Azacitidine Alone Or The Combination With Valproic Acid As a Bridge Therapy For Acute Myeloid Leukemia and Higher-Risk Myelodysplastic Syndromes Before Transplantation
Authors: Cabrera Cristina Calderón , Falantes Jose F , Gómez Marina , Parody Rocío , Márquez Malaver Francisco J , Martino María L , González José , Montero Isabel , Espigado Ildefonso , Pérez-Simón Jose Antonio 
Published: October 2019

Abstract

Introduction
Intensive chemotherapy (IC) followed by allogeneic stem cell transplantation (AlloSCT) is standard of care for intermediate and high-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS). However, morbidity and lack of response are common with IC. Retrospective data have shown similar outcomes with azacitidine (AZA) when compared to IC. Moreover, the combination of AZA with other epigenetic modifiers such as HDAC inhibitors seems to improve quality of responses.

Aim
Evaluate response, toxicity and feasibility of AlloSCT after AZA alone or the combination with valproic acid (VPA) as a bridge strategy in MDS and AML.

Patients
Nineteen consecutive patients (pts) receiving azacitidine alone (n=11) or in combination with valproic acid (VPA) (n=8) were analyzed. Median age of the cohort was 57 years (18-67). Diagnosis by WHO classification included: RAEB-2 (n=10/19; 52.6%), RAEB-1 (n=2; 10.5%), RCMD (n=2; 10.5%) and AML (n=5; 26.3%). Four out of 5 AML pts had bone marrow blast count >30% at diagnosis. In MDS patients, according to International Prognostic Scoring System (IPSS): 1 intermediate-1 (7%), 3 intermediate-2 (21.5%) and 10 high-risk (71.5%) and by IPSS-revised (IPSS-R): 1 intermediate (7%), 4 high (29%) and 9 very high (64%). Regarding karyotype, in MDS: 5 good (35.7%), 2 intermediate (14.3%), 6 poor (43%) and 1 insufficient metaphases (7%) whereas in AML Patients
1 intermediate (20%) and 4 adverse (80%). Eleven out of 19 pts (58%) received AZA as frontline therapy. The remaining 8 pts experienced disease relapse after intensive chemotherapy (IC) or had primary refractory AML, and subsequently received AZA plus VPA as salvage therapy. Median courses of previous IC were 2 (1-4). For pts receiving AZA/VPA, median bone marrow blast % and leukocyte were 31% (2-60) and 1.9x10e9/L (0.3-4.2) when therapy started. Most of these pts had refractory or relapsed disease (n=6/8; 75%) with 4 pts displaying poor karyotype. Treatment schema was AZA (75 mg/m2, 7d/4w) and VPA (20-25 mg/kg/d, 10 days).

Results
At analysis, 17/19 pts are evaluable for response. Median courses of AZA: 5 (2-53). Overall response (ORR) at 4 courses: 59% (CR=4/17; 23.5%, CRm=5/17; 29.5% and PR=1/17; 6%). For pts receiving AZA/VPA (Table 1, n=8), ORR: 83% (CR=1/6; 17% and CRm=4/6, 66%) in 6 evaluable pts. Median courses to response were 2. Among pts achieving CR/CRm/PR/SD at 4 courses (n=12), 2 pts lost response prior to AlloSCT. Most frequent toxicity was hematological (58% grade 3-4) with no treatment related mortality attributable to AZA/VPA. Eleven out of 19 pts (58%) received AlloSCT (matched related=5, matched unrelated=5, haploidentical=1). Causes for not proceeding to AlloSCT: Disease progression (n=4; 50%), infection (n=1; 12.5%), pending evaluation after 2 courses (n=2; 25%) and 1 pt (12.5%) scheduled for matched unrelated AlloSCT. Conditioning regimen: Reduced intensity (9/11) and myeloablative (2/11). Tacrolimus/sirolimus (50%) and cyclosporine/MMF (40%) as GVHD prophylaxis. With a median follow-up of 4 months after AlloSCT (1-26), only 1 pt developed acute GVHD, 1 had early relapse postransplant and 9 patients continue in CR at last follow up.

Conclusions
AZA alone and particularly the combination AZA/VPA prior to AlloSCT is a well-tolerated and highly effective schema even in pts with poor prognostic features and refractory to prior IC. Adequate selection of pts (leukocyte <10x10e9/L) and larger prospective studies are needed to assess the role of this strategy.
AML; Acute myeloid leukemia, RAEB-2; Refractory anemia with excess blasts type 2, RAEB-1; Refractory anemia with excess blasts type 1, IM; Insufficient metaphases, IC; Intensive chemotherapy, CR; Complete response, CRm; marrow CR, NA; Not assessable (pending bone marrow evaluation). 1Refractory to IC. 2Relapsed after IC. aBone marrow evaluation after 2 and 4 courses of therapy

Disclosures:
No relevant conflicts of interest to declare.