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

In this week's episode we’ll learn more about the use of ruxolitinib plus dexamethasone to treat newly diagnosed patients with adult hemophagocytic lymphohistiocytosis; lysine-specific demethylase-1 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.

Featured Articles:

• Ruxolitinib combined with dexamethasone for adult patients with newly diagnosed hemophagocytic lymphohistiocytosis in China
• Novel, potent, and orally bioavailable LSD1 inhibitors induce fetal hemoglobin synthesis in a sickle cell disease mouse model
• Clinical phenotype and pathophysiological mechanisms underlying qualitative low VWF

Episode Transcript

Speaker 1 (00:01):
Welcome to the 07/17/2025 episode of Blood
Podcast, your source forinnovative ideas and cutting
edge information. Our topics arebased on articles published in
Blood, a journal of the AmericanSociety of Hematology. Today,
we'll learn more about the useof ruxolitinib plus

(00:22):
dexamethasone to treat newlydiagnosed patients with adult
hemophagocyticlymphohistiocytosis, lysine
specific dimethylase oneinhibitors as a potential new
class of therapies for sicklecell disease and other beta
globinopathies, and insightsinto clinical characteristics of
patients with von Willebrandfactor levels that are lower

(00:43):
than normal but higher thanthose typically used to diagnose
von Willebrand disease. We firstexamined data in the blood
article entitled Bruxolitinibcombined with Dexamethasone in
newly diagnosed adulthemophagocytic
lymphohistiocytosis patients inChina by Di Zhu of the Zhejiang

(01:07):
University School of Medicine inZhejiang, China, and colleagues.
Hemophagocyticlymphohistiocytosis, or HLH, is
a rapidly progressivehyperinflammatory condition that
leads to cytopenias, organfailure, and a high mortality
rate.
HLH can be either primary orsecondary. Primary HLH is an

(01:29):
inherited disorder that usuallymanifests during infancy.
Primary HLH can often be curedusing etoposide based chemo
immunotherapy, followed bysequential allogeneic
hematopoietic stem celltransplants. Secondary HLH,
which occurs more often inadults, is triggered by
infection, rheumatic diseases,malignancies, or sometimes

(01:51):
unknown causes. Because of itsaggressive clinical
presentations, secondary HLH isoften treated with induction
therapy while its cause is underinvestigation.
Patients are then transitionedto an etiology based therapy
when and if the trigger isidentified. Induction therapy
for secondary HLH involves thesame etoposide based

(02:13):
chemoimmunotherapeutic regimensused in primary HLH. However,
these regimens are much lesseffective and can be more toxic
in adults. HLH's pathophysiologyinvolves the excessive release
of inflammatory cytokines,including interleukins II, VI,
and X, as well as interferongamma. Because the JAK STAT

(02:36):
pathway plays a central role incytokine regulation, it has been
hypothesized that HLH mightrespond to the JAK1two inhibitor
ruxolitinib.
Several small pilot studies havesuggested that ruxolitinib
dexamethasone combinationtherapy can treat secondary HLH
effectively. The authors of thefirst paper we're discussing

(02:57):
designed and conducted a PhaseII clinical trial of this
combination, which they dub RUD,as first line induction therapy
for adult patients. Twenty eightpatients with newly diagnosed
HLH with an unknown trigger wereenrolled in this single center,
single arm study, which wasconducted in China. Patients

(03:18):
received an eight week course ofRUD, in which the ruxolitinib
dose remained steady and thedexamethasone dose was gradually
tapered down. Twenty four of thetwenty eight patients responded
to RUD treatment, for an overallresponse rate, or ORR, of about
eighty six percent.
About eighteen percent of thesewere complete responses, another

(03:41):
thirty six percent had partialresponses, and thirty two
percent showed improvement insome measures of HLH. At a
median follow-up of about twoyears, the two month overall
survival, or OS, rate was alsoeighty six percent. This
compares well to a historicaltwo month OS rate of forty eight
percent derived from aretrospective study conducted in

(04:04):
the same center. The six monthoverall survival rate was sixty
eight percent, and two yearoverall survival was fifty four
percent. Most of the twentyeight patients who began
treatment with RUD wereeventually diagnosed with an
underlying trigger for theirHLH.
Sixteen had a confirmeddiagnosis of lymphoma, primarily

(04:26):
NK T cell lymphoma. Thesepatients were considerably
older, with a median age of 53years, compared with twenty
seven years for the non lymphomagroup. These patients also
received fewer weeks of RUD, fora median of fourteen point five
days, compared with twenty eightpoint five days for the full

(04:46):
cohort. Reasons for RUDdiscontinuation included
lymphoma diagnosis, HLH relapse,and lack of response. Patients
in the non lymphoma triggergroup had better outcomes with
RUD therapy compared with thosediagnosed with lymphoma.
Patients in the non lymphomagroup had an ORR of one hundred

(05:08):
percent, including five completeresponses. Those in the lymphoma
group had an ORR of seventy fivepercent, with no complete
responses. The two year OS ratewith lymphoma was only thirty
seven point five percentcompared with seventy five
percent in the non lymphomagroup. At the time of this
report, fifteen patients werestill living, including nine

(05:31):
with non lymphoma associated HLHand six with lymphoma associated
HLH. Adverse events associatedwith RUD were primarily grades
one or two with no toxicitiesthat led to dose reduction or
treatment discontinuation.
The authors concluded that RUDis a safe and effective initial

(05:52):
therapy for adult patients withnewly diagnosed HLH and unknown
triggers. They suggested that aphase three randomized
controlled trial of this regimenis warranted. In an accompanying
commentary, Adi Zaref Lorenz andMartin Ellis of the Meir Medical
Center in Kefar Saba, Israel,said that this data provides

(06:14):
support for the growing use ofruxolitinib as an early
treatment for adult HLH. Theyagreed with the need for
validation of the RUD regimen ina randomized clinical trial, but
noted that selection of acontrol arm might be
challenging, given the hightoxicity of current, standard of
care, etoposide based regimensfor treating early adult HLH.

(06:42):
Next up, we'll discuss thefindings from the blood article
entitled Novel, Potent, andOrally Bioavailable LSD1
Inhibitors Induce FetalHemoglobin Synthesis in a sickle
cell disease mouse model by YuWang of the University of
Michigan Medical School in AnnArbor, Michigan, and colleagues.

(07:03):
Hydroxyurea is a mainstay oftherapy for sickle cell disease,
in part because of its abilityto induce fetal hemoglobin
production, which interfereswith hemoglobin S polymerization
and reduces red blood cellsickling. Recently, another
class of compounds, known aslysine specific demethylase one

(07:24):
LSD1) inhibitors, has also beenshown to induce fetal hemoglobin
production in humans. LSD1 is atranscription regulator involved
in a wide range of physiologicprocesses, including both
hematopoiesis and hemostasis.LSD1 inhibitors are under
investigation for treatingsickle cell disease and other

(07:46):
disorders such as betathalassemia major that involve
the production of abnormal betaglobins. Most of the currently
available LSD1 inhibitors bindcovalently, and thus
irreversibly.
Because LSD1 is involved in somany different physiological
processes, these compounds areassociated with a high level of

(08:07):
adverse effects. The authors ofthe second paper that we're
discussing used structure aideddrug design to create newer,
reversible LSD1 inhibitors.These newer compounds have
improved pharmacologicproperties, including higher
affinity, potency, andselectivity for LSD1. To begin
their work, the authorscrystallized a truncated form of

(08:29):
LSD1 in complex with tworequired cofactors and a
reversible LSD1 inhibitor thatthey had created earlier. After
acquiring a high resolutionstructure, they designed and
synthesized over 50 newcompounds predicted to bind to
LSD1 with higher affinities thantheir original compound.

(08:50):
They selected two of these newcompounds with particularly high
binding affinities to test invitro. Both compounds
selectively inhibited LSD1activity in human adult
erythroid cells derived fromCD34 positive hematopoietic stem
and progenitor cells. Both newLSD1 inhibitors also robustly

(09:12):
increased expression of fetalhemoglobin in an in vitro model
of human erythroid celldifferentiation to levels
potentially high enough to havetherapeutic effects in humans.
Another drawback of previousLSD1 inhibitors has been their
association with anemia inpatients with sickle cell
disease, which has beenattributed to their ability to

(09:34):
skew differentiation oferythroid precursor cells
towards myeloid lineagesinstead. To overcome this
potential drawback, the authorsinvestigated whether a second
compound, a BRD4 degrader, couldrescue erythroid differentiation
by indirectly inhibiting themyeloid transcription factors
RUNX1 and PU1.

(09:56):
BRD4 is a bromodomain containingprotein whose presence is
required to support theactivities of these
transcription factors. Use ofthe LSD1 inhibitor and BRD4
degrader together rescuederythroid differentiation in the
cell culture model, albeit witha reduction in fetal hemoglobin
production that could be largelyovercome by a change in dosing

(10:20):
parameters. The authors nexttested their LSD1 inhibitors in
a mouse model of sickle celldisease, in which the mouse
alpha and beta globin genes werereplaced with human alpha
globin, gamma globin, and sicklecell mutated beta globin genes.
Oral administration of either ofthe two LSD1 inhibitors

(10:42):
increased fetal hemoglobinproduction and greatly reduced
the proportion of sickled RBCscompared with mice who received
vehicle alone. Unlike previousLSD1 inhibitors, these new
compounds showed positiveeffects on anemia in the mouse
model, increasing the number,uniformity, and lifespan of

(11:02):
mature RBCs in peripheral blood.
Analyses of precursor cells inthe bone marrow and spleen
showed that the new LSD1inhibitors had a moderate impact
on erythroid differentiation,which may have been compensated
for by stress erythropoiesis inthe spleen. Splenomegaly and
liver damage were also reducedin the LSD1 inhibitor treated

(11:26):
mice compared with those thatreceived vehicle alone. The
authors concluded that novelreversible LSD1 inhibitors have
the potential for improvedefficacy and safety as new
treatments for sickle celldisease and other beta
globinopathies. While notcurative, oral therapies such as
these are likely to be more costeffective and accessible than

(11:49):
treatments based on gene therapyor stem cell transplant. In an
accompanying commentary, YoganSontararaja of the Cleveland
Clinic in Cleveland, Ohio andDonald Lavelle of the University
of Illinois at Chicago said thatthese findings represented a
novel avenue towards developingnew therapies for sickle cell

(12:11):
disease.
They noted that it will beimportant to show that these
new, reversible LSD1 inhibitorshave no cytotoxic effects, given
the sustained, high level oferythropoiesis needed for
patients with sickle celldisease to avoid poor outcomes.

(12:31):
In the final part of today'spodcast, we'll discuss findings
in the blood article entitledClinical Phenotype and
Pathophysiological MechanismsUnderlying Qualitative Low VWF
by Ferdows Atik of ErasmusUniversity Medical Center,
Erasmus M. C. In Rotterdam, TheNetherlands, and colleagues. Von

(12:52):
Willebrand disease is typicallydiagnosed in patients when Von
Willebrand factor antigen oractivity levels are less than 30
IUdL.
However, many individuals haveVWF levels that are higher than
30 but still lower than the 50IUdL level needed to rule out

(13:14):
von Willebrand disease. Many ofthese individuals do not have
bleeding complications and arenot managed as though they have
von Willebrand disease. However,there is a subset of patients
with VWF levels between thirtyand fifty international units
per deciliter who have excessivebleeding, often manifested as
heavy menstrual bleeding orpostpartum hemorrhage. Current

(13:36):
guidelines recommend that thissubset of patients, sometimes
designated as low VWF, bemanaged similarly to those
diagnosed outright with vonWillebrand disease. Investigated
the phenotypes and pathologicmechanisms of patients with low
VWF.

(13:57):
For the purposes of theiranalysis, they divided these
patients into two groups, knownas 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

(14:17):
of between thirty and fifty IUper deciliter. These patients
might be considered analogous tothose with type two von
Willebrand disease. Patientswith low VWF QT had VWF antigen
levels in the 30 to 50international units per
deciliter range. These patientswere more analogous to those
with type one von Willebranddisease.

(14:39):
To gain more insight into lowVWF, particularly in patients
with low VWF QL, the authorscombined data sets from three
previous epidemiological studiesof von Willebrand disease
conducted in Ireland and TheNetherlands. This new study
identified two fourteen patientsin the combined data set who had

(15:01):
a historically lowest VWFantigen or activity level in the
range of 30 to 50 internationalunits per deciliter together
with a positive ISTH bleedingassessment tool score. Another
two ninety five patients withtype 2A, 2B, or two ms von
Willebrand disease wereidentified for use as a control

(15:23):
group. One hundred and threepatients, or about half of the
low VWF cohort, had low VWF QL,suggesting that low VWF QL is
quite common. Many of thesepatients had low VWF QL by
multiple activity measures,suggesting the presence of a
mildly dysfunctional VWFprotein.

(15:44):
Most patients with low VWF QLhad significant bleeding
histories. The number and typesof bleeding episodes, as well as
range of ISTH bleedingassessment tool scores at
initial diagnosis, were similarto those seen in patients with
low VWF QT. However, patientswith low VWF QL had higher

(16:07):
bleeding rates and required moretreatments over a ten year
follow-up period. The majorityof these patients showed no
evidence of a concomitantplatelet disorder that might
have accounted for thesefindings. Current guidelines
indicate that patients with vonWillebrand disease or with low
VWF and bleeding be furtherevaluated for type two disease

(16:28):
if they have a VWF activity toantigen ratio of less than 0.7.
About half of the low VWF QLpatients had activity to antigen
ratios of less than 0.7.However, these patients had
important differences whencompared with the Type two
control group. Almost allpatients with Type two disease

(16:50):
carried likely pathogenic VWFgene variants, compared with
only about fifty percent ofpatients with low VWF In
addition, patients with low VWFQL responded well when
challenged with desmopressin,unlike the patients with type
two disease. These resultssuggested that patients with low

(17:10):
VWF QL had defects in VWFbiosynthesis and secretion, such
as differences in glycosylation,that might explain reduced VWF
function in the absence ofpotentially pathologic VWF gene
variants. Of note, patients withlow VWF QT also responded well
to desmopressin, and fewer thanhalf of them carried potentially

(17:34):
pathologic gene variants.
Based on these differences, theauthors concluded that low VWFQL
and type two von Willebranddisease are two distinct
disorders that may need to bemanaged differently. In
addition, given the clinicalsimilarities between patients
with low VWFQT and low VWFQL,the authors suggested that all

(17:57):
of these patients might benefitfrom management that is similar
to that used in type one vonWillebrand disease. In an
accompanying commentary, RaviSarod of the University of Texas
Southwestern Medical Center inDallas, Texas said that the
authors made a good case formanaging patients with low VWF
and a positive bleedingassessment tool score as a

(18:20):
milder form of type one vonWillebrand disease. This new
diagnosis would also make iteasier for these patients to
access diagnostic and treatmentservices at hemophilia treatment
centers. For a list ofadditional authors, as well as
more detailed articles andcommentaries on which this
podcast is based, please go tobloodjournal.org.

(18:43):
Be sure to join us next week foranother episode of Blood
Podcast. Thank you forlistening.