TY - JOUR
T1 - Differentiation Syndrome with Ivosidenib and Enasidenib Treatment in Patients with Relapsed or Refractory IDH-Mutated AML
T2 - A U.S. Food and Drug Administration Systematic Analysis
AU - Norsworthy, Kelly J.
AU - Mulkey, Flora
AU - Scott, Emma C.
AU - Ward, Ashley F.
AU - Przepiorka, Donna
AU - Charlab, Rosane
AU - Dorff, Sarah E.
AU - Deisseroth, Albert
AU - Kazandjian, Dickran
AU - Sridhara, Rajeshwari
AU - Beaver, Julia A.
AU - Farrell, Ann T.
AU - de Claro, R. Angelo
AU - Pazdur, Richard
N1 - Funding Information:
This work was funded in part by an appointment to the Research Participation Program at the Office of Oncologic Diseases, Center for Drug Evaluation and Research at the FDA administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the FDA.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/8/15
Y1 - 2020/8/15
N2 - Purpose: Differentiation syndrome (DS) is a serious adverse reaction of isocitrate dehydrogenase (IDH) inhibitors ivosidenib and enasidenib in patients with (IDH)1- and IDH2-mutated acute myeloid leukemia (AML), respectively. Experimental Design: During FDA review of marketing applications for ivosidenib and enasidenib, data from pivotal trials were queried to identify cases of DS in patients with relapsed or refractory (R/R) AML. One hundred seventy-nine patients with R/R AML received ivosidenib and 214 received enasidenib. Adverse events, labs, and vital signs in the first 90 days of treatment were screened per diagnostic criteria, and narratives were reviewed to adjudicate DS cases. Results: We identified 72 of 179 (40%) potential cases for ivosidenib and 86 of 214 (40%) for enasidenib; 34 of 179 (19%) and 41 of 214 (19%) were adjudicated as DS. Leukocytosis was present in 79% and 61% of cases, respectively. Median (range) time to onset was 20 (1–78) and 19 (1–86) days. Grade ≥ 3 adverse reactions occurred in 68% and 66%; 6% and 5% were fatal. Univariate analyses suggested baseline bone marrow blasts ≥ 48% and peripheral blood blasts ≥ 25% and 15% for ivosidenib and enasidenib, respectively, were associated with increased risk of DS. Complete remission (CR) þ CR with partial hematologic recovery rates were lower in patients with versus without DS [ivosidenib 18% (95% confidence interval, 7%–35%) vs. 36% (28%–45%); enasidenib 18% (7%–33%) vs. 25% (18%–32%)]. Conclusions: DS is a common and potentially fatal adverse reaction of IDH inhibitors, and use of standardized diagnostic criteria may aid in earlier diagnosis and treatment.
AB - Purpose: Differentiation syndrome (DS) is a serious adverse reaction of isocitrate dehydrogenase (IDH) inhibitors ivosidenib and enasidenib in patients with (IDH)1- and IDH2-mutated acute myeloid leukemia (AML), respectively. Experimental Design: During FDA review of marketing applications for ivosidenib and enasidenib, data from pivotal trials were queried to identify cases of DS in patients with relapsed or refractory (R/R) AML. One hundred seventy-nine patients with R/R AML received ivosidenib and 214 received enasidenib. Adverse events, labs, and vital signs in the first 90 days of treatment were screened per diagnostic criteria, and narratives were reviewed to adjudicate DS cases. Results: We identified 72 of 179 (40%) potential cases for ivosidenib and 86 of 214 (40%) for enasidenib; 34 of 179 (19%) and 41 of 214 (19%) were adjudicated as DS. Leukocytosis was present in 79% and 61% of cases, respectively. Median (range) time to onset was 20 (1–78) and 19 (1–86) days. Grade ≥ 3 adverse reactions occurred in 68% and 66%; 6% and 5% were fatal. Univariate analyses suggested baseline bone marrow blasts ≥ 48% and peripheral blood blasts ≥ 25% and 15% for ivosidenib and enasidenib, respectively, were associated with increased risk of DS. Complete remission (CR) þ CR with partial hematologic recovery rates were lower in patients with versus without DS [ivosidenib 18% (95% confidence interval, 7%–35%) vs. 36% (28%–45%); enasidenib 18% (7%–33%) vs. 25% (18%–32%)]. Conclusions: DS is a common and potentially fatal adverse reaction of IDH inhibitors, and use of standardized diagnostic criteria may aid in earlier diagnosis and treatment.
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U2 - 10.1158/1078-0432.CCR-20-0834
DO - 10.1158/1078-0432.CCR-20-0834
M3 - Article
C2 - 32393603
AN - SCOPUS:85089571062
SN - 1078-0432
VL - 26
SP - 4280
EP - 4288
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 16
ER -