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Guadecitabine Maintenance Therapy Shows Promise in High Risk MDS/AML Patients

Guadecitabine (SGI-110), when given as maintenance therapy following allogeneic stem cell transplantation (allo-SCT), showed promising relapse-free survival rates (RFS) with manageable safety in high-risk patients with myelodysplastic syndromes/acute myeloid leukemia (MDS/AML), according to data presented by Betul Oran, MD, MS, Stem Cell Transplantation and Cellular Therapy, The University of Texas, MD Anderson Cancer Center, Houston, TX, at the virtual 62nd American Society of Hematology (ASH) Annual Meeting and Exposition. 

“Disease relapse remains to be one of the major reasons [for[ treatment failures after allogeneic stem cell transplantation (allo-SCT) in AML and MDS patients. 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,” wrote Dr Oran and colleagues. 

The single-arm, phase II trial consisted of 3 treatment cohorts defined by disease status after transplant, primary outcomes varied by cohort. The first cohort included AML/MDS patients with morphological relapse after transplant, the second cohort consisted of patients with minimal residual (MRD), while patients in cohort 3 demonstrated no evidence of disease following transplant. 

While the study included a total of 54 patients overall, Dr Oran et al reported on the analyses of the 22 patients in cohort 3, who received guadecitabine as post-transplant maintenance while in remission. 

Those in the maintenance cohort included high-risk AML/MDS patients aged 18-75. High-risk MDS patients are those who have poor/very poor cytogenetics by revised-IPSS, monosomal karyotype, or a bone marrow blast count greater than 5% before transplant, while high-risk AML is defined as those in the adverse risk group by European LeukemiaNet (ELN) or who had presence of MRD or active disease at transplant.

Patients who had adequate engraftment with absolute neutrophil count >/= 1.0 x 109 /L; platelet >/= 50 x 109 /L and no documented evidence of relapse received guadecitabine maintenance in the 42-100 days following allo-SCT. Those who were eligible received a guadecitabine dosage at 30mg/m2/day subcutaneously for 5 consecutive days every 28 days until all 12 cycles were completed, or the patient experienced disease relapse or unacceptable toxicity. 

The primary endpoint for cohort 3 was RFS time, defined as either time to disease progression or death, whichever happened first. 

Of 11 AML patients, 8 had an adverse ELN risk category, 2 had intermediate, and 1 was favorable, while 6 out of 11 MDS patients had poor/very poor cytogenetic abnormalities by revised-IPSS, 4 were good, and 1 was an intermediate risk. A total of 6 out of 22 patients were in complete remission with count recovery at transplant.

The median time to initiation of the first cycle of guadecitabine maintenance was 59.5 days (range, 43 to 114 days), and the median follow-up time for survivors was 13.1 months (n=17). 14 patients discontinued the study; 6 due to disease relapse, 4 completed all 12 cycles of treatment, 1 lost insurance, 1 withdrew consent, 1 due to travel issues caused by the COVID19 pandemic, and 1 had pulmonary complications unrelated to guadecitabine. Of 22 patients, 7 patients required a dose reduction to 20 mg/m2/dayX5 days, and 1 patient to 20 mg/m2/dayX3 days to be able to continue the treatment.

The RFS  at 1 year was 66.3% (95% CI=42% to 82.3%), while the overall survival (OS) was 88.9% (95%CI=61.8 to 92.2%). 

There were 353 adverse events (AEs) observed with 125 cycles of guadecitabine treatments. 287 (81.3%) of which were attributable to guadecitabine and 133 of those 287 (46.3%) were grade 3 or higher. The most common grade 3 or higher AEs were related to bone marrow (BM) suppression, with 71 (25%) being thrombocytopenia, 64 (22%) neutropenia, 67 (23%) leukopenia, and 8 (2%) anemia. Of the 22 patients, 15 had grade 4 neutropenia at least once, and 8 had grade 4 thrombocytopenia.

There were 18 infectious AEs, 11 of which were grade 3-4. No grade 5 AEs attributed to guadecitabine were observed.

“SGI-110 [guadecitabine] led to frequent grade 3-4 BM suppression in high-risk AML/MDS patients when given as maintenance therapy after allo-SCT,” added Dr Oran and colleagues.
 
“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 [a] 1-year RFS of 66.3%. The study currently is ongoing,” they concluded.—Alexandra Graziano
Betul Oran, Gheath Alatrash, Amin M. Alousi, et al. Maintenance Treatment with Guadecitabine (SGI-110) in High-Risk MDS and AML Patients after Allogeneic Stem Cell Transplantation. Presented at: the 62nd ASH Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 3328.

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