Real-world assessment of isocitrate
dehydrogenase inhibitor-associated
differentiation syndrome
Oxana Megherea, Carmen Janes, Andrew Kowalski, Jessica Baron, Esther
Ahn, Ashley Soule & Matthew Newman
To cite this article: Oxana Megherea, Carmen Janes, Andrew Kowalski, Jessica Baron,
Esther Ahn, Ashley Soule & Matthew Newman (2021): Real-world assessment of isocitrate
dehydrogenase inhibitor-associated differentiation syndrome, Leukemia & Lymphoma, DOI:
10.1080/10428194.2021.1957868
To link to this article: https://doi.org/10.1080/10428194.2021.1957868
Published online: 27 Jul 2021.
Submit your article to this journal
Article views: 60
View related articles
View Crossmark data
ORIGINAL ARTICLE
Real-world assessment of isocitrate dehydrogenase inhibitor-associated
differentiation syndrome
Oxana Meghereaa
, Carmen Janesb
, Andrew Kowalskic
, Jessica Barond
, Esther Ahne
, Ashley Soulef and
Matthew Newmanb
Department of Pharmacy, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; b
Department of Pharmacy/Oncology
Division, The Johns Hopkins Hospital, Baltimore, MD, USA; c
Department of Pharmacy, Yale New Haven Hospital, New Haven, CT, USA; d
NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY, USA; e
Sibley Memorial Hospital, Washington, DC,
USA; f
University of Kentucky HealthCare, Lexington, KY, USA
ABSTRACT
Ivosidenib and enasidenib are targeted agents that inhibit mutant isocitrate dehydrogenase
(IDH) enzymes, restoring normal cellular differentiation in affected acute myeloid leukemia
patients. Both agents carry a risk of differentiation syndrome (DS), a potentially life-threatening
complication. In this multicenter, retrospective study we sought to determine the real-world inci￾dence and characterize DS in patients with a myeloid malignancy treated with an IDH inhibitor.
Of 49 total patients, 15 patients (31%) had a documented diagnosis of DS and 8 patients (16%)
met the criteria of DS by Montesinos, et al. The most common signs and symptoms of DS were
dyspnea/hypoxia (56%), unexplained fever (56%), bone pain/arthralgia (44%), edema/weight
gain (39%), and pleural/pericardial effusions (33%). Our study reports a higher real-world inci￾dence of DS in patients treated with IDH inhibitors for myeloid malignancies than previ￾ously reported.
ARTICLE HISTORY
Received 16 February 2021
Accepted 12 July 2021
KEYWORDS
Differentiation syndrome;
IDH inhibitor; IDH-DS; acute
myeloid leukemia;
enasidenib; ivosidenib
Background
Acute myeloid leukemia (AML) is a hematologic malig￾nancy characterized by the infiltration of proliferative,
abnormally differentiated, or poorly differentiated
myeloid blasts in the bone marrow, blood, and other
tissues [1,2]. It accounts for about 1.1% of all new
annual cancer diagnoses in the United States (U.S.),
with an estimated 19,940 new diagnoses in 2020 [3].
The treatment of AML has rapidly evolved with the
introduction of targeted therapies into the standard of
care. The choice of induction therapy is influenced by
individual patient characteristics, such as age, pres￾ence of comorbid conditions, performance status, and
preexisting myelodysplasia [4]. In patients older than
60 years of age who are not candidates for intensive
remission induction, therapy selection is largely
dependent on the presence of actionable mutations,
including IDH1, IDH2, and FLT3. Despite treatment, the
disease recurs in many patients with AML within 3
years of diagnosis, with a median 5-year survival rate
of about 28% [2,3]. Treatment strategies in the
relapsed/refractory (R/R) setting are based on patient
age, performance status, previous response to
chemotherapy, and the presence of genetic mutations
that allow for the use of targeted agents [4]. IDH1 and
IDH2 mutations are present in approximately 20% of
patients with AML. Ivosidenib and enasidenib target
mutant IDH1 and IDH2 enzymes, respectively.
Presently, ivosidenib is approved by the U.S. Food and
Drug Administration (FDA) for both newly diagnosed
and R/R AML while enasidenib is approved in the R/R
setting alone. The National Comprehensive Cancer
Network currently recommends enasidenib and ivosi￾denib for the treatment of patients with AML who are
not candidates for intensive remission therapy and in
those with R/R IDH-mutant AML [4].
IDH mutations block normal cellular differentiation
by promoting the abnormal reduction of alpha-keto￾glutarate to the oncometabolite, R-2-hydroxyglutarate
(2-HG), resulting in DNA and histone hypermethylation
and inhibition of cellular differentiation [5]. The inhib￾ition of IDH1 and IDH2 by ivosidenib and enasidenib,
respectively, reduces 2-HG levels and restores hemato￾poietic differentiation [6]. While critical for anti-tumor
activity, the restoration of this process can lead to DS,
initially reported in patients with acute promyelocytic
leukemia (APL) undergoing induction therapy with
CONTACT Oxana Megherea [email protected] Hospital of the University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA, USA

2021 Informa UK Limited, trading as Taylor & Francis Group
LEUKEMIA & LYMPHOMA

https://doi.org/10.1080/10428194.2021.1957868

all-trans retinoic acid (ATRA) or arsenic trioxide (ATO).
The underlying mechanism of DS involves cytokine
imbalance, leading to tissue damage and inflammation
[7,8]. There are no pathognomonic signs and symp￾toms for DS and the presentation can be confounded
by co-occurring conditions, such as infections or leu￾kemic progression, thus potentially hindering diagno￾sis and leading to delays in management [9].
Given the variations in the presentation of DS,
determining its true incidence is difficult. The reported
incidence of DS with IDH inhibitors was approximately
11% in the original studies [10,11], while a more
recent FDA systematic analysis reported an incidence
of 19% [12]. In addition, while DS following ATRA or
ATO in patients with APL typically has an onset of
seven to twelve days from treatment initiation, the
symptom onset with IDH inhibitors can occur from
one day to five months [8,9]. Such a change from pre￾vious experiences with DS may further hinder its diag￾nosis, particularly due to the natural tendency toward
less frequent monitoring later in therapy. Furthermore,
data on risk factors for the development of DS in
patients treated with IDH inhibitors for IDH-mutant
AML is limited. Reported risk factors of IDH inhibitor￾induced DS (IDH-DS) include fewer previous anticancer
therapies, higher peripheral blast count at diagnosis,
and elevated lactate dehydrogenase levels in R/R
patients treated with enasidenib [9]. The recently pub￾lished FDA systematic analysis confirmed the associ￾ation between a higher peripheral blast at baseline
and DS and identified baseline bone marrow blasts

48% and mutations in TET2 for ivosidenib and SRSF2
for enasidenib as potential predictors of DS [12].
Patients presenting with IDH-DS may have mild to
moderate symptoms, including unexplained fever,
edema, or changes in creatinine. However, patients
presenting with severe cases may have significant
respiratory and hemodynamic compromise requiring
hospitalization and admission to a critical care unit [9].
Recognizing the significant risk associated with
undiagnosed DS in patients treated with enasidenib,
the FDA issued a safety communication in 2018 alert￾ing healthcare providers and patients of the need for
recognition of DS and prompt initiation of treatment
[13]. The treatment of IDH-DS includes administration
of dexamethasone upon presentation with symptoms
consistent with IDH-DS and hydroxyurea added in
patients with co-occurring leukocytosis [9]. IDH-DS is a
significant safety concern for patients receiving IDH
inhibitors, but there is a paucity of studies that have
evaluated its real-world incidence, severity, and man￾agement practices. The objective of this retrospective
study was to evaluate real-world data on IDH-DS
among several institutions in the U.S.
Materials and methods
We conducted a multicenter, retrospective chart
review of patients 18 years of age or older with mye￾loid malignancies and a confirmed IDH1 or IDH2 muta￾tion by next generation sequencing, treated with
ivosidenib or enasidenib between 1 August 2017 and
1 September 2019. Patients were excluded if they
were treated with an IDH inhibitor as part of a clinical
trial or pediatric oncology protocol. We collected base￾line and demographic data including age, sex, previ￾ous therapies, white blood cell (WBC) count, lactate
dehydrogenase, serum creatinine, and peripheral and
bone marrow blast percentage at the initiation of
therapy. Additional information collected included
signs and symptoms of IDH-DS, relevant laboratory
parameters at onset of symptoms, and interventions
employed in the treatment of the syndrome.
Study assessments
The primary objective of this study was to determine
the incidence of IDH-DS per the Montesinos criteria
[1], based on the presence of at least two of the fol￾lowing signs and symptoms occurring within 7 d of
one another, in the absence of significant secondary
causes: dyspnea and/or hypoxia, unexplained fever
(body temperature of 38.0 C for at least 2 d), edema
or weight gain >5 kg from therapy initiation, unex￾plained hypotension, acute kidney injury (
grade 2
per Common Terminology Criteria for Adverse Events
(CTCAE 5.0)), pulmonary edema, pulmonary infiltrates,
or pleural/pericardial effusions confirmed by imaging.
Based on the number of symptoms at presentation,
each episode of IDH-DS was classified as moderate
(two to three symptoms) or severe (four or more of
the symptoms listed above). The incidence of docu￾mented episodes of DS (clinical documentation with
or without meeting the Montesinos criteria) was also
determined. Secondary objectives included the fre￾quency of IDH-DS clinical manifestations, the severity
of IDH-DS, time to IDH-DS (defined as the time from
therapy initiation with an IDH inhibitor to time of
symptom onset), treatment practices for IDH-DS,
including the percentage of patients started on corti￾costeroids and hydroxyurea, and time to initiation of
corticosteroids and hydroxyurea (defined as the time
from onset of symptoms to time of initiation of corti￾costeroids and hydroxyurea, respectively). Other
2 O. MEGHEREA ET AL.
secondary endpoints included: percentage of patients
that had ivosidenib or enasidenib therapy held,
reduced, or discontinued secondary to IDH-DS, and
all-cause mortality while on IDH inhibitor therapy,
defined as mortality during therapy or within 14 d of
therapy discontinuation. The incidence of dissemi￾nated intravascular coagulopathy, tumor lysis syn￾drome, leukocytosis, rash, bone pain and arthralgia
were also determined.
Statistical analysis
Investigators at each clinical site determined patients
meeting inclusion criteria, conducted chart review,
and directly input the de-identified data into REDCap
hosted at The Johns Hopkins University, which was
utilized for data collection and management [14,15].
Investigators had access only to the information col￾lected for their respective institutions, except investi￾gators at the coordinating site (The Johns Hopkins
Hospital), who had access to the complete de-identi￾fied data set for the purpose of data analysis.
Combined data were analyzed using STATA 13
(StataCorp LLC, College Station, TX, USA).
Demographic characteristics and clinical outcomes
were summarized using the mean and standard devi￾ation or median and ranges, as appropriate based on
normality. Fisher’s exact tests and Kruskal-Wallis tests
were performed to compare the baseline characteris￾tics between patients that did and did not experience
IDH-DS for categorical and continuous variables,
respectively.
Results
Forty-nine patients treated with ivosidenib or enaside￾nib for a myeloid malignancy from 1 August 2017 to 1
September 2019 were included. Fifteen patients (31%)
had a documented diagnosis of IDH-DS and eight of
these patients (16%) met the criteria of IDH-DS per
Montesinos, et al. Three patients experienced two epi￾sodes of IDH-DS each. The median age of patients was
69 years (range 29 to 90). Of the patients with a docu￾mented diagnosis of IDH-DS, 27% received an IDH
inhibitor for newly diagnosed AML, while 60%
received treatment for R/R AML. In patients with R/R
AML experiencing IDH-DS, 54% had 2 or more previ￾ous anti-cancer treatments.
Patient characteristics were largely similar between
patients with and without documented IDH-DS, except
with regard to WBC count at the onset of symptoms
(Table 1). Patients that experienced IDH-DS were more
likely to have an elevated WBC count at the onset of
symptoms, with 27% of patients in the IDH-DS group
meeting the definition of leukocytosis (WBC >
10  109
/L) vs. 3% in the no-IDH-DS group (p ¼ 0.026).
All episodes of IDH-DS are characterized in Table 2.
The most common symptoms of IDH-DS per
Montesinos et al. in this cohort were dyspnea/hypoxia
(56%) and unexplained fever (56%), followed by
edema or weight gain >5 kg from therapy initiation
(39%), and pleural or pericardial effusions (33%). Other
common findings, not included in the Montesinos cri￾teria, were bone pain/arthralgia and leukocytosis,
occurring in 44% and 39% of patients, respectively.
Among patients that met the criteria of IDH-DS per
Montesinos et al. (n ¼ 8), an equal number of moder￾ate and severe episodes were noted. Hospitalization
occurred in 67% of episodes, 11% of which involved a
critical care admission. The median time to symptom
onset from IDH inhibitor initiation was 10 d (range 0
to 164 d), with 67% of episodes occurring within 30 d
of therapy initiation. In the three patients who had a
recurrent episode, the time between episodes was
10 d, 29 d, and 163 d (Table 2).
Corticosteroids were started in 72% of episodes of
documented IDH-DS at a median daily dose of
14.5 mg of dexamethasone equivalents, started within
a median of 2 d of symptom onset and continued for
a median of 10 d (range 2 to 71). All patients present￾ing with leukocytosis were started on hydroxyurea
within a median of one day of symptom onset (range
0 to 3). The IDH inhibitor regimen was interrupted for
22% of episodes of IDH-DS and 44% of episodes
resulted in therapy discontinuation. No patients had
dose reductions secondary to IDH-DS. The all-cause
mortality of patients on an IDH inhibitor was 14%.
Mutation of SRSF2 was present in 15 of 33 (45%)
patients receiving enasidenib; 6 of the 15 (40%) expe￾rienced IDH-DS. Mutation of TET2 was present in one
patient of the 16 (6%) receiving ivosidenib, who also
experienced IDH-DS. One patient receiving ivosidenib
did not have additional results for molecular abnor￾malities besides IDH1.
Discussion
IDH-DS is a potentially life-threatening complication of
IDH inhibitor therapy, occurring as a result of restored
differentiation of myeloblasts after drug initiation,
which is accompanied by cytokine imbalance, tissue
damage, and inflammation [7,8]. While a similar syn￾drome is well characterized in patients with APL, there
is limited information on signs, symptoms, or risk
IDH-DS WITH IVOSIDENIB AND ENASIDENIB 3
factors specific to IDH-DS. The clinical presentation
can be initially subtle or confounded by other co￾occurring conditions, leading to delays in recognition
and initiation of treatment.
The incidence of IDH-DS in our population appears
to be higher than that reported by DiNardo, et al. [11]
(11.2%) and Stein, et al. [10] (12.4%), both when a clin￾ically documented diagnosis of IDH-DS was present
and the stricter Montesinos criteria were utilized, at
31% and 16%, respectively. However, our incidence
was similar to that reported by Norsworthy, et al.,
which utilized the Montesinos criteria for the diagnosis
of the syndrome [12]. These findings suggest that the
actual incidence of IDH-DS may be higher than that
reported by the original studies. We chose to use
Montesinos criteria as they had been previously
applied to IDH-DS; however, as they were developed
in the context of APL, there is a need for the develop￾ment and refinement of diagnostic criteria specific to
IDH inhibitor therapy.
The most common manifestations of IDH-DS in our
population were consistent with those reported by
Montesinos et al. in patients with APL [1]. Bone pain
or arthralgia were present in 44% of all IDH-DS epi￾sodes, occurring in 13% of all patients receiving
ivosidenib and 16% of all patients receiving enaside￾nib in our cohort. The package labeling for ivosidenib
reflects arthralgia (including back pain, neck pain, pain
in extremity) in 32% and myalgia (including musculo￾skeletal pain) in 25% of patients [16]. For enasidenib
package labeling, bone pain was reported in 27% of
patients and was specifically highlighted as a symp￾tom of IDH-DS [17]. As this work was a retrospective
chart review, it is possible that bone pain and arthral￾gia may have occurred without explicit documenta￾tion, especially if low-grade. However, it appears that
bone pain, arthralgia, myalgia and related musculo￾skeletal symptoms are important and should be con￾sidered in the syndromic diagnosis of IDH-DS.
Leukocytosis (defined as WBC count >10  109
/L)
was previously identified as an independent prognos￾tic factor for moderate DS, while elevated serum cre￾atinine and WBC count >5  109
/L were identified as
independent prognostic factors for severe DS in APL
patients [1]. We found that in our population, patients
who experienced IDH-DS were more likely to have
leukocytosis at the onset of symptoms. In patients
who did not meet Montesinos criteria but had a pro￾vider-documented diagnosis of DS, 75% (6/8) of epi￾sodes presented with leukocytosis. Fathi, et al.
Table 1. Baseline characteristics.
Characteristic Documented IDH-DS (n ¼ 15) No IDH-DS (n ¼ 34) p value
Age (years), median (range) 70 (49  87) 69 (29  90) 0.56
Sex, n (%) 0.357
Female 7 (47) 11 (32)
Male 8 (53) 23 (68)
IDH inhibitor, n (%) 0.743
Ivosidenib 4 (27) 12 (35)
Enasidenib 11 (73) 22 (65)
Diagnosis, n (%) 0.630
New AML diagnosis 4 (27) 5 (15)
Relapsed/refractory AML 9 (60) 25 (73)
Othera 2 (13) 4 (12)
Prior hematopoietic cell transplant, n (%) 2 (22) 7 (78) 0.702
Prior anti-cancer regimens, median (range) 2 (2  4) 2 (0  4) 0.905
None, n (%) 2 (13) 4 (12)
1 regimen, n (%) 5 (33) 9 (26)
2 to 5 regimens, n (%) 8 (54) 21 (62)
WBC count (x 109
/L), median (range) 3.16 (0.5  50) 2.8 (0.5  18) 0.026
10  109 /L, n (%) 11 (73) 33 (97)
>10  109 /L, n (%) 4 (27) 1 (3)
Serum creatinine (mg/dL), mean (SD) 0.9 (0.3) 0.9 (0.3) 0.9689
LDH (U/L), median (range) 239 (131  1575) (n ¼ 12) 239 (183  2084) (n ¼ 26) 1.000
1  ULN, n (%) 5 (42) 11 (42)
>1  ULN, n (%) 7 (58) 15 (58)
Albumin (g/dL), mean (SD) 3.8 (0.6) 3.8 (0.6) (n ¼ 33) 0.7413
Peripheral blasts (%) (n ¼ 14) (n ¼ 26) 0.322
50%, n (%) 11 (79) 24 (92)
>50%, n (%) 3 (21) 2 (8)
Bone marrow blasts (%) (n ¼ 10) (n ¼ 26) 1.000
<20%, n (%) 6 (60) 14 (54)
20%50%, n (%) 3 (30) 8 (31)
>50%, n (%) 1 (10) 4 (15)
Other indications included: myelodysplastic syndrome (n ¼ 3), myelofibrosis (n ¼ 2), post-transplant maintenance in AML (n ¼ 1).
Abbreviations: IDH: isocitrate dehydrogenase; IDH-DS: isocitrate dehydrogenase inhibitor-associated differentiation syndrome; AML: acute myeloid leuke￾mia; WBC: white blood cell; SD: standard deviation; LDH: lactate dehydrogenase; ULN: upper limit of normal.
4 O. MEGHEREA ET AL.
Table 2. Characterization of IDH-DS Episodes.
Episodes of IDH-DS
Documented episodes of IDH-DS
Incidence 1 2 3 4Ab 4B 5 6A 6B 7 8 9 10 11A 11B 12 13 14 15
Symptoms/signs per Montesinos criteria
Dyspnea and/or hypoxia X X X X X X X X X X 56%
Pleural or pericardial effusion X X X X X X 33%
Pulmonary edema X 6%
Pulmonary infiltrates X X X X 22%
Unexplained fever X X X X X X X X X X 56%
Edema or weight gain >5 kg
from initiation
X X X X X X X 39%
Unexplained hypotension X X 11%
Creatinine increase X X X X 22%
Other signs and symptoms
DIC X X 11%
TLS X X X 17%
Leukocytosis X X X X X X X 39%
Rash X X X 17%
Bone pain/arthralgia X X X X X X X X 44%
Outcomes
IDH-DS per Montesinos X X X X X X X X X X (8/49) 16%
Time to IDH-DS episode, days 34 11 9 8 37 2 10 20 21 5 44 0 1 164 138 5 116 20 Median (range)a
10 (1–164)
Severity of IDH-DS per Montesinos – SMM M S – – –– SS M S – – M – Moderate 50%
Severe 50%
Hospitalization X X X X X X X X X X X X 67%
ICU admission X X 11%
Steroids started X X X X X X X X X X X X X 72%
Time to steroids, days 0 1 4 1 2 0 3 3 0 3 30 2 1 Median (range)
2 (0 to 3)
Dose per day in dexamethasone
equivalents, mg
12 20 6 20 8 20 20 8 8 20 6 20 20 Mean (SD)
4.5 (6.4)
Hydroxyurea started X X X X X X X X X 50%
IDH inhibitor held X X X X 22%
IDH inhibitor discontinued X X X X X X X X 44%
aTime to first episode of IDH-DS if >1 episode.
bEpisode at outside hospital.
Abbreviations: DIC: disseminated intravascular coagulopathy; TLS: tumor lysis syndrome; S: severe; M: moderate; IQR: interquartile range; IDH: isocitrate dehydrogenase; IDH-DS: isocitrate dehydrogenase inhibitor￾associated differentiation syndrome; ICU: intensive care unit.
IDH-DS WITH IVOSIDENIB AND ENASIDENIB
5
reported that IDH-DS in R/R AML patients treated with
enasidenib was significantly associated with a fewer
number of previous anticancer therapies and non-sig￾nificantly associated with higher baseline peripheral
blast counts and lactate dehydrogenase levels [9].
Norsworthy, et al. describe increased bone marrow
and peripheral blasts as potential predictors of DS in
patients treated with these agents [12]. We did not
find the above factors to be significantly different
when comparing patients with and without IDH-DS.
In the current study, SRSF2 mutations in patients
receiving enasidenib and with evidence of IDH-DS
were present in a similar proportion to the 43%
reported by Norsworthy, et al. [12] Mutation in TET2
was present in only one patient on ivosidenib, which
is less prevalent than the 21% reported by Norsworthy
et al. This may be a result of our comparatively smaller
sample size. We did not observe any novel associa￾tions between co-occurring mutations and IDH-DS,
however, this was not a focus of this study.
The time to IDH-DS in our population was similar
to other reports, with a median of 10 d, and with most
episodes occurring within the first month [9,12]. The
management of IDH-DS includes prompt initiation of
dexamethasone 10 mg twice daily upon presentation
of symptoms [16,17]. Dexamethasone was initiated in
72% of episodes of documented IDH-DS at a median
daily dose of 14.5 mg, started within a median of two
days of symptom onset. Notably, hydroxyurea was ini￾tiated within a median of one day of symptom onset
in all patients presenting with co-occurring leukocyt￾osis. The labeling for IDH inhibitors recommends treat￾ment with dexamethasone as soon as IDH-DS is
suspected, rather than meeting a minimum number of
criteria. As almost one-third of patients in our cohort
did not receive dexamethasone, there may be room
for improvement in the recognition and management
of the syndrome with these agents.
While the study was conducted retrospectively,
all investigators used common definitions for
each variable to reduce potential bias and minimize
inter-institution variability in data collection. While the
study period begins with the FDA approval of the first
IDH inhibitor, enasidenib, the limited sample size can
be explained by the relatively low incidence of IDH
mutations in patients with AML, making the conduct
of studies in this population challenging. This study
provided a unique opportunity for the evaluation of
the real-life incidence, presentation, and management
practices of IDH-DS at five institutions in the U.S. Our
findings suggest that DS may occur in more patients
treated with IDH inhibitors than initially reported and
further supports arthralgia and bone pain as manifes￾tations of IDH-DS. As such, more frequent monitoring
and inclusion of bone pain/arthralgia in the assess￾ment of IDH-DS should be considered in patients initi￾ated on these agents. While the present study did not
identify any novel prognostic factors, we found that
patients who experienced IDH-DS in our study were
more likely to have leukocytosis, a finding also
reported by Fathi et al. [9] and consistent with the
known pathophysiology of DS.
Conclusion
In this retrospective, multicenter study we found a
higher real-world incidence of DS in patients treated
with IDH inhibitors for myeloid malignancies than pre￾viously reported. In addition to the classical symptoms
of DS per Montesinos criteria, almost half of the
patients experiencing IDH-DS presented with bone
pain or arthralgia. A greater proportion of patients
had clinically documented IDH-DS versus clinical crite￾ria per Montesinos and colleagues. These findings sug￾gest that more vigilance for IDH-DS may be necessary,
particularly within the first month of initiation of IDH
inhibitor therapy, to allow for the prompt diagnosis
and management of a potentially life-threatening
complication. While many of the signs and symptoms
of IDH-DS overlap with the APL differentiation syn￾drome, further study should seek to determine criteria
unique to IDH inhibitor therapy.
Table 3. Summary of the incidence of common symptoms of DS per Montesinos.
Study Current study DiNardo CD, et al. Fathi AT, et al. Norsworthy K, et al.
Population IDH mutant hematologic malignancies R/R AML R/R AML R/R AML
IDH inhibitor Ivosidenib and enasidenib Ivosidenib Enasidenib Ivosidenib and enasidenib
Incidence of most common symptoms per Montesinos criteria, %
Dyspnea/hypoxia 56 (combined) 21.1/10.5 85/58 Ivosidenib Enasidenib
76 68
Unexplained fever 56 26.3 79 44 51
Edema or weight gain >5 kg 39 38.6 21 53 41
Pleural or pericardial effusions 33 31.6 57 76 61
Abbreviations: IDH: isocitrate dehydrogenase; AML: Acute myeloid leukemia; R/R: relapsed/refractory.
6 O. MEGHEREA ET AL.
Acknowledgments
The authors thank Kelly J. Norsworthy, MD for sharing her
experience, and advice in the development of this study
protocol. The work for the current manuscript was com￾pleted while the primary author was a pharmacy resident at
The Johns Hopkins Hospital.
Disclosure statement
No potential conflict of interest was reported by
the author(s).
References
[1] Montesinos P, Bergua JM, Vellenga E, et al.
Differentiation syndrome in patients with acute pro￾myelocytic leukemia treated with all-trans retinoic
acid and anthracycline chemotherapy: characteristics,
outcome, and prognostic factors. Blood. 2009;113(4):
775–783.
[2] Dohner H, Weisdorf DJ, Bloomfield CD. Acute myeloid €
leukemia. N Engl J Med. 2015;373(12):1136–1152.
[3] Acute myeloid leukemia – cancer stat facts. SEER
[cited 22 Sep 2020]. Available from: https://seer.can￾cer.gov/statfacts/html/amyl.html
[4] National comprehensive cancer network. Acute mye￾loid leukemia (version 2.2021). Available from: https://
www.nccn.org/professionals/physician_gls/pdf/aml.pdf
[5] Losman J-A, Kaelin WG. What a difference a hydroxyl
makes: mutant IDH, (R)-2-hydroxyglutarate, and can￾cer. Genes Dev. 2013;27(8):836–852.
[6] Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic
IDH1 and IDH2 mutations result in a hypermethyla￾tion phenotype, disrupt TET2 function, and impair
hematopoietic differentiation. Cancer Cell. 2010;18(6):
553–567.
[7] Luesink M, Jansen JH. Advances in understanding the
pulmonary infiltration in acute promyelocytic leukae￾mia. Br J Haematol. 2010;151(3):209–220.
[8] Luesink M, Pennings JLA, Wissink WM, et al.
Chemokine induction by all-trans retinoic acid and
arsenic trioxide in acute promyelocytic leukemia:
triggering the differentiation syndrome. Blood. 2009;
114(27):5512–5521.
[9] Fathi AT, DiNardo CD, Kline I, et al. Differentiation
syndrome associated with Enasidenib, a selective
inhibitor of mutant isocitrate dehydrogenase 2: ana￾lysis of a phase 1/2 study. JAMA Oncol. 2018;4(8):
1106–1110.
[10] Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in
mutant IDH2 relapsed or refractory acute myeloid leu￾kemia. Blood. 2017;130(6):722–731.
[11] DiNardo CD, Stein EM, de Botton S, et al. Durable
remissions with ivosidenib in IDH1-mutated relapsed
or refractory AML . N Engl J Med. 2018;378(25):
2386–2398.
[12] Norsworthy KJ, Mulkey F, Scott EC, et al.
Differentiation syndrome with ivosidenib and enaside￾nib treatment in patients with relapsed or refractory
IDH-mutated AML: a U.S. Food and Drug
Administration Systematic Analysis. Clin Cancer Res.
2020;26(16):4280–4288.
[13] Center for drug evaluation and research. FDA warns
that symptoms of a serious condition affecting the
blood cells are not being recognized with the leuke￾mia medicine Idhifa (enasidenib). FDA. Published
online December 20, 2019 [cited 14 Dec 2020].
Available from: https://www.fda.gov/drugs/drug￾safety-and-availability/fda-warns-symptoms-serious￾condition-affecting-blood-cells-are-not-being-recog￾nized-leukemia
[14] Harris PA, Taylor R, Thielke R, et al. Research elec￾tronic data capture (REDCap) – a metadata-driven
methodology and workflow process for providing
translational research informatics support . J Biomed
Inform. 2009;42(2):377–381.
[15] Harris PA, Taylor R, Minor BL, et al. The REDCap con￾sortium: building an international community of soft￾ware platform partners. J Biomed Inform. 2019;95:
103208.
[16] Tibsovo [package insert]. Cambridge, MA: Agios
Pharmaceuticals, Inc.; 2019 [cited 14 Dec 2020].
Available from: https://www.tibsovopro.com/pdf/pre￾scribinginformation.pdf
[17] Idhifa [package insert]. Summit, NJ: Celgene
Corporation; 2020.
IDH-DS WITH IVOSIDENIB AND ENASIDENIB 7