Maintenance Treatment with Guadecitabine (SGI-110) in High Risk MDS and AML Patients after Allogeneic Stem Cell Transplantation
Authors: Oran Betul , Alatrash Gheath , Alousi Amin M. , Mehta Rohtesh S. , Hosing Chitra , Popat Uday R. , Im Jin S. , McCarty Jessica M , Ramos Jennifer D , Keer Harold N. , Thall Peter F , Champlin Richard E. 
Published: February 2021

Background: Disease relapse remains to be the one of the major reasons of treatment failures after allogeneic stem cell transplantation (allo-SCT) in AML and MDS patients (pts).
SGI-110 is a next generation hypomethylating agent that molecularly is a dinucleotide derivative of decitabine and therefore a more potent inhibitor of DNA methyltransferase activity. We present interim results of a single arm phase II trial evaluating the efficacy and safety of SGI-110 in AML/MDS pts. to improve transplant outcomes.
Methods: In this study, there are 3 treatment cohorts defined by disease status after transplant with different primary outcomes of interest. Cohort 1 includes AML/MDS pts. with morphological relapse after transplant; cohort 2 pts with minimal residual (MRD) and cohort 3 pts with no evidence of disease. As of June 2020, 54 pts have enrolled.
Herein, we report the interim analyses of 22 pts treated in cohort 3 and received SGI-110 as post-transplant maintenance while in remission. Other cohorts' results will be reported separately.
The maintenance cohort includes high risk AML/MDS pts aged 18-75. High risk MDS is defined as having (1) poor or very poor cytogenetics by revised-IPSS or (2) monosomal karyotype or (3) bone marrow blast count &gt; 5% before transplant; high risk AML as (1) adverse risk group by European LeukemiaNet (ELN) or (2) presence of MRD or active disease at transplant. Therapy-related AML/MDS is included.
Pts. are excluded in the presence of (1) active acute graft versus host disease (GvHD), (2) uncontrolled systemic infection, or (3) concurrent use of systemic immune suppressive other than calcineurin inhibitors and sirolimus.
The study intervention includes SGI-110 given as 30 mg/m2/day subcutaneously for 5 consecutive days every 28 days until completion of 12 cycles, disease relapse, or experience of unacceptable toxicity. SGI-110 is initiated between 42 to 100 days following allo-SCT if there is adequate engraftment with absolute neutrophil count &gt;/= 1.0 x 109 /L; platelet &gt;/= 50 x 109 /L and no documented evidence of relapse. Treatment delays up to 70 days and dose reductions are allowed per protocol.
The primary endpoint for this cohort is relapse-free survival (RFS) time defined as either time to disease progression or death whichever happened first. The maximum planned sample size is 40.
Results: As of June 2020, 22 pts were enrolled; M/F, 12/10, median age, 62 (range 18 to74). Of 11 AML pts., ELN risk category was adverse in 8, intermediate in 2 and favorable in 1. Of 11 MDS pts, 6 had poor/very poor and 4 good and 1 intermediate risk cytogenetic abnormalities by revised-IPSS. Of 22, 6 were in complete remission with count recovery at transplant.
Median time to initiation of first cycle of maintenance with SGI-110 was 59.5 days (range, 43 to 114 days). So far, 14 pts of 22 were taken off the study; 6 due to disease relapse, 4 completed planned 12 cycles of treatment, 1 lost insurance, 1 withdrew the consent, 1 had travel issues due to COVID19 pandemic and 1 had pulmonary complications unrelated to study drug. Currently, 8 remain to be on the study. Median number of treatment cycles administered have been 4 (range, 1 to 12). Of 22, 7 pts. required the SGI-110 dose to be reduced down to 20 mg/m2/dayX5 days and 1 patient to 20 mg/m2/dayX3 days to be able to continue the treatment.
At a median follow-up of 13.1 months for survivors (n=17), RFS and overall survival at 1-year was 66.3% (95% confidence interval (CI)=42% to 82.3%) and 88.9% (95%CI=61.8 to 92.2%) respectively (Figure)
During the study, 353 AEs observed with 125 cycles of SGI-110 treatments. Of 353, 287 (81.3%) were attributable to SGI-110 and 133 of 287 (46.3%) were grade 3 or higher in severity. Most of the grade 3 or higher AEs were related with bone marrow suppression; 71 (25%) thrombocytopenia, 64 (22%) neutropenia, 67 (23%) leukopenia and 8 (2%) anemia. Of 22 pts, 15 had grade 4 neutropenia at least once and 8 pts grade 4 thrombocytopenia. There was 18 episodes of infectious AEs and 11 of 18 were grade 3-4. There were no grade 5 AEs observed attributable to study drug.
Conclusion: SGI-110 led to frequent grade 3-4 BM suppression in high risk AML/MDS pts when given as maintenance therapy after allo-SCT. However, bone marrow suppression was not associated with increased risk of infection and it was temporary with count recovery. The efficacy of SGI-110 has been promising with 1-year RFS of 66.3%. The study currently is ongoing.

Disclosures
Oran: Celgene: Consultancy; Arog Pharmaceuticals: Research Funding; ASTEX: Research Funding. Alousi:Incyte: Honoraria, Research Funding; Therakos: Research Funding; Alexion: Honoraria. Mehta:CSL Behring: Research Funding; Incyte: Research Funding; Kadmon: Research Funding. Hosing:NKARTA Inc.: Consultancy. Popat:Bayer: Research Funding; Novartis: Research Funding. Keer:Astex Pharmaceuticals, Inc.: Current Employment. Champlin:Actinium: Consultancy; Genzyme: Speakers Bureau; Omeros: Consultancy; Cytonus: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees; Takeda: Patents & Royalties; Johnson and Johnson: Consultancy.

OffLabel Disclosure:
The abstract presents interim analyses of a clinical trial investigating efficacy and safety of SGI-110 used as maintenance therapy in high risk AML and MDS patients after transplant.