Despite progression-free survival in multiple myeloma (MM) patients extending to 17 years due to contemporary quadruplet induction therapies, there remains a necessity for novel products in the treatment of high-risk patients. BCMA, GPRC5D, FcRH5, SLAMF7, and TACI are the principal chimeric antigen receptor T (CAR-T) cell target molecules, with dual-target treatments under development to enhance treatment efficacy. Ide-cel and cilta-cel are CAR-T cells directed against BCMA, having received approval from the U.S. Food and Drug Administration for relapsed/refractory MM based on the phase 2 KarMMa and CARTITUDE trials, respectively. Research is currently being conducted on the administration of these products in newly diagnosed patients and for maintenance therapy. Additional anti-BCMA targeted medicines, including LCAR-B38M, completely humanized CAR-T (FHVH-T), P-BCMA-ALLO-1, ALLO-715, and anti-BCMA CAR-NK, provide promising treatment options. Moreover, the anti-CD19 Fast-CAR, designed to shorten production time, and PHE885, which possesses in vivo proliferation capability, are regarded as very efficacious. Arlocel, developed for the significant target GPRC5D, has demonstrated efficacy compared to conventional treatments. The development of academic CAR-T products such as ARI0002h, HBI0101, eque-cel, zevorcel, anito-cel, and Sleeping Beauty (utilizing a non-viral vector) have importance due to their accessibility and cost-effectiveness. Real-world data have demonstrated comparable efficacy and safety outcomes in both academic and commercial CAR-T research. CAR-T cell studies are also being undertaken for smoldering MM and amyloid light-chain (AL) amyloidosis. CAR-PRISMM and CAR-HiRiSMM are regarded as extremely effective and safe therapies for patients with high-risk smoldering MM. NXC-201, which targets BCMA, has been developed for AL amyloidosis. Notwithstanding these promising outcomes, numerous difficulties still confront CAR-T therapy. These factors may be related to the tumor, the patient, and/or the CAR-T product. To overcome these issues, new strategies are being implemented, including combination therapy and the incorporation of gamma-secretase inhibitors. In conclusion, CAR-T treatments have evolved into an effective therapy modality and are anticipated to be utilized in earlier treatment phases in the future. The CRISPR gene editing method contributes to future perspectives.

Objective: Beta-thalassemia is an inherited hemoglobin disorder caused by mutations in the HBB gene encoding beta-globin chains. Severe anemia secondary to defective globin chains, chronic hemolysis, and ineffective erythropoiesis necessitate transfusion support from early childhood. Recently used treatment options with promising results in resource-limited countries include drugs that augment fetal hemoglobin (HbF), such as hydroxyurea and thalidomide. Although effective in alleviating anemia and related symptoms, these drugs, and particularly thalidomide, are also known for their immunomodulatory roles. Furthermore, repeated transfusions for patients with compromised immune systems increase the risk of infections and weakened immunity. The key regulators of immune systems include immune checkpoints, or cell surface molecules on immune cells. Limited studies are available on the expression of immune checkpoint molecules such as LAG-3, CTLA-4, TIM-3, and PD-1 in thalassemia and its treatment. This study aimed to compare LAG-3, CTLA-4, TIM-3, and PD-1 expression levels in patients treated using HbF-augmenting drugs or transfusions and with iron overload. The findings provide insight into immune regulation in beta-thalassemia and response to treatment.
Materials and Methods: Gene expression levels of LAG-3, CTLA-4, TIM- 3, and PD-1 were quantified using real-time polymerase chain reaction in patients being managed with blood transfusions (n=33) or HbFaugmenting drugs (n=140) compared to healthy controls (n=27).
Results: This study revealed increased expression of LAG-3 in patients regardless of treatment, whereas increased CTLA-4 was observed in patients receiving regular transfusions. The expression levels of TIM-3 and PD-1 were higher in patients receiving HbF augmentation therapy compared to both patients receiving blood transfusions and the healthy control group. A very weak to nonexistent correlation was found between serum ferritin and immune checkpoints.
Conclusion: The findings of this study are suggestive of alterations in immune regulation in beta-thalassemia that could be attributed to thalassemia itself, repeated exposure to blood products, recurrent infections, and the use of immunomodulatory drugs.

Objective: Inborn errors of immunity (IEIs) are caused by deficiencies or functional abnormalities in the immune system, leading to increased susceptibility to infections, autoimmunity, autoinflammatory diseases, allergies, and/or malignancies. Primary hemophagocytic lymphohistiocytosis (HLH) arises from genetic mutations affecting the function of cytotoxic T lymphocytes and natural killer cells, while secondary HLH is triggered by infections, malignancies, rheumatologic disorders, or immune deficiencies. Treatment consists of remission induction, control of triggers, maintenance of remission, rescue treatment, and hematopoietic stem cell transplantation (HSCT) as curative steps. The aim of this study is to evaluate the clinical and laboratory features, as well as the outcomes, of primary HLH patients who were diagnosed and treated in a multidisciplinary manner over the past 25 years.
Materials and Methods: The study included 30 patients with primary HLH/IEI who were diagnosed and treated in the departments of pediatric hematology, immunology, and oncology of the Ankara University Faculty of Medicine Children’s Hospital and Bone Marrow Transplantation Unit from 2000 to 2025.
Results: Of the 30 patients, 18 were boys and 12 were girls. The median age at the onset of the first symptom was 10 months (range: 0.5-204 months), while the median age at the time of admission to our center was 12.5 months (range: 1-204 months). Pedigree analysis showed that 21 patients were born to consanguineous parents. All patients had a fever lasting longer than 5 days, with a mean duration of 13.30±14.05 days (range: 5-60 days). Splenomegaly was detected in 29 patients (96.6%) and hepatomegaly in 25 (83%). Anemia was observed in 27 patients (90%), neutropenia in 23 (76.6%), and thrombocytopenia in 30 (100%). Genetic evaluation was performed for all patients and a causative gene was identified in 19 of 30 cases (63%). The most common genetic diagnosis was perforin deficiency (FHLH2), detected in 8 patients (26.6%), followed by UNC13D defect (FHLH3) in 4 patients (13,3%). HSCT was performed for 17 patients (56.6%), with 6 receiving transplants from matched related donors, 4 from matched sibling donors, 5 from matched unrelated donors, and 2 from mismatched related donors. Thirteen patients remain alive, with mean survival of 119.89 months. Seventeen patients (56.6%) died, primarily due to multiorgan dysfunction syndrome, acute respiratory distress syndrome, HLH reactivation, septic shock, or heart failure. HSCT patients had a significantly longer survival (mean: 165.6 months) compared to patients who did not undergo HSCT (45.36 months; p<0.01). Admission to the pediatric intensive care unit, organ failure, and neurological involvement were identified as adverse prognostic factors, all significantly associated with higher mortality (p<0.05).
Conclusion: Given the increasing recognition of HLH as a possible manifestation of IEIs, comprehensive immunological and genetic evaluations should be pursued without delay in suspected cases. Our findings, in line with the results of national and international cohorts, confirm that HSCT remains the only curative option for familial HLH and should be performed as early as possible after achieving disease remission. Improving access to early diagnostics and HSCT could significantly enhance outcomes, particularly in genetically predisposed populations.

Objective: Acute myeloid leukemia (AML) is a malignant tumor with high incidence and mortality. This study aimed to investigate whether insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) regulates the stability of neurexin 2 (NRXN2) mRNA in an N6-methyladenosine (m6A)-dependent manner and to explore its role in AML progression.
Materials and Methods: Differentially expressed genes of AML were identified using the DESeq2 R package and verified by the TCGA-AML database. NRXN2 silencing, IGF2BP3 downregulation, and IGF2BP3 overexpression were performed in the human HL-60 AML cell line and proliferation and apoptosis were investigated. The potential m6A site of NRXN2 mRNA was predicted with the SRAMP website. IGF2BP3 enrichment and m6A modification of NRXN2 mRNA were detected by real-time polymerase chain reaction using the Magna MeRIP m6A Kit and by RNA immunoprecipitation real-time polymerase chain reaction, respectively. An NRXN2 mutant lacking the predicted m6A site (NRXN2- mut [c.1770A>T]) was constructed and transfected into HL-60 cells.
Results: IGF2BP3 and NRXN2 were upregulated in AML and their expression was negatively correlated with overall survival. A specific m6A modification site was identified on NRXN2 mRNA. NRXN2-mut (c.1770A>T) decreased the m6A modification level and reduced the stability of NRXN2 mRNA, as well as its enrichment by IGF2BP3. NRXN2 silencing and IGF2BP3 knockdown suppressed proliferation and promoted apoptosis in HL-60 cells, accompanied by decreased Bcl-2 and PCNA protein levels and increased cleaved caspase 3. IGF2BP3 overexpression promoted proliferation and inhibited apoptosis, effects that were reversed by the co-expression of the NRXN2 mutant.
Conclusion: IGF2BP3 promoted the stability of NRXN2 mRNA in an m6A-dependent manner, thereby promoting the overproliferation of AML cells.

Objective: The prognostic significance of paraproteinemia (PP) in marginal zone lymphoma (MZL) is underexplored. We aimed to investigate the clinical and biological impact of PP and its association with survival outcomes in patients with MZL.
Materials and Methods: We retrospectively evaluated 73 patients diagnosed with MZL between 2000 and 2022 at a single center. Baseline clinical characteristics and survival outcomes were compared according to PP status.
Results: PP was present in 27.3% (20/73) of patients, predominantly of the immunoglobulin M (IgM) subtype. PP was significantly associated with older age (p<0.001), advanced disease stage (p=0.023), elevated β2-microglobulin (p=0.001), bone marrow involvement (p=0.026), and lower hemoglobin (p=0.002) and albumin (p<0.001) levels. Patients with PP had significantly shorter overall survival (OS) and progressionfree survival (PFS) compared to those without PP (mean OS: 73.8 vs. 178.8 months, p=0.046; mean PFS: 63.5 vs. 159.7 months, p=0.049). The negative prognostic impact was more pronounced among patients with IgM PP (OS: 58.8 vs. 178.2 months, p=0.006; PFS: 45.2 vs. 157.4 months, p=0.004). In histological subtype analysis, only mucosaassociated lymphoid tissue lymphoma patients with IgM PP showed significantly shorter OS (70.5 vs. 152.6 months, p=0.010). Patients with IgM PP treated with R-CHOP-like regimens experienced significantly shorter PFS and OS.
Conclusion: PP, particularly of the IgM subtype, is associated with adverse clinical and biological features and predicts inferior survival in patients with MZL. Evaluating PP status at diagnosis as a potential prognostic marker may guide treatment strategies. Prospective studies are needed to confirm the prognostic utility of PP and support its incorporation into MZL treatment management.

Objective: Erythrodermic cutaneous T-cell lymphomas (E-CTCLs), including erythrodermic mycosis fungoides (E-MF) and Sezary syndrome (SS), are aggressive and rare variants of CTCL with overlapping clinical and pathological features. Differentiating between E-MF and SS is often challenging due to non-specific symptoms and shared diagnostic criteria. This study aimed to evaluate clinical and laboratory features, progression patterns, prognostic indicators, and survival outcomes in E-CTCL patients, comparing subgroups of E-MF, de novo SS, and secondary SS.
Materials and Methods: A total of 35 patients with E-CTCL were analyzed (6 with E-MF, 15 with de novo SS, 14 with secondary SS). Comprehensive evaluations encompassed clinical and histopathological data, tumorlymph node-metastasis-blood staging, flow cytometry findings, laboratory parameters, and survival outcomes. Statistical analyses included Kaplan-Meier survival estimates and Cox regression models.
Results: Most patients were male (74.3%) and presented with advanced-stage disease (60%). Elevated serum lactate dehydrogenase and beta-2 microglobulin levels were common, particularly in cases of B2 blood involvement. Female sex and eosinophilia were independent predictors of mortality. Lymph node involvement was associated with rapid progression to erythroderma. No significant survival differences were observed among the E-MF, de novo SS, and secondary SS subgroups.
Conclusion: E-CTCL remains a diagnostic and therapeutic challenge. Female sex and eosinophilia emerged as key independent prognostic indicators in our study. While survival rates did not significantly differ between the E-MF and SS subgroups, the overall prognosis was poor. Larger prospective studies are needed to refine prognostic models and treatment strategies.

This study aimed to evaluate salvage treatment options for posttransplant relapse in children with early/very early relapse of acute lymphoblastic leukemia (ALL). Forty consecutive high-risk ALL cases were divided into two groups based on the salvage treatment for posttransplant relapse: Group 1 (n=9) received purine nucleoside analogs (fludarabine/clofarabine-based regimens), while Group 2 (n=8) received targeted agents (blinatumomab, bortezomib, and chimeric antigen receptor T-cells). In Group 1, seven children received a fludarabine-based regimen and two received a clofarabine-based regimen. In Group 2, five children received bortezomib-based regimens, two received blinatumomab, and one received chimeric antigen receptor T-cells. Group 2 showed a significantly higher cumulative survival rate (75% vs. 22%) and lower grade 3 and 4 toxicity rates (13% vs. 66%) compared to Group 1 (p<0.05). Based on our limited data, targeted agents may constitute an effective treatment option and can be directly recommended for posttransplant relapse in children with high-risk ALL.

On August 6, 1945, the United States dropped the first atomic bomb (“Little Boy”) on Hiroshima, and on August 9, 1945, it dropped the second atomic bomb (“Fat Man”) on Nagasaki. Two Canadian scientists, Ernest A. McCulloch and James E. Till, developed the spleen colony method in the 1960s based on their observations of the effects of ionizing radiation. They called the nodules that appeared on mouse spleens “colony-forming units,” or “CFUs.” The spleen colony method defined by Till and McCulloch is regarded as a revolution in hematology. In bone-marrow transplantation studies carried out with chromosomelabeled stem cells, the presence of the same chromosomal markers in cells of the thymus and lymph nodes as in spleen colonies indicated that hematopoietic and immune system cells originate from a common stem cell. McCulloch and Till’s collaboration led to entirely new understandings of the biology of blood cell production. In our understanding of diseases of blood cells in recent decades, basic knowledge in molecular and cell biology has been translated into improved diagnostic and therapeutic methods. The pioneering efforts of Till and McCulloch created a completely new paradigm in stem cell biology, genomics, immunotherapy, cellular therapies, and precision medicine approaches to tailor treatments for hematological disorders.