Ruxolitinib plus dexamethasone in newly diagnosed adult hemophagocytic lymphohistiocytosis; lysine-specific demethylase-1 inhibitors in sickle cell disease; and clinical characteristics of patients with low von Willebrand factor
Welcome to the 07/17/2025 episode of Blood Podcast, your source for innovative ideas and cutting edge information. Our topics are based on articles published in Blood, a journal of the American Society of Hematology. Today, we'll learn more about the use of ruxolitinib plus dexamethasone to treat newly diagnosed patients with adult hemophagocytic lymphohistiocytosis, lysine specific dimethylase one inhibitors as a potential new class of therapies for sickle cell disease and other beta globinopathies, and insights into clinical characteristics of patients with von Willebrand factor levels that are lower than normal but higher than those typically used to diagnose von Willebrand disease. We first examined data in the blood article entitled Bruxolitinib combined with Dexamethasone in newly diagnosed adult hemophagocytic lymphohistiocytosis patients in China by Di Zhu of the Zhejiang University School of Medicine in Zhejiang, China, and colleagues. Hemophagocytic lymphohistiocytosis, or HLH, is a rapidly progressive hyperinflammatory condition that leads to cytopenias, organ failure, and a high mortality rate.
Speaker 1:HLH can be either primary or secondary. Primary HLH is an inherited disorder that usually manifests during infancy. Primary HLH can often be cured using etoposide based chemo immunotherapy, followed by sequential allogeneic hematopoietic stem cell transplants. Secondary HLH, which occurs more often in adults, is triggered by infection, rheumatic diseases, malignancies, or sometimes unknown causes. Because of its aggressive clinical presentations, secondary HLH is often treated with induction therapy while its cause is under investigation.
Speaker 1:Patients are then transitioned to an etiology based therapy when and if the trigger is identified. Induction therapy for secondary HLH involves the same etoposide based chemoimmunotherapeutic regimens used in primary HLH. However, these regimens are much less effective and can be more toxic in adults. HLH's pathophysiology involves the excessive release of inflammatory cytokines, including interleukins II, VI, and X, as well as interferon gamma. Because the JAK STAT pathway plays a central role in cytokine regulation, it has been hypothesized that HLH might respond to the JAK1two inhibitor ruxolitinib.
Speaker 1:Several small pilot studies have suggested that ruxolitinib dexamethasone combination therapy can treat secondary HLH effectively. The authors of the first paper we're discussing designed and conducted a Phase II clinical trial of this combination, which they dub RUD, as first line induction therapy for adult patients. Twenty eight patients with newly diagnosed HLH with an unknown trigger were enrolled in this single center, single arm study, which was conducted in China. Patients received an eight week course of RUD, in which the ruxolitinib dose remained steady and the dexamethasone dose was gradually tapered down. Twenty four of the twenty eight patients responded to RUD treatment, for an overall response rate, or ORR, of about eighty six percent.
Speaker 1:About eighteen percent of these were complete responses, another thirty six percent had partial responses, and thirty two percent showed improvement in some measures of HLH. At a median follow-up of about two years, the two month overall survival, or OS, rate was also eighty six percent. This compares well to a historical two month OS rate of forty eight percent derived from a retrospective study conducted in the same center. The six month overall survival rate was sixty eight percent, and two year overall survival was fifty four percent. Most of the twenty eight patients who began treatment with RUD were eventually diagnosed with an underlying trigger for their HLH.
Speaker 1:Sixteen had a confirmed diagnosis of lymphoma, primarily NK T cell lymphoma. These patients were considerably older, with a median age of 53 years, compared with twenty seven years for the non lymphoma group. These patients also received fewer weeks of RUD, for a median of fourteen point five days, compared with twenty eight point five days for the full cohort. Reasons for RUD discontinuation included lymphoma diagnosis, HLH relapse, and lack of response. Patients in the non lymphoma trigger group had better outcomes with RUD therapy compared with those diagnosed with lymphoma.
Speaker 1:Patients in the non lymphoma group had an ORR of one hundred percent, including five complete responses. Those in the lymphoma group had an ORR of seventy five percent, with no complete responses. The two year OS rate with lymphoma was only thirty seven point five percent compared with seventy five percent in the non lymphoma group. At the time of this report, fifteen patients were still living, including nine with non lymphoma associated HLH and six with lymphoma associated HLH. Adverse events associated with RUD were primarily grades one or two with no toxicities that led to dose reduction or treatment discontinuation.
Speaker 1:The authors concluded that RUD is a safe and effective initial therapy for adult patients with newly diagnosed HLH and unknown triggers. They suggested that a phase three randomized controlled trial of this regimen is warranted. In an accompanying commentary, Adi Zaref Lorenz and Martin Ellis of the Meir Medical Center in Kefar Saba, Israel, said that this data provides support for the growing use of ruxolitinib as an early treatment for adult HLH. They agreed with the need for validation of the RUD regimen in a randomized clinical trial, but noted that selection of a control arm might be challenging, given the high toxicity of current, standard of care, etoposide based regimens for treating early adult HLH. Next up, we'll discuss the findings from the blood article entitled Novel, Potent, and Orally Bioavailable LSD1 Inhibitors Induce Fetal Hemoglobin Synthesis in a sickle cell disease mouse model by Yu Wang of the University of Michigan Medical School in Ann Arbor, Michigan, and colleagues.
Speaker 1:Hydroxyurea is a mainstay of therapy for sickle cell disease, in part because of its ability to induce fetal hemoglobin production, which interferes with hemoglobin S polymerization and reduces red blood cell sickling. Recently, another class of compounds, known as lysine specific demethylase one LSD1) inhibitors, has also been shown to induce fetal hemoglobin production in humans. LSD1 is a transcription regulator involved in a wide range of physiologic processes, including both hematopoiesis and hemostasis. LSD1 inhibitors are under investigation for treating sickle cell disease and other disorders such as beta thalassemia major that involve the production of abnormal beta globins. Most of the currently available LSD1 inhibitors bind covalently, and thus irreversibly.
Speaker 1:Because LSD1 is involved in so many different physiological processes, these compounds are associated with a high level of adverse effects. The authors of the second paper that we're discussing used structure aided drug design to create newer, reversible LSD1 inhibitors. These newer compounds have improved pharmacologic properties, including higher affinity, potency, and selectivity for LSD1. To begin their work, the authors crystallized a truncated form of LSD1 in complex with two required cofactors and a reversible LSD1 inhibitor that they had created earlier. After acquiring a high resolution structure, they designed and synthesized over 50 new compounds predicted to bind to LSD1 with higher affinities than their original compound.
Speaker 1:They selected two of these new compounds with particularly high binding affinities to test in vitro. Both compounds selectively inhibited LSD1 activity in human adult erythroid cells derived from CD34 positive hematopoietic stem and progenitor cells. Both new LSD1 inhibitors also robustly increased expression of fetal hemoglobin in an in vitro model of human erythroid cell differentiation to levels potentially high enough to have therapeutic effects in humans. Another drawback of previous LSD1 inhibitors has been their association with anemia in patients with sickle cell disease, which has been attributed to their ability to skew differentiation of erythroid precursor cells towards myeloid lineages instead. To overcome this potential drawback, the authors investigated whether a second compound, a BRD4 degrader, could rescue erythroid differentiation by indirectly inhibiting the myeloid transcription factors RUNX1 and PU1.
Speaker 1:BRD4 is a bromodomain containing protein whose presence is required to support the activities of these transcription factors. Use of the LSD1 inhibitor and BRD4 degrader together rescued erythroid differentiation in the cell culture model, albeit with a reduction in fetal hemoglobin production that could be largely overcome by a change in dosing parameters. The authors next tested their LSD1 inhibitors in a mouse model of sickle cell disease, in which the mouse alpha and beta globin genes were replaced with human alpha globin, gamma globin, and sickle cell mutated beta globin genes. Oral administration of either of the two LSD1 inhibitors increased fetal hemoglobin production and greatly reduced the proportion of sickled RBCs compared with mice who received vehicle alone. Unlike previous LSD1 inhibitors, these new compounds showed positive effects on anemia in the mouse model, increasing the number, uniformity, and lifespan of mature RBCs in peripheral blood.
Speaker 1:Analyses of precursor cells in the bone marrow and spleen showed that the new LSD1 inhibitors had a moderate impact on erythroid differentiation, which may have been compensated for by stress erythropoiesis in the spleen. Splenomegaly and liver damage were also reduced in the LSD1 inhibitor treated mice compared with those that received vehicle alone. The authors concluded that novel reversible LSD1 inhibitors have the potential for improved efficacy and safety as new treatments for sickle cell disease and other beta globinopathies. While not curative, oral therapies such as these are likely to be more cost effective and accessible than treatments based on gene therapy or stem cell transplant. In an accompanying commentary, Yogan Sontararaja of the Cleveland Clinic in Cleveland, Ohio and Donald Lavelle of the University of Illinois at Chicago said that these findings represented a novel avenue towards developing new therapies for sickle cell disease.
Speaker 1:They noted that it will be important to show that these new, reversible LSD1 inhibitors have no cytotoxic effects, given the sustained, high level of erythropoiesis needed for patients with sickle cell disease to avoid poor outcomes. In the final part of today's podcast, we'll discuss findings in the blood article entitled Clinical Phenotype and Pathophysiological Mechanisms Underlying Qualitative Low VWF by Ferdows Atik of Erasmus University Medical Center, Erasmus M. C. In Rotterdam, The Netherlands, and colleagues. Von Willebrand disease is typically diagnosed in patients when Von Willebrand factor antigen or activity levels are less than 30 IUdL.
Speaker 1:However, many individuals have VWF levels that are higher than 30 but still lower than the 50 IUdL level needed to rule out von Willebrand disease. Many of these individuals do not have bleeding complications and are not managed as though they have von Willebrand disease. However, there is a subset of patients with VWF levels between thirty and fifty international units per deciliter who have excessive bleeding, often manifested as heavy menstrual bleeding or postpartum hemorrhage. Current guidelines recommend that this subset of patients, sometimes designated as low VWF, be managed similarly to those diagnosed outright with von Willebrand disease. Investigated the phenotypes and pathologic mechanisms of patients with low VWF.
Speaker 1:For the purposes of their analysis, they divided these patients into two groups, known as low VWF QL for qualitative and low VWF QT for quantitative. Patients with low VWF QL had VWF antigen levels greater than 50, but reduced VWF activity levels of between thirty and fifty IU per deciliter. These patients might be considered analogous to those with type two von Willebrand disease. Patients with low VWF QT had VWF antigen levels in the 30 to 50 international units per deciliter range. These patients were more analogous to those with type one von Willebrand disease.
Speaker 1:To gain more insight into low VWF, particularly in patients with low VWF QL, the authors combined data sets from three previous epidemiological studies of von Willebrand disease conducted in Ireland and The Netherlands. This new study identified two fourteen patients in the combined data set who had a historically lowest VWF antigen or activity level in the range of 30 to 50 international units per deciliter together with a positive ISTH bleeding assessment tool score. Another two ninety five patients with type 2A, 2B, or two ms von Willebrand disease were identified for use as a control group. One hundred and three patients, or about half of the low VWF cohort, had low VWF QL, suggesting that low VWF QL is quite common. Many of these patients had low VWF QL by multiple activity measures, suggesting the presence of a mildly dysfunctional VWF protein.
Speaker 1:Most patients with low VWF QL had significant bleeding histories. The number and types of bleeding episodes, as well as range of ISTH bleeding assessment tool scores at initial diagnosis, were similar to those seen in patients with low VWF QT. However, patients with low VWF QL had higher bleeding rates and required more treatments over a ten year follow-up period. The majority of these patients showed no evidence of a concomitant platelet disorder that might have accounted for these findings. Current guidelines indicate that patients with von Willebrand disease or with low VWF and bleeding be further evaluated for type two disease if they have a VWF activity to antigen ratio of less than 0.7.
Speaker 1:About half of the low VWF QL patients had activity to antigen ratios of less than 0.7. However, these patients had important differences when compared with the Type two control group. Almost all patients with Type two disease carried likely pathogenic VWF gene variants, compared with only about fifty percent of patients with low VWF In addition, patients with low VWF QL responded well when challenged with desmopressin, unlike the patients with type two disease. These results suggested that patients with low VWF QL had defects in VWF biosynthesis and secretion, such as differences in glycosylation, that might explain reduced VWF function in the absence of potentially pathologic VWF gene variants. Of note, patients with low VWF QT also responded well to desmopressin, and fewer than half of them carried potentially pathologic gene variants.
Speaker 1:Based on these differences, the authors concluded that low VWFQL and type two von Willebrand disease are two distinct disorders that may need to be managed differently. In addition, given the clinical similarities between patients with low VWFQT and low VWFQL, the authors suggested that all of these patients might benefit from management that is similar to that used in type one von Willebrand disease. In an accompanying commentary, Ravi Sarod of the University of Texas Southwestern Medical Center in Dallas, Texas said that the authors made a good case for managing patients with low VWF and a positive bleeding assessment tool score as a milder form of type one von Willebrand disease. This new diagnosis would also make it easier for these patients to access diagnostic and treatment services at hemophilia treatment centers. For a list of additional authors, as well as more detailed articles and commentaries on which this podcast is based, please go to bloodjournal.org.
Speaker 1:Be sure to join us next week for another episode of Blood Podcast. Thank you for listening.