/American Indians contributing 31%, 13% and 6%, respectively. Three patients had CD8+ PCAETL, 5 had PCGDTL and 8 had SPTCL. All patients had advanced disease stage with multiple skin lesions and 11 (69%) patients had extracutaneous involvement. Seven (88%) patients with SPTCL had hemophagocytic syndrome. The median number of systemic treatment regimens prior to pralatrexate was 1 (range 0-4). The administered dosage of pralatrexate ranged from 15-30 mg/m2 weekly for 3 out of every 4 weeks with a median duration of treatment of 14 (range 8-43) weeks. Overall, ORR was 100% with 12 (75%) patients achieving a CR. Median PFS and OS were 18 months and not reached (NR), respectively. CR rates were 0%, 75% and 100% in CD8+ PCAETL, PCGDTL and SPTCL, respectively. Median PFS and OS were 10.2 months and 28.8 months in CD8+ PCAETL, 15.6 months and NR in PCGDTL and 25.2 months and NR in SPTCL. At the time of pralatrexate discontinuation, 12 (75%) patients were in CR and 3 (19%) had disease progression. At a median follow-up time of 29.9 months, 6 (38%) patients remain in continuous remission. Out of the 3 CD8+ PCAETL patients who had a partial response, 2 (67%) experienced durable responses with 6.6 and 10.2 months on pralatrexate. One patient with PCGDTL underwent consolidative allogeneic stem cell transplant after 9.9 months of continuous remission on pralatrexate. All SPTCL patients were in CR at time of pralatrexate discontinuation. Five (63%) SPTCL patients subsequently relapsed after a median time of 2.9 (range 1.6-32.3) months from treatment discontinuation; all received retreatment with pralatrexate which resulted in a second CR rate of 100%. Three (38%) and 2 (25%) SPTCL patients transitioned to bexarotene and cyclosporine maintenance therapy after achieving a CR with pralatrexate, respectively.
Conclusions
Pralatrexate is effective and associated with durable responses in cytotoxic CTCL. Upon disease relapse, retreatment with pralatrexate was effective with high rates of second complete remissions observed in SPTCL.