Page 74 - 2019_08-Haematologica-web

M. Sebert et al.
and the median overall survival (OS) of 18-24 months obtained with azacitidine remains modest.1 Moreover, median survival after HMA failure is only approximately six months.2
The hypomethylating activity of AZA and decitabine depends on their incorporation during the S phase of the cell cycle into RNA or DNA, respectively.3 This suggests a relationship between duration of drug exposure and effec- tiveness of the HMA. Half-life of first generation HMA is approximately 30 minutes, which might limit their activi- ty in slowly dividing MDS cells.4 Furthermore, a recent study found a high response rate of 67% in unfavorable risk MDS/AML (specifically TP53 mutated patients) after serial 10-day cycles of decitabine, a regimen with a longer exposure to decitabine than the classical 5-day schedule.5
Guadecitabine (SGI-110) is a novel, second-generation hypomethylating drug. It is a dinucleotide of decitabine (the active metabolite) and deoxyguanosine, resistant to cytidine deaminase, the main enzyme responsible for decitabine degradation. Cleavage of the phosphodiester bond between the two parts of the dinucleotide results in a slow release of decitabine, prolonging the HMA expo- sure in cells.6 A phase I/II study found a 52% (55 of 107) response rate to guadecitabine in treatment naïve AML with tolerable toxicity.7 Guadecitabine was also studied in 19 patients with relapsed or refractory MDS after HMA, with a 32% response rate.8
These results prompted the GFM group to propose guadecitabine as a salvage treatment in a larger series of higher-risk MDS and low blast count AML patients after AZA failure, not candidates for intensive chemotherapy or allo-SCT.
Methods
Trial design
This was a national, GFM-sponsored multicenter phase II clini- cal trial (clinicaltrials.gov identifier: 02197676) evaluating the efficacy of guadecitabine in higher-risk MDS and low-blast count AML patients, refractory or relapsing after AZA treatment. A first cohort of 21 patients was planned with the objective to stop the study if four patients or less would respond after six cycles of guadecitabine or experience a high toxicity. After review by an independent Data Safety Monitoring Board (DSMB), toxicity was considered acceptable and five patients were responders. The extended cohort included 36 patients. Because late responders had been reported in previous studies (Issa et al., 2019, personal commu- nication), response was also evaluated after nine cycles of guadecitabine in the extended cohort (Online Supplementary Figure S1).
Patients
Inclusion criteria were: i) age >18 years; i) diagnosis of MDS or chronic myelomonocytic leukemia (CMML), with white blood cell (WBC) count <13x109/L according to the World Health Organization (WHO) 2008 criteria9 with international prognostic scoring system (IPSS) intermediate-2 or high-risk MDS10 or AML with 20-30% marrow basts [AML/refractory anemia with excess blasts in transformation (RAEB-t) according to the French- American-British (FAB) classification11]; iii) refractoriness to azaci- tidine, i.e. at least six cycles without response [complete response (CR), partial response (PR), marrow CR or stable disease with hematologic improvement (HI), according to International Working Group (IWG) 2006 criteria]12 or relapse after a response.
Non-responders were eligible only in the absence of overt progres- sion, i.e. at least doubling of marrow blast percentage between start of HMA and protocol screening. Patients eligible for intensive chemotherapy or allo-SCT were excluded.
Other eligibility criteria included an Eastern Co-operative Oncology Group (ECOG) performance status of 0-2, and adequate liver and hepato-renal functions (creatinine <1.5 times the upper limit of normal, and creatinine clearance ≥+50 mL/min, total bilirubin and transaminase <1.5 times the upper normal limit). The protocol was approved by the Comité de Protection des Personnes Paris-Ile de France, the ethical committee whose approval is valid for all participating French institutions. All patients provided written informed consent.
Treatment
Patients received 60 mg/m2 subcutaneous guadecitabine on days 1-5 of 28-day treatment cycles (the recommended drug regi- men in previous studies).7,8 Treatment was continued until pro- gression, death, unacceptable toxicity, or no response after six cycles (extended to 9 cycles after the first 20 patients). Dose reduc- tions to 45 and even 30 mg/m2/d were allowed to manage toxicity.
Biological studies
Somatic mutations were screened on bone marrow cells by a next-generation sequencing (NGS) assay for a selected panel of 36 genes (Online Supplementary Appendix and Online Supplementary Table S1) at inclusion for all patients and on sequential bone mar- row samples in some responders.
Global DNA methylation was measured in 53 patients by the long interspersed nuclear element (LINE1) methylation assay, and changes in methylation from baseline were assessed as described in the Online Supplementary Appendix.
End points
The primary end point was hematologic response (CR, PR, mar- row CR or stable disease with HI according to IWG 2006 criteria)12 Secondary end points were duration of response, rate of progres- sion to AML, overall survival, toxicity profile of guadecitabine. All patients who achieved a CR, PR, marrow CR or HI after 3, 6 or 9 (for the 36 patients of the extended cohort) cycles of guadecitabine were considered responders and were allowed to continue treat- ment until loss of response, progression, or death.
Statistical analysis
Based on the results of phase III trials of decitabine for the treat- ment of MDS13 and AML,14 it was expected that guadecitabine would achieve at least 30% hematologic responses. A Bryant and Day 2-stage phase II design was used. Assuming a 20% response rate (CR+PR+ marrow CR + HI according to IWG 2006 criteria) under the null, controlling for type I and II error rates at α=0.05 and β=0.2 respectively, 19 patients had to be accrued for stage 1 of the trial to demonstrate a benefit of 20% (i.e. a response rate of >40%). At the end of Stage 1, the study would stop if there were four responders or less. If there were at least five responders, 35 additional patients had to be included in the study. We assumed that approximately 10% of the population may not be evaluable for response and that 56 patients should, therefore, be included.
The response rate was estimated in the intention-to-treat sam- ple, with 95% exact confidence interval. (95%CI:) The Kaplan and Meier method was used for analysis of progression-free survival and overall survival. Median and 25% and 75% quartiles, were estimated.
Analysis was performed on SAS (SAS Cary, NC, USA) and R v.3.3.2 (https://www.R-project.org/) softwares. Two-sided P<0.05 was considered statistically significant.
1566
haematologica | 2019; 104(8)