Clinical characteristics, treatment patterns, and outcomes of cytotoxic cutaneous T‐cell lymphomas
Authors: Eric Mou, Sebastian Fernandez‐Pol, Shufeng Li, Kerri E. Rieger, Roberto Novoa, Carlos J. Suarez, Rebekah Wieland, Wen‐Kai Weng, Youn H. Kim, Michael S. Khodadoust
Journal: American Journal of Hematology (2024)

Cytotoxic cutaneous T-cell lymphomas (CCTCLs) are uncommon neoplasms involving skin-tropic T cells expressing cytotoxic markers (e.g. TIA-1, granzyme, and/or perforin). They are comprised of both standalone entities and subsets therein, as defined by the World Health Organization (WHO) fifth edition.1 In addition, we refer to CCTCLs that do not otherwise fit a specific category as cytotoxic cutaneous T-cell lymphoma, not otherwise specified (CCTCL-NOS).2 CCTCLs present variably, with either indolent or aggressive phenotypes, further influenced by disease-related factors such as concurrent hemophagocytic syndrome (HPS).3 Comparatively little is known about the clinical presentation, molecular characterization, and long-term outcomes of patients with CCTCLs; herein, we present a detailed retrospective experience spanning three decades. We reviewed our institution's cutaneous lymphoma database from 1995 to 2020, identifying patients diagnosed with CCTCLs, defined as lymphoproliferative disorders involving the skin with histopathologic expression of at least one cytotoxic marker. Our analysis focused on subcutaneous panniculitis-like T-cell lymphoma (SPTCL), primary cutaneous gamma/delta T-cell lymphoma (PCGDTCL), primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma (PCAECTCL), and CCTCL-NOS. Diagnoses were confirmed by expert dermatopathologists (S.F.P., K.R., R.N.). TCR gamma/delta staining was performed where not previously evaluated. Cases with available tissue were tested with a validated high-throughput sequencing panel for hematopoietic neoplasms covering 164 genes (Stanford Heme-STAMP) (Figure S1) and for HAVCR2 coding variants. Clinical data, including suspicion for HPS (defined as documented concern in the medical record based on the collective integration of a patient's clinical and laboratory data) were abstracted via the electronic medical record. Patients with inadequate follow-up were excluded. Regarding treatment, oral corticosteroids used as a temporizing measure prior to definitive therapy were not counted as a distinct line of therapy. Combination therapies (other than multiagent chemotherapy), investigational agents, and drugs used in a singular instance were designated 'other' (Table S1). Radiotherapy started in the midst of an active systemic therapy was not treated as a new line of therapy if the systemic therapy was continued. There are no standardized response criteria for CCTCLs; thus, in lieu of progression-free survival, we measured median time to next treatment (mTTNT), calculated as the start date of one line of therapy to the start date of the next line of therapy. Overall survival (OS) was calculated from date of diagnosis to date of death or last follow-up. Time-to-event outcomes were summarized using Kaplan–Meier curves and inter-group comparisons conducted using log-rank tests. All tests were two-sided, with p < .05 considered significant. Forty-six patients comprised the overall cohort. Twenty-two patients (48%) were diagnosed with SPTCL, 13 (28%) PCGDTCL, 3 (7%) PCAECTCL, and 8 (17%) CCTCL-NOS. Median follow-up from diagnosis was 2.5 years (range: 0.4–10.4). Median age at diagnosis was 59.6 years (range: 14.9–87.4). Sixty-one percent of patients were female and 61% were White. Most patients (87%) presented with generalized skin lesions, while involvement of lymph nodes (22%), viscera (9%), or bone marrow (3%) was uncommon (Table S2). Clinical suspicion for HPS was documented in 23 (50%) patients. Patients received a median of 2.5 lines of therapy (range: 1–12). The most frequently utilized treatments included combination chemotherapy in 18 (39%) patients, pralatrexate in 17 (37%), and romidepsin in 17 (37%). Nine (20%) patients were observed as primary management. Nine (20%) patients underwent allogeneic stem cell transplantation (allo-SCT) (Table S3). In the 22 patients with SPTCL, median age was 44.7 years, and suspicion for HPS was documented in 15 (68%). mTTNT following first- and second-line therapy was 10.2 and 24.0 months, respectively. The most common treatments were combination chemotherapy (n = 9; mTTNT 30.2 months), pralatrexate (n = 7; mTTNT 18.1 months), and romidepsin (n = 9; mTTNT 10.2 months) (Table 1). Four patients with generalized but minimally symptomatic skin involvement were initially observed (mTTNT 19.4 months). Survival outcomes were favorable, with 5-year OS 84% (Figure 1A). Five patients underwent allo-SCT, all with suspected HPS, and all of whom were alive and in remission at last follow-up. In the 13 patients with PCGDTCL, median age was 61.5 years, and suspicion for HPS was present in 6 (46%). mTTNT following first-line therapy was 11.1 months, sharply declining thereafter (Table 1). Initial treatment was heterogeneous, including three patients with generalized but minimally symptomatic skin involvement managed with observation. Two-year OS was 64%. Three patients underwent allo-SCT, all with suspected HPS, and all of whom were alive and in remission at last follow-up. The three patients with PCAECTCL were diagnosed at the median age of 83.2 years and suspicion for HPS was present in two. All three patients died within 18 months of diagnosis. Among the overall cohort, allo-SCT (n = 9) was associated with superior outcomes (2-year OS 100% vs. 66%, p = .03) (Figure 1B). Increasing age negatively impacted survival (2-year OS 42% vs. 100% in patients ≥60 vs. <60 years, respectively, p < .001). Documented clinical suspicion for HPS did not confer a worse outcome (p = .21) (Figure 1C), nor did the presence of lymph node/visceral involvement (p = .50). At last follow-up, 22 (48%) patients remained alive and in remission, 10 (22%) were alive with disease, and 14 (30%) died. Causes of death included lymphoma (n = 8), infection (n = 2), secondary malignancy (n = 1), multiorgan failure (n = 1), mechanical fall (n = 1), and unknown (n = 1). In our cohort of patients with CCTCLs, those with SPTCL exhibited the most favorable outcomes, including patients with low tumor burden, asymptomatic presentations amenable to observation, consistent with prior series.3 For patients requiring treatment, combination chemotherapy and pralatrexate were commonly employed and effective, confirming the previously described activity of chemotherapy, and adding to experiences suggesting pralatrexate may be a preferred option that reasonably balances efficacy and toxicity.4 Prior data have shown that HPS imparts a higher risk of morbidity and mortality in patients with SPTCL.3 While clinical suspicion for HPS was documented in two thirds of our SPTCL cohort, it was not associated with poorer survival (p = .17). This could be explained by our patients more frequently receiving combination chemotherapy, pralatrexate, and allo-SCT—therapies we observed to be most effective. Our data underscore the importance of prioritizing the most potent therapies, including transplant, to optimize outcomes of patients with SPTCL and concurrent HPS. Patients with PCGDTCL and PCAECTCL often presented with widespread, ulcerating skin lesions, and followed an aggressive course with fewer long-term survivors. However, a minority of patients with PCGDTCL exhibited an indolent phenotype and were observed. Patients with aggressive presentations responding to induction therapy and able to proceed to allo-SCT achieved long-term remission, confirming prior descriptions of durable disease control following transplantation in heavily pretreated patients with PCGDTCL.5 In our overall cohort, only two of nine patients receiving allo-SCT were bridged with combination chemotherapy, suggesting that patients with CCTCLs achieving an adequate response to single-agent therapies may be spared more intensive treatment ahead of transplantation. The composition of cases labeled 'CCTCL-NOS' has varied over time amidst nonuniform disease definitions and evolving classification schemes. Our definition included CTCLs expressing at least one cytotoxic marker and not otherwise categorizable under an established WHO entity. For the eight patients in our series, median age was 74.4 years. Suspicion for HPS, laboratory abnormalities, and extracutaneous involvement were uncommon (Table S2). Historical survival statistics in CCTCL-NOS vary, including descriptions of both indolent and aggressive variants. In our cohort, 2-year OS was 71%. Recent work has allowed for improved clinicopathologic distinction of CCTCL-NOS from other defined entities, though additional study is needed to disentangle its heterogeneity.2 Thirteen (26%) patients had targeted DNA sequencing performed; 10 patients (22%; 6 PCGDTCL, 3 CCTCL-NOS, 1 SPTCL) had samples harboring a total of 42 instances of somatic mutations. The most frequent mutations involved TERT (n = 4), and JAK1, FAS, and TP53 (n = 3 each) genes (Table S4). The molecular landscape of CCTCLs is increasingly defined, with disruption of JAK/STAT signaling and abnormalities of chromatin-modifying genes implicated heavily in their pathogeneses.2 Patients in our cohort harbored an array of somatic mutations involving JAK/STAT signaling, epigenetic regulation, signal transduction, and tumor suppressor pathways. The poor outcomes in our patients with PCAECTCL, an entity in which JAK2 aberrations play a critical role,2 offer a rational basis for the exploration of JAK/STAT inhibitors as a novel therapeutic modality in CCTCLs, as has been investigated in PTCLs. Germline variants in HAVCR2, encoding TIM3, have been associated with increased risk of developing SPTCL and a more severe diagnostic category.6 In our cohort, eight patients with SPTCL had germline HAVCR2 testing performed, and one had a HAVCR2 E273K mutation located on exon 7, outside of the classic location on exon 2 (i.e. Y62C, I97M, T101I variants) described previously6; this patient had suspicion for HPS at initial diagnosis. Notably, six of seven patients who tested negative also had suspected HPS. Strengths of this study include its granular examination of clinicopathologic and treatment data, and our primary endpoint of TTNT, a clinically practical measure in rare diseases lacking standardized response criteria. Limitations include the study's retrospective nature, and that some histologic subtypes contained small patient numbers not encompassing the heterogeneity in presentation and management across broader practice settings. Nevertheless, we provide comprehensive data on a defined set of therapeutics that may allow for more confident use of these drugs when encountering such uncommon entities in routine practice. In conclusion, CCTCLs are heterogeneous, and our findings collectively highlight the importance of individualized care, matching treatment intensity to each patient's specific diagnostic, clinical, and molecular phenotype. Project conception: E.M., M.K., and Y.K. Data collection: E.M., S.F.P., K.R., C.J.S., R.W., R.N., W.K.W., M.K., and Y.K. Pathology review: S.F.P., K.R., C.J.S., and R.W. Statistical analysis: S.L. Manuscript preparation and review: All authors. The authors have no relevant disclosures or conflicts of interest. As this was a retrospective study, patient consent was not obtained. All included material herein is original content. The data that support the findings of this study are available from the corresponding author upon reasonable request. Table S1. 'Other' treatment regimens. Table S2. Baseline patient and clinical characteristics, overall and by disease subtype. Table S3. Treatment patterns, overall and by disease subtype. Table S4. Recurring somatic mutations identified by next-generation sequencing (n = 10). Figure S1. List of genes included in the Stanford Tumor Actionable Mutation Panel for Hematopoietic and Lymphoid Neoplasms (Heme-STAMP). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.