Outcomes after Plerixafor Plus FLAG-IDA (PLERIFLAG) Versus FLAG-IDA +/- Gentuzumab for Adult Patients with First Relapsed/Refractory AML: A Propensity Score Analysis from the Pethema Registry
Authors: Bergua Burgues Juan Miguel M. , Cano-Ferri Isabel , Martínez-Cuadron David , Boluda Blanca , Martínez-Sánchez Pilar , Rodríguez-Veiga Rebeca , Esteve Jordi , Vives Susana , Serrano Josefina , Vidriales Maria-Belen , Salamero Olga , Carretero Carlos , Jimenez-Ubieto Ana , Casas Ignacio , Cardesa Rocio , Diaz-Beyá Marina , Brunet Salut , Benavente Celina , Pérez-Simón Jose Antonio , Moscardo Federico , Aguiar Eliana , Perez Encinas Manuel , Martínez Aurelio López , Rguez Carlos , Cabello A. , Labrador Jorge , Costilla Lissette Del Pilar , Sossa Claudia , Bernal Del Castillo Teresa , Sanz Miguel A. , Montesinos Pau 
Published: November 2019

BACKGROUND AND OBJECTIVES: Chemosensitization using plerixafor combined with FLAG-IDA (PLERIFLAG regimen) showed promising results (48% CR/CRi) in a phase 2 trial for primary refractory and early relapsed (duration of first CR &lt;12 months) Adult AML patients. We aim to compare retrospectively results of the PLERIFLAG cohort versus historical cohorts of patients salvaged with FLAG-IDA (Fludarabine, Idarubicine, Cytarabine, G-CSF as priming agent), or FLAGO-IDA (Gemtuzumab plus FLAG-IDA) registered in the PETHEMA epidemiologic AML registry (NCT02006004). To match different cohorts, we used two risk-score classifications: EPI/HOVON (De Breems, JCO 2005) and SALFLAGE (Bergua, BJH 2016). The purpose is to analyse the complete remission (CR+CRi) rate, the rate of patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT). The disease-free survival (DFS) and overall survival (OS) were adjusted using established risk factors (time to relapse (TTR), karyotype, FLT3-ITD, previous stem cell transplant (SCT)) using propensity score analysis.
Patients: Of the 540 patients in the data base we analysed 300 patients relapsed or resistant to induction therapy, which had all data available. 241 patients were treated with FLAG-IDA, 41 with FLAGO-Ida, and 42 with PLERIFLAG. Differences between treatment cohorts were tested using Fisher exact test. Treatment cohorts (PLERIFLAG vs FLAG-IDA vs FLAGO-IDA) were similar in Age (p=0.5), Sex (p=0.5), FLT3-ITD mutated (p=0.5), EPI/HOVON cytogenetics score (p=0.5) and previous myelodisplasia (p=0.2). The three cohorts differed in time to relapse (p=0.001), previous stem cell transplantation (0.001), HOVON score (p=0.03) and SALFLAGE score (0.001).
RESULTS
There were no differences in terms of CR+CRi between the three types of treatment adjusted by Hovon risk score (Pleriflag: 48%, FLAG-IDA: 50% or FLAGO-IDA: 58%; Chrochan Maentel-Haenszel test, p=0.466) or SALFLAGE score (Chrochan-Maentel-Haenszel test, p=0.23). More patients were allografted in the PLERIFLAG (61%) group even not achieving CR/Cri, as compared to FLAG-IDA (38%) or FLAGO-Ida (61% vs 38% vs. 18%, p=0.0001).
To compare PLERIFLAG against the other two types of salvage treatment we performed a Propensity Score in a proportion 1:3. We adjust variables like age, previous allogeneic transplant, time to relapse (refractory, &lt;12 months and &gt;12 months), karyotype using MRC, and FLT3-ITD status. Karyotype risk was considered by HOVON criteria (inv16, t(8;21) vs others), and SALFLAGE (inv 16, intermediate risk, and unfavourable risk by MRC risk plus t(8;21)). The propensity score analyses showed that Compared to FLAG-IDA, PLERIFLAG was associated to increased survival (median OS 10.56 months vs. 5.6, p=0.03), but not improved EFS (2.83 months vs 1.41 months, p=0.8). The benefit in OS but not in EFS could be explained in part by frequent use of Allo SCT in patients who had not achieve CR/CRi in the PLERIFLAG cohort. In conclusion, our historical control study show that PLERIFLAG regimen is an acceptable therapeutic option for first relapsed/refractory adult AML patients.

Disclosures
Esteve: Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Roche: Consultancy; Astellas: Consultancy, Speakers Bureau. Salamero:Novartis: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; Daichii Sankyo: Honoraria. Perez Encinas:CELGENE: Consultancy; JANSSEN: Consultancy; GILEAD SCIENCES: Research Funding. Montesinos:Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau.