Pralatrexate is effective in cytotoxic cutaneous T-cell lymphomas Open Access

Cytotoxic cutaneous T-cell lymphomas (CTCLs) represent a small subset of CTCLs characterized by the proliferation of malignant T cells with a cytotoxic phenotype, typically expressing markers such as CD8, TIA-1, granzyme B, and perforin.^1,2 These lymphomas, such as primary cutaneous CD8⁺ aggressive epidermotropic cytotoxic T-cell lymphoma (CD8⁺ PCAETL), primary cutaneous γδ T-cell lymphoma (PCGDTL), and subcutaneous panniculitis-like T-cell lymphoma (SPTCL), exhibit a diverse clinical presentation ranging from ulcerative or necrotic skin lesions, subcutaneous tumor nodules, to diffuse erythroderma, frequently accompanied by systemic B symptoms or hemophagocytic lymphohistiocytosis (HLH).³ Unlike the more common CTCL subtypes, such as mycosis fungoides (MF) or Sézary syndrome (SS), cytotoxic CTCL subtypes often have a more aggressive clinical course, with a high propensity for rapid disease progression and worse prognosis.^4-6 

Due to their rarity, there is no universally accepted standard of care for cytotoxic CTCLs, making treatment decisions particularly challenging. Multiagent chemotherapy remains the most commonly used treatment approach, although it typically yields limited efficacy with transient responses.⁷ Many patients experience primary refractory disease or relapse shortly after achieving an initial response, highlighting the urgent need for novel, more effective treatment strategies.

Pralatrexate, a folate analog metabolic inhibitor, is approved for the treatment of relapsed or refractory peripheral T-cell lymphoma, and has also shown promising activity in noncytotoxic CTCL subtypes such as MF and SS.^8,9 A dose de-escalation study demonstrated that pralatrexate, administered at 15 mg/m² weekly for 3 out of every 4 weeks, was well tolerated and showed high disease control in relapsed or refractory MF, SS, and primary cutaneous anaplastic large-cell lymphoma.¹⁰ Furthermore, a subgroup analysis of the PROPEL study, which evaluated the efficacy of pralatrexate in T-cell lymphomas, demonstrated pralatrexate to be effective for large-cell transformed MF.¹¹ 

Because of its efficacy in peripheral T-cell lymphoma and noncytotoxic CTCL, pralatrexate represents a potential therapeutic option for patients with aggressive cutaneous diseases. However, there is a paucity of data for pralatrexate in cytotoxic CTCL. To address this knowledge gap, we conducted a retrospective analysis to evaluate pralatrexate’s clinical activity in these patients. Our findings provide novel insight into the role of pralatrexate in managing this challenging disease and highlight its potential as a viable treatment option for patients with few alternatives.

We identified patients with CD8⁺ PCAETL, PCGDTL, and SPTCL, who were treated with ≥1 dose of pralatrexate between January 2015 and December 2024 at the University of Washington/Fred Hutchinson Cancer Center. Patient demographics and disease characteristics, such as age, sex, date of diagnosis, comorbidities, findings on histopathology, prior therapies and associated responses, date of relapse or progression, subsequent lines of treatment and associated responses, and date of last follow-up and death, were obtained. The primary end point was overall response rate (ORR). Secondary efficacy end points included complete response (CR) rate, progression-free survival (PFS) and overall survival (OS).

Demographic and clinical data were summarized using descriptive statistics, including frequencies and percentages. Response rates (ORR and CR) were determined by the treating physician.^12,13 PFS was defined as the time from pralatrexate initiation to the earliest occurrence of documented disease progression, relapse, or death from any cause. Patients without an event were censored at last known follow-up. OS was defined as the time from pralatrexate initiation to death from any cause or censored at the last known follow-up. Duration of response (DOR) was defined as the time from first response (partial response [PR] or CR) until disease progression or death or censored at the last known follow-up. Fisher exact test was used to evaluate the association between pralatrexate dose (15 mg/m² vs 30 mg/m²) and CR rate. The Kaplan-Meier method was used to estimate survival, and statistical significance was examined with the log-rank test. Median follow-up time was calculated using the reverse Kaplan-Meier method.^14,15 This study was approved by the University of Washington Institutional Review Board.

Eighteen patients met inclusion criteria (Table 1). Males comprised 56% of patients. Median age at diagnosis was 54 (range, 18-76)years. Eight patients (44%) were non-Hispanic Whites, with Asians/Pacific Islanders, African Americans, and Alaskan Natives/American Indians contributing 33%, 17%, and 5.6%, respectively. Three (17%) patients had CD8⁺ PCAETL, 6 (33%) had PCGDTL, and 9 (50%) had SPTCL, including 8 with the αβ subtype and 1 with the γδ subtype. All patients had multiple cutaneous lesions, 7 (38.9%) with cutaneous ulcerations. Thirteen (61%) patients had extracutaneous involvement, including 10 (56%) with bone marrow involvement. Eight (89%) and 2 (33%) patients with SPTCL and PCGDTL had HLH at diagnosis, respectively. The median number of systemic treatment regimens prior to pralatrexate was 1 (range, 0-4). Five (28%) patients previously received multiagent chemotherapy, and 1 (5.6%) had prior autologous stem cell transplant (SCT). The pralatrexate dose was selected by the treating physician on an individual basis, guided by anticipated tolerability. Patients received either 15 mg/m² weekly for 3 weeks of a 4-week cycle,¹⁰ or 30 mg/m² weekly for 6 weeks of a 7-week cycle.⁸ The median treatment duration was 14 (range, 8-43) weeks.

Ten (56%) and 8 (44%) patients received pralatrexate at doses of 15 mg/m² and 30 mg/m², respectively. The ORR was 100%, with 12 (67%) patients achieving CR. Median PFS and OS were 5.6 months and not reached (NR), respectively (Figures 1 and 2). For patients who achieved CR, the median DOR was 22 months. Reasons for pralatrexate discontinuation were achieving CR in 12 (67%) patients, disease progression in 3 (17%) patients, and toxicity in 1 (5.6%) patient. At a median follow-up time of 45 months, 6 (33%) patients remained progression-free, whereas all 5 deceased patients succumbed to progressive disease. Those who discontinued pralatrexate due to progression had a median post-treatment survival duration of 40 days (Figure 3). The dose of pralatrexate (15 mg/m² vs 30 mg/m²) was not associated with significant differences in CR rate, PFS or OS.

When considered by disease subtype, 1 (33%) patient with CD8⁺ PCAETL received pralatrexate at 15 mg/m², whereas the remaining 2 (67%) received 30 mg/m². All 3 of the patients achieved a PR, with 2 showing a durable response at 6.6 and 10.2 months. Two (67%) patients progressed on pralatrexate and subsequently received doxorubicin without response. Median PFS and OS were 10 months and 28 months, respectively (Figures 1 and 2).

Among 6 PCGDTL patients, all but 1 (83%) received pralatrexate at 15 mg/m². Four (67%) patients achieved CR, and 2 (33%) PR. Median PFS was 4.8 months and OS was NR (Figures 1 and 2). Five (83%) patients were in continuous remission at pralatrexate discontinuation. The one patient who received pralatrexate at 30 mg/m² underwent consolidative allogeneic SCT after 9.9 months of continuous CR on pralatrexate. Another patient achieved PR after 2 doses of pralatrexate, but experienced possible pralatrexate vs allopurinol-induced toxic epidermal necrolysis.

In patients with SPTCL, 4 (44%) received pralatrexate at 15 mg/m², whereas 5 received 30 mg/m². Eight (89%) patients achieved CR and 1 achieved PR. Median PFS and OS were 15 months and NR, respectively (Figures 1 and 2). At pralatrexate discontinuation, 8 (89%) patients were in CR. Six (67%) patients subsequently relapsed after a median time of 2.9 (range, 1.6-32) months from treatment discontinuation. All received retreatment with pralatrexate, which resulted in a second ORR and CR rate of 100% and 83%, respectively. Three (38%) and 2 (25%) patients transitioned to bexarotene and cyclosporine maintenance, respectively, after achieving a CR with pralatrexate.

Multiple studies have previously demonstrated the efficacy of pralatrexate in noncytotoxic CTCL; however, to our knowledge, our center is the first to report its effectiveness across multiple cytotoxic CTCL subtypes. Our initial findings stemmed from a case series of 4 patients with SPTCL and associated HLH, all of whom achieved CR with pralatrexate.¹⁶ Building on this, our current retrospective analysis further corroborates these findings, demonstrating high efficacy with pralatrexate in a racially and ethnically diverse group of patients with cytotoxic CTCL. Additionally, pralatrexate retreatment in patients with SPTCL who relapsed resulted in high second CR rates. These results highlight its potential as a critical therapeutic option in this highly aggressive disease, warranting further prospective evaluation.

Many patients achieved durable responses with pralatrexate, though long-term disease-free survival was not universal. This reflects the generally refractory nature of cytotoxic CTCL, highlighting the need to enhance pralatrexate’s efficacy with combination strategies or consolidative therapies like allogeneic SCT. Previous studies have explored this approach, such as a study by Duvic et al,¹⁷ which found that pralatrexate plus bexarotene achieved a high ORR of 60% with minimal toxicity in noncytotoxic CTCL. Similarly, Talpur et al¹⁸ observed a median DOR of 27 months in advanced-stage MF using the same combination. Consistent with this, most patients with SPTCL in our study experienced durable responses when transitioned to cyclosporine or bexarotene maintenance after pralatrexate discontinuation.

The tolerability profile of pralatrexate in our study aligned with previous reports, with low rates of treatment discontinuation due to toxicity. Notably, 67% of patients discontinued therapy after achieving CR, primarily to reduce the time and logistical burden of weekly infusions rather than intolerable adverse effects. Only 1 patient in our cohort discontinued pralatrexate due to possible pralatrexate vs allopurinol-induced toxic epidermal necrolysis. Strategies to mitigate toxicity, including mucositis, with leucovorin, vitamin B₁₂, and folic acid supplementation, were utilized in all patients to maintain dose intensity and maximize benefit.^19-21 

Limitations to our study include a small sample size, potential selection bias, and the lack of a control group, which may limit generalizability and prevent direct efficacy comparisons. Variability in prior treatments and disease burden may also confound results. Additionally, this retrospective analysis relied on treating physician-assessed responses, introducing potential subjectivity. Despite these limitations, this real-world retrospective analysis is the first to evaluate pralatrexate in cytotoxic CTCL, addressing a key gap.

In conclusion, pralatrexate demonstrates meaningful activity in cytotoxic CTCL, offering a viable treatment option for patients with limited alternatives. Given the poor prognosis of cytotoxic CTCL, these findings lay the groundwork for advancing treatment and addressing a critical unmet medical need by means of a larger prospective study.

Contribution: C.P. collected, analyzed and interpreted the data, and wrote the manuscript; J.M.V. performed the statistical analysis; M.M.S. and A.K.G. contributed to the writing of the manuscript; and all authors approved the final manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Christina Poh, Division of Hematology and Oncology, University of Washington, 825 Eastlake Ave, J4-419, Seattle, WA 98109; email: cpoh10@uw.edu.