Praveen Ramakrishnan Geethakumari

Authors’ response to ‘Caution in interpreting retrospective comparisons of acitretin and bexarotene in mycosis fungoides’, by Oleg Akilov.

Secondary central nervous system (CNS) large B-cell lymphoma (SCNSL) occurs in the de novo setting, as a CNS-isolated relapse, or synchronous (concomitant CNS and systemic) relapse. SCNSL is a devastating event without therapeutic consensus. Thus, we aimed to evaluate treatment outcomes in an international cohort. Progression-free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR, estimated using competing-risk models) were reported. Prognostic factors were identified in a 6-month landmark multivariate analysis. Outcomes after thiotepa autologous stem cell transplant (ASCT) and chimeric antigen receptor (CAR) T-cell therapy (CAR-T) delivered at relapse were compared after propensity score matching (PSM). A total of 1139 patients were included in the analysis (de novo: 537; relapsed SCNSL: 602). Two-year PFS estimates were 40.4%, 43.9%, and 16.2% for de novo SCNSL, CNS-isolated relapse, and synchronous relapse, respectively. Patients with CNS-isolated relapse demonstrated low rates of systemic recurrence (24-month CIR, 6%). Thiotepa-ASCT correlated with longer survival in de novo SCNSL (PFS: hazard ratio [HR], 0.57; P = .005; and OS: HR, 0.62; P = .023) and CNS-isolated relapses (PFS: HR, 0.55; P = .002; and OS: HR, 0.39; P< .0001). ASCT (thiotepa or no thiotepa) also associated with improved survival in synchronous relapses (PFS: HR, 0.57; P = .023; and OS: HR, 0.48; P = .019). Higher survival with thiotepa-ASCT than CAR-T was observed after PSM (PFS: HR, 0.45; P = .005 and OS: HR, 0.41; P = .014). These data support thiotepa-ASCT in eligible patients, particularly de novo disease and CNS-isolated relapses. CNS-isolated relapse was infrequently associated with systemic recurrence, supporting treatment regimens adopted from primary CNS lymphoma.

Dear Editor, Cutaneous T-cell lymphomas (CTCLs) are rare non-Hodgkin lymphomas, affecting 8.8 per 1 000 000 people annually.¹ Bexarotene is the only retinoid approved by the US Food and Drug Administration for mycosis fungoides (MF),² the most common CTCL subtype, but its use is limited by high cost and adverse effects, particularly thyroid and lipid abnormalities.³ Acitretin, a less expensive second-generation retinoid used in psoriasis, is prescribed off-label in MF, yet supporting data remain limited to small retrospective case series.⁴ However, our clinical experience suggests dose-dependent efficacy with acitretin, supporting formal evaluation of its dose–response pattern in MF.

Background: Sézary syndrome (SS) and leukaemic mycosis fungoides (MF) are aggressive cutaneous T‐cell lymphomas (CTCLs) with poor prognosis and limited treatment options. Single‐cell RNA sequencing (scRNA‐seq) offers an opportunity to dissect malignant heterogeneity and immune dysregulation yet has been underutilized in leukaemic CTCL. Objectives: To define transcriptional heterogeneity within malignant T cells, identify immunomodulatory signals shaping the tumour microenvironment and uncover actionable vulnerabilities in SS and leukaemic MF. Methods: We analysed 144,321 peripheral blood mononuclear cells from 22 patients (SS or leukaemic MF) and 7 healthy controls using scRNA‐seq, with CITE‐seq and TCR‐seq in subsets. Public and prospectively collected datasets were integrated after rigorous per‐sample quality control, batch correction and malignancy assignment. Differential gene expression and cell–cell communication analyses were performed using complementary modelling approaches with correction for sparsity and multiple testing. Results: Three transcriptionally distinct malignant T‐cell (MTC) subtypes were identified: central memory‐like (MTC CM), effector/effector memory‐like (MTC E/EM) and regulatory‐like (MTC Reg), each with unique expression programmes and putative vulnerabilities. MTC CM, the dominant population, expressed central memory markers, Th2/Th22 skewing and a broader KIR repertoire ( KIR3DL2, KIR3DL1, KIR2DL3 ) than previously reported. MTC E/EM and MTC Reg were enriched for NR4A1 and ITGB1 , respectively. Cell–cell communication analysis revealed KIR–MHC‐I signalling and suggested that MTC‐derived TNF and IL‐10 may drive JAK/STAT pathway activity in non‐T cells, indicating an underrecognized dimension of tumour‐induced immune reprogramming. Conclusions: This is one of the most comprehensive single‐cell studies of leukaemic CTCL to date. We uncover new malignant T‐cell states, broaden the known repertoire of KIR expression, and propose mechanisms of immune evasion that may contribute to treatment resistance. These findings lay the groundwork for subtype‐specific and microenvironment‐informed therapeutic strategies in Sézary syndrome, with potential implications for guiding targeted therapy selection but require validation in larger, independent cohorts.

Supplemental Figure 2. MEDI-570 effects on lymphocyte and leukocyte populations. Baseline-normalized, absolute counts (ABS) of circulating cell populations were plotted on study days 1, 7, 14 and 21 from patients enrolled in each dose group as indicated. A) Total CD3+CD8+ cytotoxic T cells B) CD14+ monocytes C) CD3-CD56+ and/or CD16+ NK cells D) CD3-CD19+ B cells.

Supplemental Figure 1. CD4 count recovery after end of treatment (by local site collection)

Supplemental Tables and Protocol Description

Supplemental Figure 3. Representative baseline pre-treatment tumor specimen of a patient with AITL (H&E, ICOS staining and CD3 staining by IHC)

Purpose:Proliferation of T-follicular helper (TFH) CD4+ T cells is a postulated pathogenic mechanism for T-cell non-Hodgkin lymphomas (T-NHL). The inducible T-cell costimulator (ICOS) is highly expressed by TFH, representing a potential target. MEDI-570 is a monoclonal antibody against ICOS, which eliminates ICOS+ cells in preclinical models.Patients and Methods:We report the safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of MEDI-570 in T-NHL. NCI-9930 is a phase I, first-in-human study of MEDI-570 in relapsed/refractory malignant T-NHL known to express ICOS. MEDI-570 was administered intravenously every 3 weeks for up to 12 cycles. Primary endpoints were safety, dose-limiting toxicities (DLT), and recommended phase II dose (RP2D). Secondary and exploratory endpoints included efficacy parameters and various correlative studies. This study is supported by the National Cancer Institute (NCT02520791).Results:Twenty-three patients were enrolled and received MEDI-570 at five dose levels (0.01–3 mg/kg). Sixteen (70%) had angioimmunoblastic T-cell lymphoma (AITL); median age was 67 years (29–86) and the median prior lines of therapies was 3 (1–16). Most common grade 3 or 4 adverse events were decreased CD4+ T cells (57%), lymphopenia (22%), anemia (13%), and infusion-related reactions (9%). No DLTs were observed. The RP2D was determined at 3 mg/kg. Analysis of T-cell subsets showed reductions in CD4+ICOS+ T cells reflecting its effects on TFH cells. The response rate in AITL was 44%.Conclusions:MEDI-570 was well tolerated and showed promising clinical activity in refractory AITL. MEDI-570 resulted in sustained reduction of ICOS+ T lymphocytes.

Background: Sézary syndrome (SS) is a rare and aggressive leukemic variant of cutaneous T-cell lymphoma (CTCL) with limited therapeutic options and a median survival of fewer than five years. Despite advances in how single-cell RNA sequencing (scRNA-seq) has improved the understanding and treatment of other cancer types, such insights in SS remain limited. The drivers of disease progression and immunologic dysfunction are incompletely defined, underscoring the need to characterize both malignant T cells (MTCs) and their interactions with surrounding immune populations. Objectives: To systematically characterize malignant and non-malignant immune cells in CTCL, identify distinct malignant T-cell subtypes, and uncover transcriptional programs and immune evasion pathways with therapeutic relevance. Methods: We analyzed scRNA-seq data on peripheral blood mononuclear cells (PBMCs) from 22 SS patients and 7 healthy controls. MTC subtypes were identified using a combination of transcriptional profiling, copy number variation (CNV) analysis, and T-cell receptor (TCR) clonotyping. CITE-seq was utilized on a subset of samples to correlate genetic findings with surface protein expression. Results: We identified three MTC subtypes: (1) MTC central memory (CM), a Th2-skewed CM phenotype that constituted the dominant malignant population; (2) MTC effector/effector-memory (E/EM), a subset enriched in Th1-associated genes; and (3) MTC regulatory (Reg), a regulatory-like, exhausted phenotype, along with shared and subtype-specific gene signatures. The predominance of MTC CM suggests a stable malignant state, while relative rarity of MTC E/EM and MTC Reg may reflect treatment effects or disease progression. In addition to KIR3DL2 , we identified KIR2DL3 and KIR3DL1 as upregulated immune-evasive receptors on MTCs and surrounding cells. Tensor factorization of ligand-receptor interactions revealed pro-inflammatory yet immunosuppressive signaling in myeloid cells converging on STAT3 activation. Conclusions: This study defines three transcriptionally and functionally distinct MTC subtypes in SS, highlighting subtype-specific vulnerabilities that may inform personalized treatment strategies. Our findings suggest that targeting not only MTCs but also KIR-family receptor signaling and JAK-STAT activation in the immune microenvironment may have therapeutic implications. The identification of novel immunosuppressive pathways and cell survival mechanisms opens avenues for tailored interventions – including widespread KIR inhibition, repurposing JAK inhibitors, and other novel therapies – to improve patient outcomes in SS. Contributor Statement: B.A. Childs conducted the conceptualization (equal), data curation (equal), formal analysis (lead), investigation (lead), methodology (equal), validation (equal), visualization (equal), writing – original draft (lead), writing – review & editing (supporting). E. Elghonaimy provided conceptualization (equal), data curation (equal), formal analysis (equal), investigation (equal), methodology (equal), resources (equal), supervision (equal), validation (equal), visualization (equal), writing – original draft (supporting), and writing – review & editing (supporting). P. R. Geethakumari provided data curation (supporting), investigation (supporting), resources (supporting), writing – review & editing (supporting). K. Kumar contributed conceptualization (supporting), data curation (supporting), resources (supporting), and writing – review & editing (supporting). J. F. Merola provided conceptualization (supporting), investigation (supporting), resources (supporting), writing – review & editing (supporting). H.W. Goff contributed conceptualization (equal), data curation (equal), formal analysis (supporting), funding acquisition (lead), investigation (supporting), methodology (supporting), resources (supporting), supervision (equal), visualization (equal), writing – review & editing (equal). T. A. Aguilera provided conceptualization of the project (equal), data curation (equal), formal analysis (equal), funding acquisition (equal), investigation (equal), methodology (equal), project administration (equal), resources (lead), supervision (lead), visualization (supporting), writing – original draft (supporting), writing – review & editing (equal). T.A. Aguilera is the guarantor and accepts full responsibility for the overall content, had access to all the data, and controlled the decision to publish. Bulleted Statements: What is already known about this topic?: Sézary syndrome is a rare, aggressive CTCL subtype associated with poor survival; a minority of patients achieve long-term remission with allogeneic stem cell transplant. KIR3DL2 is an investigational target with ongoing trials (e.g., lacutamab, anti- KIR3DL2 agent). JAK inhibitors have shown mixed effects, with anecdotal benefit and potential harm. The heterogeneous biology of Sezary cells remains poorly characterized, limiting diagnostic and therapeutic advancement. What does this study add?: We define three distinct malignant T-cell subtypes in Sézary syndrome, each with clinical and therapeutic implications, and a unifying genetic signature. In addition to KIR3DL2 , a known CTCL marker, we identify KIR2DL3 and KIR3DL1 , inhibitory receptors implicated in viral and autoimmune regulation, as additional immune evasion mechanisms. JAK/STAT activation in neighboring myeloid cells may be driven by Sezary cell signaling through S100A8 , S100A9 , CD74 , IL-10 , and TNF , a potentially targetable axis. What is the translational message?: The predominance of a central memory–like malignant phenotype, alongside other distinct subsets reveal an opportunity for subtype-guided treatment strategies. Optimal therapeutic targeting may include both malignant T cells and interacting immune cells. Our findings identify targets that may be actionable, including KIR-family receptors and STAT3-related signaling. Insights from other T-cell disorders may guide repurposing of existing therapies to improve outcomes. Lay Summary: How Sezay Syndrome, a Type of Skin Lymphoma, Impacts the Immune System: Sézary syndrome (SS) is a rare and aggressive form of skin cancer that starts in the blood. It is a type of cutaneous T-cell lymphoma (CTCL), where cancerous T cells (a kind of white blood cell) spread from the bloodstream to the skin. SS mainly affects adults and has limited treatment options, with most people living less than five years after diagnosis. This study, based in the United States, aimed to understand how cancerous T cells behave in SS and how they interact with other immune cells. We used a method called single-cell RNA sequencing to examine over 100,000 individual immune cells from the blood of 22 patients with SS and 7 healthy individuals. This allowed us to see which genes were active in each cell. We found that the cancerous T cells in SS are not all the same. Instead, they fall into three distinct groups: one resembled central memory T cells that typically live in the blood, one looked more aggressive and inflammatory, and one resembled exhausted regulatory immune cells. We also discovered that cancer cells and surrounding immune cells expressed molecules called KIRs, which may help them avoid being attacked. Other immune cells released signals that turned on a pathway called JAK-STAT, which may further protect the cancer. These findings reveal new ways that SS protects itself and avoids the immune system. Understanding these escape routes may help guide future treatments, including drug combinations that block these signals and improve patient outcomes. Abbreviated Single-cell RNA and protein profiling of Sézary syndrome reveals three distinct malignant T-cell subtypes and uncovers convergent immunosuppressive signaling through KIR-family receptors and STAT3 activation. These findings expose targetable pathways driving immune evasion and offer a foundation for more personalized therapeutic strategies in this aggressive form of cutaneous T-cell lymphoma.