Validation of the Cibmtr Score in Predicting the Outcome of Hematopoietic Stem-Cell Transplantation in AML Patients Not in Complete Remission At the Time of Conditioning: A Retrospective Analysis On Behalf of the Gruppo Italiano Trapianto Di Midollo Osseo (GITMO)
Authors: Todisco Elisabetta , Ciceri Fabio , Oldani Elena , Van Lint Maria Teresa , Donnini Irene , Patriarca Francesca , Alessandrino Emilio Paolo , Bonifazi Francesca , Arcese William , Iori Anna Paola , Marenco Paola , Terruzzi Elisabetta , Cortelazzo Sergio , Santarone Stella , Proia Anna , Corradini Paolo , Tagliaferri Elena , Falcioni Sadia , Irrera Giuseppe , Dallanegra Laura , Castagna Luca , Camboni Agnese , Bosi Alberto , Bacigalupo Andrea , Rambaldi Alessandro 
Published: October 2019

Abstract
Abstract 2005

Background and Aim
The dismal prognosis of AML patients undergoing allogeneic stem cell transplantation not in complete remission at time of conditioning poses challenging clinical decisions. In these patients, a recent, large retrospective analysis conducted by the CIBMTR showed that a myeloablative HCST can induce an overall 19% long term survival. Based on five adverse pretransplantation variables (first CR duration less than 6 months, circulating blasts, donor other than HLA-identical sibling, Karnofsky or Lansky score less than 90, and poor-risk cytogenetics) this analysis allowed to set up a pre-HSCT score (from 0 to ≥3) able to identify four risk groups defining a 3-years overall survival (OS) probability ranging from 6% up to 42% (Duval M, JCO 2010). However, this CIBMTR analysis was limited to patients with the following characteristics: a) de novo AML or secondary AML to a previous MDS b) patients receiving a TBI or busulfan based myeloablative conditioning regimens (MAC) and a BM or PB derived stem cell graft. Here we report data obtained in Italy in a similar cohort of AML patients that also included those receiving a reduced-intensity conditioning (RIC) regimen and those grafted with a cord blood unit.

Study design, patients and transplants characteristics
We retrospectively analyzed data reported to the GITMO registry by 20 Italian centers on 523 AML patients who underwent a first HSCT being not in complete remission (CR) at time of conditioning, between 1999 and 2010. The median age at HSCT was 47,6 years (18–72), the male/female ratio 50%. At diagnosis 71,5% were de novo AML, 23% were secondary to a previous MDS/CMML, while in 5,5% the AML was therapy related or secondary to a previous CMN. Before HSCT conditioning, patients were primary refractory (PIF) in 34%, in first or subsequent untreated relapse in 45% and 16%, respectively or an untreated MDS to AML evolution in 5%. Before HSCT, 79% of PIF received ≥2 chemotherapy cycles and for relapsed patients the duration of the first CR was < 6 months in 50%. An intermediate-II or adverse karyotype was detected in 43% of patients, a greater than 25% marrow blast infiltration or any level of peripheral blood (PB) blasts was found in 53% and a pre-HSCT Karnofsky score less than 90 was present in 38%. The stem cell source was the PB in 65%, the bone marrow in 28% and the cord blood in 6%. Donors were HLA identical sibling or matched unrelated donor in 69%, a family or unrelated mismatched in 25% and a cord blood unit in 6%. Anti-CMV antibodies were present in 87% of patients and in 66% of the donors, while donor-recipient pair were sex-matched in 50% of the cases. More than 60% patients received a MAC and 37% a RIC program.

Results
After HSCT, a myeloid and platelets engraftment was achieved in 87% of patients after a median of 17 (9–63) and 18 (2–117) days, respectively. Acute GVHD (grade ≥2 60%) was registered in 46% while chronic GVHD developed in 31%. The median follow up of the whole patients cohort was 5,36 months (0.09–133) while that of survivors was 26 months (1–133) with 96 patients alive and 77 leukemia-free. A multivariate analysis identified 7 pre-HSCT adverse variables that significantly influenced survival: an AML secondary to a previous chronic myeloproliferative neoplasm or a therapy related AML (HR 1,83, 95%CI 1,14–2,96, p 0,013), a relapsed AML with a first CR duration < 6 months (HR 1,39, 95%CI 1,06–1,82, p 0,018), an AML with a PIF after ≥2 chemotherapy cycles pre-HSCT (HR 1,74, 95%CI 1,11–2,74, p 0,016), an intermediate II/adverse cytogenetics (HR1,71, 95%CI 1,11–2,62, p 0,015), BM blasts ≥25% or any level of PB at HSCT (HR 1,65, 95%CI, 1,31–2,07, p 0.000) and a mismatched related/unrelated donor (HR 1,56, 95%CI, 1,23–1,98, p 0.000). At 3-years, the OS and LFS of our patients was 16% and 21%. Interestingly, when applied to our results, the CIBMTR score was fully validated in our patients with a 3-year survival rate decreased from 40% (score 0, HR1) to 26% (score 1, HR 1,39; 95%CI 0.88–2,12, p 0,142), to 18% (score 2, HR 1,58; 95%CI 1–2,43, p 0,04) to 5% (score 3, HR 2,83; 95%CI 1,71–4,16, p 0,000) (Figure 1).

Conclusions
Our results confirm that a) HSCT is a potentially curative option for a significant proportion of AML patients undergoing transplant not in remission, b) these patients may benefit from either a MAC or a RIC conditioning regimens and c) the CIBMTR score applied to this poor prognosis AML cohort is a useful tool for patient counseling and for planning the HSCT activity.

Disclosures:
No relevant conflicts of interest to declare.