This Week in Hematology — Jul 15, 2026

Welcome to This Week in Hematology. This week we are covering ten notable papers spanning clinical advances in malignant hematology, evolving strategies in non-malignant disorders like hemophilia and sickle cell disease, and critical safety insights in stem cell transplantation. Let us dive in.

We begin in the realm of malignant hematology, where optimizing therapy for high-risk and medically unfit patients remains a major clinical challenge. In a randomized phase two trial published in the journal Leukemia, researchers evaluated whether standard-dose CPX-351 or the intensive regimen CLAG-M, which consists of cladribine, cytarabine, granulocyte colony-stimulating factor, and mitoxantrone, is more effective for medically unfit adults with untreated acute myeloid leukemia or other high-grade myeloid neoplasms [1]. Historically, treating these vulnerable patients is highly challenging, and the best path forward has been unclear. In this trial of sixty adults, where more than two-thirds of the patients had an ECOG performance status of three or four, only the CLAG-M group met the primary endpoint of achieving a three-month overall survival rate of sixty-three percent or higher, actually reaching seventy percent compared to sixty percent in the CPX-351 group. CLAG-M also showed a non-significant trend toward a higher complete remission rate. While overall survival and relapse-free survival were statistically similar between the two arms for the entire cohort, a crucial subgroup analysis revealed that patients with highly proliferative disease experienced a significant survival advantage with CLAG-M, showing a median overall survival of eighteen and a half months compared to just under four months with CPX-351. This finding suggests that intensive cytarabine-based therapy still has an important role to play in unfit patients who present with proliferative disease, rather than defaulting to less intensive options.

Meanwhile, in the treatment of relapsed or refractory multiple myeloma, managing patients who relapse after receiving therapies targeting B-cell maturation antigen, or BCMA, is an increasingly common dilemma. A systematic review and meta-analysis of thirty-four studies published in Blood Cancer Journal evaluated salvage therapies, comparing chimeric antigen receptor T-cell therapy, or CAR-T, against engineered antibody therapies in this post-BCMA setting [3]. The pooled overall response rate across more than twelve hundred patients was sixty percent, but CAR-T therapy achieved a significantly superior overall response rate of seventy-seven percent compared to fifty-two percent for engineered antibodies. When looking closely at the specific targets, CAR-T therapies targeting GPRC5D yielded a substantially higher response rate of eighty-six percent compared to sixty-six percent for those re-targeting BCMA. The study also highlighted that patients who had prior exposure to BCMA bispecific antibodies had lower response rates than those with prior CAR-T exposure. Furthermore, patients who had a treatment-free interval of ten months or more between therapies responded significantly better. These results suggest that clinicians should prioritize earlier CAR-T use, consider GPRC5D as a preferred subsequent target, and carefully evaluate the timing and sequencing of these advanced immunotherapies.

Moving to lymphoma, the British Journal of Haematology published a real-world, multicenter retrospective study of one hundred patients with advanced-stage classical Hodgkin lymphoma treated with the BrECADD regimen, which combines brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone [6]. While advanced Hodgkin lymphoma is highly curable, traditional regimens like escalated BEACOPP carry substantial acute and long-term toxicities. In this real-world cohort, which included highly representative, high-risk patients, the overall response rate was one hundred percent, and ninety-five percent of patients achieved a complete response. Crucially, eighty-three percent of patients achieved early positron emission tomography negativity after two cycles, which allowed clinicians to safely de-escalate therapy from six to four cycles. At a median follow-up of nearly fourteen months, the estimated one-year progression-free survival was ninety-six percent, and overall survival was one hundred percent. Although severe neutropenia and febrile neutropenia were common, ninety-five percent of patients successfully completed all planned cycles, and only four percent required radiotherapy. This study strongly supports the real-world feasibility, outstanding efficacy, and favorable tolerability of BrECADD, reinforcing its role in minimizing long-term chemotherapy and radiotherapy exposure without compromising cure rates.

Rounding out our malignant hematology coverage, another study in the journal Leukemia investigated triple-negative essential thrombocythemia, a subtype that lacks the classic driver mutations in JAK2, CALR, or MPL, making diagnosis and risk stratification exceptionally difficult [8]. By analyzing two hundred and forty-one patients who underwent myeloid panel sequencing and confirmatory bone marrow biopsies, researchers identified pathogenic or likely pathogenic variants in approximately one-fifth of the cohort. These mutation carriers were typically older and had a higher rate of previous thrombotic events. The presence of these pathogenic variants was associated with a dramatic, twelve-fold increase in the risk of leukemic progression and a tripled risk of death, with specific mutations in ASXL1, CBL, EZH2, and ZRSR2 linked to worse leukemia-free survival. The study also validated the usefulness of the Revised IPSET-thrombosis score and the ARTS score for predicting arterial thrombosis risk. These findings underscore the critical clinical importance of performing comprehensive molecular profiling in triple-negative essential thrombocythemia patients to identify those with high-risk mutations who require closer surveillance and more aggressive management.

We transition now to non-malignant hematology, starting with venous thromboembolism. The clinical decision to stop or indefinitely continue anticoagulation after an initial venous thromboembolism is often challenging, especially when evaluating the impact of thrombophilia. A comprehensive systematic review and meta-analysis published in Blood Advances examined fifty-one studies representing over thirty-four thousand patients to clarify this risk [2]. The investigators found that high-risk thrombophilias, including antiphospholipid antibody syndrome, antithrombin deficiency, homozygous factor V Leiden, and compound heterozygous mutations, were associated with an approximate two- to three-fold increased risk of recurrent venous thromboembolism after stopping anticoagulation. In contrast, heterozygous factor V Leiden or prothrombin gene mutations carried a more modest, one-and-a-half-fold increased risk, while the evidence regarding protein C and protein S deficiencies remained inconclusive. These findings provide clinicians with clearer, evidence-based risk estimates to share with patients when discussing the benefits and risks of lifelong anticoagulation therapy.

In hemophilia care, the therapeutic landscape has expanded rapidly, but significant unmet needs persist. The ECHO study, published in Blood Advances, evaluated the real-world efficacy of efanesoctocog alfa, a first-in-class, ultra-long-acting factor VIII concentrate, within a French compassionate access framework [4]. The study included fifty patients with hemophilia A, nearly half of whom transitioned to weekly efanesoctocog alfa prophylaxis from emicizumab due to persistent breakthrough bleeding or complex clinical scenarios. Over a nine-month follow-up, weekly prophylaxis led to an eighty-nine percent reduction in treated bleeds and an eighty-five percent reduction in joint bleeds, a benefit that remained consistent even among those who previously failed emicizumab. However, the study uncovered a critical laboratory monitoring challenge: local one-stage clotting assays significantly overestimated factor VIII levels, yielding a median of fourteen international units per deciliter compared to only seven international units per deciliter when using a centralized, drug-calibrated chromogenic substrate assay. This discrepancy represents a major safety concern, as relying on standard one-stage assays could lead clinicians to believe a patient has double the protective factor level actually present. Clinicians must be highly vigilant and utilize calibrated chromogenic assays when monitoring patients on efanesoctocog alfa.

At the same time, the Journal of Thrombosis and Haemostasis published real-world data from the prospective PedNet Registry, which tracked eighty infants with severe hemophilia A who started early emicizumab prophylaxis as previously untreated or minimally treated patients [5]. While emicizumab has revolutionized pediatric hemophilia care by providing excellent bleeding control, real-world data on inhibitor development in this very young population have been limited. In this cohort, infants started emicizumab at a median age of eight and a half months and were followed for a median of nineteen and a half months. The therapy was highly effective, with a mean annualized bleeding rate of just zero point six bleeds per year. However, fifty-nine percent of the infants ultimately required factor VIII exposure for bleeding or minor procedures. Among those exposed, the cumulative incidence of factor VIII inhibitor development was thirty-five percent after a median of only four to eighteen exposure days. This preliminary analysis suggests that early emicizumab prophylaxis does not decrease the overall risk of developing inhibitors when these children are eventually exposed to factor VIII. Clinicians must continue to perform rigorous, routine inhibitor screening whenever an infant on emicizumab receives factor VIII.

Our final theme explores optimizing long-term outcomes and safety in sickle cell disease and stem cell transplantation. For children with sickle cell anemia, routine immunizations are vital, but there has been concern that disease-related immune dysfunction or concurrent hydroxyurea therapy might impair vaccine responses. A retrospective cohort study published in Blood Advances addressed this concern by evaluating measles vaccine seroprotection in children enrolled in the TREAT trial [9]. The researchers found that ninety-four percent of children achieved adequate seroprotection after their first measles vaccine, and ninety-two percent were protected after their second dose, which is highly comparable to the general population. Crucially, concurrent hydroxyurea treatment at the time of vaccination did not reduce seroprotection. In fact, starting hydroxyurea earlier in life was associated with a more than four-fold increase in the odds of achieving seroprotection. This reassuring study confirms that children with sickle cell anemia develop robust immunity to measles and highlights that early, timely vaccination combined with early hydroxyurea initiation offers the best immunologic protection, especially important given the rising global transmission of measles in the United States and worldwide.

Also in Blood Advances, researchers looked beyond clinical symptom resolution to evaluate subclinical physiology in patients with sickle cell disease who underwent curative therapies, comparing forty-three allogeneic stem cell transplant recipients and eleven gene therapy recipients to fifteen patients on optimal hydroxyurea therapy [10]. By analyzing blood rheology, which measures red blood cell deformability and sickling behavior, the study revealed that patients who received stem cell transplants from donors with sickle cell trait had significantly superior rheological parameters compared to both gene therapy recipients and those on optimal hydroxyurea. For instance, the point of sickling was zero in the transplant group, compared to twenty-six in the gene therapy group and thirty-six in the hydroxyurea group. The rheological profiles of patients who received gene therapy were comparable to those on optimal hydroxyurea, showing persistent subclinical abnormalities despite clinical improvement. Because abnormal rheology is closely linked to long-term sickle cell complications, these findings suggest that clinical symptom resolution does not equate to physiological normalization, and incorporating rheology testing into long-term post-therapy follow-up could help monitor for subclinical disease.

Lastly, we examine infectious complications in the setting of mismatched unrelated donor hematopoietic cell transplantation. The ACCESS trial, also published in Blood Advances, evaluated the infection burden in two hundred and sixty-eight adults who underwent mismatched transplant using post-transplant cyclophosphamide as graft-versus-host disease prophylaxis [7]. While this transplant strategy has achieved an impressive overall survival rate of eighty-one percent, post-transplant cyclophosphamide is known to suppress the immune system. The investigators recorded four hundred and sixty-five infections, with more than sixty percent occurring within the first one hundred days post-transplant. The density of infections was highest between days zero and thirty, and was similar regardless of the intensity of the conditioning regimen or the degree of donor HLA mismatch. A multivariable analysis revealed that the development of acute graft-versus-host disease was the strongest predictor of infection, and nearly eight percent of patients ultimately died from infectious causes. This study establishes a critical benchmark for the high infectious burden associated with post-transplant cyclophosphamide in mismatched unrelated donor transplants, emphasizing the need for intensive, early antimicrobial surveillance, particularly in patients who develop graft-versus-host disease.

If you only have time for one paper this week, make it the real-world study on efanesoctocog alfa in Hemophilia A published in Blood Advances [4]. This paper is the top pick because it provides highly practical, dual-edged clinical insights: it confirms the outstanding real-world efficacy of this ultra-long-acting factor in patients who have failed emicizumab, while delivering an urgent, practice-changing warning that standard one-stage assays can dangerously overestimate factor VIII levels, potentially masking a lack of adequate protection.

Here are the key takeaways from this week in Hematology. First, for medically unfit patients with acute myeloid leukemia, intensive CLAG-M chemotherapy remains a highly effective option and should be strongly considered over CPX-351 for those presenting with proliferative disease. Second, in patients with relapsed multiple myeloma who have failed BCMA-targeted therapies, GPRC5D-targeted CAR-T therapy offers superior response rates compared to engineered antibodies, especially when sequenced after a treatment-free interval of ten months or more. Third, high-risk thrombophilias like antiphospholipid antibody syndrome and antithrombin deficiency carry a two- to three-fold increased risk of recurrent venous thromboembolism, reinforcing the need for indefinite anticoagulation. Fourth, while weekly efanesoctocog alfa provides excellent bleed control in severe hemophilia A, clinicians must monitor factor levels using drug-calibrated chromogenic assays, as standard one-stage assays falsely double the measured factor levels. Finally, early initiation of hydroxyurea in children with sickle cell anemia does not impair measles vaccine efficacy and is actually associated with significantly improved seroprotection.

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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