T-cell acute lymphoblastic leukemia (T-ALL) originates from the malignant transformation of immature lymphoblasts committed to the T-cell lineage. Relapsed or refractory T-ALL patients show a dismal outcome with limited therapeutic options and cure rates below 10%. Accurate risk stratification is essential for optimizing first-line treatments and maximizing initial complete response rates. Minimal residual disease (MRD) assessment is the most relevant clinical parameter in T-ALL and a direct measure of treatment response, but it requires an initial treatment course that reduces the time for decision-making. Consequently, there is an urgent need to identify novel biomarkers that can predict the response to first-line treatments at diagnosis. By integrating clinical and transcriptomic data from diagnostic T-ALL samples, we found that high MRD patients show a specific transcriptional profile. Moreover, we identified a transcriptional signature characterized by the differential expression of HSH2D, LAT2, BCL2, MAST4, METRN, and PITPNM2 genes that is tightly associated with an increased MRD, which could improve the prediction of poor treatment response in T-ALL patients, especially during early treatment phases.

ABSTRACT:We performed a retrospective multicenter study including 791 patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) who underwent autologous stem cell transplantation (ASCT). After a median follow-up of 74 months from infusion, 65% were alive and 84% free of disease. Progression-free survival (PFS) and overall survival (OS) at 6 years were 51% and 63%, respectively. Non-relapse mortality at 1 year was 9%. Age >60 years at ASCT (hazard ratio [HR], 1.31; 95% CI, 1.06-1.62; P = .011), ASCT as ≥3rd line (HR, 1.81; 95% CI, 1.42-2.31; P < .001), and partial response (PR) vs complete response (CR) at ASCT (HR, 1.46; 95% CI. 1.18-1.81; P < .001) were independent variables influencing PFS. Age >60 years at ASCT (HR, 1.62; 95% CI, 1.24-2.12; P < .001), time period before 1 November 2012 (HR, 1.40; 95% CI, 1.07-1.83; P = .014), ASCT as ≥3rd line (HR, 1.77; 95% CI, 1.32-2.37; P < .001), PR vs CR (HR, 1.58; 95% CI, 1.22-2.05; P < .001), and stable disease vs CR pre-ASCT (HR, 3.41; 95% CI, 1.81-6.45; P < .001) were variables associated with worse OS. Refractory/early relapse did not significantly influence survival (6-year PFS and OS in patients with refractory, early, and late relapse were 54% and 64%, 46% and 62%, and 49% and 63%, respectively). To our knowledge, this is the largest series analyzing the efficacy of ASCT in patients with R/R LBCL after rituximab-containing frontline therapy. Our results indicate that ASCT is a curative option for patients with chemosensitive disease.

Introduction Frailty in multiple myeloma (MM) patients is linked to higher mortality, disease progression, and treatment toxicity. However, frailty assessments in MM patients have traditionally focused on elderly adults, ineligible for auto-HCT and excluded using arbitrary age cut-offs. In addition, the assessments were often complex and time consuming, limiting their application in clinical practice. Since April 2022, 15 institutions members of the GETH-TC have participated in a multicenter observational study to assess frailty dynamics in all adult MM patients eligible for auto-HCT and its impact on outcomes. This abstract summarizes prospective findings from this collaborative effort. Methods All eligible MM patients for auto-HCT were assessed for frailty after providing informed consent, irrespective of age and comorbidities. Frailty was evaluated at the first consultation and HCT admission using the HCT Frailty Scale, which classifies patients as fit, pre-frail, or frail. Evaluations, conducted by HCT teams without additional external resources, took 8-10 minutes per patient, including Mini-Cog and EQ-5D-3L quality of life (QoL) tests. Prospective data was updated in July 2024. Results 296 MM patients were included. The median age was 57 (range:31-75)) with 28.3% patents over 64 years old. 53.3% patients were male, 39.1% had a KPS < 90%, and 23.0% had an HCT-CI > 3. At diagnosis, 42.9% were ISS I, 32.7% ISS II, and 24.4% ISS III. Most patients (89.1%) received one line of treatment before auto-HCT, primarily using VTD/VRD (44.2%) and DARA-VRD (23.9%). The first consultation occurred at a median of 52 days (IQR 25-120) before HCT, mostly before stem cell collection. Initially, 64 (23.2%) patients were classified as fit, 160 (58.0%) as pre-frail, and 52 (18.0%) as frail. Binary logistic multivariate regression analysis (MVA) indicated that frailty phenotype correlated with a KPS < 90% (OR 3.52, P<0.01), an abnormal Mini-Cog (OR 7.28, P<0.01), and ISS II (OR 4.21, P=0.026) or III (OR 7.03, P<0.01). However, frailty did not correlate with age ≥ 65 years (OR 1.06, P=0.89) and comorbidities (HCT-CI > 3: OR 0.66, P=0.50). At HCT admission, 50 (18.1%) patients were classified as fit, 174 (63.0%) as pre-frail, and 52 (18.8%) as frail. By this time, 53.0% patients were in CR, 45.2% in VGPR or PR, and 1.7% had stable disease, with no differences across frailty states (P=0.21). Interestingly, some patients changed their frailty categories between consultations with 1.6% of fit and 12.5% of pre-frail worsening to frail states, while 59.6% of frail patients remaining frail, with 38.5% of them improving to pre-frail and 1.9% to fit states. Differences in auto-HCT outcomes of patients across frailty levels at admission were examined. The results showed similar hospitalization durations across frail, pre-frail and fit status (median: 15, 15, and 14 days, P=0.29), but a trend towards higher readmission rates for frail patients than for the rest (13.5% vs. 8.6% and 2.0%, P=0.06). Admission QoL assessments revealed better auto-recorded global health scores in fit patients compared to pre-frail and frail ones (80%, 70%, and 60%, P<0.01). With a median follow-up of 13 months, 21 (7.6%) patients relapsed, and 14 (5.1%) died: 10 of them due to infections, in a median of 8 months after the HCT and not during the admission. The 1-year relapse incidence was comparable among fit, pre-frail, and frail patients (8.9% vs. 5.6% and 6.5%, P=0.903), and fit patients had higher OS than pre-frail and frail ones (1-year OS: 98.9%, 95.8%, and 84.3%, P<0.01). The observed associations between frailty and lower OS (Frail vs. others: HR 3.27, P=0.047) and higher mortality non-related with relapse (HR 3.24, P=0.075) were confirmed on MVA controlling by age (≥70), KPS (<90%), and comorbidities (HCT-CI>3). Lastly, the ability of the scale for identifying frail patients at risk for mortality when measured earlier, at first consultation was additionally confirmed. Conclusions Frailty of MM patients before auto-HCT had a prevalence of 18%, could be diagnosed irrespective of chronological age, and was associated with worse outcomes and QoL. Results underscore the importance of introducing early frailty assessments in predicting risks, and exploring the effect of pre-transplant interventions for preventing and reversing frailty before auto-HCT in MM patients.

Precursor T-cell neoplasms (T-ALL/LBL) are aggressive hematological malignancies that arise from the malignant transformation of immature thymocytes. Despite the JAK/STAT pathway is recurrently altered in these neoplasms, there are not pharmacological inhibitors officially approved for the treatment of T-ALL/LBL patients that present oncogenic JAK/STAT pathway mutations. In the effort to identify potential therapeutic targets for those patients, we followed an alternative approach and focused on their transcriptional profile. We combined the analysis of molecular data from T-ALL/LBL patients with the generation of hematopoietic cellular models to reveal that JAK/STAT pathway mutations are associated with an aberrant transcriptional profile. Specifically, we demonstrate that JAK/STAT pathway mutations induce the overexpression of the PIM1 gene. Moreover, we show that the pan-PIM inhibitor, PIM447, significantly reduces the leukemogenesis, as well as the aberrant activation of c-MYC and mTOR pathways in cells expressing different JAK/STAT pathway mutations, becoming a potential therapeutic opportunity for a relevant subset of T-ALL/LBL patients.

Introduction Frailty in allo-HCT patients is associated with higher morbidity and mortality, making its assessment before transplantation crucial. Nevertheless, most frailty assessments in allo-HCT settings have utilized complex and time-consuming methodologies, limiting their application in clinical practice. Thirteen institutions, members of the Spanish Group of Hematopoietic Transplantation and Cellular Therapy (GETH-TC), participated in a multicenter observational study to evaluate the viability and potential usefulness of the HCT Frailty Scale for managing frailty in allo-HCT settings. This abstract summarizes the prospective findings from this collaborative effort. Methods From April 2022 to September 2023, 403 adult candidates for allo-HCT were assessed for frailty using the HCT Frailty Scale after providing informed consent. Patents were classified as fit, pre-frail, or frail according to their results. The assessment took place at the first consultation for allo-HCT, at HCT admission, at day +100, and at +1 year. Simultaneously, QoL was measured using the EQ-5D-3L test. Evaluations took 8-10 minutes per patient and were conducted by the HCT teams without additional external resources. Prospective data were updated in July 2024. Results The median age of patients was 56 years (range: 18-76), with 88 (21.8%) patients over 64 years old. 260 (65.5%) patients were male, 141 (35.0%) had a KPS < 90%, and 52 (12.9%) had an HCT-CI > 3. Acute myeloid leukemia (n=150, 37.2%) and myelodysplastic syndromes (n=69, 17.1%) were the most prevalent diagnoses. The median time from first consultation to HCT admission was 27 days, and 61 (15.1%) patients from a single institution underwent pre-habilitation. With a median follow-up of 14 months, 87 (21.6%) patients relapsed and 119 (29.5%) died, 72 (17.9%) due to NRM. At the first consultation, 106 (26.4%) patients were classified as fit, 247 (61.3%) as pre-frail, and 50 (12.4%) as frail. Binary logistic multivariate regression analysis (MVA) indicated that the likelihood of being frail was higher in patients undergoing allo-HCT with active disease (Odds Ratio [OR] 5.92, P=0.003) and with an abnormal Mini-Cog (OR 3.91, P=0.010). However, frailty did not correlate with age (>65), sex, and comorbidities (HCT-CI>3). At HCT admission, 86 (21.3%) patients were fit, 247 (61.3%) pre-frail, and 70 (17.8%) frail. MVA revealed that frail patients were more likely to have worse KPS (<90%: OR 2.63, P=0.003), with no correlation with age, sex, comorbidities, and disease status (active disease vs. other). Notably, joining a pre-habilitation program decreased the odds of presenting frailty at admission (OR 0.20, P=0.033). Of the 325 adults who reached 100 days of follow-up, 71 (21.8%) were fit, 192 (59.1%) pre-frail, and 62 (19.1%) frail. Frailty was more probable in patients with grade 3-4 aGVHD (OR 3.11, P=0.017) than in patients without this complication. Nevertheless, frailty could be diagnosed irrespective of age, sex, comorbidities, conditioning regimen intensity, and the use of PTCY-based prophylaxis. Lastly, among the 172 adults with 1-year follow-up without disease relapse, the proportion of fit patients increased to 41.3% (n=71); 90 (52.3%) patients were pre-frail, and only 11 (6.4%) patients were frail. At this time point, frailty could be diagnosed irrespective of baseline diagnosis and the onset of cGVHD. Frail patients had lower OS than fit and pre-frail ones regardless of when this syndrome was evaluated (1-year OS of fit, pre-frail, and frail patients at first consultation: 80.3%, 71.0%, and 67.1%, P=0.05; at admission: 87.5%, 71.4%, and 61.2%, P=0.01 and at day +100: 93.9%, 86.3%, and 70.9%, P<0.01; and at 18-month in patients evaluated 1-year after allo-HCT: 98.5%, 95.5%, and 85%, P=0.01). Causes of death among frail patients were mainly due to NRM. Similarly, the QoL of frail patients was worse than that observed in fit and pre-frail ones. Conclusions This collaborative study has demonstrated the dynamic nature of frailty in allo-HCT patients and its significant impact on survival and QoL. Frailty assessments conducted efficiently reveal that frail patients face higher risks and worse outcomes, independent of age or comorbidities. Pre-habilitation interventions show promise in reducing frailty before transplantation. Regular frailty monitoring could be integrated to better tailor interventions and improve allo-HCT outcomes.

T-cell lymphoblastic lymphoma is an uncommon lymphoid neoplasm in adults, although more frequent in children and teenagers, that often affects the mediastinum and bone marrow, requiring intensive chemotherapy protocols. Its prognosis is poor if a cure is not achieved with first-line treatments. We present a case report of a 19-year-old man diagnosed with this type of lymphoma due to significant respiratory distress and a mediastinal mass. He received treatment according to the hyper-CVAD regimen, with a complete metabolic response. However, seven months later a new mediastinal growth was observed, leading to salvage treatment with a combination of nelarabine and daratumumab. We observed not only refractoriness, but also leukemization, which prompted consideration of hematopoietic stem cell transplantation. Based on this case, we conducted a review of pharmacological treatment options for refractory or relapsed lymphoblastic lymphoma, as well as the role of radiotherapy in managing mediastinal disease. This case report highlights the limited evidence available regarding later-line treatments, with unusual reports regarding employing our combination of daratumumab and nelarabine, and emphasizes the importance of achieving cures in the first line of treatment.

The British Journal of Haematology publishes original research papers in clinical, laboratory and experimental haematology. The Journal also features annotations, reviews, short reports, images in haematology and Letters to the Editor.

INTRODUCTION Including frailty in the evaluation of patients before HCT is recommended, but more needs to be done to reach a consensus on how to evaluate and manage this syndrome in clinical practice. Since 2021, sixteen institutions members of the Grupo Español de Trasplante Hematopoyético y Terapia Celular (GETH-TC) have participated in a multicenter and prospective study with the purpose of investigating the state of frailty of adult patient candidates to HCT and evaluate the effect of frailty in transplant outcomes. METHODS All Spanish institutions members of the Group were invited to participate in the study and finally 16 of them were actively involved in it. All patient candidates for HCT were eligible to be included in the study after providing informed consent. Frailty was evaluated at first consultation, at admission, and after the stem cell infusion, using the HCT Frailty Scale (Salas et al. BMT 2023) as described in Table 1. According to their respective total frailty score, patients were classified into three levels of frailty: fit, pre-frail, and frail. The frailty assessment was made by the hematologists and nurse team as part of the clinical practice, utilizing existing human resources and without requiring additional medical appointments for patients. The median time to complete the evaluation ranged from 8 to 10 minutes. The evaluation of physical frailty was complemented with the Mini-Cog test. The results obtained from the frailty assessment were not used to determine HCT eligibility and/or to design the HCT process. This study did not have external funding. RESULTS Between February 2021 and May 2023, 916 consecutive adult candidates for HCT in any of the participating institutions were included in the project. Of all of them, the results reported here correspond only to the 341 adult candidates for allogeneic (allo)-HCT. Median patients' age was 56 (range, 18-76); 65.3% were males; the most prevalent baseline diagnosis was myeloid malignancies (57.5%). Prior to HCT, 36.8% adults had an KPS<90% and 11.5% an HCT-CI>3, 53.1% patients received reduced intensity conditioning regimens, 25.5% alternative donor grafts, and 61.6% received PTCY-based prophylaxis. At the first consultation, 94 (27.6%) adults were classified as fit, 203 (59.5%) as pre-frail, and 44 (12.9%) as frail. Frail patients were more likely to have a KPS<90% (OR 2.80, p<0.01) and an abnormal result of the Mini-Cog test (<3) (OR 8.21, P<0.001). The probability of being frail was independent of age (continuous) (p=0.654), sex (p=0.323), and comorbidities (HCT-CI>3) (p=0.196) (multivariate binary regression analysis). As shown in Table 1, the state of frailty changed throughout the study period, confirming the dynamic nature of the frailty syndrome. A total of 59 (17.3%) patients went through a pre-transplant rehabilitation (pre-hab) program. With this information, the dynamics of frailty of these patients was compared with that of patients who did not join a pre-hab program. At HCT admission, the distribution of patients across the frailty categories was different between the two groups (p=0.028). The proportion of fit patients was higher in the pre-hab group (55.1% vs. 26.7%) because part of the pre-frail patients changed to the fit category. The power of the HCT Frailty Scale to predict OS was evaluated in the subsample of 216 patients that had a minimum follow-up of 120 days among survivors. Table 1 shows that the probability of OS at 1-year increases with the level of fitness of the patients at first consultation, as follows: 35.6% (frail), 70.5% (pre-frail) and 72% (fit), (p<0.001). Secondly, the effect of the level of fitness in the probability of 1-year OS was higher with frailty measured at the time of HCT admission; respectively, 20%, 66.8% and 78.9%. (p<0.001) ( Figure 1). The difference is explained by the improvement in fitness of the patients that participated in a pre-hab program between first consultation and admission. CONCLUSIONS This study validates the applicability of the HCT Frailty Scale at HCT institutions that are part of a health care system different from that where it was first implemented. The HCT Frailty Scale classifies adult patients to allo-HCT in three categories of frailty, frail that have predictive power over transplant outcomes. Frailty syndrome is independent of age and comorbidities and can be improved through pre-hab programs with the positive result of improving the OS of transplanted patients.

Human immunodeficiency virus (HIV) infection is known to be associated with the development of Hodgkin's lymphoma (HL). Exclusive extranodal bone marrow involvement is less common. Co-infection by other viruses, such as the Epstein-Barr virus (EBV), increases the incidence of a frequent complication denominated by hemophagocytic lymphohistocytosis (HLH). We present the case of a 50-year-old patient with the above clinical spectrum who develops several serious complications during treatment.

Waldenström macroglobulinemia (WM) is a slowly progressive hematologic malignancy that usually responds rapidly to treatment. Being a lymphoplasmacytoid neoplasm, it is associated with a monoclonal IgM component, which may be associated with multiple manifestations and symptoms. We report the case of a 77-year-old woman diagnosed with WM following the development of severe and sudden pancytopenia associated with a cold agglutinin syndrome. In order to treat the WM and the underlying hemolysis, treatment with rituximab, corticosteroids and cyclophosphamide was started. Despite the improvement in hemolysis parameters, pancytopenia persisted, and we started a second line with ibrutinib. During treatment the patient developed an uncommon invasive fungal infection (IFI) with bone marrow granulomatosis and myelofibrosis. This case shows an unusual clinical course with a poor hematopoietic response to treatment and a large number of intercurrent complications.

Despite the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway being frequently altered in T-ALL/LBL, no specific therapy has been approved for T-ALL/LBL patients with constitutive signalling by JAK/STAT, so there is an urgent need to identify pathway members that may be potential therapeutic targets. In the present study, we searched for JAK/STAT pathway members potentially modulated through aberrant methylation and identified SOCS3 hypermethylation as a recurrent event in T-ALL/LBL. Additionally, we explored the implications of SOCS3 deregulation in T-ALL/LBL and demonstrated that SOCS3 counteracts the constitutive activation of the JAK/STAT pathway through different molecular mechanisms. Therefore, SOCS3 emerges as a potential therapeutic target in T-ALL/LBL.

T-cell acute lymphoblastic leukemia (T-ALL) arises from the malignant transformation of T-cell progenitors at various differentiation stages. Given that patients who relapse have a dismal prognosis, there is an urgent need to identify the molecular alterations that are present in such patients and promote leukemogenesis to implement personalized therapies with higher efficacy and fewer adverse effects. In the present manuscript, we identified the JAK3(Q988P) mutation in a T-ALL patient who did not achieve a durable response after the conventional treatment and whose tumor cells at relapse presented constitutive activation of the JAK/STAT pathway. Although JAK3(Q988P) has been previously identified in T-ALL patients from different studies, the functional consequences exerted by this mutation remain unexplored. Through the combination of different hematopoietic cellular models, we functionally characterize JAK3(Q988P) as an oncogenic mutation that contributes to leukemogenesis. Notably, JAK3(Q988P) not only promotes constitutive activation of the JAK/STAT pathway in the absence of cytokines and growth factors, as is the case for other JAK3 mutations that have been functionally characterized as oncogenic, but also functions independently of JAK1 and IL2RG, resulting in high oncogenic potential as well as resistance to ruxolitinib. Our results indicate that ruxolitinib may not be efficient for future patients bearing the JAK3(Q988P) mutation who instead may obtain greater benefits from treatments involving other pharmacological inhibitors such as tofacitinib.

Primary effusion lymphoma (PEL), Kaposi's sarcoma (KS), and multicentric Castleman's disease (MCD) is an uncommon group of diseases included in the same spectrum with related characteristics. The coexistence of all of them in the same individual is a rare occurrence. We present the case of a 25-year-old patient diagnosed with human immunodeficiency virus (HIV) and the development of all these related pathologies. Despite the use of intensive treatment according to the latest recommendations, the evolution was unfavorable. This case reflects the need for new therapies and research in this field.

Introduction: High dose therapy and Autologous Stem Cell Transplantation (ASCT) has remained the treatment of choice for transplant-eligible patients with relapsed/refractory (R/R) large B cell lymphoma (LBCL) and chemosensitive disease. Recently, CART therapy has been approved in second line for patients with primary refractory disease or early relapse (<1 year of first-line therapy) and the current role of ASCT has been questioned. However, several studies have shown that despite early failure of first line, patients with chemosensitive disease after salvage therapy can be cured with ASCT consolidation. Our objective was to analyze the efficacy of ASCT in patients with R/R LBCL after a long-term follow up and try to define the optimal role of ASCT. Patients and methods: We performed a retrospective multicenter study based on GETH-TC database of ASCT. We included patients from centers of GETH-TC/GELTAMO with R/R LBCL who underwent ASCT from January 2010 to December 2021. All the patients received rituximab and anthracycline-based frontline therapy. Diffuse LBCL NOS, high-grade B-cell lymphoma double/triple hit and NOS, primary mediastinal, transformed follicular lymphoma (tFL) and other less frequent LBCL subtypes were included. Plasmablastic and primary central nervous system lymphoma were excluded. Patients who underwent ASCT in first CR were also excluded except patients with tFL who had received previous anthracycline-based frontline therapy for the indolent lymphoma. The primary endpoints were progression-free survival (PFS) and overall survival (OS) in the overall series and according to different prognostic factors, including disease status at ASCT. Disease status was defined as complete remission (CR), partial response (PR) and refractory disease (stable disease or progression) assessed by PET/CT. Results: Seven-hundred and ninety-one patients fulfilled the inclusion criteria. Patients characteristics are summarized in Table 1. After a median follow-up of 74 months (95%CI 68-81), 65% of the patients were alive and 84% of them free of disease. Six-year-PFS and OS were 51% (95%CI 47-54) and 63% (95%CI 60-67), respectively. Non-relapse mortality at 1 year was 9% (95%CI 7-11). The main causes of death were progression in 161 (58%), ASCT-related toxicity in 18 (6%) and other causes in 98 (35%). PFS was significantly influenced by age at ASCT, treatment lines prior to ASCT and disease status at ASCT (p<0.01). OS was influenced by age at diagnosis, R-IPI at diagnosis, age at ASCT, treatment lines prior to ASCT and disease status at ASCT (p<0.01). In the multivariate analysis, age >60 years at ASCT [HR 1.31 (95%IC: 1.06-1.62), p=0.011], ASCT as ≥3 th line [HR 1.81 (95%IC: 1.42-2.31), p<0.001] and PR versus CR at ASCT [HR 1.46 (95%IC: 1.18-1.81), p<0.001] were the only independent variables influencing PFS, Figure 1. Age >60 years at ASCT [HR 1.62 (95%IC: 1.24-2.12), p<0.001], ASCT as ≥3 th line [HR 1.77 (95%IC: 1.32-2.37), p<0.001] and PR versus CR at ASCT [HR 1.58 (95%IC: 1.22-2.05), p<0.001] were the only independent variables for OS. From 307 (39%) patients who relapsed after ASCT, 59 received CART therapy (median PFS 8.9 months) and 69 allo-SCT (median PFS 10.8 months). Refractory disease or early relapse did not significantly influenced survival. Analyzing this population separately (n=477), disease status at ASCT (PR versus CR) and ASCT as ≥3 th line were the only independent variables for both PFS [HR 1.46 (95%IC: 1.11-1.92), p=0.007; HR 1.79 (95%IC: 1.32-2.43), p<0.001, respectively] and OS [HR 1.92 (95%IC: 1.38-2.67), p<0.001; HR 1.91 (95%IC: 1.35-2.69), p<0.001, respectively]. Conclusions: To our knowledge, this is the largest series analyzing the efficacy of ASCT in patients with R/R LBCL after rituximab-containing frontline therapy. Our results indicate that ASCT is a curative option for patients with chemosensitive disease (especially in CR after salvage), regardless of the timing of relapse after frontline treatment. These data support that ASCT could be considered in patients with primary refractory or early relapse, provided the disease is sensitive to salvage therapy.

A 32-year-old man presented with a 7-month history of progressive painless, nonpruritic skin and soft tissue lesion on his left leg. He had no systemic or B symptoms. The physical examination showed a violaceus lesion soft in consistency on the left leg (Figures 1 and 2). MRI showed an oval lesion with hypointensity signal in T1 and hyperintensity in T2, with homogeneous enhance postcontrast study, and diffusion-restriction. There was no palpable lymphadenopathy or hepatosplenomegaly. The skin lesion was biopsied and showed atypical cells (Figure 3). Immunohistochemical analysis showed cells that were positive for CD4, CD56, CD123, SPIB, TdT, and negative for MNDA (Figure 4), which supported the diagnosis of blastic plasmacytoid dendritic-cell neoplasm (BPDCN). Complete blood count was unremarkable and peripheral blood smear did not show immature cells. Bone marrow aspirate/biopsy did not reveal the presence of neoplastic plasmacytoid dendritic cells. An 18(F)–FDG-PET-CT imaging did not reveal evidence of other lesions (Figure 5). The next-generation sequencing (NGS) of the skin lesion biopsy specimen revealed NRAS mutation. NGS of the bone marrow biopsy specimen showed no pathogenic mutations. BPDCN is a rare, but aggressive, hematologic malignancy. The clinical features and evolution consist of two main patterns: (A) Indolent onset dominate by skin lesions followed by tumor dissemination (70–90%) and (B) Acute leukemia features with systemic involvement from the beginning (10-30%) [1, 2]. Skin lesions can be extremely heterogeneous, but more often they are multiple and can involve any body site [2]. Typically affect older men and precede dissemination extracutaneous by a few months [1]. Confirmation of a diagnosis can pose a significant challenge in many cases, and therefore, the clinician and pathologist must have a high degree of suspicion, particularly in patients presenting with skin lesions and cytopenias. Although lack of systemic involvement at presentation may seem reassuring, survival is poor regardless of presentation [1, 2]. This work was supported by grants from the Instituto de Salud Carlos III (ISCIII) of the Spanish Ministry of Economy and Competence (MINECO, FEDER, RTICC ISCIII, and Centro de Investigación Biomédica en Red Cáncer - CIBERONC) (SAF2013-47416-R, RD06/0020/0107-RD012/0036/0060, and Plan Nacional I+D+I: PIE15/0081, PI16/01294, PI17/2172, PI17/00272 and PI19/00715), GILEAD (GL18/00019), Asociación Española Contra el Cáncer (AECC; PROYE18054PIRI), and the Madrid Autonomous Community. The authors report no conflict of interest. All authors wrote and edited the manuscript. The patient provided written informed consent for the publication of this Clinical Picture.