Retrospective cohort study of US veterans reporting rates of bleeding-related hospitalizations associated with anticoagulant therapy in patients with cancer.
Posttransplant cyclophosphamide (PTCy) to prevent graft-versus-host disease (GVHD) improves outcomes in recipients of HLA mismatched unrelated donor (MMUD) allogeneic hematopoietic cell transplantation (allo HCT). Outcomes of MMUD HCT using PTCy in patients requiring reduced intensity or non-myeloablative conditioning (RIC/NMA) are not well described. The Phase II, prospective, ACCESS trial sought to evaluate PTCy-based GVHD prophylaxis in adult recipients of MMUD using peripheral blood stem cell allografts. Here, we report combined results of RIC/NMA recipients treated in the initial study (N = 70) and a planned expansion cohort (N = 123). The number of centers participating in the expansion protocol was 33 compared to 13 in the initial study. Median participant age was 65.0 (range: 22.9-78.9) and the HCT comorbidity index was high-risk (≥ 3) in 65 (33.7%). Donor HLA matching was < 7/8 in 62 (32.1%) participants. One-year survival was 79.6% (95% confidence interval: 73.2-84.7) and was similar between HLA 7/8- and HLA < 7/8-matched donor recipients. Survival was similar between participants in the initial study (78.6%) and the expansion cohort (80.3%) indicating generalizability of this strategy. One-year incidence of severe infection (Grade 3-5) was 39% (32%-46.9%). The 1-year incidence of non-relapse mortality and relapse estimates were 12.5% (8.3%-17.6%) and 17.3% (12.3%-23%), respectively. MMUD with PTCy-based GVHD prophylaxis and RIC/NMA conditioning was safe and effective to facilitate HCT. Outcomes were similar in the expansion cohort that enrolled from a greater number of centers. Post-HCT infections were prevalent.
Plasma cell leukemia (PCL) is a form of high-risk multiple myeloma comprising 1%-2% of new myeloma diagnoses, and defined by ≥ 5% circulating plasma cells. Classified as primary, de novo or secondary, from relapsed/refractory myeloma, PCL carries worse outcomes than conventional myeloma despite advances. Genomically, PCL demonstrates high-risk abnormalities like del(17p), 1q21 gain/amplification and overrepresentation of t(11;14), marking a distinct biological subgroup. Contemporary management involves quadruplet induction, early autologous stem cell transplantation in eligible patients, and multi-agent consolidation/maintenance. Immune effector therapies, especially BCMA-directed CAR-T, show promise for deeper, more durable responses. This review covers PCL biology, clinical features, prognosis, and treatment, emphasizing emerging therapies.
Mutations in FLT3 are present in approximately 30% of patients with AML. The addition of midostaurin (MIDO) to intensive chemotherapy (IC) became standard of care following the RATIFY trial, but comprehensive real-world data spanning the full adult age spectrum and including both FLT3-ITD and FLT3-TKD mutations remain limited. We retrospectively analyzed 1658 adults aged 14-85 years with newly diagnosed FLT3-mutated AML from 129 PETHEMA registry centers: 469 received IC + MIDO and 1189 IC alone. Composite complete remission was higher with IC + MIDO than IC (81.4% vs. 71.7%; p < 0.001) and Day 30 mortality was substantially lower (2.1% vs. 7.1%; p < 0.001). Median overall survival was 47.2 versus 19.3 months (HR 0.64; 95% CI, 0.53-0.76; p < 0.001), and the benefit was sustained after multivariable adjustment (HR 0.73; p = 0.017). In 261 propensity score-matched pairs, the effect was attenuated, remaining significant for event-free survival (HR 0.77; p = 0.029) and showing a nonsignificant trend for OS (HR 0.77; p = 0.06). Allogeneic hematopoietic stem cell transplantation in first remission was more frequent in the IC + MIDO cohort (48.9% vs. 41.3%; p = 0.023). Time-dependent analyses showed the largest MIDO effect among autologous and non-transplanted patients (OS HR 0.45; p = 0.138, and HR 0.69; p = 0.014, respectively). The benefit of MIDO was consistent irrespective of FLT3 mutation type, FLT3-ITD allelic burden, cytogenetic risk, and gender, while less improvement occurred among NPM1 wild type and secondary AML patients. This large real-world cohort confirms the survival benefit of MIDO plus IC across the full adult age spectrum, supporting its standard-of-care status in FLT3-mutated AML.
Children with SCD have elevated stroke risk, correlated with cerebral blood flow velocity (CBFV). HOPE Kids 2 was a phase 3, multicenter, double-blind, placebo-controlled trial evaluating the effect of voxelotor on CBFV. Participants aged 2 to < 15 years with SCD (HbSS/HbSβ0) and conditional CBFV (170 to < 200 cm/s) were randomized 1:1 to voxelotor (N = 120) or placebo (N = 116) for 96 weeks; 195 (83%) were in sub-Saharan Africa. The primary endpoint, CBFV change from baseline to Week 24, was significantly greater with voxelotor (least-squares mean change: voxelotor [n = 114] -12.06 cm/s, placebo [n = 108] -4.29 cm/s; difference -7.77 cm/s; 95% CI -13.18 to -2.37; p = 0.0048), with significant difference sustained through Week 48. Hemoglobin levels increased at Weeks 24 and 48 with voxelotor. Drug administration was paused in May 2024 when an imbalance of deaths was observed between treatment groups; subsequently, the trial discontinued when all active voxelotor trials were discontinued in September 2024. At study end, median (range) exposure was 84 (3-104) weeks for voxelotor and 84 (3-106) weeks for placebo. The most common SCD-related treatment-emergent adverse event was sickle cell anemia with crisis (voxelotor 59.2%; placebo 37.9%). All deaths (voxelotor n = 8; placebo n = 2) were considered unrelated to study drug by treating investigators. Overall, voxelotor showed CBFV reduction in children with SCD and conditional CBFV, suggesting HbS polymerization inhibition has a potential therapeutic role for this group; nevertheless, additional studies evaluating potential regional risks for sickle cell anemia with crisis or mortality are warranted. Trial Registration: ClinicalTrials.gov identifier: NCT04218084.
Thrombopoietin receptor agonists (TPO-RAs), such as romiplostim, are commonly utilized to facilitate timely platelet recovery and administration of chemotherapy in patients with cancer and chemotherapy-induced thrombocytopenia (CIT). However, there are limited data on the effect of TPO-RAs on clinically important outcomes. A target trial emulation study was implemented to assess the effects of romiplostim in patients with solid tumors and persistent CIT, compared to controls. Patients were exact-matched on chemotherapy, cancer type, degree of thrombocytopenia, and 1:1 propensity-score-matched on clinical/laboratory variables on Day 1 of romiplostim treatment or quasi-index date for controls. Study outcomes included overall survival over 24 months and venous thromboembolism (VTE) at 6 months. This study included 165 romiplostim-treated patients and 165 controls. Baseline characteristics were well-balanced. The median age was 61 years and 52% were female. The median romiplostim duration was 1.38 months. Median overall survival was 13 months (95% CI: 9.9-23) in the romiplostim group and 9.5 months (95% CI: 7.1-14.0) in controls (hazard ratio [HR] 0.86 [95% CI: 0.65-1.13]). There was a numerical improvement in survival with romiplostim (0.80 [95% CI: 0.60-1.06]) which was statistically significant in the subgroup of patients with metastatic disease (HR 0.70 [95% CI: 0.52-0.95]). The 6-month cumulative incidence of VTE was 10.0% (95% CI: 6.3%-16.0%) in the romiplostim group and 8.0% (95% CI: 4.5%-13.0%) in controls (HR 1.31 [95% CI: 0.64-2.70]), with death as a competing risk. In conclusion, these results support the safety of romiplostim in CIT with observed numerical improvement in overall survival at 2 years.
DIAGNOSIS:The diagnosis of multiple myeloma requires ≥ 10% clonal bone marrow plasma cells or a biopsy proven plasmacytoma plus evidence of one or more multiple myeloma defining events (MDE): CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) attributable to the plasma cell disorder, bone marrow clonal plasmacytosis ≥ 60%, serum involved/uninvolved free light chain (FLC) ratio ≥ 100 (provided involved FLC is ≥ 100 mg/L and urine monoclonal protein is ≥ 200 mg/24 h), or > 1 focal lesion on magnetic resonance imaging. RISK STRATIFICATION:High-risk multiple myeloma is defined by the presence of del(17p), p53 mutation, or bi-allelic del(1p); t(4;14), t(14;16), t(14;20) in combination with gain(1q) or del(1p); or gain(1q) plus del(1p). INITIAL THERAPY:Initial therapy consists of a quadruplet regimen consisting of anti-CD38 monoclonal antibody (daratumumab or isatuximab) plus bortezomib, lenalidomide, dexamethasone (VRd) followed by autologous stem cell transplantation in eligible patients. Selected standard risk patients can delay transplant until first relapse. Frail patients who are not candidates for transplant are treated with a triplet regimen, either anti-CD 38 antibody plus lenalidomide and dexamethasone, or VRd. MAINTENANCE THERAPY:Standard maintenance is lenalidomide in combination with daratumumab or isatuximab. Lenalidomide is discontinued after 2 years in standard-risk patients. Bortezomib plus lenalidomide is an alternative option for high-risk myeloma. MANAGEMENT OF RELAPSED DISEASE:Major options are chimeric antigen receptor T (CAR-T) cell therapy, bispecific antibodies, various triplet regimens, and belantamab mafadotin. MANAGEMENT OF SMOLDERING MULTIPLE MYELOMA:Daratumumab for 3 years should be considered in high-risk smoldering multiple myeloma.
Asparaginase is a critical treatment component for patients with acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL). However, the successful delivery of asparaginase-based therapy remains challenging across care settings due to its complex administration, distinct toxicity profile, prolonged treatment duration, and the need for coordinated multidisciplinary care. These challenges are further compounded by variability in institutional infrastructure, provider experience, and access to specialized supportive services. In this article, we describe key operational and clinical barriers to the safe, timely, and complete delivery of asparaginase therapy for patients with ALL/LBL and present recommendations developed using a modified Delphi process incorporating literature review and expert consensus. We provide practical recommendations organized across three core areas: (1) defining essential members of the specialized care team and outlining the necessary infrastructure for safe and effective asparaginase administration; (2) identifying key steps in the asparaginase treatment journey for ALL/LBL patients and providing recommendations for successful patient navigation and improved outcomes; and (3) sharing practical resources and solutions used by pharmacists, advanced practice providers, and nurses to optimize asparaginase delivery and ensure treatment completion. These recommendations are intended to provide actionable guidance to harmonize multidisciplinary efforts, minimize avoidable treatment interruptions, and support completion of planned asparaginase therapy. Broad implementation across specialized and nonspecialized centers may improve treatment adherence, mitigate toxicity-related discontinuation, and ultimately optimize outcomes for patients with ALL/LBL receiving asparaginase.
Outcomes in older patients with Hodgkin lymphoma (HL) are compromised by the interplay of patient frailty and disease aggressiveness; however, current stratification tools, including the International Prognostic Score (IPS) and Comprehensive Geriatric Assessment (CGA), lack sufficient prognostic discrimination in the older HL population. We developed and validated a prognostic model integrating metabolic tumor burden and geriatric assessment. In this retrospective study across 14 centers in China between 2006 and 2024, we enrolled 306 patients aged ≥ 60 years with histologically confirmed HL. Patients were randomly partitioned into training (n = 250) and validation (n = 56) cohorts. Among the 306 patients, 98 deaths and 130 progression events were recorded during follow-up. We analyzed 21 candidate variables. The least absolute shrinkage and selection operator (LASSO) analysis and multivariable Cox regression identified five independent predictors for 5-year overall survival (OS): age > 73 years, baseline 18F-FDG PET/CT-derived total lesion glycolysis (TLG) > 200, hemoglobin ≤ 101 g/L, activities of daily living (ADL) dependence, and lymphocyte-depleted classical Hodgkin lymphoma (LDCHL). A weighted Geriatric Risk Score stratified patients into low-, intermediate-, and high-risk groups. In the validation cohort, the Geriatric Risk Score showed higher discriminatory accuracy than the CGA for both OS (C-index, 0.770 [95% CI, 0.674-0.867] vs. 0.671 [0.581-0.762]) and PFS (0.761 [0.668-0.853] vs. 0.635 [0.535-0.735]). Among advanced-stage (Ann Arbor stage III-IV) patients, it also outperformed the IPS-7 and IPS-3. By integrating metabolic tumor burden and geriatric assessment, the Geriatric Risk Score improves risk stratification over existing tools in older patients with HL.
The therapeutic landscape of β-thalassemia has evolved rapidly over the past decade, shifting from a historical reliance on transfusion support and iron chelation toward disease-modifying and potentially curative therapies. This review summarizes the clinical development of novel treatments for both non-transfusion-dependent and transfusion-dependent β-thalassemia, including approved therapies, agents in active development, and programs that have been discontinued. Disease-modifying strategies have focused on improving ineffective erythropoiesis, correcting iron dysregulation, and restoring red blood cell metabolism. Luspatercept and mitapivat have demonstrated clinically meaningful improvements in hemoglobin levels and reduction of transfusion burden and are now approved in multiple jurisdictions. Additional pyruvate kinase activators, such as etavopivat, are undergoing clinical evaluation. Curative approaches have advanced substantially through gene addition, gene editing, and base editing technologies. Approved therapies, including betibeglogene autotemcel and exagamglogene autotemcel, have achieved high rates of durable transfusion independence, while emerging platforms aim to further improve efficacy, safety, and accessibility. At the same time, several promising approaches targeting fetal hemoglobin induction, iron metabolism, and ineffective erythropoiesis have failed to demonstrate sufficient clinical benefit despite preclinical proof of concept, highlighting the complexity of therapeutic development in β-thalassemia. Future priorities include refining patient selection, generating real-world and comparative effectiveness data, developing clinically meaningful response criteria, expanding pediatric access, and addressing the substantial cost and accessibility challenges associated with novel therapies.
Acquired gastrointestinal vascular malformations not due to congenital disorders such as hereditary hemorrhagic telangiectasia are a common cause of chronic and acute hemorrhage, particularly in older adults. These lesions cause severe anemia, dependence on intravenous iron and/or red-cell transfusion, and recurring hospitalizations. Hemostatic procedures are temporizing and no standard treatment, including the somatostatin analogs, addresses the underlying angiogenic dysregulation driving vascular malformation formation and recurrence. Therefore, bevacizumab, an anti-VEGF-A monoclonal antibody, is a promising targeted therapeutic. In this observational cohort study, we analyzed 32 patients (median age 75 years, 44% female) with acquired gastrointestinal vascular malformations due to idiopathic angiodysplasia, chronic liver disease, or deficiencies of von Willebrand factor who were treated on a predefined institutional bevacizumab pathway. The median Hematologic Support Score (a composite endpoint integrating red-cell units transfused and elemental iron infused) improved from 15.04 (95% CI, 11.16-21.80) red-cell unit equivalents during 6 months pretreatment to 4.08 (4.00-8.00) during Months 1-6 of bevacizumab treatment (p < 0.001) and further to 0.00 (0.00-5.40) during months 7-12 (p < 0.001). Units of red cells transfused and quantity of elemental iron infused were analyzed independently; both significantly improved after bevacizumab initiation. Annualized hospitalization/ED visit rate improved from 3 (year before bevacizumab) to 1 (year after bevacizumab) (p = 0.01), and median hemoglobin improved by 3.1 g/dL after bevacizumab (p < 0.001). Proteinuria and hypertension occurred in 8 (25%) and 5 (16%) patients, respectively, leading to bevacizumab discontinuation in 3 (9%). In conclusion, bevacizumab is a novel, targeted therapeutic approach for acquired gastrointestinal vascular malformations that may be safe and effective.
Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant precursor to multiple myeloma (MM). While development of end-organ damage in MM largely reflects increasing clonal burden, emerging evidence indicates that qualitative properties of the monoclonal immunoglobulins in MGUS can be directly pathogenic, leading to serious organ injury independent of disease burden. This has led to the recognition of a broader spectrum of disorders collectively termed monoclonal gammopathy of clinical significance (MGCS). MGCS can be further subclassified based on the organ system involved; for example, monoclonal gammopathy of renal significance specifically refers to monoclonal immunoglobulin-driven renal injury. Along these lines, we propose monoclonal gammopathy of thrombotic significance (MGTS) as encompassing thrombotic disorders in which there is definitive, mechanistically supported evidence that a monoclonal (M)-protein associated with a clonal plasma or B-cell disorder directly contributes to thrombosis. Based on current evidence, monoclonal protein-induced immune thrombocytopenia and thrombosis is the only disorder that meets our criteria for MGTS. Other thrombotic disorders, such as thrombotic microangiopathy and antiphospholipid syndrome, may occur in the setting of a monoclonal protein and have biologically plausible M-protein-mediated mechanisms; however, direct evidence implicating the M-protein in thrombosis is currently lacking. Accordingly, we provisionally classify these disorders as thrombotic syndromes associated with M-proteins, pending causal validation. We also highlight thrombotic disease associations with multifactorial pathogenesis that should not be classified as MGTS. Broader recognition of MGTS is essential to advance consensus definitions, establish diagnostic criteria, and develop evidence-based management strategies for this clinically important group of disorders.
