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SORAFENIB MAINTENANCE IN FLT3-ITD MUTATED ACUTE MYELOID LEUKEMIA AFTER ALLOGENEIC STEM CELL TRANSPLANT
Author(s):
Sairah Ahmed
,
Sairah Ahmed
Affiliations:
Stem cell transplant and cellular therapy,UNIVERSITY OF TEXAS, MD ANDERSON CANCER CENTER,Houston,United States
Rima Saliba
,
Rima Saliba
Affiliations:
Stem cell transplant and cellular therapy,UNIVERSITY OF TEXAS, MD ANDERSON CANCER CENTER,houston,United States
Gabriela Rondon
,
Gabriela Rondon
Affiliations:
Stem cell transplant and cellular therapy,UNIVERSITY OF TEXAS, MD ANDERSON CANCER CENTER,houston,United States
Amin Alousi
,
Amin Alousi
Affiliations:
Stem cell transplant and cellular therapy,UNIVERSITY OF TEXAS, MD ANDERSON CANCER CENTER,houston,United States
Qaiser Bashir
,
Qaiser Bashir
Affiliations:
Stem cell transplant and cellular therapy,UNIVERSITY OF TEXAS, MD ANDERSON CANCER CENTER,houston,United States
Stefan Ciurea
,
Stefan Ciurea
Affiliations:
Stem cell transplant and cellular therapy,UNIVERSITY OF TEXAS, MD ANDERSON CANCER CENTER,houston,United States
Gheath Al-Atrash
,
Gheath Al-Atrash
Affiliations:
Stem cell transplant and cellular therapy,UNIVERSITY OF TEXAS, MD ANDERSON CANCER CENTER,houston,United States
Keyur Patel
,
Keyur Patel
Affiliations:
Hematopathology,UNIVERSITY OF TEXAS, MD ANDERSON CANCER CENTER,Houston,United States
Amanda Olson
,
Amanda Olson
Affiliations:
Stem cell transplant and cellular therapy,UNIVERSITY OF TEXAS, MD ANDERSON CANCER CENTER,houston,United States
David Marin
,
David Marin
Affiliations:
Stem cell transplant and cellular therapy,UNIVERSITY OF TEXAS, MD ANDERSON CANCER CENTER,houston,United States
Katy Rezvani
,
Katy Rezvani
Affiliations:
Stem cell transplant and cellular therapy,UNIVERSITY OF TEXAS, MD ANDERSON CANCER CENTER,houston,United States
Partow Kebriaei
,
Partow Kebriaei
Affiliations:
Stem cell transplant and cellular therapy,UNIVERSITY OF TEXAS, MD ANDERSON CANCER CENTER,houston,United States
Uday Popat
,
Uday Popat
Affiliations:
Stem cell transplant and cellular therapy,UNIVERSITY OF TEXAS, MD ANDERSON CANCER CENTER,houston,United States
Elizabeth Shpall
,
Elizabeth Shpall
Affiliations:
Stem cell transplant and cellular therapy,UNIVERSITY OF TEXAS, MD ANDERSON CANCER CENTER,houston,United States
Richard Champlin
,
Richard Champlin
Affiliations:
Stem cell transplant and cellular therapy,UNIVERSITY OF TEXAS, MD ANDERSON CANCER CENTER,houston,United States
Betul Oran
Betul Oran
Affiliations:
Stem cell transplant and cellular therapy,UNIVERSITY OF TEXAS, MD ANDERSON CANCER CENTER,houston,United States
(Abstract release date: 05/18/17) EHA Library. Oran B. 06/25/17; 182079; S792
Dr. Betül Oran
Dr. Betül Oran
Contributions
PDF Abstract
Abstract

Abstract: S792

Type: Oral Presentation

Presentation during EHA22: On Sunday, June 25, 2017 from 08:45 - 09:00

Location: Room N101

Background
The fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation is a genetic alteration found in approximately 30% of patients with acute myeloid leukemia (AML). Although patients with FLT3-ITD AML achieve remission rates similar to those with FLT3 wildtype status with induction chemotherapy regimens; patients with FLT3-ITD have significantly shorter remission durations and increased rates of relapse. Even though allogeneic SCT improves outcomes, patients still have higher rates of relapse comparatively with poor prognosis post relapse. Sorafenib(SFB) is a TKI with activity against RAF, VEGF and FLT3-ITD and its use as maintenance therapy after allogeneic SCT has been shown as a promising approach to decrease relapse. Several studies report that SFB maintenance post SCT provides durable complete responses; however, there are also descriptions of sorafenib post SCT triggering acute GVHD, cytopenias, rash and diarrhea. 

Aims
To assess the outcomes, including progression free survival (PFS) and overall survival (OS), in patients with FLT3-ITD mutated AML who receive SFB maintenance after allogeneic SCT.  

Methods
We analyzed adult patients (age≥18) with a diagnosis of FLT3-ITD mutated AML who received an allogeneic SCT between 1/1/2010 and 10/28/16 at our institution. Using a case control analysis and matching patients who received maintenance SFB (maintenance  group) with control patients, FLT3-ITD mutated AML who did not receive maintenance post SCT(control group); we matched each case to two control patients accounting for disease status, type of conditioning, donor type, cytogenetic risk factors and age. To be considered as maintenance, SFB had to be started within 101 days of the SCT.  To reduce bias from disease risks and transplant-related mortality (TRM), all patients were required to be in complete remission (CR) at study entry -  defined as the date of SFB initiation for cases and the same time point after SCT for their matched controls without maintenance.  

Actuarial OS and PFS were estimated from study entry using Kaplan-Meier method.  OS and PFS were compared between cases and controls using log rank test and cox proportional hazards regression analysis.  Patient-, transplant- and disease characteristics were compared between cases and controls using chi square and Fisher exact tests.

Results
Among the 214 AML patients with FLT3-ITD mutation that underwent SCT during study period, we identified 13 cases (maintenance) and 26 controls (no maintenance). Median follow-up of survivors were 12 months and 30 months for maintenance and control group respectively.

Disease and transplant characteristics were comparable between groups as presented in Table 1. Patients were classified by the European Leukemia Net (ELN) classification and 23% in both groups were categorized as adverse risk while 77% were intermediate risk.  All patients received myeloablative conditioning and diseases status at SCT was first/second complete remission (CR1/2) with or without count recovery (Cri/p) in 69% while it was active disease in 31%.
PFS at 24 months post SCT was 82% in the maintenance and 45% in control group HR 0.3; 95% CI (0.1-1.3) p=0.1. Overall survival at 24 months was also higher in SFB cases as 100% compared with 60% in control group p=0.035.
Only, 2 patients relapsed post SCT on SFB maintenance, one with new TP53 mutation at relapse, and other received only <30 days of SFB. However, more than half the patients had disease progression within the control period.
The most commonly administered dose was 400 mg daily (5 patients) for 28 days cycle; only 2 patients tolerated higher doses and 6 patients received SBF as 300mg daily or less. There were delays in subsequent cycles in 10 of 12 patients, and the most common reasons for delays included cytopenias, liver function test abnormalities, and fatigue

Conclusion
Sorafenib maintenance is safe and can produce long term durable remissions after allogeneic stem cell transplant in a high risk population with FLT3-ITD mutated AML.

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): Flt3 inhibitor, AML, Allogeneic hematopoietic stem cell transplant, Flt3-ITD

Abstract: S792

Type: Oral Presentation

Presentation during EHA22: On Sunday, June 25, 2017 from 08:45 - 09:00

Location: Room N101

Background
The fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation is a genetic alteration found in approximately 30% of patients with acute myeloid leukemia (AML). Although patients with FLT3-ITD AML achieve remission rates similar to those with FLT3 wildtype status with induction chemotherapy regimens; patients with FLT3-ITD have significantly shorter remission durations and increased rates of relapse. Even though allogeneic SCT improves outcomes, patients still have higher rates of relapse comparatively with poor prognosis post relapse. Sorafenib(SFB) is a TKI with activity against RAF, VEGF and FLT3-ITD and its use as maintenance therapy after allogeneic SCT has been shown as a promising approach to decrease relapse. Several studies report that SFB maintenance post SCT provides durable complete responses; however, there are also descriptions of sorafenib post SCT triggering acute GVHD, cytopenias, rash and diarrhea. 

Aims
To assess the outcomes, including progression free survival (PFS) and overall survival (OS), in patients with FLT3-ITD mutated AML who receive SFB maintenance after allogeneic SCT.  

Methods
We analyzed adult patients (age≥18) with a diagnosis of FLT3-ITD mutated AML who received an allogeneic SCT between 1/1/2010 and 10/28/16 at our institution. Using a case control analysis and matching patients who received maintenance SFB (maintenance  group) with control patients, FLT3-ITD mutated AML who did not receive maintenance post SCT(control group); we matched each case to two control patients accounting for disease status, type of conditioning, donor type, cytogenetic risk factors and age. To be considered as maintenance, SFB had to be started within 101 days of the SCT.  To reduce bias from disease risks and transplant-related mortality (TRM), all patients were required to be in complete remission (CR) at study entry -  defined as the date of SFB initiation for cases and the same time point after SCT for their matched controls without maintenance.  

Actuarial OS and PFS were estimated from study entry using Kaplan-Meier method.  OS and PFS were compared between cases and controls using log rank test and cox proportional hazards regression analysis.  Patient-, transplant- and disease characteristics were compared between cases and controls using chi square and Fisher exact tests.

Results
Among the 214 AML patients with FLT3-ITD mutation that underwent SCT during study period, we identified 13 cases (maintenance) and 26 controls (no maintenance). Median follow-up of survivors were 12 months and 30 months for maintenance and control group respectively.

Disease and transplant characteristics were comparable between groups as presented in Table 1. Patients were classified by the European Leukemia Net (ELN) classification and 23% in both groups were categorized as adverse risk while 77% were intermediate risk.  All patients received myeloablative conditioning and diseases status at SCT was first/second complete remission (CR1/2) with or without count recovery (Cri/p) in 69% while it was active disease in 31%.
PFS at 24 months post SCT was 82% in the maintenance and 45% in control group HR 0.3; 95% CI (0.1-1.3) p=0.1. Overall survival at 24 months was also higher in SFB cases as 100% compared with 60% in control group p=0.035.
Only, 2 patients relapsed post SCT on SFB maintenance, one with new TP53 mutation at relapse, and other received only <30 days of SFB. However, more than half the patients had disease progression within the control period.
The most commonly administered dose was 400 mg daily (5 patients) for 28 days cycle; only 2 patients tolerated higher doses and 6 patients received SBF as 300mg daily or less. There were delays in subsequent cycles in 10 of 12 patients, and the most common reasons for delays included cytopenias, liver function test abnormalities, and fatigue

Conclusion
Sorafenib maintenance is safe and can produce long term durable remissions after allogeneic stem cell transplant in a high risk population with FLT3-ITD mutated AML.

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): Flt3 inhibitor, AML, Allogeneic hematopoietic stem cell transplant, Flt3-ITD

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