American Journal of Hematology

Managing acute venous thromboembolism (VTE) in patients with thrombocytopenia is challenging. We used data from the RIETE registry to investigate the impact of baseline thrombocytopenia on early VTE‐related outcomes, depending on the initial presentation as pulmonary embolism (PE) or isolated lower‐limb deep vein thrombosis (DVT). From March 2003 to November 2022, 90 418 patients with VTE were included. Thrombocytopenia was categorized as severe (< 50 000/μL, n = 303) or moderate (50 000–99 999/μL, n = 1882). The primary outcome, fatal PE within 15 days after diagnosis, and secondary outcomes, including major bleeding and recurrent VTE, were analyzed using multivariable‐adjusted models. Among 52 703 patients with PE, the 15‐day case‐fatality rates from PE were 5.8% for severe thrombocytopenia, 4.5% for moderate thrombocytopenia, and 1.1% for normal platelet counts. In 37 715 patients with isolated DVT, the cumulative incidence of fatal PE were 0, 0.2%, and 0.05%, respectively. Multivariable analysis revealed a five‐fold increase in the risk for fatal PE in severe thrombocytopenia (adjusted HR: 4.89; 95%CI: 2.55–9.39) without significant differences between severe and moderate thrombocytopenia. Thrombocytopenia, either moderate or severe, was also associated with increased risk for both, major bleeding and recurrent VTE at 15 days. Initial presentation with PE substantially worsened prognosis compared to isolated DVT. In conclusion, in patients with acute VTE, thrombocytopenia at baseline was associated with increased risk of early death from PE, a finding that was driven by the subgroup whose initial presentation was PE.

Patients with chronic inflammation are burdened with anemia of inflammation (AI), where inflammatory cytokines inhibit erythropoiesis, impede erythropoietin production, and limit iron availability by inducing the iron regulator hepcidin. High hepcidin hinders iron absorption and recycling, thereby worsening the impaired erythropoiesis by restricting iron availability. AI management is important as anemia impacts quality of life and potentially affects morbidity and mortality. The bone morphogenetic protein (BMP)‐SMAD pathway is crucial for hepcidin regulation. Here, we characterized a research antibody against BMP receptor ALK2, RKER‐216, and investigated its mechanism in suppressing hepcidin and improving anemia in acute/chronic inflammation. Additive effects of RKER‐216 and recombinant human erythropoietin (rhEPO) on erythropoiesis and iron utilization were also explored. We showed that RKER‐216 neutralized ALK2 activity by competing with the binding of BMP6. RKER‐216 reduced hepcidin transcription in Hep3B cells, and a subcutaneous dose of RKER‐216 at 3 mg/kg suppressed serum hepcidin and increased circulating iron for 3–4 days in wildtype mice. Moreover, RKER‐216 decreased hepcidin by inhibiting SMAD1/5/9 signaling in lipopolysaccharide‐mediated inflammation and liberated iron from the recycling pathway to alleviate anemia in mice with adenine‐induced chronic kidney disease (CKD), a mouse model of AI. Finally, RKER‐216 reversed iron‐restricted erythropoiesis in CKD mice and supplied the iron requirement for complete resolution of anemia when coupled with rhEPO in addressing AI. Our data support that ALK2 is a key hepcidin regulator and that a neutralizing ALK2 antibody has the potential to restore iron homeostasis as monotherapy or in combination with rhEPO to ameliorate AI.

This meta‐analysis examined the association between minimal residual disease (MRD) negativity and survival outcomes in 15 304 patients with multiple myeloma (MM) enrolled in randomized controlled trials published until June 2, 2024. Overall, there was a significant, negative and strong association between MRD negativity odds ratios and survival hazard ratios (β_PFS = ‐0.20, p < 0.001, β_OS = ‐0.12, p = 0.023). These associations remained significant for newly diagnosed patients (β_PFS = ‐0.35, p < 0.001), and they were consistent but not significant for relapsed/refractory patients (β_PFS = ‐0.06, p = 0.635). Sustained MRD negativity at 1 year was strongly correlated with prolonged PFS (β_PFS = ‐0.30, p < 0.001). In conclusion, this comprehensive meta‐analysis supports MRD as a surrogate for survival in MM.

Oral budesonide exerts local effects with negligible systemic glucocorticoid activity, due to rapid first‐pass metabolism, therefore, could potentially be efficacious in preventing gastrointestinal (GI) acute GVHD (aGVHD). We explored the use of budesonide, added to posttransplant cyclophosphamide (PTCy), tacrolimus, and mycophenolate mofetil, for prevention of GI aGVHD after allogeneic hematopoietic stem cell transplantation (AHSCT) in a prospective observational study and treated 80 patients with a median age of 53 years (range 19–74). Results were compared with a publicly available CIBMTR dataset of 646 patients who received PTCy‐based GVHD prophylaxis (CIBMTR Study # GV17‐02) (control). Cumulative incidence (CI) of 3‐month grade 2–4 and grade 3–4 aGVHD in the budesonide and control groups were 3.8% vs. 34.4% (p < 0.001) and 1.3% vs. 9.8% (p = 0.029), respectively. One‐year GRFS (70.5% vs. 31.5%, p < 0.001), PFS (73.4% vs. 52.8%, p = 0.003), and OS (80.1% vs. 64.2%, p = 0.038) were significantly higher in the budesonide group compared with control group. Propensity score‐adjusted analyses showed that the addition of budesonide significantly decreased risk of aGVHD grade 2–4 (HR 0.29, p < 0.001), grade 3–4 (HR 0.12, p = 0.045), and cGVHD (HR 0.22, p < 0.001), which resulted in better GRFS (HR 0.38, p < 0.001), PFS (HR 0.58, p = 0.012), and OS (HR 0.72, p = 0.044). Similar results were found when using propensity score‐matched analysis restricted to recipients of haploidentical transplantation. In conclusion, addition of budesonide to PTCy‐based GVHD prophylaxis is safe and effective in preventing severe acute GI GVHD with significantly improved GRFS. These results could facilitate transition to peripheral blood grafts for all allogeneic transplant recipients.

Acute myeloid leukemia (AML) is a genetically heterogeneous disease with high rates of relapse after initial treatment. Identifying measurable residual disease (MRD) following initial therapy is essential to assess response, predict patient outcomes, and identify those in need of additional intervention. Currently, MRD analysis relies on invasive, serial bone marrow (BM) biopsies, which complicate sample availability and processing time and negatively impact patient experience. Additionally, finding a positive result can generate more questions than answers, causing anxiety for both the patient and the provider. Peripheral blood (PB) evaluation has shown promise in detecting MRD and is now recommended by the European Leukemia Net for AML for certain genetic abnormalities. PB‐based sampling allows for more frequent testing intervals and better temporal resolution of malignant expansion while sparing patients additional invasive procedures. In this review, we will discuss the current state of PB testing for MRD evaluation with a focus on next‐generation sequencing methodologies that are capable of MRD detection across AML subtypes.

Despite advances in treatment, approximately 15% of patients with diffuse large B‐cell lymphoma (DLBCL) who achieve complete remission (CR) after first‐line therapy will experience a relapse. However, there is no consensus on the optimal follow‐up strategies for detecting relapse after achieving CR. This population‐based study, based on the Danish Lymphoma Registry (LYFO), identified a total of 1634 patients diagnosed with DLBCL between 2010 and 2017, including 105 patients who achieved CR following first‐line R‐CHOP‐like therapy and subsequently relapsed. The median follow‐up time was 6 years (range 3–8 years). Most cases of relapse were symptomatic (83%), with B symptoms and peripheral lymphadenopathy being the most common. Asymptomatic relapses were identified through physical examination (1%), blood tests (3%), or imaging findings (13%). The proportion of relapses identified outside routine visits was 70%. Only 5% of scheduled routine visits led to a relapse diagnosis, whereas 74% of unscheduled visits initiated by the patient outside routine follow‐up resulted in relapse detection. Our findings highlight that systematic, scheduled monitoring of patients in remission after first‐line treatment contributes only modestly to the early detection of disease recurrence. Future studies should explore alternative methods of relapse surveillance rather than relying solely on pre‐scheduled clinical follow‐up.

Adding inotuzumab ozogamicin (InO) to hyper‐CVAD and blinatumomab may improve outcomes in newly diagnosed Philadelphia chromosome (Ph)‐negative B‐cell acute lymphoblastic leukemia (B‐ALL). Patients with newly diagnosed B‐ALL received up to four cycles of hyper‐CVAD followed by four cycles of blinatumomab. Beginning with patient #39, InO 0.3 mg/m² was added on Days 1 and 8 to two cycles of high‐dose methotrexate and cytarabine, and two cycles of blinatumomab. The primary endpoint was the relapse‐free survival (RFS) rate. Seventy‐five patients were treated (median age of 33 years; range, 18–59), of whom 37 (49%) received hyper‐CVAD with blinatumomab and InO (cohort 2). Measurable residual disease (MRD) negativity by next‐generation sequencing (sensitivity: 1 × 10⁻⁶) was achieved in 79% of patients in cohort 2. The median follow‐up was 44 months (range, 13–90) overall, and 26 months (range, 8–39) in cohort 2. For the entire cohort, the estimated 3‐year RFS rate was 82% and the 3‐year overall survival rate was 90%. These rates were 90% versus 74% (p = 0.06) and 100% versus 82% (p = 0.01) in patients who did or did not receive InO, respectively. No sinusoidal obstruction syndrome was observed. In summary, hyper‐CVAD with blinatumomab and InO improved the outcomes of patients with newly diagnosed B‐ALL.

Patients who develop acute myeloid leukemia (AML) after having received treatment for myelodysplastic syndrome (MDS) or related conditions have particularly poor outcomes. This study analyzed adult patients with newly diagnosed AML who previously had MDS, chronic myelomonocytic leukemia (CMML), or MDS/myeloproliferative neoplasm (MPN) overlap syndrome, and who had received hypomethylating agents, chemotherapy, and/or allogeneic stem cell transplantation (HSCT) for these antecedent disorders. From January 2012 to August 2023, we included 673 patients with a median age of 70 years (range, 19–94); 536 (80%) had transformed from MDS, and the remainder from CMML or MDS‐MPN. Additionally, 149 patients (22%) had prior therapy for nonmyeloid malignancies. Among 497 evaluable patients, 289 (58%) had adverse‐risk (AR) cytogenetics, 34% had TP53 mutation/s, and 71% were classified as AR by the ELN 2017 criteria. Most patients (67%) received low‐intensity therapy (LIT) for AML, and 27% were treated with venetoclax. The overall response rate was 37%, and venetoclax improved the odds of response (OR = 2.5, 95% CI 1.6–3.7) in LIT–treated patients. At a median follow‐up of 43 months, the median relapse‐free survival (RFS) and overall survival (OS) were 4.6 and 4.8 months, respectively. Multivariate analysis showed that prior therapy for nonmyeloid disorders (HR = 1.30), ≥ 2 lines of therapy for antecedent myeloid disorders (HR = 1.23), and ELN AR risk (HR = 1.47) increased the hazards of death, while HSCT (HR = 0.50) was beneficial and validated on gradient‐boosted regression. TS‐AML is associated with poor outcomes irrespective of AML genomics and treatment, highlighting the need for its inclusion as an independent AR category for accurate prognostication and clinical trial reporting.

Chimeric antigen receptor (CAR) T‐cell therapy has revolutionized treatment of aggressive large B‐cell lymphoma (aLBCL). Patients with transformed indolent non‐Hodgkin lymphoma (tiNHL) were included in key CAR trials, but outcomes of CAR for this distinct, historically high‐risk group are poorly understood. We conducted a multicenter retrospective study of 1182 patients with aLBCL receiving standard‐of‐care CAR T between 2017 and 2022, including 338 (29%) with tiNHL. Rates of grade ≥ 3 cytokine release syndrome (CRS) were similar between tiNHL and de novo cohorts (7% vs. 8%, p = 0.6), while grade ≥ 3 immune effector cell‐associated neurotoxicity syndrome was lower in tiNHL (21% vs. 27%, p = 0.02). Overall response rate was similar in both cohorts (83% vs. 81%, p = 0.3), while complete response rate was higher in tiNHL (67% vs. 59%, p = 0.017). With a median follow‐up of 22.3 months, the progression/relapse‐free (PFS) and overall survival (OS) were similar between the tiNHL and de novo cohorts (24‐month PFS 41% [95% CI: 35%–46%] vs. 38% [95% CI: 35%–42%]; 24‐month OS 58% [95% CI: 52%–63%] vs. 52% [95% CI: 48%–56%], respectively). After adjusting for key risk factors, there was a trend toward a lower hazard of disease progression, relapse or death post‐CAR for tiNHL patients compared to de novo aLBCL patients (HR: 0.84 [95% CI: 0.69–1.0], p = 0.07). Elevated LDH, advanced stage, prior bendamustine within 12 months of CAR, receipt of bridging therapy, CNS involvement, and ≥ 3 prior lines of therapy were each associated with inferior PFS. In conclusion, CAR T therapy is highly effective with an acceptable toxicity profile in patients with tiNHL.

Community‐acquired respiratory viral infections (CARV) significantly impact patients with hematological malignancies (HM), leading to high morbidity and mortality. However, large‐scale, real‐world data on CARV in these patients is limited. This study analyzed data from the EPICOVIDEHA‐EPIFLUEHA registry, focusing on patients with HM diagnosed with CARV during the 2023–2024 autumn–winter season. The study assessed epidemiology, clinical characteristics, risk factors, and outcomes. The study examined 1312 patients with HM diagnosed with CARV during the 2023–2024 autumn–winter season. Of these, 59.5% required hospitalization, with 13.5% needing ICU admission. The overall mortality rate was 10.6%, varying by virus: parainfluenza (21.3%), influenza (8.8%), metapneumovirus (7.1%), RSV (5.9%), or SARS‐CoV‐2 (5.0%). Poor outcomes were significantly associated with smoking history, severe lymphopenia, secondary bacterial infections, and ICU admission. This study highlights the severe risk CARV poses to patients with HM, especially those undergoing active treatment. The high rates of hospitalization and mortality stress the need for better prevention, early diagnosis, and targeted therapies. Given the severe outcomes with certain viruses like parainfluenza, tailored strategies are crucial to improving patient outcomes in future CARV seasons.