Pilot Study of Safety and Efficacy of Chidamide in Allogenic Peripheral Hematopoietic Stem Cell Transplantation: Better Disease Control and Positively Lower Graft Versus Host Disease

Introduction

The combination of busulfan (Bu) and fludarabine (Flu) is an effective and well-tolerated hematopoietic stem cell transplantation (HCT) conditioning regimen for patients with acute leukemia. However, relapse remains the main reason for treatment failure. Increasing intensity of conditioning therapy leads to not only better control of disease, but more treatment related mortality including graft versus host disease (GVHD). Song and Partow demonstrated that introducing histone deacetylase inhibitor (HDACi) vorinostat into busulfan/fludarabine/clofarabine (Bu/Flu/Clo) could augment disease control in vitro and in vivo, without increasing toxicity. Pavan and Choi showed vorinostat decrease GHVD while preserving graft versus leukmia effect. We conducted a clinical trial to evaluate the role of a selective HDACi chidamide in allogenic HCT.

Methods

Chidamide was given orally twice weekly at dose of 20 mg from day -7 to 2 weeks post transplantation. Busulfan was administered intravenously at fixed dose of 3.2 mg/kg for 4 days from day -6 to -3. Fludarabine and cytarabine were given intravenously at dose of 30 mg/m² and 1g//m² respectively for 5 days from day -6 to -2. GVHD prophylaxis was based on post-transplantation cyclophosphamide (50 mg/kg on day +3, +4) and cyclosporine started from day +5. The presence of minimal residual disease (MRD) was determined by multi-parameter flow cytometry.

Results

Forty patients (24 AML, 6 MDS, 10 ALL) with median age 41 years (range 16-60) received an allogeneic matched sibling (n=34) or unrelated donor (n=6) HCT in CR1 (n=15), CR2 (n=6), with residual disease (n=10), or with active disease (n=9). Seventeen patients had adverse risk karyotype according to European LeukemiaNet risk stratification. Median time to ANC > 0.5 x 10⁹/L and platelets > 20 x 10⁹/L were 16 (range 9-36) and 18 days (11-44), respectively. Short-term (before recovery of ANC and platelets) adverse events included neutropenic fever (80%), reversible grade 2 elevation of liver enzyme (42.5%), and grade 2 mucositis (27.5%). Median follow-up time of the whole cohort was 11.5 months (3-24.7). All patients achieved CR and clearance of MRD by day +30 after HCT. All patients achieved 100% donor chimerism at 30 days following HCT. The incidence of grades II-IV and grade III-IV acute GVHD is 11% and 5% respectively. Only one patient died of aGVHD. Chronic extensive GVHD among 38 evaluable patients is 9%. Median follow-up time of the whole cohort is 11.5 month (3-24.7). Estimated progression free survival and overall survival at 1 year are 75% and 84.6% respectively (Figure1-A). Patients with MRD have inferior survival compere with patients without MRD (81.2% vs 68% p=0.336) (Figure 1-B).

Conclusion

Short-term results indicate introducing chidamide into allogeneic HCT could lead to better control of disease and possible lower GVHD.

Figure 1

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Figure 1

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