Leung E, Fragola NR, Sharp EW
… +14 more, Harrison RA, Peterson E, Varghese J, Jackson S, You XJ, VanderVeer E, Trinder M, Sutherland A, Dutz J, Kaniewski P, McClain KL, Abla O, Fajgenbaum DC, Chen LYC
A combined clinical and computational pharmacophenomic study from the Coastal Rare Inflammatory Diseases Program and Every Cure.A combined clinical and computational pharmacophenomic study from the Coastal Rare Inflammatory Diseases Program and Every Cure.
Renal impairment (RI), defined as estimated glomerular filtration rate less than 60 mL/min with or without the need for dialysis, is a frequent and severe complication in patients with relapsed/refractory multiple myelom...Renal impairment (RI), defined as estimated glomerular filtration rate less than 60 mL/min with or without the need for dialysis, is a frequent and severe complication in patients with relapsed/refractory multiple myeloma (RRMM), as it can affect patient prognosis, drug metabolism and treatment options. Although bispecific antibodies (BsAbs) have been approved in RRMM patients, their safety and efficacy in patients with RI remain insufficiently characterized, as most clinical trials excluded individuals with significant renal dysfunction. This systematic review was conducted in accordance with the PRISMA guidelines. PubMed, Scopus, and ScienceDirect were searched up to February 2, 2026, for clinical trials and retrospective real-world studies evaluating BsAbs in RRMM patients with reported data from patients with RI. Abstracts presented in major international scientific congresses over the preceding 3 years, including ASH, IMS, ASCO, EHA, EMN, were also systematically screened. A total of 11 eligible studies were identified, including 3 pivotal trials and 8 real-world cohorts, encompassing 1117 patients. ORR, PFS and OS were comparable between patients with and without RI. Safety profile, including incidence of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity (ICANS), infections and hematologic toxicities were also comparable across renal subgroups. Only the incidence of thrombocytopenia was significantly increased in patients with RI. Overall, BsAbs demonstrate substantial efficacy and manageable safety in RRMM patients with renal dysfunction. Outcomes were similar to those of patients with preserved renal function. These findings support the use of BsAbs in this high-risk population both in clinical practice and in future clinical trials.
Am J Hematol
· 2026 Jul · PMID 41927315
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Kidney complications, referred to as nephropathy, develop early in sickle cell disease (SCD). In addition to its known morbidity, abundant data show that chronic kidney disease (CKD) is associated with an increased morta...Kidney complications, referred to as nephropathy, develop early in sickle cell disease (SCD). In addition to its known morbidity, abundant data show that chronic kidney disease (CKD) is associated with an increased mortality risk in SCD. Increasing evidence suggests that the natural history of SCD nephropathy is progressive. Initial glomerular hyperfiltration without albuminuria appears to precede increasingly severe albuminuria, kidney function decline, and eventual kidney failure. Based on the current understanding of the natural history of SCD nephropathy, intervention before the development of overt kidney disease may prevent albuminuria and CKD progression and perhaps decrease mortality.
Immunosuppressive therapy (IST) is the standard treatment for acquired pure red cell aplasia (aPRCA), but predictors of treatment response and long-term prognosis remain unclear. The clinical significance of somatic muta...Immunosuppressive therapy (IST) is the standard treatment for acquired pure red cell aplasia (aPRCA), but predictors of treatment response and long-term prognosis remain unclear. The clinical significance of somatic mutations in aPRCA is not fully understood. We retrospectively analyzed 69 adult aPRCA patients who underwent targeted next-generation sequencing of 69 genes associated with clonal hematopoiesis and myeloid neoplasms. Somatic mutations, T-cell receptor (TCR) gene rearrangements, treatment response at 6 months, overall survival (OS), and progression-free survival (PFS) were evaluated. Somatic mutations were detected in 62.3% of patients, mainly in epigenetic regulators like DNMT3A and TET2. Although mutations did not predict 6-month response to IST, higher mutation burden was associated with worse treatment outcomes (p = 0.01). TP53 and DNMT3A mutations were linked to shorter OS and PFS. Survival worsened with increasing mutation numbers, while mutations in TET2, ASXL1, GATA2, and STAT3 had no significant effect. TCR gene rearrangements were common in large granular lymphocyte leukemia-associated aPRCA but did not affect treatment response or survival. Somatic mutations are common in aPRCA and reflect clonal hematopoiesis. Mutation burden is a key determinant of IST response, while TP53 and DNMT3A mutations signal poorer long-term outcomes. Mutational profiling may improve risk stratification and guide personalized management.
Patients with relapsed/refractory multiple myeloma (RRMM) who are penta-drug refractory, defined as resistant to two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 monoclonal antibody, face a dismal...Patients with relapsed/refractory multiple myeloma (RRMM) who are penta-drug refractory, defined as resistant to two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 monoclonal antibody, face a dismal prognosis, particularly after exposure to T-cell-redirecting therapies. Selinexor, an oral exportin-1 inhibitor, offers a distinct mechanism of action and may retain efficacy in this difficult setting. We conducted a retrospective analysis at six German tertiary centers (2023-2025) to evaluate the efficacy and safety of selinexor plus bortezomib and dexamethasone (SVd) in penta-refractory MM after both BCMA- and GPRC5D-targeted therapies. Eighteen patients were identified, with a median of seven prior lines of therapy. High-risk cytogenetic abnormalities were present in seven cases, including del17p in six. The overall response rate (ORR) was 61%, including one complete, five very good partial, and five partial responses, and median progression-free survival (PFS) was 4.3 months. Among nine patients (50%) with extramedullary disease (EMD), three achieved complete and one near-complete EMD resolution. Two patients who had relapsed after CAR T-cell treatment with idecabtagene vicleucel achieved partial and very good partial responses and were successfully transitioned to a second CAR T-cell therapy with ciltacabtagene autoleucel. Hematologic toxicities under SVd were manageable, and no treatment-related deaths occurred. SVd demonstrates meaningful activity in patients with penta-refractory MM and prior failure of BCMA/GPRC5D-targeted immunotherapies. The ORR of 61%, disease control in 78% of patients, and median PFS of 4.3 months support further evaluation of SVd in this highly refractory setting after failure of BCMA- and GPRC5D-directed approaches.
Am J Hematol
· 2026 Jun · PMID 41913093
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Myelodysplastic syndromes/neoplasms (MDS) represent a heterogeneous group of clonal hematopoietic stem cell diseases with high risks of acute myeloid leukemia (AML) transformation. To emphasize the characteristics of AML...Myelodysplastic syndromes/neoplasms (MDS) represent a heterogeneous group of clonal hematopoietic stem cell diseases with high risks of acute myeloid leukemia (AML) transformation. To emphasize the characteristics of AML transformation, the International Consensus Classification (ICC) has classified MDS with excess blasts (10%-19%) as MDS/AML. Recently, a clinical-molecular prognostic model International Prognostic Scoring System Molecular (IPSS-M) is developed, which improves the risk stratification of MDS. However, these molecular risk factors were analyzed in a cohort of highly heterogeneous patients with MDS including MDS/AML. Herein, we re-evaluated and compared the molecular risk factors in MDS (blasts < 10%) and MDS/AML (blasts 10%-19%) defined by ICC. Notably, there is a significant difference in molecular landscape between MDS and MDS/AML. Importantly, most of the risk factors presented in MDS was not shown in MDS/AML except for TP53 aberrations and FLT3-ITD mutation. Since the IPSS-R and IPSS-M showed a poorly prognostic separation for MDS/AML patients, we further established a new prognostic model MDS/AML-IPSS-M and significantly improved its prognostic discrimination ability. Taking together, our research findings enhance the understanding of the molecular biology of MDS and can provide important guidance for the clinical identification of MDS/AML patients that might benefit clinical decision-making and therapeutic research.
Gillis N, Colin-Leitzinger C, Tang YH
… +23 more, Otterstatter M, Sherman S, Zhang L, Moscinski LC, Walker ME, Painter JS, Abel GA, Al Baghdadi T, Deeg HJ, Foran JM, Gore SD, Harrington AM, Kroft SH, Liu JJ, Saber W, Virani S, Bejar R, Lindsley RC, Padron E, Walter MJ, Komrokji R, DeZern AE, Sekeres MA
Am J Hematol
· 2026 Jun · PMID 41906220
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The epidemiology of myelodysplastic syndromes/neoplasms (MDS) is challenging to define due to inconsistent reporting, complex diagnostic procedures, and evolving diagnostic criteria. Using the National MDS Natural Histor...The epidemiology of myelodysplastic syndromes/neoplasms (MDS) is challenging to define due to inconsistent reporting, complex diagnostic procedures, and evolving diagnostic criteria. Using the National MDS Natural History Study-a prospective cohort with centrally adjudicated histopathology and genetic variant review-we characterized the landscape of MDS across the United States and identified differences across demographics. Among 2115 participants, 64% (1346) had an MDS spectrum condition, including MDS (24%), MDS/myeloproliferative neoplasm (5%) and precursor conditions-clonal cytopenia of undetermined significance (22%) and idiopathic cytopenia/dysplasia of undetermined significance (13%). The median age was 74 years, and participants were predominantly male (66%), White (91%), and Non-Hispanic (92%). Myeloid-associated variants were detected in 68% of participants, most commonly in TET2, DNMT3A, ASXL1, SF3B1, and SRSF2. Black, compared to White, participants were younger at diagnosis (69 vs. 74 years, p = 0.01), had equal or increased prevalence of higher-risk MDS, lower hemoglobin, and higher peripheral blood blasts, yet were less likely to receive MDS-directed therapy (14% vs. 42%, p = 0.008). Black and Hispanic participants had fewer detectable gene mutations than White participants. Females had lower variant allele frequencies and fewer RNA splicing gene mutations than males. After multivariable adjustment, TP53 mutations, MDS diagnosis, and higher-risk disease were associated with worse progression-free and overall survival; age was also associated with overall survival. Black race trended toward improved progression-free survival. These findings highlight the need for enhanced understanding of MDS pathogenesis across patient groups and refined prognostic tools to improve personalized management of MDS spectrum conditions. Trial Registration: ClinicalTrials.gov identifier: NCT02775383.
Facchinelli D, Mazzai L, Marchesi F
… +18 more, Angotzi F, Appio L, Ortu La Barbera E, Busca A, Buzzatti E, Cattaneo C, Criscuolo M, Del Principe MI, Gugole E, Malafronte R, Memoli M, Morsia E, Papayannidis C, Piedimonte M, Sartor C, Terrenato I, Zannier ME, Pagano L
Am J Hematol
· 2026 Jun · PMID 41896710
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Khurana A, Hayashi H, Thach B
… +12 more, Yang ZZ, Negaard BJ, Cerhan JR, Novak AJ, Link BK, Habermann TM, Feldman AL, Parikh SA, Slager SL, Ansell SM, Maurer MJ, Faustman DL
Am J Hematol
· 2026 Jun · PMID 41891328
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Soluble tumor necrosis factor receptor 2 (sTNFR2) is a member of the TNF superfamily whose normal bodily distribution is largely limited to low level expression on lymphoid cells. It has emerged as an important inducible...Soluble tumor necrosis factor receptor 2 (sTNFR2) is a member of the TNF superfamily whose normal bodily distribution is largely limited to low level expression on lymphoid cells. It has emerged as an important inducible receptor that activates a signaling pathway for cancer growth. We evaluated sTNFR2 as a prognostic biomarker for overall survival (OS) in newly diagnosed lymphoma using a prospective cohort study with banked pretreatment serum samples. sTNFR2 was higher in 1513 lymphoma patients compared to 499 age and sex matched controls (p < 0.0001). Using Kaplan-Meier curves and Cox proportional hazards models to estimate hazard ratios [HR] (high vs. low tertile), higher levels of sTNFR2 at diagnosis were associated with inferior OS across all seven major lymphoma subtypes: Hodgkin lymphoma (p < 0.0001; HR = 12.6), diffuse large B-cell lymphoma (p < 0.0001; HR = 2.6), follicular lymphoma (p = 0.00017; HR = 2.5), mantle cell lymphoma (p < 0.0001; HR = 4.2), small lymphocytic lymphoma (p = 0.012; HR = 2.4), marginal zone lymphoma (p = 0.0012; HR = 3.1), and T-cell lymphoma (p < 0.0001; HR = 3.1). Using CITE-seq profiling of tumor microenvironment tissue, we sought to identify cellular source(s) of circulating sTNFR2. In tumor tissue from follicular lymphoma, high TNFR2-expressing cells were found to be T-regulatory (Treg) cells, suggestive of a Treg-driven cancer. In tissue from a case of marginal zone lymphoma, high TNFR2 expression was found on CD4+ and CD8+ T cells, B cells, and monocytes but also directly on tumor cells. We conclude sTNRF2 is a strong prognostic biomarker of OS across major lymphoma subtypes and may be useful to guide therapeutic choices, including targeted therapies against immunosuppressive TNFR2-expressing Tregs.
Borad A, Andersen M, Guffey D
… +7 more, Shang H, Jiang JY, Fernandez Turizo MJ, Berry J, Zwicker JI, Patell R, Li A
Am J Hematol
· 2026 Jun · PMID 41891315
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Data to guide management of isolated bland cancer-associated splanchnic vein thrombosis (CA-SpVT) are limited. We aimed to assess the role of anticoagulation (AC) and bleeding and thrombosis in patients with CA-SpVT. We...Data to guide management of isolated bland cancer-associated splanchnic vein thrombosis (CA-SpVT) are limited. We aimed to assess the role of anticoagulation (AC) and bleeding and thrombosis in patients with CA-SpVT. We conducted a dual-center retrospective cohort study of adults with incident, isolated, bland CA-SpVT from 2011 to 2020. The primary outcome was major bleeding (MB); other outcomes included usual-site venous thromboembolism (VTE) recurrence and progression/recanalization of CA-SpVT. Time-to-event outcomes were analyzed with weighted Cox models adjusting for cancer type, stage, SpVT location, and whether symptomatic. For SpVT recanalization/progression, differences were estimated using weighted average treatment effects (ATEs). After excluding tumor thrombus, we included 437 patients with notable characteristics of median age 60 years, portal vein thrombosis (81.2%), and underlying hepatocellular cancer (35.9%). Of these, 29.5% received therapeutic AC. At 6 months, there were 11.9% MB and 6.4% incident usual-site VTE events. Among 308 patients with follow-up imaging, the 1-year thrombus progression rate was 19.8% and thrombus recanalization was 28.6%. In the adjusted analysis, there were numerically higher rates of MB with AC (adjusted hazard ratio [aHR] 1.93, 95% confidence interval [CI] 0.97-3.87) and no significant difference in the incidence of VTE (aHR 1.41, 95% CI 0.56-3.51). AC was associated with significantly higher likelihood of venous recanalization (ATE +24% 95% CI 13%-35%) and significantly lower likelihood of thrombus progression (ATE -14% 95% CI -23% to -5%). In patients with isolated bland CA-SpVT, AC was associated with thrombus recanalization and limited thrombus progression; effects were offset by a potentially higher risk of MB.
Park CM, Shi S, Chen X
… +2 more, Parks AL, Kim DH
Am J Hematol
· 2026 Jun · PMID 41887762
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In this retrospective cohort of 18 066 Medicare fee-for-service beneficiaries ≥ 65 years with acute VTE (2015-2019), we compared apixaban, rivaroxaban, and warfarin using propensity score (PS) overlap weighting and inten...In this retrospective cohort of 18 066 Medicare fee-for-service beneficiaries ≥ 65 years with acute VTE (2015-2019), we compared apixaban, rivaroxaban, and warfarin using propensity score (PS) overlap weighting and intention-to-treat analyses across total, non-frail, and frail strata defined by a claims-based frailty index. After PS weighting (all SMDs < 0.10), apixaban versus warfarin was associated with a lower 1-year composite of recurrent VTE or death in the total population (189.1 versus 216.1 per 1000 PY; HR 0.86, 95% CI 0.77-0.96), with benefit evident in non-frail patients (114.5 versus 143.6; HR 0.78, 0.66-0.92) and attenuated in frail patients (330.9 versus 349.9; HR 0.93, 0.82-1.07). Recurrent VTE rates favored apixaban but were not statistically significant overall (40.5 versus 54.8; HR 0.86, 0.68-1.08). Major bleeding was lower with apixaban (19.4 versus 26.0; HR 0.73, 0.53-1.00). Home-time loss was reduced with apixaban compared with warfarin in the total population (mean 54.9 versus 67.0 days; RR 0.89, 0.83-0.96) and was directionally similar across both frailty strata. Rivaroxaban showed no clear advantage over warfarin for the composite (216.9 versus 216.1; HR 1.00, 0.90-1.11) or bleeding (HR 0.99, 0.73-1.32) and yielded greater home-time loss than apixaban (RR 1.08, 1.01-1.17). Overall, apixaban demonstrated the most favorable balance of effectiveness, safety, and patient-centered benefit, with patterns generally consistent across frailty levels.
Rashkin SR, Kang G, Takemoto CM
… +5 more, Weiss MJ, Ataga KI, Saraf SL, Lebensburger J, Zahr RS
Am J Hematol
· 2026 Jun · PMID 41870384
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Progressive kidney injury is a major cause of morbidity and mortality in sickle cell anemia (SCA). The high risk APOL1 G1/G2 variants contribute to the development of kidney disease in individuals of African ancestry, in...Progressive kidney injury is a major cause of morbidity and mortality in sickle cell anemia (SCA). The high risk APOL1 G1/G2 variants contribute to the development of kidney disease in individuals of African ancestry, including those with SCA. However, few studies have evaluated the longitudinal effect of APOL1 variants in children and young adults. We analyzed the association of APOL1 risk variants with kidney function in 494 individuals aged 1 to 25 in the Sickle Cell Clinical Research and Intervention Program (SCCRIP) longitudinal cohort study (clinicaltrials.gov #NCT02098863). Before age 10, APOL1 G1/G2 alleles were not associated with time to CKD (hazard ratio [HR] = 1.87; p = 0.14), hyperfiltration (HR = 0.96; p = 0.88), or continuous eGFR (β = -0.0090; p = 0.71). However, after age 10, APOL1 G1/G2 variants were associated with higher baseline eGFR (β = 0.098; P = 0.016), a steeper downward slope of eGFR over time (β = -0.014; P = 1.60 × 10), and increased odds of having an accelerated rate of eGFR decline (individual-specific eGFR slopes in the most negative tertile; odds ratio [OR] = 2.18; p = 0.040). Among 111 individuals with measurements before and after 10 years of age, those with hyperfiltration before age 10 or APOL1 risk alleles were at increased risk of having an accelerated rate of eGFR decline (OR = 2.96; p = 0.019). These findings support the hypothesis that genetic risk stratification and early renal surveillance can help identify patients most at risk for the progression of kidney injury. Trial Registration: Clinicaltrials.gov #NCT02098863.
Am J Hematol
· 2026 Jun · PMID 41867085
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DISEASE OVERVIEW: Marginal zone lymphoma (MZL) is a heterogeneous group of indolent mature B-cell neoplasms with classically three major subtypes: nodal, splenic, and extranodal MZL of mucosa-associated lymphoid tissue (...DISEASE OVERVIEW: Marginal zone lymphoma (MZL) is a heterogeneous group of indolent mature B-cell neoplasms with classically three major subtypes: nodal, splenic, and extranodal MZL of mucosa-associated lymphoid tissue (MALT). DIAGNOSIS: Diagnosis and disease evaluation of MZL is further advanced by the use of genomic testing and PET/CT with emerging evidence for the use of circulating tumor DNA. The RECLASS classification system proposed a hierarchical approach to classifying MZL while the FIL-NF10 investigators introduced a fourth MZL subtype, disseminated MZL. Though the prognosis of MZL varies between subtypes and stages, the MZL IPI and FLIPI24 indices can be used for prognostication. TREATMENT: Frontline treatment of MZL varies between localized disease and advanced-stage diseases. The former favor the use of local therapies such as radiotherapy and anti-microbial in certain subtypes with a selective role of rituximab monotherapy. The latter requires systemic immunotherapy ± chemotherapy with emerging data for cytotoxic-free and covalent Bruton tyrosine kinase inhibitor (cBTKi)-based regimens. cBTKi and immunomodulators are established in relapsed/refractory MZL, while data for antibody-drug conjugates, T-cell engagers, and potentially CAR T-cell therapies are maturing.