Abstract: Background: Over the past century, numerous pharmacological regimens have been developed for multiple myeloma (MM), yet relapse remains inevitable. Although these regimens prolong overall survival (OS), repetitive treatment cycles and cumulative toxicity progressively impair quality of life (QoL). This study aimed to compare conventional stepwise therapies with CAR-T cell therapy in terms of QoL, toxicity, cost, and ethical value.Methods: Kaplan-Meier survival curves were analyzed to estimate overall (OS) and progression-free survival (PFS). Based on these durations, treatment costs were calculated. A simple and transparent utility-based model was developed to enable clinicians, researchers, and health policy authorities to easily estimate quality-adjusted life years (QALY) and incremental cost-effectiveness ratios (ICER).Results: Among heavily pretreated patients, CAR-T therapy approximately doubled OS and PFS compared with other late-line regimens and provided markedly better quality of life with lower overall treatment burden. While daratumumab-based combinations improved survival and patient well-being, they were associated with very high treatment costs (~USD 1 million per patient). Carfilzomib-based regimens remained essential for managing high-risk disease despite their expense. In contrast, VMP represented a practical and accessible option, especially for transplant-ineligible or resource-limited patients.Conclusion: CAR-T therapy provided significant improvements in survival and quality of life compared with conventional regimens among patients who had received three or more prior lines of therapy. Its earlier use appears promising. However, the limited availability of CAR-T across only a few countries raises ethical concerns regarding treatment accessibility. Contrary to common assumptions, CAR-T can be less expensive than many traditional therapies, though its single-payment structure poses barriers for patients with limited financial means. Further analyses are needed to refine toxicity management and optimize its broader clinical application in multiple myeloma.

Abstract: Background: Despite advances in frontline therapy, most patients with relapsed or refractory multiple myeloma (RRMM) eventually progress, and optimal sequencing of monoclonal antibody–based regimens remains uncertain. Daratumumab and elotuzumab, each combined with lenalidomide and dexamethasone (SOC), have demonstrated overall survival (OS) benefits in randomized controlled trials. However, no head-to-head comparison exists. This study indirectly compared these regimens using reconstructed individual patient data (IPD) derived from published Kaplan–Meier curves. Materials and Methods: A literature search identified randomized trials evaluating daratumumab-SOC or elotuzumab-SOC versus SOC alone. Digitized OS curves from POLLUX and ELOQUENT-2 were processed using the IPDfromKM artificial-intelligence algorithm to reconstruct patient-level datasets. After assessing heterogeneity between SOC arms, pooled control data were used to conduct indirect comparisons. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression. Results: Reconstructed HRs closely matched published trial estimates for daratumumab (0.787 vs 0.73) and elotuzumab (0.845 vs 0.82). SOC arms differed significantly between trials, with POLLUX controls demonstrating better outcomes than ELOQUENT-2 controls. In the indirect comparison using pooled SOC outcomes from the two trials, daratumumab-SOC significantly improved OS versus SOC alone (HR 0.64; 95% CI 0.52–0.78), while elotuzumab-SOC did not (HR 1.08; 95% CI 0.91–1.29). The head-to-head indirect comparison favored daratumumab over elotuzumab (HR 0.59; 95% CI 0.45–0.77). Conclusions: AI-assisted reconstruction of IPD enabled an indirect comparison of daratumumab- and elotuzumab-based triple regimens in RRMM. Results suggest superior OS for daratumumab-SOC compared with elotuzumab-SOC, supporting daratumumab as the preferred monoclonal antibody partner to lenalidomide-dexamethasone when selecting third-agent therapy for RRMM.

Abstract: Background/Objectives: Mechanisms underlying treatment resistance in hematopoietic malignancies such as acute lymphoblastic leukemia (ALL) include: 1) enhanced activity of anticancer drug efflux mechanisms (MRP1); 2) suppressed activity of anticancer drug influx mechanisms (ENT-1); 3) enhanced drug detoxification activity (AKR1B10, AKR1C3, CYP3A4); 4) influence of the tumor microenvironment (GRP94) etc. We conducted this study to comprehensively and clinically examine treatment resistance due primarily to a decrease in the tumor intracellular anticancer drug concentrations. Methods: The subjects were 19 ALL patients who underwent initial induction therapy with alternating Hyper CVAD/MA therapy. Antibodies against 23 types of treatment resistance-associated proteins were used for immunohistochemical analysis of tumor specimens obtained from the patients, and correlations between the results of immunohistochemistry and the overall survival (OS) were retrospectively analyzed using the Kaplan-Meier method. Results: Based on the patterns of expression of the enzymes involved in treatment resistance, we classified the patients (Urayasu classification for ALL, which we believe would be very useful for accurately stratifying patients with ALL according to the predicted prognosis), as follows: Good prognosis group; n =1, 5%: AKR1B1(+)/AKR1B10(-), 5-year overall survival (OS), 100%; Intermediate prognosis -1 group; n= 9, 5%: AKR1B1(-)/AKR1B10(-) plus MRP1(-), 5-year OS, 68%; Intermediate-2 prognosis group; n = 6.3%: AKR1B1(-)/AKR1B10(-) plus MRP1(+), median survival, 17 months, 5-year OS, 20%; Poor prognosis group; n = 3, 16%: AKR1B1(-)/AKR1B10(+), median survival, 18 months, 5-year OS, 0%. n=2. Conclusions: The Urayasu classification for ALL is considered as being reliable for predicting the prognosis of patients with ALL after the initial Hyper CVAD/MA remission induction therapy.

Abstract:

Objectives: Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults, and consolidation with autologous hematopoietic stem cell transplantation (HSCT) in AML patients represents an alternative therapeutic option in the absence of related or unrelated donors, in the elderly or in patients with good or standard risk. In this retrospective analysis, the data were evaluated from a total of 47 AML patients who underwent autologous hematopoietic stem cell transplantation between November 2012 and March 2023 at the Bone Marrow Transplantation Unit of Medicalpark Izmir Hospital. The present study also investigates the factors affecting overall survival (OS) and progression-free survival (PFS). Methods: This study is a retrospective evaluation of the data obtained from 47 patients with AML who underwent an autologous HSCT. Results: 24 patients were female, and 23 patients were male. The median age at diagnosis was 39 years (range: 18-68 y). The mean OS from diagnosis to the last follow-up or death was 26 months (4-116 months), and the PFS was 20 months (3-69 months). An assessment of the factors that influenced OS and PFS showed no significant association of NPM positivity, gender, risk group, response to first-line chemotherapy, transplantation at CR (Complete remission) 1 or CR2, LDH (lactade dehidrogenase) , CD34 count, and the day of neutrophil engraftment with OS or PFS. In patients with FLT3(fms benzeri tirozin kinaz 3) positivity, OS was significantly shorter (p < 0.05), while PFS was not significantly different (p=0.21). Conclusions: Consolidation with auto-HSCT in AML patients can be preferred in subjects with good or intermediate 1 risk category according to ELN (European leukemia net )criteria, or in subjects with intermediate 2 or poor-risk category who have no related or unrelated donor.

Abstract: ABSTRACT Aim. We aimed to compare patients receiving cyclophosphamide treatment post-transplant with those receiving standard graft versus host disease (GVHD) prophylaxis in terms of GVHD development, disease relapse, overall survival, transplant-related mortality and infection development. Methods: The data of 78 patients who underwent allogeneic stem cell transplantation (AHSCT)at Medicana Izmir Hospital between January 2022 and June 2024 were retrospectively evaluated. Results: Of the patients, 36 (46.2%) were female, and 42 (53.8%) were male. Myeloablative related AHSCT was performed on 38 patients (48.7%), myeloablative unrelated on 26 patients (33.3%), and haploidentical on 14 patients (17.9%). Acute GVHD developed in 42 patients (53.8%),Regarding the clinical and laboratory variables affecting acute GVHD, only ferritin (p=0.016) was found to be significantly lower in the group with acute GVHD, and acute GVHD was significantly less observed in the group that received post-transplant cyclophosphamide (p. 0.032).In 15 patients (19.2%), chronic GVHD developed following acute GVHD. It was found that chronic GVHD developed more frequently in those who did not receive post-transplant cyclophosphamide (p=0.0001), in sibling transplants (p=0.037), in those without febrile neutropenia (p=0.021), and in those with high CMV-DNA levels (p=0.040). The median OS (months) was determined as 79.16 months. Median OS (months) was higher in patients with good AML cytogenetic risk group (p< 0.001) and in patients who underwent transplantation in first remission (p=0.021) has been found. In conclusion; Cyclophosphamide administration after allogeneic bone marrow transplantation can significantly reduce the development of acute and chronic GVHD.

Abstract:

Background/Objectives: Chronic lymphocytic leukemia (CLL) is characterized by genetic and epigenetic alterations. This study aimed to assess the methylation status of E-Cadherin and MMP-9 gene promoters and to explore their relationships with disease pathogenesis and hematological parameters in CLL patients. Methods: A case–control study was conducted including 70 newly diagnosed CLL patients and 70 age- and sex-matched healthy controls. Promoter methylation of E-Cadherin and MMP-9 genes was evaluated using methylation-specific PCR (MSP) and methylation-sensitive restriction enzyme PCR (MSRE-PCR), respectively. Results: The median patient age was 62 years, and 68.5 % were males. Binet stage A was the most common (57.3 %). E-Cadherin promoter methylation was detected in 75.7 % of CLL patients and 77.1 % of controls (p = 0.91), showing no significant association with disease occurrence, however, it showed a significant correlation with higher lymphocyte counts (p = 0.01). In contrast, MMP-9 promoter methylation was significantly less frequent in CLL cases (70.0 %) than in controls (100 %, p = 0.001). Unmethylated MMP-9 correlated significantly with female gender (p = 0.02), lower hemoglobin (p = 0.031), and reduced platelet counts (p = 0.001) and higher lymphocytes counts (p = 0.035). Conclusion: MMP-9 promoter hypomethylation may play a pathogenic role in CLL and is associated with female gender and cytopenia, whereas E-Cadherin methylation appears non-specific. MMP-9 methylation status could therefore serve as a potential biomarker for CLL biology and prognosis.

Abstract: Objective: This study aimed to analyze the demographic characteristics, clinical preliminary diagnoses, biopsy indications, and histopathological findings of adult bone marrow biopsies to construct a framework that aids clinicians and pathologists in evaluating bone marrow biopsy results. Materials and Methods: Bone marrow biopsy reports from 900 cases referred to the Department of Internal Diseases Hematology at Afyonkarahisar Health Sciences University from January 1, 2017, to December 31, 2021, were retrospectively analyzed. Patients with insufficient material (18) and those sent for treatment response evaluation (184) were excluded, resulting in 698 patients being included in the study. Data analysis was performed using SPSS v26, employing the McNemar test to assess clinicopathological concordance, with a significance level set at p< 0.05. Results: Of the 698 patients analyzed, 388 (55.6%) were male and 310 (44.4%) were female, with ages ranging from 18 to 87 years. The most common indications for biopsy were lymphoma (16.09%), pancytopenia (16.05%), and anemia with a high sedimentation rate (14.06%). The most frequently noted preliminary diagnosis was myeloma (22.02%), followed by lymphoma (16.09%) and acute leukemia (10.03%). Significant clinicopathological concordance was observed in diagnoses such as aplastic anemia and lymphoplasmacytic lymphoma, whereas discordance was noted in conditions such as follicular lymphoma and acute myeloid leukemia (AML), reflecting the complexity and challenge of accurate diagnosis in hematologic conditions. Conclusion: This study documented a high incidence of lymphoma and myeloma as preliminary diagnoses, with myeloma confirmed in 52% of cases with an initial suspicion based on clinical presentation. Notable discrepancies between clinical suspicion and histopathological findings were evident in conditions such as follicular lymphoma and acute myeloid leukemia (AML), with a significant discordance rate. These findings highlight the need for enhanced diagnostic precision and the development of sophisticated diagnostic algorithms to improve the predictive accuracy of preliminary clinical diagnoses. Ultimately, this study calls for a refined approach to the clinical and pathological evaluation of bone marrow biopsies to better support therapeutic decision making and patient management.

Abstract: Sex-based variations are significant among the major subtypes of leukemia. This review briefly discusses the current understanding and knowledge gaps related to sex differences in epidemiology; mortality and survival rates; risk factors, and epigenetic, metabolomic, and sex-specific patterns. Males have higher incidence rates and mortality rates of leuke-mia than females do, highlighting the significance of biological and epidemiologic factors. Sex-based differences were reported in only 0.5% of the clinical trials, an underreporting may be resulting from a persistent lack of awareness or prioritization of integrating sex as a significant variable in research findings. Interesting sex-based patterns arise that sub-stantially impact disease epidemiology. An intriguing medical enigma in leukemia is treatment response, where women have higher overall survival rates but more severe treatment-related toxicity. However, ALL in pediatric patients contradicts this enigma, suggesting that gender differences may be less pronounced during childhood when hor-monal levels are low. Sex-based risk factors are discussed at both the environmental and genetic levels where epigenetic variations, such as DNA methylation, affect gene expres-sion differently in males versus females. Hematological and biochemical patterns are shown from a sex-based perspective in this review. Furthermore, there are clear signs of sex-based differences in the recognition of various metabolites in males and females, which could support the foundation for future research. We encourage researchers not only to perform sex-stratified analyses in their ongoing studies but also to design sex-based clinical trials.

Abstract: Immunothrombosis can affect substantially the course and outcomes of severe infections and immune-mediated diseases. While inflammatory thrombi are neutrophil-rich, impact of neutrophils on clot contraction, a key modulator of thrombus stability and obstructiveness, was unknown. This study investigated how neutrophils and neutrophil extracellular traps (NETs) affect the rate and extent of platelet-driven clot contraction. Isolated human neutrophils were activated with phorbol-12-myristate-13-acetate (PMA) to induce NETosis, confirmed by fluorescence microscopy and scanning electron microscopy. Thrombin-induced clots, formed from whole blood or platelet-rich plasma, were supplemented with non-activated or PMA-activated neutrophils. Clot contraction kinetics and viscoelasticity were analyzed. PMA-activated neutrophils significantly enhanced the rate and final extent of clot contraction compared to controls. This promoting effect was abolished by DNAse I, confirming that it was mediated by NETs embedded in the fibrin network. The factor Xa inhibitor rivaroxaban also abrogated this effect, indicating a role for NET-induced endogenous thrombin generation and platelet hyperactivation. Thromboelastography revealed that NETs made clots softer and more deformable. We conclude that activated neutrophils promote clot contraction via NETs embedded into the fibrin network, which enhance platelet contractility via endogenous thrombin production and increase clot deformability, suggesting that inflammatory thrombosis may require treatments addressing this enhanced contractility.

Abstract: Gastric cancer has historically relied on cytotoxic chemotherapy, yet its considerable mo lecular heterogeneity has limited therapeutic efficacy. The development of anti-body-mediated therapies has marked a new era in precision oncology, enabling selective targeting of biomarkers such as HER2, VEGFR2, PD-1/PD-L1, and CLDN18.2. This review summarizes the evolution of antibody-based strategies in gastric cancer, beginning with trastuzumab, the first HER2-targeted treatment, followed by the decade-long stagnation after the failure of T-DM1, and the recent establishment of trastuzumab deruxtecan (T-DXd) as a new standard of care. We further examine advances in anti-angiogenic therapy with ramucirumab, the incorporation of immune checkpoint inhibitors such as nivolumab and pembrolizumab into first-line regimens, and the clinical validation of CLDN18.2, culmi-nating in the approval of zolbetuximab. Emerging modalities—including next-generation antibody–drug conjugates (ADCs), bispecific antibodies, TROP2-directed agents, and CLDN18.2-targeted CAR-T cells—are also discussed. Finally, key challenges such as treatment resistance, real-time biomarker monitoring, and optimal sequencing in mul-ti-biomarker–positive patients are explored. Collectively, antibody-mediated therapy con-tinues to shift gastric cancer management toward increasingly personalized and durable treatment strategies.

Abstract: Background/Objectives: Sickle cells disease (SCD) and -thalassemia are autosomal recessive disorders of erythroid cells due to gene mutations occurring at the level of the -globin gene. The severe forms of these hemoglobinopathies observed in individuals homozygous for these defective genes need intensive treatments, are associated with a poor quality of life and allogeneic hematopoietic stem cell represents the only curative treatment option that can be offered only to a limited proportion of patients. Methods: This work is a narrative review supported by a systematic literature search and analysis. Results: To bypass this limitation, autologous hematopoietic stem cell transplantation has been developed in these patients in which patients’ HSCs are harvested and genetically modified ex vivo, then transplanted back into patients after conditioning for stem cell transplantation. There are two different approaches for gene therapy of hemoglobinopathies’, one based on gene addition or gene silencing using lentiviruses as vectors and the other based on gene editing strategies using CRISPR-Caspase 9 technology or base editing. Several gene therapy products have been successfully evaluated in these patients achieving transfusion independence and correction of hematological abnormalities durable in the time. Conclusions Several gene therapy products have been approved for the treatment of SCD and -thalassemic patients and offer a potentially curative treatment for these patients.

Abstract: Diffuse large B-cell lymphoma (DLBCL) is the most common and clinically aggressive subtype of non-Hodgkin lymphoma (NHL). Although novel therapeutic agents, in-cluding rituximab and polatuzumab vedotin, have improved outcomes, almost one-third of patients ultimately develop relapsed or refractory disease. MicroRNAs (miRNAs), a class of endogenous single-stranded RNAs approximately 22 nucleotides in length, play a pivotal role in the regulation of gene expression at the post-transcriptional level through interactions with complementary target RNAs and contribute significantly to the de-velopment, progression, and treatment response of DLBCL. Oncogenic miRNAs, such as miR-155, miR-21, and the miR-17–92 cluster, promote proliferation, survival, immune evasion, and therapy resistance by modulating pathways including PI3K/AKT, NF-κB, and MYC. Conversely, tumor-suppressive miRNAs such as miR-34a, miR-144, miR-181a, and miR-124-3p inhibit oncogene activity and enhance apoptosis, with their loss often associated with adverse outcomes. Among these, miR-155 and miR-21 are particularly well studied, playing central roles in both tumor progression and remodeling of the tumor microenvironment. This review summarizes current evidence on the biological and clinical relevance of miRNAs in DLBCL, emphasizing their diagnostic and prognostic potential.

Abstract:

Background: Autologous stem cell transplantation (ASCT) remains a cornerstone in the management of multiple myeloma (MM). However, the optimal timing of ASCT and the factors determining whether patients ultimately undergo transplantation remain unclear in real-world practice. The Revised Myeloma Comorbidity Index (R-MCI) was developed to quantify patient fitness but its influence on transplant eligibility and timing has not been fully characterized. Methods: We conducted a retrospective single-center study including 137 patients with newly diagnosed MM between 2015 and 2025. Clinical parameters recorded at diagnosis included age, sex, performance status, renal and pulmonary function, cytogenetic risk, International Staging System (ISS) stage, and bone marrow plasma cell infiltration. The R-MCI was calculated for all patients [1]. Transplant timing was categorized as early (≤12 months) or delayed (>12 months) after diagnosis. Logistic regression analyses were performed to identify predictors of ASCT eligibility and timing. Results: ASCT was performed in 61 patients (44.5%). Transplanted patients were significantly younger (<65 years: 82.0% vs. 25.0%, p<0.001) and had lower R-MCI scores (median 0 vs. 1, p<0.001) compared with nontransplanted patients, while plasma cell infiltration and ISS stage did not differ. Among transplanted patients, 42.6% underwent early ASCT. In multivariate analysis, R-MCI was the only variable showing a trend toward predicting early transplantation (OR 0.27, 95% CI 0.07–1.06, p=0.06). Conclusions: In real-world MM management, patients quantified by R-MCI appear to play a more prominent role than disease burden in determining both eligibility for and timing of ASCT. Incorporating comorbidity indices alongside ISS may enhance individualized transplant decisionmaking and optimize treatment outcomes.

Abstract:

Acute chest syndrome (ACS) is a life-threatening complication of sickle cell disease (SCD) with complex infectious and non-infectious etiologies. Bacterial pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, and atypical organisms such as Mycoplasma pneumoniae, play crucial roles in ACS pathogenesis, particularly in immunocompromised SCD patients with functional asplenia. Despite the importance of infectious triggers, regional data on pathogen identification rates and antimicrobial management strategies in ACS remain limited, especially from high-prevalence SCD regions. This study aimed to investigate the infectious etiologies, pathogen identification patterns, and antimicrobial management outcomes of ACS in adult SCD patients in Eastern Saudi Arabia. A five-year retrospective analysis was conducted on adult patients (≥14 years old) with SCD who were admitted with ACS to Dammam Medical Complex between 2018 and 2022. Comprehensive microbiological evaluation included blood cultures, sputum cultures, and atypical pathogen testing (Mycoplasma pneumoniae, Chlamydia pneumoniae). Data on antimicrobial regimens, pathogen identification rates, vaccination status against encapsulated bacteria, and clinical outcomes were systematically analyzed. Empirical antibiotic strategies and their effectiveness in this immunocompromised population were evaluated. A total of 60 adult SCD patients experiencing 80 episodes of ACS were included. Despite comprehensive microbiological workup, specific infectious pathogens were identified in only 8 (10.0%) episodes, highlighting the complex multifactorial etiology of ACS. Blood cultures yielded pathogens in 5 (6.3%) cases, sputum cultures in 4 (5.0%) cases, and Mycoplasma pneumoniae was identified in 3 (3.8%) episodes. All patients received empirical broad-spectrum antimicrobial therapy, with ceftriaxone and azithromycin combination being the most frequent regimen 76 (95.0%), providing coverage for both typical and atypical bacterial pathogens. Antibiotic escalation was required in 16 (20.0%) episodes. Vaccination rates against Streptococcus pneumoniae were suboptimal at 30 (50.0%), representing a significant risk factor for invasive bacterial infections in this functionally asplenic population. The intensive care unit (ICU) admission rate was 15 (18.8%), and in-hospital mortality was 3 (3.8%), with infectious complications contributing to severe outcomes. In this cohort of adult SCD patients, ACS demonstrated low rates of specific pathogen identification despite systematic microbiological investigation, supporting the multifactorial infectious and non-infectious etiology of this syndrome. The predominant use of broad-spectrum antimicrobial therapy targeting both typical and atypical bacterial pathogens proved effective in this immunocompromised population. However, suboptimal vaccination rates against encapsulated bacteria represent a critical gap in infection prevention strategies. These findings emphasize the importance of empirical antimicrobial coverage for suspected bacterial pathogens in ACS management and highlight the urgent need for enhanced vaccination programs to prevent infectious complications in functionally asplenic SCD patients.

Abstract: Background: Mediastinal gray zone lymphoma (MGZL) is a rare B-cell lymphoma which shares clinicopathologic and molecular features between primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (CHL). Although included as provisional disease entity back in 2008 WHO classification after initial description in 1998, the concept of MGZL has since evolved, with latest WHO-HEMA5 and ICC limiting the entity to EBV-negative mediastinal lesion. Methods: This review summarizes the historical evolution, epidemiology, clinicopathologic characteristics, immunophenotypic and genetic features, diagnostic challenges, and therapeutic strategies for MGZL. Data from retrospective series, prospective cohorts, and recent molecular studies are synthesized to provide a comprehensive perspective. Results: MGZL generally affects young adults, especially males, and presents with bulky mediastinal disease. Transitional morphology, pleomorphic Reed–Sternberg–like cells, and variable B-cell and activation markers make its diagnosis challenging. Molecular studies have shown that they share changes with PMBL and CHL such as 9p24. 1 (JAK2/PD-L1/PD-L2); however, specific alterations, including HOXA5 hypomethylation and MYC gains, argue for its designation as a separate entity. Therapeutically, DA-EPOCH-R is one of the most effective regimens, but prognosis is still worse than PMBL or CHL, 5-year OS ~40–60%. Salvage chemotherapy and autologous transplantation are frequently necessary for relapsed/refractory disease. Novel therapies, especially brentuximab vedotin and PD-1 inhibitors, appear to be effective, especially in combination. Conclusion: MGZL continues to be a diagnostically challenging, and therapeutically complex lymphoma with an inferior prognosis compared to related entities. Advancements in molecular profiling and immunotherapy suggest the promise of personalized therapy. Yet, prospective clinical trials and international cooperation are urgently needed to develop guidelines for therapy of this rare lymphoma.

Abstract: Mesenchymal stem/stromal cells (MSCs) exhibit broad differentiation capability and strong immunoregulatory potential mediated through intercellular communication and the release of diverse paracrine mediators. These features render MSCs a promising therapeutic option for managing complications associated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). This review provides an updated synthesis of MSC biology, their bidirectional interaction with immune cells, and their functional contribution to the hematopoietic niche. It also evaluates current clinical evidence regarding the therapeutic roles of MSCs and MSC-derived extracellular vesicles (EVs) in acute and chronic graft-versus-host disease (aGVHD/cGVHD) as well as in poor graft function. Mechanistic insights encompass macrophage polarization toward an anti-inflammatory phenotype, inhibition of dendritic cell maturation, enhancement of regulatory T-cell expansion, and modulation of cytokine signaling pathways. Within the bone marrow milieu, MSCs contribute to stromal restoration and angiogenic repair. Data from phase II/III clinical trials and real-world cohorts in steroid-refractory aGVHD consistently confirm the safety of MSC therapy, although response rates vary—typically higher in pediatric patients and when administered early—while survival outcomes remain inconsistent. For poor graft function, limited prospective studies indicate hematopoietic recovery following third-party MSC infusions, and combination approaches such as co-administration with thrombopoietin receptor agonists are under investigation. MSC-derived EVs emulate many immunomodulatory effects of their parental cells with a potentially safer profile, though clinical validation remains in its infancy. MSC-oriented interventions hold substantial biological and therapeutic promise, offering a favorable safety margin; however, clinical translation is hindered by product variability, suboptimal engraftment and persistence, and inconsistent efficacy across studies. Future directions should emphasize standardized manufacturing and potency assays, biomarker-driven patient and timing selection, optimized conditioning and dosing strategies, and the systematic appraisal of EV-based or genetically modified MSC products through controlled trials.

Abstract: Indolent lymphoproliferative diseases or disorders (LPD) derived from T cells or Natural Killer (NK) cells may be neoplastic or non-neoplastic, which are often difficult to distinguish from each other and from the aggressive counterparts. The etiology and pathogenesis are mostly nebulous and may be related to infections or immune dysfunction. Indolent lymphomas differ from the high-grade aggressive counterparts by a prolonged clinical course of persistent or relapsing disease, histology, immunophenotype and genetics. In the recent decades, indolent lymphomas or LPD of T or NK cell derivation have been increasingly recognized, causing diagnostic and nosologic confusion. The issue is particularly challenging in the arena of indolent intestinal lymphomas and LPD, as evidenced by the myriad of names given to the indolent intestinal T- and NK-cell lymphomas and LPD. Confounding the picture are also reports of Epstein-Barr virus (EBV)-positivity in various indolent non-intestinal LPD and rarely even in indolent intestinal T-cell lymphoma, which have been widely accepted to be typically EBV-negative. This review aims to curate current information and understanding of these diseases with the goal to resolve these issues. The recently described indolent T-lymphoblastic proliferation (iTLBP) and the re-classified indolent primary cutaneous CD4-positive small or medium T-cell LPD and primary cutaneous acral CD8-positive T-cell LPD also require greater awareness and recognition. It is important to diagnose these indolent entities in order to avoid over-treatment and unnecessary therapeutic intervention, and to provide for accurate prognostic prediction and appropriate follow up.

Abstract: We describe a patient with post-essential thrombocythemia myelofibrosis treated with intermittent hydroxyurea (Hu) therapy (20mg/Kg, given as a single dose, thrice weekly), achieving sustained disease control and regression of bone marrow fibrosis; and, discuss the efficacy of and rationale for use of intermittent Hu therapy in patients with myeloproliferative neoplasms, including those deemed to be Hu-resistant or intolerant on the commonly used continuous therapy.

Abstract: Leukemia encompasses heterogeneous hematologic malignancies characterized by dysregulated hematopoiesis, metabolic reprogramming, and therapy resistance, with relapse driven by persistent leukemic stem cells (LSCs). This comprehensive review delineates the pivotal role of the taurine–TauT (SLC6A6) axis as a metabolic vulnerability across acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL). Taurine, a sulfur-containing β-amino acid, modulates redox homeostasis via taurine chloramine (TauCl) formation, stabilizes mitochondrial tRNA uridine modifications for oxidative phosphorylation (OXPHOS), and regulates calcium fluxes and apoptosis. SLC6A6-mediated taurine uptake is upregulated in leukemic blasts and LSCs, correlating with adverse cytogenetics (e.g., FLT3-ITD, TP53 mutations), chemoresistance to cytarabine, doxorubicin, methotrexate, vincristine, tyrosine kinase inhibitors (TKIs), and BCL2 inhibitors (venetoclax), and minimal residual disease persistence in hypoxic bone marrow niches. Transcriptomic analyses from TCGA, BeatAML, and TARGET cohorts substantiate SLC6A6 as a prognostic biomarker. Therapeutic strategies, including selective SLC6A6 inhibition and chemosensitization, exploit this dependency to amplify ROS-induced apoptosis and eradicate LSCs, potentially enhancing remission durability. Future directions emphasize structure-guided inhibitor development and integrative metabolomic profiling for precision oncology.

Abstract:

Background/Objectives: Mechanisms underlying treatment resistance in hematopoietic malignancies such as acute lymphoblastic leukemia (ALL) include: 1) enhanced activity of anticancer drug efflux mechanisms (MRP1); 2) suppressed activity of anticancer drug influx mechanisms (ENT-1); 3) enhanced drug detoxification activity (AKR1B10, AKR1C3, CYP3A4); 4) influence of the tumor microenvironment (GRP94) etc. We conducted this study to comprehensively and clinically examine treatment resistance due primarily to a decrease in the tumor intracellular anticancer drug concentrations. Methods: (1) Case report: The subjects were 19 ALL patients who underwent initial induction therapy with alternating Hyper CVAD/MA therapy. Antibodies against 23 types of treatment resistance-associated proteins were used for immunohistochemical analysis of tumor specimens obtained from the patients, and correlations between the results of immunohistochemistry and the overall survival (OS) were retrospectively analyzed using the Kaplan-Meier method. (2) A Review of the Literature in the mechanisms underlying treatment resistance in hematopoietic malignancies. Results: (1) Case report: Based on the patterns of expression of the enzymes involved in treatment resistance, we classified the patients (Urayasu classification for ALL, which we believe would be very useful for accurately stratifying patients with ALL according to the predicted prognosis), as follows: Good prognosis group; n =1, 5%: AKR1B1(+)/AKR1B10(-), 5-year overall survival (OS), 100%; Intermediate prognosis -1 group; n= 9, 5%: AKR1B1(-)/AKR1B10(-) plus MRP1(-), 5-year OS, 68%; Intermediate-2 prognosis group; n = 6.3%: AKR1B1(-)/AKR1B10(-) plus MRP1(+), median survival, 17 months, 5-year OS, 20%; Poor prognosis group; n = 3, 16%: AKR1B1(-)/AKR1B10(+), median survival, 18 months, 5-year OS, 0%. n=2. (2) Review of Literature: A total of 27 types (32 subtypes) of anti-hematologic malignancy drugs were classified into nine categories based on the combined effects on the drugs of the four major drug-metabolic pathways present within the hematologic malignant cells. Conclusions: (1) Case report: The Urayasu classification for ALL is considered as being reliable for predicting the prognosis of patients with ALL after the initial Hyper CVAD/MA remission induction therapy. (2) Review of Literature: A total of 27 anti-hematologic malignancy agents were classified into nine categories based on the combined effects on the drugs of the four major intracellular metabolic pathways found within the hematologic malignant cells.