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Abstract

Abstract: PS980

Type: Poster Presentation

Presentation during EHA23: On Saturday, June 16, 2018 from 17:30 - 19:00

Location: Poster area

Background
Enasidenib (AG-221) is a small-molecule, oral inhibitor of mutant IDH2 (mIDH2) proteins. The clinical efficacy of enasidenib is derived in part by differentiation of immature leukemic cells. Unlike cytotoxic therapies, lower-intensity therapies, including differentiating agents such as enasidenib, can induce first responses months after treatment (Tx) initiation.

Aims
Investigate efficacy outcomes for patients (pts) with R/R AML in the phase 1/2 AG221-C-001 study (NCT01915498) who maintained stable disease (SD) during early Tx with enasidenib.

Methods
Response and overall survival (OS) were assessed for pts with mIDH2 R/R AML who received enasidenib 100 mg/day and maintained SD, defined by the European LeukemiaNet (Döhner, Blood, 2017) as no formal IWG response and no evidence of progressive disease (PD) during the first 90 days on-study.

Results
Of 214 pts with R/R AML who received enasidenib 100 mg/day, 82 pts (38%) maintained SD during the first 90 days of Tx. As of data cutoff (1-Sep-2017), 25 pts (30%) achieved an IWG-defined response after day 90 (“Late Responders”), including 16 pts who attained complete remission. Twenty-nine pts (35%) retained SD at all subsequent response assessments (“SD Only”), and 28 pts (34%) developed PD after day 90 (Table). Median time to response for Late Responders was 121 days (range 91-286). Median Tx duration for Late Responders was 259 days, for SD Only pts was 164 days, and for pts who developed PD after day 90 was 107 days. At baseline, Late Responders were less likely than pts who later developed PD to have received >2 prior anti-cancer Tx (8% vs 32%, respectively) or to have poor-risk cytogenetics (8% vs 43%). Seven Late Responders (28%) went to transplant. Median OS for Late Responders was 15.1 months (95%CI 10.7, not reached [NR]), for SD Only pts was 9.0 months (7.7, 11.4), and for pts who developed PD after day 90 was 5.8 months (5.4, 8.3); estimated 1-year survival rates were 57.7%, 23.9%, and 8.2%, respectively. Risk of death was significantly reduced in Late Responders by 59% compared with SD Only pts (hazard ratio [HR] 0.41; 95%CI 0.21, 0.82), and by 79% compared with pts who later developed PD (HR 0.21; 0.10, 0.42). Similarly, maintaining SD after day 90 was associated with a significant 51% reduction in risk of death vs early SD followed by PD (HR 0.49; 0.28, 0.87).

Conclusion
SD may represent sustained but controlled proliferation of leukemic cells that, in some cases, later differentiate and lead to clinical responses. In the first 90 days of enasidenib Tx, 38% of pts with mIDH2 R/R AML maintained SD. Of them, almost one-third responded after day 90 during continued Tx. Late Responders had a significant OS benefit compared with pts with no later response. However, pts who maintained SD at all response evaluations received a median of ~5.5 months of enasidenib Tx and had a median OS of 9 months. These data suggest pts who sustain SD during early enasidenib Tx should continue Tx for at least 6 cycles or until PD. SD during early enasidenib therapy does not predict Tx failure, and pts who maintain SD may benefit from continuing enasidenib Tx.

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): AG-221, Enasidenib, Relapsed acute myeloid leukemia, Stable disease

Abstract: PS980

Type: Poster Presentation

Presentation during EHA23: On Saturday, June 16, 2018 from 17:30 - 19:00

Location: Poster area

Background
Enasidenib (AG-221) is a small-molecule, oral inhibitor of mutant IDH2 (mIDH2) proteins. The clinical efficacy of enasidenib is derived in part by differentiation of immature leukemic cells. Unlike cytotoxic therapies, lower-intensity therapies, including differentiating agents such as enasidenib, can induce first responses months after treatment (Tx) initiation.

Aims
Investigate efficacy outcomes for patients (pts) with R/R AML in the phase 1/2 AG221-C-001 study (NCT01915498) who maintained stable disease (SD) during early Tx with enasidenib.

Methods
Response and overall survival (OS) were assessed for pts with mIDH2 R/R AML who received enasidenib 100 mg/day and maintained SD, defined by the European LeukemiaNet (Döhner, Blood, 2017) as no formal IWG response and no evidence of progressive disease (PD) during the first 90 days on-study.

Results
Of 214 pts with R/R AML who received enasidenib 100 mg/day, 82 pts (38%) maintained SD during the first 90 days of Tx. As of data cutoff (1-Sep-2017), 25 pts (30%) achieved an IWG-defined response after day 90 (“Late Responders”), including 16 pts who attained complete remission. Twenty-nine pts (35%) retained SD at all subsequent response assessments (“SD Only”), and 28 pts (34%) developed PD after day 90 (Table). Median time to response for Late Responders was 121 days (range 91-286). Median Tx duration for Late Responders was 259 days, for SD Only pts was 164 days, and for pts who developed PD after day 90 was 107 days. At baseline, Late Responders were less likely than pts who later developed PD to have received >2 prior anti-cancer Tx (8% vs 32%, respectively) or to have poor-risk cytogenetics (8% vs 43%). Seven Late Responders (28%) went to transplant. Median OS for Late Responders was 15.1 months (95%CI 10.7, not reached [NR]), for SD Only pts was 9.0 months (7.7, 11.4), and for pts who developed PD after day 90 was 5.8 months (5.4, 8.3); estimated 1-year survival rates were 57.7%, 23.9%, and 8.2%, respectively. Risk of death was significantly reduced in Late Responders by 59% compared with SD Only pts (hazard ratio [HR] 0.41; 95%CI 0.21, 0.82), and by 79% compared with pts who later developed PD (HR 0.21; 0.10, 0.42). Similarly, maintaining SD after day 90 was associated with a significant 51% reduction in risk of death vs early SD followed by PD (HR 0.49; 0.28, 0.87).

Conclusion
SD may represent sustained but controlled proliferation of leukemic cells that, in some cases, later differentiate and lead to clinical responses. In the first 90 days of enasidenib Tx, 38% of pts with mIDH2 R/R AML maintained SD. Of them, almost one-third responded after day 90 during continued Tx. Late Responders had a significant OS benefit compared with pts with no later response. However, pts who maintained SD at all response evaluations received a median of ~5.5 months of enasidenib Tx and had a median OS of 9 months. These data suggest pts who sustain SD during early enasidenib Tx should continue Tx for at least 6 cycles or until PD. SD during early enasidenib therapy does not predict Tx failure, and pts who maintain SD may benefit from continuing enasidenib Tx.

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): AG-221, Enasidenib, Relapsed acute myeloid leukemia, Stable disease

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