Minimal Residual Disease Eradication with Guadecitabine (SGI-110) in the Post-Transplant Setting
Authors: Oran Betul , Alousi Amin M. , Mehta Rohtesh S. , Marin David , Kebriaei Partow , Popat Uday R. , Olson Amanda L. , McCarty Jessica M , Ramos Jennifer D , Bassett Roland , Keer Harold N. , Thall Peter F , Champlin Richard E. 
Published: November 2020

Background: Disease relapse remains to be the one of the major reasons of treatment failures after allogeneic stem cell transplantation (allow-SCT) in AML and MDS patients (pts.).
Guadecitabineis (SGI-110) a next generation hypomethylating agent that molecularly is a dinucleotide derivative of decitabine and achieves a more effective hypomethylation activity due to extended exposure window of the active metabolite decitabine. 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 outcomes. Cohort 1 includes AML/MDS pts. with morphological relapse; cohort 2 with minimal residual (MRD) and cohort 3 with no evidence of disease. As of June 2020, 54 pts. have enrolled.
Herein, we report the interim analyses cohort 2 pts. aged 18-75 with detectable MRD by flow cytometry or cytogenetic or molecular testing after allo-SCT. Pts. are excluded in the presence of (1) any anti-leukemic agents used after MRD detection (2) active acute or chronic graft versus host disease (GvHD), (3) uncontrolled systemic infection (4) Concurrent use of systemic immune suppressive other than calcineurin inhibitors and sirolimus.
The study intervention includes SGI-110 given as 40 mg/m2/day subcutaneously for 5 consecutive days every 28 days in addition to 3 planned donor lymphocyte infusions (DLI) if clinically feasible. The pts. are allowed to receive maximum 6 cycles of SGI-110 to achieve response which was defined as eradication of MRD. Pts. achieving response continue the treatment with SGI-110 given as maintenance to complete 12 cycles of treatment. DLI is planned to be given on the 6th day of the 2nd, 4th and 6th cycles of SGI-110 if clinically feasible.
Pts. are taken off the study if there is (1) relapse or no response within the first 6 cycles of SGI-110 (2) related and unexpected serious adverse events (AEs) (3) withdrawal of consent or death or lost to follow up.
Study is designed to take a response probability of .20 or larger as considered promising. A maximum of 25 pts. with MRD will be treated.
Results: As of June 2020, 17 pts. enrolled; M/F was 6/11, median age 63 (range 28 to70) and 11 had AML. Of 17 pts., 6 had their second allo-SCT. European LeukemiaNet risk category was adverse in 8, intermediate in 2 and favorable in 1 AML pts. Of 6 MDS pts., 6 had poor or very poor risk cytogenetics by revised-IPSS.
Median time to MRD detection after the last transplant was 94 days (range, 28 to 504 days). Chimerism was checked in 16 pts. at the time of MRD detection; median T and myeloid cell chimerism was 100% (range, 35% to 100% for T and 24% to 100% for myeloid cell lineages). Pts. started SGI-110 within a median of 17 days after MRD detection (range, 1 to 58 days).
Of 17 pts., 14 were evaluable for response; 2 have been undergoing the treatment with no response evaluation yet done and one died of respiratory complications not related to study drug before response evaluation was possible. Of 14, 6 achieved response with MRD eradication (posterior probability of response=41.3% with 95% credible interval (CI) 18.0% to 65.3%). The number of SGI-110 treatment cycles before response varied from 1 to 6 with a median of 3. All but 1 responders received at least one DLI infusion before achieving MRD eradication. Of the 6 responders, only 1 had disease relapse and another died due to GvHD related complications, both 20 months after MRD detection.
For pts. who had response with MRD eradication, relapse-free survival (RFS) at 1-year after response determination was 100% (95%CI=21%-69.6%) and it was 0% for non-responders (Figure 1a). Similarly, OS was 100% for responders and 0% for non-responders at 1-year after response determination (Figure 1b).
During the study, 130 AEs observed during the 53 cycles of SGI-110 treatment applied. Of 130, 108 (83%) were attributable to SGI-110 and 70 of 108 (65%) were grade 3 or higher in severity. Most of the AEs were related with bone marrow suppression; of 70 AEs grade 3 or higher, 23 (33%) were thrombocytopenia, 15 (21%) were neutropenia, and 2 were anemia. There was no grade 5 AE observed attributable to study drug.
Conclusion: SGI-110 given with or without DLI is well tolerated and yields encouraging response rates that are durable to prevent morphological relapse after MRD detection in the post-transplant setting. The study has been ongoing.
Figure 1

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

OffLabel Disclosure:
Guadecitabine was used off-label for relapse prevention in the post-transplant setting.