INTRODUCTION: Heparin-induced thrombocytopenia (HIT) is associated with a high risk for thrombosis. The role of direct oral anticoagulants (DOACs) is still emerging and data are limited considering efficacy and safety am...INTRODUCTION: Heparin-induced thrombocytopenia (HIT) is associated with a high risk for thrombosis. The role of direct oral anticoagulants (DOACs) is still emerging and data are limited considering efficacy and safety among patients with HIT. The aim of this review is to evaluate current data on DOACs as primary or secondary treatment among patients with HIT. METHODS: This is a systematic review utilising Pubmed, Scopus and Embase online databases. Eligible studies were published up to December 2024 evaluating DOACs as primary or secondary treatment among patients with HIT and/or associated thrombosis (HITT). Primary outcomes included thrombosis rate (TR) and bleeding rate (BR) during follow-up. RESULTS: A total of 44 publications were included (29 case reports, 5 case studies and 10 cohort studies [n > 10 patients]). Regarding treatment, 19 articles evaluated only rivaroxaban, 7 articles only apixaban, 11 articles only dabigatran and 7 articles more than one regimen. A total of 352 patients were included. Overall, 190 patients (53.8%) were given DOAC as primary treatment whereas 162 patients were given a parenteral treatment first and continued with a DOAC. Mean nadir platelet count at diagnosis was 63 000/μL. HITT rate was 190/352 (53.9%; 8% had arterial thrombosis). Mean follow-up was 7.6 months. TR was 20/352 (Pooled proportion = 0.064 [95% CI = 0.042-0.092]) (30% of them were new thromboses without initial thrombosis), and BR was 9/352 (Pooled proportion = 0.039 [95% CI = 0.022-0.062]). Finally, there was no difference found regarding TR and BR between primary or secondary treatment, and among different regimens. CONCLUSIONS: DOACs are associated with low rates of thrombosis and major bleeding among patients treated for HIT or HITT, either as primary or secondary treatment. However, the certainty of evidence is very low because of the quality and limitations of the available studies.
Sickle cell disease (SCD) is characterized by both acute and chronic complications. The clinical manifestation of these complications differs between genotypes. Given the large amount of research already published, this...Sickle cell disease (SCD) is characterized by both acute and chronic complications. The clinical manifestation of these complications differs between genotypes. Given the large amount of research already published, this systematic review aims to offer a complete overview of types of sickle cell complications between adults in the most common genotypes Hemoglobin SS (HbSS) and Hemoglobin SC (HbSC), putting options for further research into perspective. An extensive literature search was performed to study all available evidence on these complications. This review was performed according to the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses" (PRISMA) statement guidelines, and was performed on January 2, 2024. A total of 710 references were identified. After careful screening, 521 records were excluded based on title and abstract and other exclusion criteria. In total, 158 articles were excluded after full-text assessment. Our analysis of 31 studies highlights key differences in complications between HbSS and HbSC genotypes in sickle cell disease (SCD). Vaso-occlusive crises (VOCs) remain the most common acute complication in both genotypes. HbSS patients experience more frequent VOCs, while HbSC patients generally have a milder clinical course when it comes to acute complications. Chronic complications, particularly in the ocular and pulmonary systems, are more prevalent in HbSC patients. However, as acute complications are more common in HbSS and chronic complications more common in HbSC, both genotypes face progressive organ damage due to recurrent ischemic injury and inflammation.
OBJECTIVES: This cross-sectional study evaluated the 12-lead electrocardiogram (ECG) corrected QT (QTc) interval as an accessible marker for organ-specific iron burden in adult patients with transfusion-dependent thalass...OBJECTIVES: This cross-sectional study evaluated the 12-lead electrocardiogram (ECG) corrected QT (QTc) interval as an accessible marker for organ-specific iron burden in adult patients with transfusion-dependent thalassemia (TDT). METHODS: We considered 273 adult TDT patients (37.48 ± 8.75 years; 53.8% females), enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network. All patients underwent magnetic resonance imaging (MRI) for the quantification of hepatic, pancreatic, and myocardial iron ( technique) and the assessment of biventricular size and function, alongside a standard ECG within 3 months. RESULTS: QTc interval showed a significant negative correlation with pancreatic (R = 0.220; p < 0.0001) and cardiac (R = -0.201; p = 0.001). A QTc > 425 ms predicted myocardial iron overload (MIO; < 20 ms). A significant stepwise prolongation of the QTc interval was observed across groups: no iron overload (405.45 ms), isolated pancreatic siderosis (421.76 ms), and combined pancreatic/myocardial siderosis (433.01 ms) (p = 0.001). In patients without MIO, a QTc > 416 ms predicted pancreatic siderosis ( < 26 ms) and a multivariable regression analysis confirmed pancreatic iron, female sex, and splenectomy as independent predictors of QTc duration. CONCLUSIONS: The QTc interval may serve as an early "metabolic sensor" of multi-organ iron toxicity. A QTc > 416 ms is associated with pancreatic siderosis and possible cardiac risk before MRI detects cardiac iron. While QTc alone is unlikely to be sufficient for individual patient risk stratification, this inexpensive and widely available parameter may help inform decisions regarding advanced imaging.
OBJECTIVE: To evaluate the overall second primary malignancy (SPM) burden in patients with B-cell lymphomas treated with Bruton's tyrosine kinase (BTK) inhibitors and compare SPM risk versus non-BTK inhibitor or placebo...OBJECTIVE: To evaluate the overall second primary malignancy (SPM) burden in patients with B-cell lymphomas treated with Bruton's tyrosine kinase (BTK) inhibitors and compare SPM risk versus non-BTK inhibitor or placebo controls. METHODS: We searched major databases from inception to September 30, 2025. The primary outcome was SPM incidence. Consistent treatment backgrounds were defined as comparable baseline clinical and treatment characteristics, with BTK inhibitor exposure as the main between-arm difference. RESULTS: Fifty-two studies involving 9337 patients were included, mainly CLL/SLL; MCL was the largest non-CLL/SLL subtype. Pooled SPM incidence was 8% (95% CI: 6%-11%) with a median follow-up of 31.5 months. Multivariable meta-regression identified follow-up duration as the only independent predictor, whereas disease subtype, inhibitor generation, prior therapy lines, study design, and age were not significant. Furthermore, SPM patterns were comparable between CLL/SLL and non-CLL/SLL cohorts. Compared with controls, BTK inhibitors did not significantly increase SPM risk (RR = 1.30, 95% CI: 0.95-1.78), a finding confirmed in analyses with consistent treatment backgrounds (RR = 1.03, 95% CI: 0.85-1.25). CONCLUSIONS: SPMs occur across disease backgrounds and are mainly influenced by follow-up duration. Current evidence does not establish a direct carcinogenic effect of BTK inhibitors.
OBJECTIVES: Neurocognitive changes in hematological malignancies (HM) and as a sequela of hematopoietic stem cell transplantation (HSCT) remain under-recognized. These changes may substantially affect patients' quality o...OBJECTIVES: Neurocognitive changes in hematological malignancies (HM) and as a sequela of hematopoietic stem cell transplantation (HSCT) remain under-recognized. These changes may substantially affect patients' quality of life. Therefore, this review systematically evaluated longitudinal neurocognitive changes in patients with HM undergoing HSCT. METHODS: Following PRISMA guidelines, PubMed, Scopus, and CINAHL were searched on October 30, 2025. Longitudinal studies assessing neurocognitive changes in patients with HM undergoing HSCT, with or without healthy controls, were included. Risk of bias was assessed using an adapted National Institutes of Health quality assessment tool for before-after studies. Effect sizes with 95% confidence intervals were calculated to quantify changes in neurocognitive performance. RESULTS: Nine of 2012 studies met the inclusion criteria, with overall moderate study quality. Improvements may occur post-HSCT; however, allogeneic HSCT and myeloablative conditioning were main risk factors identified for persistent cognitive decline. In line with white matter damage, executive function and attention/processing speed impairments likely represent core deficits, which may affect other cognitive impairments. Post-HSCT changes depend on task characteristics, cognitive load, and conditioning intensity. CONCLUSIONS: Future research should emphasize regular neurocognitive assessment to guide cognitive rehabilitation, implement pre-transplant cognitive rehabilitation strategies to mitigate post-HSCT cognitive decline, and enhance treatment outcomes.
BACKGROUND: Real-world data on transfusion needs of patients with myelodysplastic syndromes (MDS), and the impacts of disease-modifying therapies (DMTs) are sparse. In 2011, 5-azacitidine became the first funded DMT for...BACKGROUND: Real-world data on transfusion needs of patients with myelodysplastic syndromes (MDS), and the impacts of disease-modifying therapies (DMTs) are sparse. In 2011, 5-azacitidine became the first funded DMT for MDS and chronic myelomonocytic leukaemia (CMML) patients in Australia and national patient blood management (PBM) guidelines were published. AIMS: Describe red blood cell transfusion (RBC-T) and platelet transfusion (PLT-T) burden in MDS/CMML and any changes since 2011. METHOD: Retrospective longitudinal cohort study of all MDS/CMML patients in the state of Victoria (population 6.5 million) from 2009 to 2022, linking hospital admissions dataset, cancer and death registries. RESULTS: 7043 patients (5715 MDS; 1328 CMML), with median follow-up 1.8 years (interquartile range [IQR]: 0.5-4.0 years), had 55 048 RBC-T and 10 749 PLT-T episodes. By 5 years post-diagnosis, patients had on average 14 RBC-T and 3 PLT-T admissions, with transfusion burden affected by MDS subtype. PLT-T were significantly higher post-2011 versus pre-2011 (0.8 more PLT-T admissions by 2 years, p < 0.001), with no difference in RBC-T admissions. CONCLUSION: Since 2011, RBC-T burden has remained stable, but PLT-Ts have increased. Given the potential costs and limited PLT inventories, this impacts blood supply planning and highlights the need for research to optimise PLT-T in MDS/CMML patients.
Multiple myeloma (MM) is an incurable malignancy of terminally-differentiated plasma cells that represents a major clinical challenge despite unprecedented therapeutic advances, particularly for patients with cytogenetic...Multiple myeloma (MM) is an incurable malignancy of terminally-differentiated plasma cells that represents a major clinical challenge despite unprecedented therapeutic advances, particularly for patients with cytogenetically-defined high-risk MM (HR-MM). Updated in 2025, the evolving cytogenetic classification of HR-MM includes gains or amplifications in chromosome 1q. One gene of emerging interest on chromosome 1q is F11R, which codes for a protein called Junctional Adhesion Molecule-A (JAM-A). Upregulation of JAM-A has been linked with the development of several aggressive malignancies, most recently MM. In the current study, F11R gene expression was found to be significantly higher in gain/amp(1q) MM patients from the CoMMpass database, and to correlate with poorer overall survival in MM patients. Furthermore, elevated F11R expression was accompanied by an increased burden of circulating CD138 cells, potentially an early hallmark of extramedullary disease (EMD). As JAM-A signalling putatively promotes tumorigenic behaviour through cis-dimerization-dependent adhesion signalling, structure-based rational design principles were utilised to design novel peptide inhibitors that selectively disrupt JAM-A cis-dimerization. In vitro testing of novel peptides across a panel of MM cell lines and primary CD138+ cells from MM patients demonstrated anti-proliferative and pro-senescence properties of the novel peptides. Moreover, candidate peptide P4 significantly inhibited the growth of CD138+ plasmacytoma-like tumours in an in vivo xenograft model involving implantation onto the chick chorioallantoic membrane. Collectively, these findings support the validity of JAM-A as an emerging druggable target and provide a strong rationale for further preclinical investigations of JAM-A inhibitors in MM.
AIMS: Paroxysmal nocturnal haemoglobinuria (PNH) is an ultra-rare, acquired, non-malignant haematological disorder that, if left untreated, can lead to significant morbidity. This systematic literature review (SLR) summa...AIMS: Paroxysmal nocturnal haemoglobinuria (PNH) is an ultra-rare, acquired, non-malignant haematological disorder that, if left untreated, can lead to significant morbidity. This systematic literature review (SLR) summarized real-world evidence (RWE) for pegcetacoplan, a complement 3/3b inhibitor (C3i) available since 2021. METHODS: The SLR (PROSPERO-CRD420251043506) followed 2020 PRISMA guidelines and included RW studies of pegcetacoplan (n > 1 pts.; English; to April 2025) in adults (age ≥ 18 years) with PNH. RESULTS: Of 409 identified records, 39 qualified, representing 12 distinct studies. Six studies (n = 4-39) reported median haemoglobin (Hb) with baseline 8.1-9.6 g/dL. Ending median Hb and maximum pegcetacoplan durations were: 12.0 g/dL at 12 months, 11.1-12.1 g/dL at 6 months (3 studies), and 11.1 g/dL at 3 months (1 study). In 4 other studies (n = 48-70), ending mean Hb (maximum pegcetacoplan duration) was: 11.3 g/dL (7.2 months), 11.5 g/dL (6.6 months), 11.5 g/dL (5.9 months), and 11.58 g/dL (3 months). Six studies reported reduced absolute reticulocyte count (ARC; n = 4-39) from baseline median 155-301 × 10/L to median 56-106 × 10/L from 14 days of pegcetacoplan, maintained to maximum pegcetacoplan of 1-12 months. Three studies reported lactate dehydrogenase (LDH; n = 4-62); all showed reductions from baseline median 543.0 to 161.7 U/L after 3 months, and baseline median 299.5-316.0 U/L to 193.5-187.0 U/L after 6 months of pegcetacoplan. In complement 5 inhibitor-naïve, LDH reduced from 977.8 to 358.9 U/L after 8.4 months, and 503.6 to 292.5 U/L in C5i-experienced after 7.2 months. Three studies (n = 4-63) reported reduced LDH from above the upper limit of normal levels. Six studies (n = 23-70) reported reduced red blood cell transfusions (RBCt) after maximum pegcetacoplan durations of up to 12 months, and median durations of 3.0 and 10.2 months. Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale scores in 1 study increased from baseline (mean 28.4) to 38.6 at 3 months, 36.3 at 6 months, and 34.9 at 9 months of pegcetacoplan treatment. Two studies reported FACIT-Fatigue scores of 34.6-40.1 with pegcetacoplan for ≥ 1 month. EQ-5D mean utility scores (0.85-0.94) in 2 studies were comparable to population normative values. On the Short-Form 36 Health Survey, mental and physical component scores were slightly lower than US normative values. CONCLUSIONS: RWE indicates pegcetacoplan is associated with improved haematological outcomes, reduced RBCt dependence and fatigue, and enhanced HRQoL. These findings from real-world studies with diverse cohorts support generalizability and are broadly comparable with clinical trial evidence.
Acute Myeloid Leukemia predominantly affects older adults, who often present with comorbidities, functional impairment, and frailty, limiting eligibility for intensive chemotherapy or allogeneic transplantation. Historic...Acute Myeloid Leukemia predominantly affects older adults, who often present with comorbidities, functional impairment, and frailty, limiting eligibility for intensive chemotherapy or allogeneic transplantation. Historically, treatment options were restricted to hypomethylating agents, low-dose cytarabine, hydroxyurea, or supportive care, with poor outcomes. The introduction of hypomethylating agents combined with Venetoclax and the availability of targeted therapies have expanded therapeutic possibilities, challenging the notion that elderly AML is uniformly incurable. In this evolving context, accurate assessment of fitness and frailty is essential to guide treatment decisions. This review summarizes current concepts of frailty in older AML patients, including general geriatric tools and hematology-specific indices. It discusses the role of Comprehensive Geriatric Assessment, frailty phenotypes, and comorbidity scores such as the transplantation-specific comorbidity index and the Charlson index, alongside AML-focused tools like the Ferrara criteria and integrated molecular risk models. Most existing tools were developed in intensively treated cohorts, and their applicability to patients receiving non-intensive regimens remains uncertain. Fitness is increasingly recognized as a dynamic, multidimensional construct incorporating clinical, functional, cognitive, social, and biological factors. A multiparametric approach is proposed, integrating these variables into decision-making models, potentially enhanced by artificial intelligence to optimize treatment selection in older AML patients.
Pediatric acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy that accounts for about 15%-20% of childhood leukemias. Despite therapeutic advances, relapses remain common, and survival for high-risk pa...Pediatric acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy that accounts for about 15%-20% of childhood leukemias. Despite therapeutic advances, relapses remain common, and survival for high-risk patients is below 60%. Unlike adult AML, pediatric AML displays distinct genetic mutations, including FLT3-ITD, NPM1, KMT2A rearrangements, and core-binding factors (CBF) fusions, as well as extensive epigenetic dysregulation. Aberrant DNA methylation, histone modifications, and altered non-coding RNA expressions disrupt hematopoietic differentiation and activate oncogenic transcriptional networks. Recent advances in silico transcriptomic analysis have transformed the study of pediatric AML by integrating gene expression and epigenetic data to identify molecular drivers and regulatory networks. Computational RNA-seq pipelines and pathway analyses have highlighted key epigenetic regulators, including DNMT3A, TET2, and HDACs, as potential therapeutic targets. Multi-omics approaches combining transcriptomic, methylomic, and chromatin accessibility data are increasingly used to define biomarkers for diagnosis, prognosis, and therapeutic response. This review provides a comprehensive overview of the molecular and epigenetic landscape of pediatric AML, emphasizing the power of in silico transcriptome analysis to uncover disease mechanisms, refine patient stratification, and guide the development of precision-based epigenetic therapies aimed at improving long-term outcomes in children with AML.
BACKGROUND: Acute kidney injury (AKI) is a frequent and clinically relevant complication in allogeneic hematopoietic cell transplantation (HCT) recipients, particularly during the early post-HCT period. Although AKI has...BACKGROUND: Acute kidney injury (AKI) is a frequent and clinically relevant complication in allogeneic hematopoietic cell transplantation (HCT) recipients, particularly during the early post-HCT period. Although AKI has been extensively reported in long-term follow-up studies, data focusing on the initial hospitalization phase remain limited, despite its potential impact on subsequent clinical outcomes. OBJECTIVE: To evaluate the incidence, severity, and clinical and transplant-related determinants of AKI during the first 3 weeks after allogeneic HCT. METHODS: We conducted a retrospective cohort study including 634 consecutive recipients undergoing allogeneic HCT between 2002 and 2023. AKI was defined according to KDIGO criteria and assessed from day +1 to day +21. Cumulative incidence was estimated, and associations were evaluated using Cox proportional hazards models. Pre-AKI exposure to calcineurin inhibitors was analyzed. RESULTS: By day 21, AKI occurred in 346 patients (55%), and 27% of cases reached KDIGO stages 2-3. Median time to AKI was 12 days, with earlier onset among stage 3 events (median 5 days). In multivariable analysis, AST > 40 U/L was independently associated with an increased risk of any-stage AKI (HR 1.58, 95% CI 1.17-2.12; p = 0.003), whereas albumin > 3.5 g/dL was protective (HR 0.56, 95% CI 0.44-0.71; p < 0.001). Severe AKI was associated with AST > 40 U/L (HR 1.93, 95% CI 1.08-3.44; p = 0.025) and year of transplantation, with higher risk observed in earlier categories (2002-2008: HR 3.68, 95% CI 1.75-7.72; p < 0.001), while higher albumin levels remained inversely associated (HR 0.42, 95% CI 0.26-0.70; p < 0.001). Higher pre-AKI cyclosporine trough levels (HR 1.11, 95% CI 1.05-1.17; p < 0.001) and a greater proportion of supratherapeutic days (HR 1.06, 95% CI 1.02-1.10; p = 0.005) were also associated with AKI. CONCLUSION: Early AKI in HCT recipients is strongly associated with baseline clinical vulnerability, hepatic dysfunction, and calcineurin inhibitor exposure. Elevated AST and lower albumin levels identify patients at increased risk, while higher cyclosporine exposure contributes to early renal injury. In contrast, transplant-related characteristics show limited independent influence. These findings support early risk stratification, careful therapeutic monitoring, and individualized immunosuppression to reduce renal complications during the initial post-HCT period.
Surgical interventions have been integral to the management principles of paediatric lymphomas, but recent advancement of perioperative care standards and treatment protocols have led to new evidence that alters historic...Surgical interventions have been integral to the management principles of paediatric lymphomas, but recent advancement of perioperative care standards and treatment protocols have led to new evidence that alters historical concepts regarding the optimal upfront management of these lesions. In patients presenting with mediastinal disease, general anaesthesia in the upfront setting was previously largely avoided due to significant perioperative cardiorespiratory risks. However, improved risk-determination frameworks and introduction of newer anaesthetic agents into current practice now permit safer conduct of upfront biopsies under deep sedation. This is important as accurate lesional sampling has become even more critical with the growing importance of accurate molecular subtyping. In patients with gastrointestinal lymphoma, upfront resection was advocated to surgically downstage disease and address the risk of impending bowel obstruction. Yet, unnecessarily extensive upfront surgery can delay commencement of systemic therapy, and many of such attempts do not achieve sufficiently clear resection margins. The improved efficacy of newer chemotherapy protocols may reduce the relative benefit of attempted surgical downstaging, but now introduce new issues with risks of delayed stricture formation. This review will evaluate emerging evidence, synthesising potential new practice recommendations for upfront surgical management of paediatric lymphomas, with a focus on mediastinal and gastrointestinal sites.
Vitamin C (l-ascorbic acid) is an essential dietary micronutrient needed for iron absorption, collagen synthesis, antioxidant activity, and immune regulation. This retrospective analysis examines 23 patients seen in a cl...Vitamin C (l-ascorbic acid) is an essential dietary micronutrient needed for iron absorption, collagen synthesis, antioxidant activity, and immune regulation. This retrospective analysis examines 23 patients seen in a classical hematology clinic in Appalachia between 2020 and 2025 who had severe vitamin C deficiency (< 0.1 mg/dL). Most patients presented with anemia, fatigue, or other dermatologic findings, and over half lived in food-desert regions. Micronutrient testing often revealed overlapping deficiencies, and 17% of patients experienced a bone marrow biopsy. Principal component analysis of laboratory data identified two main phenotypic clusters: socioeconomic status, which accounted for most of the variability in the data, followed by cell counts and laboratory values. Treatment approaches varied. Normalization of vitamin C levels and cytopenias was seen in patients who attended follow-up, typically within 2-3 months. This work suggests that vitamin C deficiency remains a contemporary and reversible contributor to cytopenias in hematology practice and highlights the importance of dietary and socioeconomic risk assessment during diagnostic evaluation.
Elsey G, Davis JA, Julian K
… +22 more, Gonzalez R, Snyder J, Rice M, Nachar VR, McElwee J, Atrash S, Cahoon C, Bryan B, Sborov DW, Granger K, Warrick M, Dominick A, Hansen DK, Grajales-Cruz A, Mahmoudjafari Z, Rudoni J, Kissam J, Vince M, Khouri J, Ahmed I, Pianko M, Moore DC
OBJECTIVE: To compare the incidence and severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) between two different step-up dosing (SUD) schedules with talquetamab...OBJECTIVE: To compare the incidence and severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) between two different step-up dosing (SUD) schedules with talquetamab, the standard SUD schedule of Days 1, 4, 7, and 10 and a condensed SUD schedule of Days 1, 3, 5, and 7. METHODS: We conducted a multicenter retrospective study across seven academic medical centers in the United States and included patients who received talquetamab for the treatment of relapsed/refractory multiple myeloma. The incidence and grade of severity of CRS and ICANS were compared between patients receiving the standard SUD schedule and the condensed SUD schedule. RESULTS: A total of 144 patients were included in our analysis; 33 received the standard SUD schedule and 111 received the condensed SUD schedule. The incidence of CRS (76% vs. 56%; p = 0.101) and ICANS (9% vs. 16%; p = 0.41) was similar between the standard and condensed SUD cohorts. There was no significant difference in the severity of CRS and ICANS between both cohorts. CONCLUSION: Shortening the interval between talquetamab SUDs appears feasible and well-tolerated in routine clinical practice.
OBJECTIVE: To determine whether early dexamethasone response provides complementary prognostic information to minimal residual disease (MRD) and whether integrating both markers refines risk stratification in pediatric a...OBJECTIVE: To determine whether early dexamethasone response provides complementary prognostic information to minimal residual disease (MRD) and whether integrating both markers refines risk stratification in pediatric acute lymphoblastic leukemia (ALL). METHODS: We retrospectively analyzed pediatric ALL patients treated at a single center according to the CCCG-ALL-2015 protocol. Day 5 steroid response was classified as dexamethasone good response (DGR) or dexamethasone poor response (DPR). Bone marrow MRD was measured on Days 19 and 46 of induction. A four-quadrant classification was constructed by combining Day 5 steroid response with Day 46 MRD status (DGR/MRD-, DGR/MRD+, DPR/MRD-, DPR/MRD+) to evaluate event-free survival (EFS) and cumulative incidence of relapse (CIR). RESULTS: Among 312 patients, 220 were DGR and 92 were DPR. MRD negativity rates on Days 19 and 46 were significantly lower in DPR. Among 304 patients with paired MRD measurements, 181, 102, 18, and 3 patients were classified as D19-/D46-, D19+/D46-, D19+/D46+, and D19-/D46+, respectively, with progressively worse 5-year EFS and increasing 5-year CIR. In the four-quadrant analysis, EFS differed significantly across groups, and compared with DGR/MRD-, the other quadrants exhibited higher event risk. In multivariable Cox models, Day 46 MRD remained independently associated with inferior EFS (HR = 2.429, 95% CI: 1.286-4.590; p = 0.006). When the four-quadrant classification was entered into the multivariable model (reference: DGR/MRD-), DGR/MRD+ (HR = 4.319, 95% CI 1.792-10.414; p = 0.001), DPR/MRD- (HR = 2.207, 95% CI: 1.253-3.888; p = 0.006), and DPR/MRD+ (HR = 3.718, 95% CI: 1.608-8.598; p = 0.002) were each associated with increased event risk. CONCLUSIONS: MRD kinetics identify patients with delayed clearance or persistent positivity at higher relapse risk. Integrating early steroid response with MRD using a four-quadrant framework may complement MRD-based assessment and further refine risk stratification by highlighting clinically meaningful discordant subgroups.
Chronic lymphocytic leukemia (CLL) is most frequently diagnosed at early, asymptomatic stages (Rai 0/Binet A), in which a watch-and-wait strategy remains the standard of care, based on historical trials demonstrating no...Chronic lymphocytic leukemia (CLL) is most frequently diagnosed at early, asymptomatic stages (Rai 0/Binet A), in which a watch-and-wait strategy remains the standard of care, based on historical trials demonstrating no overall survival benefit from early treatment. Over the past two decades, however, substantial advances in genomic profiling-including immunoglobulin heavy-chain variable region (IGHV) mutational status, TP53 disruption, recurrent gene mutations, and complex karyotype-have uncovered marked biological heterogeneity among early-stage patients and substantially improved prediction of disease progression. In parallel, targeted therapies such as Bruton tyrosine kinase (BTK) inhibitors and venetoclax-based combinations have transformed the management of symptomatic CLL, raising renewed interest in whether early intervention might favorably alter the natural history of biologically high-risk disease. In this review, we critically examine the evolution of prognostication in early-stage CLL, integrate contemporary molecular and clinical risk models, and summarize evidence from both historical chemotherapy-era studies and modern early-intervention trials. We discuss key unresolved controversies, including reliance on surrogate endpoints, the risks of overtreatment, and the persistent absence of an overall survival benefit across all early-treatment strategies. Finally, we outline future research priorities, including refined genomic stratification, minimal residual disease-driven (MRD)-driven approaches, and combination targeted therapies currently under investigation. Despite renewed interest in preemptive treatment, available evidence supports continued observation for asymptomatic patients outside clinical trials.