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QUIZARTINIB AND BRIDGE TO TRANSPLANT IN FLT3-ITD AML PATIENTS AFTER FAILURE OF SALVAGE CHEMOTHERAPY: A HISTORICAL COMPARISON WITH UK NATIONAL CANCER RESEARCH INSTITUTE (NCRI) DATA
Author(s): ,
Robert Hills
Affiliations:
Centre for Trials Research,Cardiff University,Cardiff,United Kingdom
,
Guy Gammon
Affiliations:
formerly Daiichi Sankyo,San Diego,United States
,
Denise Trone
Affiliations:
Daiichi Sankyo,San Diego,United States
Alan Burnett
Affiliations:
Blackwaterfoot,Isle of Arran,United Kingdom
(Abstract release date: 05/18/17) EHA Library. Hills R. 06/24/17; 181762; S475
Prof. Robert Hills
Prof. Robert Hills
Contributions
Abstract

Abstract: S475

Type: Oral Presentation

Presentation during EHA22: On Saturday, June 24, 2017 from 17:00 - 17:15

Location: Hall D

Background
The presence of a FMS-like tyrosine kinase 3 (FLT3) Internal Tandem Duplication (ITD) mutation in pts with AML is associated with an increased early relapse rate and a dismal prognosis. Quizartinib is a potent, selective oral FLT3 receptor tyrosine kinase inhibitor that conferred median OS (mOS) of 23 weeks and remission rate of 46% in a single-arm phase 2 study (AC220-002) in pts with AML with a FLT3-ITD mutation who were relapsed or refractory (R/R) to second line therapy. (Levis, et al., ASH 2012) As context, a study of AML pts, regardless of FLT3 mutation status, receiving second-salvage therapy reported mOS of only 1.5 months. (Giles F, et al. Cancer 104 (3), 2005) .  Such poor-risk pts may benefit from a stem cell transplant (SCT), if available.

Aims
The primary aim was to compare SCT rates and outcomes of pts on quizartinib from an exploratory selected cohort in the AC220-002 study with those from a historical cohort of 1388 AML pts with confirmed FLT3-ITD mutations in the UK NCRI database. 

Methods
Within AC220-002, 58 pts with a FLT3-ITD mutation were identified who had received intensive chemotherapy, and were relapsed (n=53), or refractory (n=5) to salvage therapy prior to entry. Applying the same entry criteria to the NCRI database, we identified 118 pts who received only recognized chemotherapy regimens prior to eligibility (relapsed n=99; refractory n=19). To avoid biases where those dying early would predominantly contribute to the NCRI group (reflecting that pts in AC220-002 had to be fit enough to be enrolled), pts in this cohort entered analysis 14 days following being identified as R/R.  Multivariable Cox/logistic regression was used to compare remission rates and survival stratified for known prognostic factors. A landmark analysis excluding deaths before day 90 (allowing for those too unfit for SCT) was performed on the pooled sample (n=176) of the AC220-002 and NCRI cohorts to compare survival between transplanted and non-transplanted pts.

Results
Overall, quizartinib-treated pts had significantly greater remission rates, consisting mainly of complete remission without normal blood counts (CRi), vs NCRI pts (40% vs 3%, adjusted OR 0.05 (0.01-0.21), p<0.0001) and improved mOS (140d vs 54d, adjusted HR 0.38 (0.25-0.58) p<.0001).   A greater proportion of pts in AC220-002 proceeded to SCT: 23/58 (40%) vs 9/118 (8%).  Comparing survival in SCT vs no-SCT in a landmark analysis, 18-month survival was significantly greater in the SCT group (29% vs 7%, adjusted HR 0.36 (0.20-0.65) p=0.0005). Significance persisted in sensitivity analyses with the landmark set at 120 or 150 days indicating an association between long-term survival and SCT. A similar analysis in an unmatched cohort consisting of SCT-naïve pts in first relapse also found better survival for SCT vs no-SCT, confirming a potential benefit of SCT in this poor risk population.    

Conclusion
When compared to a large historical cohort, quizartinib was associated with greater remission rates and opportunity to receive SCT in pts who relapsed after salvage therapy. While varying practice patterns and patient factors obviously influence treatment choices and outcomes, pts with AML with FLT3-ITD mutation appeared to benefit with longer survival observed with SCT.   This data suggests quizartinib may show promise in potentially improving long-term survival by bridging patients to SCT.

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): Flt3 inhibitor, Acute Myeloid Leukemia

Abstract: S475

Type: Oral Presentation

Presentation during EHA22: On Saturday, June 24, 2017 from 17:00 - 17:15

Location: Hall D

Background
The presence of a FMS-like tyrosine kinase 3 (FLT3) Internal Tandem Duplication (ITD) mutation in pts with AML is associated with an increased early relapse rate and a dismal prognosis. Quizartinib is a potent, selective oral FLT3 receptor tyrosine kinase inhibitor that conferred median OS (mOS) of 23 weeks and remission rate of 46% in a single-arm phase 2 study (AC220-002) in pts with AML with a FLT3-ITD mutation who were relapsed or refractory (R/R) to second line therapy. (Levis, et al., ASH 2012) As context, a study of AML pts, regardless of FLT3 mutation status, receiving second-salvage therapy reported mOS of only 1.5 months. (Giles F, et al. Cancer 104 (3), 2005) .  Such poor-risk pts may benefit from a stem cell transplant (SCT), if available.

Aims
The primary aim was to compare SCT rates and outcomes of pts on quizartinib from an exploratory selected cohort in the AC220-002 study with those from a historical cohort of 1388 AML pts with confirmed FLT3-ITD mutations in the UK NCRI database. 

Methods
Within AC220-002, 58 pts with a FLT3-ITD mutation were identified who had received intensive chemotherapy, and were relapsed (n=53), or refractory (n=5) to salvage therapy prior to entry. Applying the same entry criteria to the NCRI database, we identified 118 pts who received only recognized chemotherapy regimens prior to eligibility (relapsed n=99; refractory n=19). To avoid biases where those dying early would predominantly contribute to the NCRI group (reflecting that pts in AC220-002 had to be fit enough to be enrolled), pts in this cohort entered analysis 14 days following being identified as R/R.  Multivariable Cox/logistic regression was used to compare remission rates and survival stratified for known prognostic factors. A landmark analysis excluding deaths before day 90 (allowing for those too unfit for SCT) was performed on the pooled sample (n=176) of the AC220-002 and NCRI cohorts to compare survival between transplanted and non-transplanted pts.

Results
Overall, quizartinib-treated pts had significantly greater remission rates, consisting mainly of complete remission without normal blood counts (CRi), vs NCRI pts (40% vs 3%, adjusted OR 0.05 (0.01-0.21), p<0.0001) and improved mOS (140d vs 54d, adjusted HR 0.38 (0.25-0.58) p<.0001).   A greater proportion of pts in AC220-002 proceeded to SCT: 23/58 (40%) vs 9/118 (8%).  Comparing survival in SCT vs no-SCT in a landmark analysis, 18-month survival was significantly greater in the SCT group (29% vs 7%, adjusted HR 0.36 (0.20-0.65) p=0.0005). Significance persisted in sensitivity analyses with the landmark set at 120 or 150 days indicating an association between long-term survival and SCT. A similar analysis in an unmatched cohort consisting of SCT-naïve pts in first relapse also found better survival for SCT vs no-SCT, confirming a potential benefit of SCT in this poor risk population.    

Conclusion
When compared to a large historical cohort, quizartinib was associated with greater remission rates and opportunity to receive SCT in pts who relapsed after salvage therapy. While varying practice patterns and patient factors obviously influence treatment choices and outcomes, pts with AML with FLT3-ITD mutation appeared to benefit with longer survival observed with SCT.   This data suggests quizartinib may show promise in potentially improving long-term survival by bridging patients to SCT.

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): Flt3 inhibitor, Acute Myeloid Leukemia

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