This Week in Hematology — Jul 31, 2026

Welcome to This Week in Hematology. This week we're covering 9 notable papers spanning advances in myeloid neoplasms and clonal hematopoiesis, optimization of frontline lymphoma and leukemia therapies, and new insights into managing cellular therapy toxicities. Let's dive in.

We begin with a prospective study published in Blood that tackles the challenging boundary between clonal cytopenia of undetermined significance, or CCUS, and lower-risk myelodysplastic syndromes [2]. Because current diagnostic criteria rely heavily on semi-quantitative morphologic thresholds, distinguishing these two entities is often difficult despite their clinical and molecular overlap. Researchers evaluated 409 patients with CCUS and 241 with lower-risk MDS using harmonized criteria, centralized pathology, and uniform genomic profiling. By applying two independent models—the Clonal Hematopoiesis Risk Score and the Clonal Cytopenia Risk Score—they discovered that patients categorized as high-risk CCUS exhibited clinical features and event rates comparable to those with lower-risk MDS. Conversely, those with low- or intermediate-risk CCUS had significantly better outcomes, supporting a conservative management approach. This clinical and genomic convergence suggests that patients with high-risk CCUS should be considered for enrollment in prospective clinical trials designed for lower-risk MDS, moving us toward a more risk-adapted therapeutic framework. This theme of refining risk stratification is also highly relevant in chronic myelomonocytic leukemia, or CMML. Writing in Blood Advances, investigators evaluated the prognostic utility of the International Prognostic Scoring System-Molecular, or IPSS-M, in a multicenter retrospective cohort of 511 patients with CMML [6]. CMML has a highly variable clinical course, making prognostication difficult. The study found that the IPSS-M effectively stratified patients into distinct risk groups for overall survival and cumulative incidence of acute myeloid leukemia progression. By merging overlapping intermediate-risk categories, they created a simplified four-tier model that maintained strong predictive power across both the myelodysplastic and myeloproliferative CMML subsets. This adapted IPSS-M performed comparably to the established iCPSS and outperformed the CPSS-Mol, supporting its broader clinical application to guide therapeutic strategies in CMML. When evaluating patients with suspected myelodysplastic syndromes in a real-world setting, clinical guidelines increasingly recommend looking for underlying germline predispositions. A study published in Blood Advances investigated the feasibility and clinical yield of systematic germline follow-up in an unselected cohort of 716 patients at a typical adult MDS clinic [7]. By analyzing diagnostic targeted sequencing data for variants in CEBPA, DDX41, ETV6, GATA2, and RUNX1 with a variant allele frequency of 35% or higher, they identified 98 variants in 87 patients. Ultimately, pathogenic or likely pathogenic germline variants were confirmed in nearly 3% of the overall cohort, with the vast majority of these variants occurring in the DDX41 gene. Among patients under the age of 50, the prevalence of a germline predisposition rose to nearly 17% when incorporating testing for genes not routinely covered on standard somatic panels. These findings demonstrate that routine germline follow-up is highly feasible and yields critical clinical insights, particularly for younger patients who require broader genetic testing. The clinical implications of clonal hematopoiesis also extend to nonmalignant hematology, particularly in the context of cellular therapies for sickle cell disease. A study in Blood examined the characteristics of donor and recipient clonal hematopoiesis in 98 individuals with sickle cell disease and 72 non-sickle cell donor controls undergoing nonmyeloablative allogeneic hematopoietic cell transplantation [8]. Because of reports of myelodysplastic syndrome and acute myeloid leukemia following cellular therapies for sickle cell disease, understanding these precursor clonal states is vital. The researchers found that while baseline clonal hematopoiesis prevalence was similar between recipients and donors, sickle cell disease recipients had a nearly four-fold higher odds of harboring DNA Damage Response-mutant clonal hematopoiesis, involving genes such as TP53, PPM1D, ATM, and CHEK2. Following transplantation, the proportion of recipients with clonal hematopoiesis increased, driven by newly emergent mutations, engrafted donor-derived clones, and persistent recipient clones. Notably, persistent recipient clonal hematopoiesis was characterized by DNA damage response mutations, and the cohort included three fatal cases of TP53-mutant myeloid malignancies, emphasizing the critical need to monitor and optimize cellular therapy safety in this population. Rounding out our coverage of bone marrow failure and clonal disorders, the British Journal of Haematology published a 2-year interim analysis of an observational study evaluating the long-term efficacy and safety of combining romiplostim with immunosuppressive therapy as a first-line treatment for patients with aplastic anemia [9]. While the published abstract does not detail specific survival or response percentages, this trial represents an important ongoing effort to define long-term outcomes and safety profiles for first-line thrombopoietin receptor agonist combinations in severe aplastic anemia.

Next, we turn to major therapeutic advances in leukemia and lymphoma, where clinical trials are redefining standard care and explaining regional differences in treatment outcomes. In Blood Advances, researchers reported a prespecified subset analysis of the phase three SWOG S1826 trial, which compared frontline nivolumab plus AVD against brentuximab vedotin plus AVD in patients with advanced-stage classic Hodgkin lymphoma [1]. Historically, patients with Epstein-Barr virus-positive disease or non-nodular sclerosis histology have faced a poorer prognosis. Among the patients with known Epstein-Barr virus status, nivolumab-AVD significantly improved three-year progression-free survival in the Epstein-Barr virus-positive group to 91% compared to 70% with brentuximab-AVD, and showed a similar trend in the virus-negative group. Furthermore, in patients with non-nodular sclerosis histology, nivolumab-AVD prolonged three-year progression-free survival to 86% compared to 63% in the brentuximab-AVD arm. These findings demonstrate that frontline nivolumab-AVD substantially abrogates the historically poor prognosis associated with these high-risk biological subgroups, strongly supporting its role as the frontline standard of care. Meanwhile, in the setting of acute myeloid leukemia, a post-hoc analysis of the phase three BMT CTN 1506 MORPHO trial, also published in Blood Advances, sheds light on why post-transplant maintenance with the FLT3 inhibitor gilteritinib showed a survival benefit in North America but not in Europe or Asia [3]. The investigators analyzed the impact of timing and pre-transplant therapy on measurable residual disease, or MRD. They found that patients transplanted within 120 days of diagnosis, or those who received pre-transplant FLT3 inhibitors, had higher levels of pre-transplant MRD and derived a significant survival benefit from post-transplant gilteritinib. In contrast, geographic regions with longer times to transplant and successive courses of chemotherapy combined with FLT3 inhibition achieved lower pre-transplant MRD levels, which ultimately eliminated the survival benefit of post-transplant maintenance. This highlights how regional variations in clinical practice directly influence MRD kinetics and the subsequent utility of post-transplant maintenance therapies.

Our final theme focuses on the management and biological mechanisms of toxicities associated with chimeric antigen receptor, or CAR, T-cell therapies. While immune effector cell-associated neurotoxicity syndrome, or ICANS, is well-recognized, atypical non-ICANS neurotoxicities, known as NINTs, represent a serious challenge after ciltacabtagene autoleucel therapy for relapsed or refractory multiple myeloma. A study in Science Translational Medicine investigated a cohort of 109 patients treated with cilta-cel to identify risk factors for these atypical toxicities [4]. The authors discovered that a high-peak absolute lymphocyte count in the peripheral blood was a strong predictor of non-ICANS neurotoxicities. This CAR lymphocytosis was characterized by a polyclonal expansion with a distinct bias toward CD4-positive CAR T-cells expressing memory markers and showing increased inflammatory pathway gene expression. Identifying these specific CD4-positive CAR T-cell populations provides a potential therapeutic target to mitigate these challenging, atypical neurotoxicities in the future. For patients who develop standard ICANS, corticosteroid-refractory cases carry a high risk of morbidity. Anakinra, an interleukin-one receptor antagonist, is increasingly used in this scenario, but predictive data have been limited. A study in Blood Advances evaluated 101 patients treated with anakinra for ICANS, 90 of whom had corticosteroid-refractory symptoms [5]. The median time to ICANS resolution from anakinra initiation was 8 days, with a 28-day cumulative incidence of resolution of 86%. Crucially, the researchers found that achieving a significant neurologic improvement, defined as a two-grade or greater improvement in ICANS within 72 hours of starting anakinra, was a powerful predictor of positive outcomes. Patients who achieved this early response had a faster median time to resolution of 3 days compared to 9 days for non-responders, shorter hospital stays, lower cumulative steroid exposure, and zero treatment-related mortality at 28 days compared to 21% in those without an early response. This 72-hour clinical assessment provides a practical decision point for identifying patients who may require additional, intensified therapeutic strategies.

If you only have time for one paper this week, make it the subset analysis of the SWOG S1826 trial published in Blood Advances [1]. This study provides definitive evidence that frontline nivolumab-AVD overcomes the historically poor prognosis of Epstein-Barr virus-positive and non-nodular sclerosis classic Hodgkin lymphoma, solidifying its place as the preferred frontline standard of care for advanced-stage disease.

Here are the key takeaways from this week in Hematology. First, frontline nivolumab-AVD should be considered the standard of care for advanced classic Hodgkin lymphoma, particularly in high-risk biological subgroups such as those with Epstein-Barr virus-positive disease or non-nodular sclerosis histology. Second, high-risk clonal cytopenia of undetermined significance shows clinical and genomic convergence with lower-risk myelodysplastic syndromes, suggesting these patients should be managed similarly and considered for clinical trials. Third, the benefit of post-transplant gilteritinib maintenance in FLT3-ITD acute myeloid leukemia is highly dependent on pre-transplant MRD, which is driven by regional differences in the timing of transplant and the intensity of pre-transplant FLT3 inhibition. Fourth, in patients treated with anakinra for severe or steroid-refractory ICANS, a two-grade or greater neurologic improvement within 72 hours serves as a critical prognostic marker for rapid resolution and lower treatment-related mortality. And finally, systematic germline screening in myelodysplastic syndrome clinics is highly feasible, revealing pathogenic predispositions—most commonly in DDX41—in nearly 3% of unselected adult patients and up to 17% of patients under the age of 50.

That's your roundup for This Week in Hematology. The full transcript and references are available on the episode page in your AudioScholar library. This is an AI-curated summary — for clinical decisions, always consult primary sources and current guidelines. See you next week.

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