High Dose Flamsa, CLAG or FLAG-Based Sequential Conditioning Regimen Followed By Allogeneic Hematopoietic Transplantation Results in Favorable Outcome for High Risk Acute Myeloid Leukemia, Myelodysplastic Syndrome, Myeloproliferative Neoplasia Patients: A Multicenter Study in Singapore
Authors: Koh Yin Jie , Poon Michelle , Linn Yeh Ching , Hwang William YK , Neo Elson , Ho Aloysius YL , Tan Lip Kun , Koh Liang Piu 
Published: November 2019

Introduction:
Allogeneic haematopoietic cell transplant ( allo-HCT) is an effective consolidative treatment for patients with certain haematological malignancies and gives the best outcome when done in remission. However patients with refractory acute myeloid leukemia (AML) or some myeloproliferative neoplasia (MPN) and myelodysplastic syndrome (MDS) deemed unable to achieve remission with standard induction are often excluded from allo HCT with conventional conditioning regimen as pre-transplant remission could not be achieved. Recently, a sequential transplant approach, as developed by the Munich group, comprising of intensive cytoreductive chemotherapy FLAMSA (Fludarabine/Amsacrine/Cytarabine) to decrease leukemia cell burden shortly prior to conditioning regimen, has been successfully used for high-risk (HR) AML/MDS with promising results.
Methods:
We studied 48 patients (median age 53 years, range 26 - 68) with high risk AML (n=38), as defined by refractory, relapsed disease, secondary leukemia, complete remission with adverse-risk cytogenetics according to ELN criteria, or high/very risk refined Disease Risk Index (DRI), MPN(n=2) and HR MDS (n=8) according to IPSS-R, undergoing allo-HCT using the sequential transplant approach in 2 transplant centers in Singapore between January 2009 and October 2018. The sequential transplant approach combined a cytoreductive chemotherapy, which consisted of either FLAMSA (n=17), FLAG +/- Ida (fludarabine/Cytarabine/Granulocyte Colony Stimulating factor (GCSF) +/- Idarubicin] (n=23), or CLAG (Clofarabine / Cytarabine / GCSF) (n=8), followed by reduced intensity (RIC) (N=43) or myeloablative (MAC) (N=5) conditioning regimen. All patients received peripheral blood stem cell from matched related donors (N=27), matched unrelated donors (N=14), or mismatched unrelated donors (N=7). Post-grafting immunosuppression consisted of calcineurin inhibitor and mycophenolate mofetil in all patients. Thymoglobuline was added for GVHD prophylaxis for unrelated donor transplant.
Results:
The median time to neutrophil > 1000/μL was 10 days (range, 9-25). With a median follow-up of 48 months (range, 9 to 111 months), the Kaplan-Meier estimate of overall survival (OS) and leukemia-free (LFS) at 5 years were 48 % (95% CI, 33-62), 45% (95% CI, 30-58), respectively. At 2 years cumulative incidence of relapse and non-relapse mortality (NRM) were 51% (95% CI, 33-67) and 15% (95% CI, 7-27), respectively. Patients receiving FLAG or CLAG based sequential regimen showed, lower cumulative incidence of NRM (2-year CI NRM: 7% vs 40%; p=0.037), and similar relapse (2 year CI relapse: 49% vs 53%; p=0.63) as compared to patients given FLAMSA-based sequential regimen, resulting in a trend towards more favourable OS (5 year OS: 53% vs 40%; p=0.33) and LFS (5 year LFS: 54% vs 35%; p=0.23). In multivariable analysis, only refined DRI showed significant impact on OS (p=0.04), but has no significant impact on LFS, NRM and relapse. The 5-year OS for patients with intermediate/high risk and very high risk DRI were 60% and 24%, respectively (p=0.024), and the corresponding 5-year LFS were 57%, and 27% (p=0.065), respectively (Figure 1 & Figure 2). The intensity of conditioning regimen did not significantly impact on OS, LFS, relapse and NRM.
Conclusions:
Sequential transplant conditioning with FLAMSA, FLAG or CLAG followed by allo-HCT is an effective strategy in overcoming the dismal prognosis of high risk AML, MDS and MPN, and enabling favourable long-term disease free survival. More studies on effective strategies such as post-transplant maintenance therapy with prophylactic donor lymphocyte infusion, are needed to further eliminate the risk of relapse, without increasing risk of treatment related toxicity.

Disclosures
No relevant conflicts of interest to declare.