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

SAFETY STUDY OF CRENOLANIB, A TYPE I FLT3 INHIBITOR, WITH CYTARABINE/DAUNORUBICIN OR CYTARABINE/IDARUBICIN INDUCTION AND HIGH-DOSE CYTARABINE CONSOLIDATION IN NEWLY DIAGNOSED FLT3+ AML
Author(s): ,
Eunice Wang
Affiliations:
Roswell Park Cancer Institute,Buffalo,United States
,
Richard Stone
Affiliations:
Dana-Farber Cancer Institute,Boston,United States
,
Martin Tallman
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
James Thompson
Affiliations:
Roswell Park Cancer Institute,Buffalo,United States
,
Evelena Ontiveros
Affiliations:
Roswell Park Cancer Institute,Buffalo,United States
,
Gretchen Olson
Affiliations:
Roswell Park Cancer Institute,Buffalo,United States
,
Ilene Galinsky
Affiliations:
Dana-Farber Cancer Institute,Boston,United States
,
Blake Pond
Affiliations:
University of Texas Southwestern,Dallas,United States
,
Aki Uchida
Affiliations:
Arog Pharmaceuticals Inc,Dallas,United States
,
Vinoo Urity
Affiliations:
Arog Pharmaceuticals Inc,Dallas,United States
,
Ornela Xhori
Affiliations:
Arog Pharmaceuticals Inc,Dallas,United States
,
Meghan Macaraeg
Affiliations:
Arog Pharmaceuticals Inc,Dallas,United States
,
Madhuri Vusirikala
Affiliations:
University of Texas Southwestern,Dallas,United States
,
Prapti Patel
Affiliations:
University of Texas Southwestern,Dallas,United States
,
Roland Walter
Affiliations:
Fred Hutchinson Cancer Research Center,Seattle,United States
Robert Collins
Affiliations:
University of Texas Southwestern,Dallas,United States
(Abstract release date: 05/19/16) EHA Library. Wang E. 06/10/16; 133174; P186
Dr. Eunice Wang
Dr. Eunice Wang
Contributions
Abstract
Abstract: P186

Type: Poster Presentation

Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45

Location: Poster area (Hall H)

Background
Combining tyrosine kinase inhibitors (TKIs) of FLT3, such as midostaurin, with chemotherapy in FLT3+ mutant AML has improved CR rates (59% vs. 53%) as well as overall survival (OS). Crenolanib is a novel, type I, oral pan-FLT3 TKI demonstrating encouraging single-agent activity against multiply relapsed FLT3-ITD and tyrosine kinase domain (TKD) mutant AML. We here report interim data from a Phase II trial to evaluate the safety and efficacy of crenolanib in combination with upfront chemotherapy (cytarabine plus idarubicin or daunorubicin) in patients (pts) with newly diagnosed FLT3+ AML. 

Aims
To assess the safety and tolerability of crenolanib (100 mg TID) with induction and consolidation chemotherapy in newly diagnosed FLT3+ AML. Secondary objectives are to assess CR rate and relapse-free survival following crenolanib and chemotherapy. 

Methods
Patients >18 years (y), with newly diagnosed FLT3+ AML (ITD and/or TKD mutants including secondary AML) are eligible. Crenolanib, 100 mg TID, is given daily from day (d) 9 following 7+3 induction (cytarabine 100 mg/m2/d and either daunorubicin d1-3 (<60y: 90 mg/m2; ≥60y: 60 mg/m2) or idarubicin 12 mg/m2 d1-3). Re-induction is permitted for inadequate leukemia cytoreduction on days 15-28. Consolidation with 6 doses of high dose cytarabine (HiDAC) (<60y: 3 g/m2; ≥60y: 1g/m2) is given with daily crenolanib (100 mg TID) starting d7. Eligible pts can proceed to allogeneic SCT. Crenolanib maintenance can be given for 1y post HiDAC or SCT. Crenolanib is held if total bilirubin is abnormal.

Results
19 pts with newly diagnosed FLT3+ AML have so far been enrolled (11 females, 8 males) with a median age of 55y (range 23-74y). Median baseline WBC was 27,740/μL (range 1,760-248,800; 4 pts had WBC >100,000/μL). 13/17 (76%) of pts had normal karyotype, 2 pts had trisomy 8, 1 pt was pseudodiploid and 1 pt had complex karyotype. Majority of pts, 79% (15/19), were FLT3-ITD+ve with 10/15 also carrying NPM1 mutation. 4/19 (28%) pts were FLT3-D835+ve with 1 pt also carrying NPM1 mutation and 1 pt carrying D835Y and N841T mutations. 11/19 pts were tested for other mutations present at baseline: DNMT3A in 6/11 pts (55%), SF3B1, IDH1, TET2 and RUNX1 each in 2/11 pts (18%), and IDH2, MLL, SRSF2 and WT1 each in 1/11 pts (9%). All 19 pts have received induction chemotherapy: 13 received daunorubicin (8 pts at 90 mg/m2, 5 pts at 60 mg/m2) and 6 received idarubicin (12 mg/m2) No pt has required a second induction. 2 pts died prior to starting crenolanib during induction 1 (due to sepsis and respiratory failure) and are not evaluable.Crenolanib 100 mg TID has been well-tolerated in combination with cytarabine/anthracycline induction with only 2 pts requiring dose reductions (due to rash and periorbital edema, respectively). Common AEs are consistent with what is seen with crenolanib monotherapy, including grade 1 or 2 nausea, vomiting, diarrhea and rash. Crenolanib did not appear to delay count recovery; median count recovery for WBC was 28d (range 16-43d) and platelet was 27d (22-46d).A high CR rate was seen in the 14 pts who are currently evaluable: 13/14 pts (93%) achieved CR with full count recovery, and all pts became FLT3–ve. Only 1 pt was refractory after first cycle of induction therapy and was taken off study. To date, 9 pts have received a total of 13 cycles of consolidation with HiDAC and crenolanib. 2 pts have undergone allogeneic SCT.

Conclusion
Crenolanib can be safely administered at full doses with cytarabine/anthracycline induction chemotherapy and HiDAC consolidation. Initial CR rates after just one cycle of induction with 7+3 and crenolanib are high. To date, no patients have relapsed. Accrual to this trial continues.

Session topic: Acute myeloid leukemia - Clinical 1

Keyword(s): Chemotherapy, Flt3 inhibitor, Relapsed acute myeloid leukemia, Tyrosine kinase inhibitor
Abstract: P186

Type: Poster Presentation

Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45

Location: Poster area (Hall H)

Background
Combining tyrosine kinase inhibitors (TKIs) of FLT3, such as midostaurin, with chemotherapy in FLT3+ mutant AML has improved CR rates (59% vs. 53%) as well as overall survival (OS). Crenolanib is a novel, type I, oral pan-FLT3 TKI demonstrating encouraging single-agent activity against multiply relapsed FLT3-ITD and tyrosine kinase domain (TKD) mutant AML. We here report interim data from a Phase II trial to evaluate the safety and efficacy of crenolanib in combination with upfront chemotherapy (cytarabine plus idarubicin or daunorubicin) in patients (pts) with newly diagnosed FLT3+ AML. 

Aims
To assess the safety and tolerability of crenolanib (100 mg TID) with induction and consolidation chemotherapy in newly diagnosed FLT3+ AML. Secondary objectives are to assess CR rate and relapse-free survival following crenolanib and chemotherapy. 

Methods
Patients >18 years (y), with newly diagnosed FLT3+ AML (ITD and/or TKD mutants including secondary AML) are eligible. Crenolanib, 100 mg TID, is given daily from day (d) 9 following 7+3 induction (cytarabine 100 mg/m2/d and either daunorubicin d1-3 (<60y: 90 mg/m2; ≥60y: 60 mg/m2) or idarubicin 12 mg/m2 d1-3). Re-induction is permitted for inadequate leukemia cytoreduction on days 15-28. Consolidation with 6 doses of high dose cytarabine (HiDAC) (<60y: 3 g/m2; ≥60y: 1g/m2) is given with daily crenolanib (100 mg TID) starting d7. Eligible pts can proceed to allogeneic SCT. Crenolanib maintenance can be given for 1y post HiDAC or SCT. Crenolanib is held if total bilirubin is abnormal.

Results
19 pts with newly diagnosed FLT3+ AML have so far been enrolled (11 females, 8 males) with a median age of 55y (range 23-74y). Median baseline WBC was 27,740/μL (range 1,760-248,800; 4 pts had WBC >100,000/μL). 13/17 (76%) of pts had normal karyotype, 2 pts had trisomy 8, 1 pt was pseudodiploid and 1 pt had complex karyotype. Majority of pts, 79% (15/19), were FLT3-ITD+ve with 10/15 also carrying NPM1 mutation. 4/19 (28%) pts were FLT3-D835+ve with 1 pt also carrying NPM1 mutation and 1 pt carrying D835Y and N841T mutations. 11/19 pts were tested for other mutations present at baseline: DNMT3A in 6/11 pts (55%), SF3B1, IDH1, TET2 and RUNX1 each in 2/11 pts (18%), and IDH2, MLL, SRSF2 and WT1 each in 1/11 pts (9%). All 19 pts have received induction chemotherapy: 13 received daunorubicin (8 pts at 90 mg/m2, 5 pts at 60 mg/m2) and 6 received idarubicin (12 mg/m2) No pt has required a second induction. 2 pts died prior to starting crenolanib during induction 1 (due to sepsis and respiratory failure) and are not evaluable.Crenolanib 100 mg TID has been well-tolerated in combination with cytarabine/anthracycline induction with only 2 pts requiring dose reductions (due to rash and periorbital edema, respectively). Common AEs are consistent with what is seen with crenolanib monotherapy, including grade 1 or 2 nausea, vomiting, diarrhea and rash. Crenolanib did not appear to delay count recovery; median count recovery for WBC was 28d (range 16-43d) and platelet was 27d (22-46d).A high CR rate was seen in the 14 pts who are currently evaluable: 13/14 pts (93%) achieved CR with full count recovery, and all pts became FLT3–ve. Only 1 pt was refractory after first cycle of induction therapy and was taken off study. To date, 9 pts have received a total of 13 cycles of consolidation with HiDAC and crenolanib. 2 pts have undergone allogeneic SCT.

Conclusion
Crenolanib can be safely administered at full doses with cytarabine/anthracycline induction chemotherapy and HiDAC consolidation. Initial CR rates after just one cycle of induction with 7+3 and crenolanib are high. To date, no patients have relapsed. Accrual to this trial continues.

Session topic: Acute myeloid leukemia - Clinical 1

Keyword(s): Chemotherapy, Flt3 inhibitor, Relapsed acute myeloid leukemia, Tyrosine kinase inhibitor

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