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Translocations involving CCND1 are well described in multiple myeloma (MM), most frequently t(11;14), but rearrangements involving the immunoglobulin kappa (IGK) locus are rare. We present a case of a 71-year-old female with MM harboring t(2;11)(p11.2;q13), resulting in IGK::CCND1, with cyclin D1 and BCL-2 overexpression. Her disease was refractory to multiple conventional therapies. On confirmation of this rearrangement by comprehensive genomic profiling, the decision was made to utilize a venetoclax-based regimen. The patient achieved a stringent complete response that has remained durable for over 3 years. This case highlights a novel and targetable genomic subtype of MM and reinforces the importance of molecular diagnostics in guiding precision therapy. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.
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ABL2 rearrangements represent a subtype of acute lymphoblastic leukaemia (ALL) associated with poor prognosis and survival. This study reports a high-risk T-cell ALL (T-ALL) case with a novel TPR::ABL2 gene fusion resulting from a chromosomal deletion. Overexpression of TPR::ABL2 in Ba/F3 cells promoted cytokine-independent growth, demonstrating its oncogenic nature. Both primary patient and Ba/F3 cells carrying TPR::ABL2 exhibited kinase activation and sensitivity to tyrosine kinase inhibitors (TKIs). This study expands the repertoire of ABL2 fusions identified in ALL and supports the incorporation of TKIs into T-ALL treatment regimens to improve outcomes for this subtype.
Large B-cell lymphomas (LBCLs) are a common subtype of non-Hodgkin lymphomas. CD19 chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized LBCL treatment, with high remission rates but also significant toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Venous thromboembolism (VTE) in CAR-T therapy patients is understudied. This study aims to determine the incidence and characteristics of acute VTE in LBCL patients treated with CAR-T therapy and identify baseline clinical features associated with VTE. Methods: We retrospectively reviewed 172 adult LBCL patients treated with CAR-T therapy from January 2018 to November 2019 at MD Anderson Cancer Center. Data on demographics, clinical characteristics, and adverse events were collected. VTE events within 6 months post-CAR-T therapy were confirmed by diagnostic imaging. Statistical analyses included univariate analyses and cumulative incidence functions. The cohort was predominantly male (70%), with a median age of 59 years and advanced-stage disease (76.16%). The 6-month incidence of VTE was 7.6%, primarily involving upper extremity events related to central venous catheters. Significant associations were found between VTE and disease histology (p = 0.033) and high-grade ICANS (p = 0.013). PMBCL patients had a higher VTE incidence (30%) compared to DLBCL and TFL. Most VTE events occurred within the first month post-CAR-T therapy. LBCL patients receiving CAR-T therapy have a significant risk of VTE, particularly within the first month and among those with PMBCL and high-grade ICANS. This highlights the need to study the role of venous thromboprophylaxis in this context.
Plasma cell leukemia and central nervous system involvement are two poor prognostic factors in myeloma, and such patients are often excluded from clinical trials. A 59-year-old patient with primary plasma cell leukemia developed leptomeningeal CNS disease following autologous transplant. Intrathecal chemotherapy and selinexor, pomalidomide, and dexamethasone failed to clear cerebrospinal fluid plasma cells. Elranatamab achieved complete serological and CNS response. The patient recovered from bedbound status to full independence and proceeded to receive CAR-T therapy. At 8 months post CAR-T, he remains in sustained MRD negativity. Sequential bispecific antibody and CAR-T therapy demonstrates exceptional efficacy in CNS multiple myeloma, offering new hope for this historically terminal condition and supporting the systematic study of novel immunotherapies in high-risk myeloma populations. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.
The participation of transplant centres in research studies that request detailed follow-up data on included patients can be challenging due to the amount of time centre Data Managers have to complete additional requests. The Research Data Manager (RDM) Pilot Project was designed to support Anthony Nolan's longitudinal Patient/Donor project and provide real-world evidence of the benefit of additional and dedicated data management resources in transplant centres. For Anthony Nolan to continue advancing the field of donor selection, up-to-date and accurate follow-up data is needed. This 12-month pilot project aimed to demonstrate how on-the-ground support could improve access to outcome data. Following RDM placements at two participating centres, we reviewed the data quality and quantity collected, thus ensuring the methods used remain effective and are likely to result in successful and continuous data improvement. The cohort covered a broad timespan and included historical patient records, posing challenges in availability of prior data and long-term follow-up of discharged patients. Following the placements, over 400 patients now have the most up-to-date and complete patient clinical outcome data available within the EBMT/BSBMTCT registry database for any group to study, reducing the burden on these centres to complete research data requests for these individuals. The authors have confirmed clinical trial registration is not needed for this submission.
Refractory Burkitt lymphoma (BL) has a dismal prognosis after failure of frontline therapy. New treatment options are urgently needed. We describe a 60-year-old HIV-positive patient with refractory and secondary primary BL after frontline and salvage therapy failure, treated off-label with glofitamab successfully. Twelve cycles of glofitamab were well tolerated and led to complete metabolic remission confirmed by imaging and biopsy, sustained for nine months post-treatment. Glofitamab may represent a promising stand-alone option in relapsed BL, when conventional cytotoxic therapies are exhausted. Clinical Trial Registration: The authors have confirmed that clinical trial registration is not needed for this submission.
Immunosuppressive therapy (IST) is standard first-line treatment for severe aplastic anaemia (AA) in patients ineligible for allogeneic transplantation. Thrombopoietin receptor agonists (TPO-RAs) are increasingly added to IST to improve haematologic recovery, but long-term safety remains uncertain. We conducted a PRISMA-guided systematic review and meta-analysis. MEDLINE, EMBASE and CENTRAL were searched from inception to April 2025. Randomised controlled trials and observational studies comparing TPO-RA plus IST with IST alone were analysed separately using random-effects models. The primary outcome was overall haematologic response at 6 months; secondary outcomes included response at 3 and 12 months, complete response, survival, relapse and clonal evolution. Twenty studies (2 randomised and 18 observational) were included. In randomised trials, TPO-RA plus IST showed a non-significant trend towards higher overall response at 6 months (OR 2.01; 95% CI 0.76-5.28), while complete response was significantly higher at 3 and 6 months. Observational studies consistently demonstrated higher overall and complete response rates. No significant differences were observed in survival, relapse or clonal evolution. Limited randomised evidence does not demonstrate statistically significant benefit across all outcomes, while observational data suggest potential haematologic advantages. Further high-quality trials are required to clarify the effectiveness and long-term safety of adding a TPO-RA to IST in AA. The authors have confirmed clinical trial registration is not needed for this submission.
Paroxysmal nocturnal haemoglobinuria (PNH) is an uncommon, life-threatening disease, caused by intravascular haemolysis by the complement system. In this review, we aim to compare the efficacy of the available agents across patient-centred outcomes in complement inhibitor-naive patients. Following PRISMA guidelines, a comprehensive literature search was conducted on PubMed, Cochrane CENTRAL and ClinicalTrials.gov for studies published up to 30th May 2025. A frequentist model network meta-analyses were conducted in RStudio (v5.4.1) using a common-effects model. A total of four randomized controlled trials evaluating four complement inhibitor agents (ravulizumab, crovalimab, eculizumab and pegcetacoplan) were included in this systematic review and network meta-analysis, involving 589 complement inhibitor-naïve adults with PNH. Across outcomes, all active treatments demonstrated benefit compared with placebo or supportive care. In the exploratory network meta-analysis of transfusion avoidance, no consistent statistically significant differences were observed between active treatments, although ravulizumab showed higher odds compared with crovalimab (OR = 2.69, 95% CI: 1.13-6.41; p = 0.0256). For change in FACIT-Fatigue score, all active treatments improved fatigue versus placebo, with some statistically significant differences observed between agents; however, these comparisons were based on indirect evidence from a sparse network. This study suggests that available complement inhibitors improve key outcomes versus placebo/supportive care in complement inhibitors naive PNH. However, the evidence network is sparse (four trials) and the cross-trial differences limit reliable inference regarding relative efficacy between active agents. Comparative findings should be interpreted as hypothesis-generating.
To evaluate disease burden among paroxysmal nocturnal hemoglobinuria (PNH) patients prescribed C5 inhibitors (C5i). Data were drawn from the Adelphi Real World PNH Disease Specific Programme, a cross-sectional survey of physicians and PNH patients in Australia, Canada, France, Germany, Italy, Spain, the United Kingdom, and Japan from January-December 2022. Physicians reported patient demographics, laboratory parameters, and treatments. Patients completed the EQ-5D-5L, Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-Fatigue), and Work Productivity and Activity Impairment (WPAI) questionnaire. Analyses were descriptive. Overall, 81 physicians reported on 288 patients receiving C5i. Median (IQR) age was 50.0 (38.3-65.0) years, 79.2% were white, and 54.5% were male. Median (IQR) C5i duration was 1.0 (0-3.0) years; 77.4% received eculizumab, 22.6% ravulizumab. At time of survey, median (IQR) hemoglobin (Hb) was 11.0 (9.9-12.0) g/dL, 73.5% of patients had Hb < 12 g/dL. Lactate dehydrogenase was >1.5× upper limit of normal for 16.7% of patients. Mean (SD) EQ-5D-5L was 0.76 (0.20), FACIT-Fatigue was 36.1 (9.7), WPAI work impairment was 27.5% (22.3) and activity impairment was 35.3% (24.6). Despite C5i treatment, a notable proportion of patients remained anemic and reported impaired quality of life, indicating the need for novel, efficacious therapies.
Paediatric classical Hodgkin lymphoma (cHL) is the most common malignancy in adolescents, and despite excellent survival, a subset of patients experiences treatment failure or severe long-term toxicity, underscoring the need for improved risk stratification. Early response assessment is particularly important, as it guides decisions on radiotherapy, where overtreatment can lead to substantial late effects. In the context of a large-scale systems-level immunomonitoring initiative, we specifically examined paediatric cHL and profiled their systemic immunology alongside children with intra- and extracranial solid tumours and other lymphomas. Through longitudinal sampling before and after treatment, we aimed to identify diagnostic and prognostic biomarkers relating immune profiles to early treatment response and risk of developing neutropenic fever. Plasma CCL17 and MCP-4 were markedly elevated in cHL compared with other paediatric lymphomas and other solid tumours, with distinct immune cell compositions, particularly between cHL and extracranial tumours. CCL17 and MCP-4 negatively correlated with age in extracranial and intracranial tumours but not in cHL, indicating disease-specific regulation. Chemotherapy induced consistent protein changes in cHL and eliminated CCL17 and MCP-4 differences between cHL and other lymphomas. Lower baseline MCP-4 and greater CCL17 reduction after chemotherapy were associated with favourable early response, while lower granzyme levels identified patients at higher neutropenic fever risk. Together, these exploratory findings highlight clinically relevant biomarkers in a paediatric oncology context, with the potential to enhance diagnostic precision, guide response-adapted therapy and effectively allocate supportive care, thereby improving outcomes for children with cHL. The authors have confirmed clinical trial registration is not needed for this submission.
Histiocytic sarcoma (HS) is a rare neoplasm derived from non-Langerhans histiocytic cells, exceptionally arising from B-ALL. We present the case of a child with high-risk B-ALL with PAX5 P80R mutation. Despite initial remission, a chemoresistant paravertebral mass was identified as HS. A shared IGK/TCRB rearrangements and PAX5 alterations between the leukaemic and histiocytic clones suggested transdifferentiation driven by PAX5. A somatic MAP2K1 mutation in the HS component prompted selumetinib treatment, leading to a rapid response. This case underscores the role of PAX5 in lineage plasticity and highlights the potential of targeted MEK inhibition in MAPK-driven HS arising from B-ALL. The authors have confirmed clinical trial registration is not needed for this submission.
Real-world data on teclistamab in relapsed or refractory multiple myeloma (R/R MM), particularly in elderly patients, remain limited. We analysed efficacy and safety outcomes in patients ≥ 75 years from the French RetrosTECtive cohort. Among 303 patients, 90 were aged ≥ 75 years and compared with 213 younger patients. Elderly patients had fewer high-risk cytogenetic abnormalities and a longer disease history. Remarkably, teclistamab appeared more effective in this population, with 74% achieving at least a very good partial response, compared with 62% of younger patients. Median progression-free survival was 15.1 months in the elderly cohort versus 12.4 months in younger patients. This improved efficacy did not come at the cost of increased toxicity: adverse event rates were comparable, although older patients more frequently received prophylactic measures. These findings support teclistamab as a safe and effective therapeutic option for geriatric patients with R/R MM. The authors have confirmed clinical trial registration is not needed for this submission.
Tyrosine kinase inhibitor (TKI) resistance remains a critical challenge in chronic myeloid leukemia (CML). While mechanistic studies implicate miR-202-5p in resistance, its clinical relevance as a biomarker at diagnosis requires validation. A nested case-control design was employed within a prospective cohort of 797 newly diagnosed chronic-phase CML patients. Of these, 31 patients who developed TKI resistance (per ELN 2020 criteria, without ABL mutations) were matched 1:4 to 124 TKI-sensitive controls on age, sex, Sokal score, and baseline white blood cell count. miR-202-5p expression was quantified by qRT-PCR from diagnostic peripheral blood mononuclear cells (PBMCs). Statistical analyses included conditional logistic regression and receiver operating characteristic (ROC) curve analysis. The expression level of miR-202-5p was significantly elevated in the TKI-resistant group (1.68 ± 0.45) compared to the TKI-sensitive group (1.26 ± 0.32) (p < 0.001). Conditional logistic regression analysis revealed that elevated miR-202-5p expression was strongly correlated with an increased risk of TKI resistance (OR = 15.21, 95% CI: 4.87-47.51; p < 0.001). ROC curve analysis demonstrated that miR-202-5p had moderate diagnostic accuracy for identifying TKI resistance (AUC = 0.73, 95% CI: 0.65-0.81). Using the optimal cut-off value of 1.63 determined by the Youden Index, the proportion of TKI resistance was significantly higher in the high-expression group (61.29% vs. 12.10%, p < 0.001). Elevated miR-202-5p expression at diagnosis is significantly associated with TKI resistance in CML. These findings support its potential as a clinical biomarker for identifying high-risk patients, which could aid in early risk stratification and guide therapeutic strategy. The authors have confirmed clinical trial registration is not needed for this submission.
Chronic graft-versus-host disease (cGVHD) is a major late complication following allogeneic hematopoietic stem cell transplantation (HSCT), in which musculoskeletal involvement, particularly isolated myositis, is extremely rare. We report a case of cGVHD-associated myositis in a man in his 40s who underwent allogeneic bone marrow transplantation from a mismatched unrelated donor for Philadelphia chromosome-positive acute lymphoblastic leukemia. The patient developed acute GVHD, which was successfully managed with corticosteroid therapy. As GVHD did not recur, corticosteroids were gradually tapered and discontinued 1 year after transplantation. Forty-three days after discontinuation, the patient developed fever and progressive myalgia, leading to hospital admission. He presented with proximal muscle weakness and marked elevation of serum creatine kinase (CK). Infectious myositis and idiopathic inflammatory myopathies were carefully excluded. Muscle biopsy demonstrated inflammatory myopathy with infiltration of CD3-positive lymphocytes, a subset of which expressed programmed cell death protein 1 (PD-1), suggesting an immune-mediated process compatible with cGVHD-associated myositis. High-dose corticosteroid therapy resulted in partial clinical improvement; however, serum CK levels showed only transient reduction and failed to achieve sustained normalization, indicating an insufficient biochemical response. The addition of ruxolitinib was associated with subsequent normalization of CK levels and sustained clinical recovery, allowing for the successful tapering of corticosteroids. This case highlights a rare manifestation of cGVHD and suggests that ruxolitinib may represent an effective therapeutic option for steroid-refractory muscular involvement after allogeneic HSCT.
We report a 65-year-old man with FLT3 D835V-mutated acute myeloid leukemia (AML) and BCR::ABL1-positive chronic myeloid leukemia (CML) that coexisted as genetically independent clones. Cytogenetic and targeted sequencing analyses demonstrated that the AML and CML clones coexisted as distinct entities. During treatment with gilteritinib, the AML blasts regressed, and then the CML clone expanded. Subsequently, the CML burden declined as the AML clone regrew. This case highlights the importance of accurately assessing clonal changes using genetic analysis when implementing molecular targeted therapy for hematologic malignancies.
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T-prolymphocytic leukemia (T-PLL) is a rare lymphoid malignancy with a poor prognosis. B-cell acute lymphoblastic leukemia (B-ALL) also confers a poor prognosis, especially in patients with high-risk features without an option for transplant. Here, we present a case of a patient with T-PLL initially treated with multi-agent chemotherapy who then developed B-ALL, the management strategies, and possible pathogenesis of two concurrent rare malignancies. One proposed mechanism for the development of both hematologic malignancies in this patient is the acquisition of a KMT2A rearrangement, raising the possibility of clonal evolution resulting in therapy-related or secondary leukemia. Another explanation is the presence of a common clonal stem cell progenitor harboring a JAK3 mutation.
A 28-year-old male with paroxysmal nocturnal haemoglobinuria (PNH) presented with headache, nasal bridge discomfort and haemoglobinuria. He developed a macular-papular rash which rapidly progressed into purpura, necrosis and peri-orbital oedema. Investigations demonstrated severe haemolytic anaemia and acute parvovirus B19 infection. A skin biopsy confirmed extensive necrotising vasculitis with intravascular thrombi, affecting the dermal and subcutaneous vessels. Eculizumab, corticosteroid and intravenous immunoglobulin were given, and within 24 h, symptoms markedly improved. The patient later developed breakthrough haemolysis in the setting of varicella zoster virus infection, which responded well to additional anti-complement therapy. This case demonstrates that viral infections can precipitate acute thrombosis and severe haemolysis in PNH patients and that a combined treatment approach confers good recovery. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.
Sickle cell disease (SCD) is a chronic genetic disorder causing severe pain, anemia, and systemic complications that negatively affect patients' physical and mental well-being. The aim of this global cross-sectional study was to evaluate the relationship between oral pain medication (OPM) use frequency and health outcomes, emotional well-being, social participation, and satisfaction with care among people with SCD. Data were collected via an online survey across five continents from February to September 2024. A total of 123 participants were divided into two groups based on OPM use frequency: weekly or more (n = 62) and once or twice a month (n = 61). Participants in OPM weekly group reported poorer self-rated health, shortness of breath, more frequent hospitalizations, and missed school days due to SCD crises compared to the monthly group (p < 0.05). However, use of treatments such as hydroxyurea and preventive screenings like transcranial Doppler was similar across groups. Emotional well-being also significantly differed in the weekly group, with lower happiness levels, difficulty in emotional regulation, and reduced social participation (p < 0.01). Satisfaction with medical care was significantly lower among weekly OPM users (p < 0.001). These findings suggest that higher OPM use is associated with poorer physical, emotional, and social outcomes. The results highlight the importance of comprehensive and multidisciplinary care approaches that may support the overall well-being of individuals with SCD and utilize OPM as a relevant clinical metric to assess disease burden in SCD. The authors have confirmed clinical trial registration is not needed for this submission.