EHA Library - The official digital education library of European Hematology Association (EHA)

Abstract

Abstract: P215

Type: Poster Presentation

Presentation during EHA22: On Friday, June 23, 2017 from 17:15 - 18:45

Location: Poster area (Hall 7)

Background

Enasidenib (AG-221) is an oral, selective, small-molecule inhibitor of mIDH2 enzymes. Preclinical studies showed that exposing myeloblasts from patients (pts) with acute myeloid leukemia (AML) to enasidenib ex vivo resulted in differentiation of leukemic marrow blasts into mature, fully functional neutrophils (Yen et al, Cancer Discov, 2017).  Enasidenib can result in IDH-inhibitor-associated differentiation syndrome (IDH-DS) in treated pts, with manifestations akin to retinoic acid syndrome seen during therapy of acute promyelocytic leukemia. 

Aims
To characterize the prevalence, characteristics, and course of IDH-DS in pts with relapsed or refractory (R/R) AML receiving enasidenib 100 mg daily in a phase 1 dose-escalation and expansion study (NCT01915498). This dose is currently under study in a multicenter, randomized, phase 3 trial comparing enasidenib with conventional care regimens in R/R AML pts (NCT02577406).

Methods
An independent Differentiation Syndrome Review Committee (DSRC) was formed to review potential cases of IDH-DS. The DSRC identified and agreed upon a series of signs and symptoms possibly characteristic of IDH-DS, including fever, lung infiltrates, pleural or pericardial effusions, rapid weight gain, edema, and azotemia. In all, 27 cases (8 of investigator-reported IDH-DS and 19 with characteristics suggestive of IDH-DS) were identified and retrospectively reviewed by the DSRC to determine their consistency with IDH-DS.

Results
The DSRC determined 13 cases (11.9% of 109 R/R AML pts in the enasidenib 100 mg/day dosing cohort) to be consistent with IDH-DS. Median time to onset was 30 days (range 7-116). Manifestations of IDH-DS in >2 pts were dyspnea (n=10), pyrexia (9), lung infiltrates (8), pleural effusion (5), and kidney injury (3). IDH-DS was effectively managed with systemic corticosteroids in 12/13 cases. Leukocytosis accompanied 4/13 cases, for which hydroxyurea was employed for cytoreduction. Enasidenib was interrupted for 9 pts (for a median of 7 days), but dose reductions or enasidenib discontinuation were not required for pts with IDH-DS. Six of the 13 pts had clinical responses (2 complete remissions [CR], 2 CRs with incomplete hematologic recovery, 1 partial remission, and 1 morphologic leukemia-free state), 6 pts had stable disease, and 1 pt had progressive disease.

Conclusion

Systemic corticosteroids, close hemodynamic management, and hydroxyurea (in the presence of leukocytosis) are effective IDH-DS management strategies; they should be administered promptly when IDH-DS is suspected, and continued until improvement. Enasidenib interruption can be considered if initial intervention is unsuccessful. IDH-DS represents a novel clinical finding in pts with mIDH2 AML treated with enasidenib, and is likely due to its suggested mechanism of action, myeloblast differentiation.

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): Clinical Trial, Acute Myeloid Leukemia, Safety, Mutation

Abstract: P215

Type: Poster Presentation

Presentation during EHA22: On Friday, June 23, 2017 from 17:15 - 18:45

Location: Poster area (Hall 7)

Background

Enasidenib (AG-221) is an oral, selective, small-molecule inhibitor of mIDH2 enzymes. Preclinical studies showed that exposing myeloblasts from patients (pts) with acute myeloid leukemia (AML) to enasidenib ex vivo resulted in differentiation of leukemic marrow blasts into mature, fully functional neutrophils (Yen et al, Cancer Discov, 2017).  Enasidenib can result in IDH-inhibitor-associated differentiation syndrome (IDH-DS) in treated pts, with manifestations akin to retinoic acid syndrome seen during therapy of acute promyelocytic leukemia. 

Aims
To characterize the prevalence, characteristics, and course of IDH-DS in pts with relapsed or refractory (R/R) AML receiving enasidenib 100 mg daily in a phase 1 dose-escalation and expansion study (NCT01915498). This dose is currently under study in a multicenter, randomized, phase 3 trial comparing enasidenib with conventional care regimens in R/R AML pts (NCT02577406).

Methods
An independent Differentiation Syndrome Review Committee (DSRC) was formed to review potential cases of IDH-DS. The DSRC identified and agreed upon a series of signs and symptoms possibly characteristic of IDH-DS, including fever, lung infiltrates, pleural or pericardial effusions, rapid weight gain, edema, and azotemia. In all, 27 cases (8 of investigator-reported IDH-DS and 19 with characteristics suggestive of IDH-DS) were identified and retrospectively reviewed by the DSRC to determine their consistency with IDH-DS.

Results
The DSRC determined 13 cases (11.9% of 109 R/R AML pts in the enasidenib 100 mg/day dosing cohort) to be consistent with IDH-DS. Median time to onset was 30 days (range 7-116). Manifestations of IDH-DS in >2 pts were dyspnea (n=10), pyrexia (9), lung infiltrates (8), pleural effusion (5), and kidney injury (3). IDH-DS was effectively managed with systemic corticosteroids in 12/13 cases. Leukocytosis accompanied 4/13 cases, for which hydroxyurea was employed for cytoreduction. Enasidenib was interrupted for 9 pts (for a median of 7 days), but dose reductions or enasidenib discontinuation were not required for pts with IDH-DS. Six of the 13 pts had clinical responses (2 complete remissions [CR], 2 CRs with incomplete hematologic recovery, 1 partial remission, and 1 morphologic leukemia-free state), 6 pts had stable disease, and 1 pt had progressive disease.

Conclusion

Systemic corticosteroids, close hemodynamic management, and hydroxyurea (in the presence of leukocytosis) are effective IDH-DS management strategies; they should be administered promptly when IDH-DS is suspected, and continued until improvement. Enasidenib interruption can be considered if initial intervention is unsuccessful. IDH-DS represents a novel clinical finding in pts with mIDH2 AML treated with enasidenib, and is likely due to its suggested mechanism of action, myeloblast differentiation.

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): Clinical Trial, Acute Myeloid Leukemia, Safety, Mutation

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies