Chidamide, a HDAC Inhibitor, Combined with Cladribine, High Dose Gemcitabine and Busulfan with Autologous Stem Cell Transplantation in Patients with Relapsed/Refractory and Poor-Risk Lymphoma

Introduction

High dose chemotherapy (HDC), such as carmustine/etoposide/cytarabine/melphalan (BEAM), followed by autologous stem cell transplantation (ASCT) was a standard of care for patients with relapsed/refractory and poor-risk lymphomas for over decades. However, with the introduction of new drugs, such as rituximab, patients relapsed from or refractory to first line therapy benefit less from HDC with ASCT. To improve the survival of these patients with ASCT, better HDC combination is urgently needed. Our previous research indicated the combination of cladribine/gemcitabine/busulfan (CGB) had strong synergistic effect against lymphoma cell lines. Adding Histone deacetylases inhibitor (HDACi), vorinostat or chidamide (chi), to CGB further enhanced cytotoxicity, which warrant the clinical use of ChiCGB combination as conditioning chemotherapy. We started a phase II clinical trial to evaluate the efficacy and safety of ChiCGB followed by ASCT in patients with relapsed/refractory and poor-risk lymphomas

Patients and methods

Eligibility included ages 18 to 65 and one of the following lymphomas: High-risk and relapsed/refractory (R/R) diffuse large B cell lymphomas (DLBCL), T and natural killer/T (NK/T) cell lymphoma, and hodgkin lymphoma (HL). Additional eligibility criteria included adequate renal, hepatic, pulmonary, cardiac function, performance status 0 to 1, no active hepatitis B or C.

Patients received oral chidamide 30mg on days -7, -4, 0, +3. Cladribine was administered intravenously at the dose of 10 mg from days -6 to -2. Gemcitabine was administered intravenously 4 hours after the finish of cladribine at the dose of 2500 mg/m² on days -6 and -2. Busulfan was administered intravenously at dose of 3.2 mg/kg on days -6 to -2. Dexamethasone 10 mg i.v. was given from day -6 to -2. Infusion of peripheral blood stem cells was on day 0.

CR, OS and progression free survival(PFS) were calculated using standard methods. Statistical analysis was done using Fishers exact test or Chi-square test / Kruskal-Wallis test. Kaplan-Meier method was used for time-to-event analysis including overall survival and progression free survival. The Wilcoxon test was used to evaluate the difference in time-to-event endpoints between patient groups.

Results

Forty-three patients were enrolled between Apr. 2015 and Apr. 2017. Median age was 34 years (range, 22-62). The diagnoses were DLBCL (N=19), T&NK-NHL (N=20), HL (N=4). Eight patients had double/triple protein expression of C-myc, Bcl-2 or Bcl-6 protein identified by immunohistochemistry; 2 had IVLBCL; 1 had transformed DLBCL; 13 had stage IV extranodal natural killer/T cell lymphoma (ENKTCL); and 2 had lymphoblastic T cell lymphoma. Twenty-tow patients were in first CR, 21 had R/R disease, and 5 had PET positive tumor before HDC.

Stem cells source was peripheral blood. Median infused CD34+cells count was 2.1×10⁶/Kg (range, 1.0 to 11.6×10⁶/Kg). Neutrophils and platelets were engrafted on a median day +11 (range, days +8 to +14) and day +12 (range, days +9 to +22), respectively.

The median follow-up is 10.3 months (range, 3-26.5 months). The progression free survival (PFS) and overall survival (OS) of the whole cohort are 78.2% and 89.5%, respectively (Figure-1A). The PFS and OS in DLBCL group are 81.7% and 100% respectively (Figure-1B). Of 19 patients with DLBCL, only 2 with IVLBCL relapsed at 5.7 and 11.1 months post transplantation respectively. The EFS and OS in T&NK/T group are 73.7% and 78.8%, respectively (Figure-1C). Twelve of 16 patients with ENKTCL, 1 of 2 patients with lymphoblastic T cell lymphoma and 1 of 2 patients with T-NHL remain alive in CR at last follow-up. The EFS and OS in HL group are 75% and 100%, respectively. For the whole cohort, patients who had active disease before HDC demonstrated poorer EFS (80.9% vs. 53.3%; P=0.039) (Figure-1D).

The most common adverse event was infection. Thirty-nine (90.7%) patients developed grade 3 neutropenic fever. Other notable toxicities included grade 2 (55.8%) and 3 (9.3%) mucositis, grade 2 (13.9%) and 3 (4.7%) dermatitis, grade 2 (9.3%) diarrhea and self-limited transaminase elevation. All these toxicities were manageable and there was no therapy-related mortality.

Conclusion

Our study showed ChiCGB combination can be safely administered as HDC before ASCT for patients with R/R or high-risk lymphomas. This combination showed promising early outcomes and warrant further clinical investigations.

Figure 1

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Figure 1

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