Chidamide with PEL regimen (prednisone, etoposide, lenalidomide) for elderly or frail patients with relapsed/refractory diffuse large B‐Cell lymphoma ‐results of a single center, retrospective cohort in China

Abstract Treatment for relapsed/refractory Diffuse Large B‐Cell Lymphoma (R/R DLBCL) is evolving rapidly due to the emergence of novel drugs, of which histone deacetylase inhibitors (HDACis) are an important example. This study showed efficacy in patients with R/R DLBCL after failure of conventional therapies. We conducted a single‐center, retrospective study of 34 frail or elderly R/R DLBCL patients who had been treated off‐label with chidamide‐containing regimens from 2018 to 2020. X 2 or Fisher test were used to compare response rate and Kaplan‐Meier method was used to perform the survival analyses which compared with log‐rank test between different groups. The test standard was p < 0.05. In total, 34 patients with R/R DLBCL received CPEL+/‐R for at least 1 cycle were included. Most of them were refractory patients (n = 28,82.4%). The interim objective response rate (ORR) was 73.5% (32.4% complete remission [CR]), and the ultimate ORR was 50.0% (35.3% CR). After a median follow‐up of 13.1 months, the median progression‐free survival (PFS) was 10.5 months (95%CI 6.4–14.6) and the median overall survival (OS) was 19.3 months (95%CI 11.8–26.9). The 1 year expected PFS and OS rate was 43.0% and 73.7%, respectively. The most common grade 3/4 hematologic adverse events (AEs) were neutropenia (n = 11,32.3%) and anemia (n = 4, 11.8%) 0.23.5% (8/34) of all patients experienced grade 3/4 nonhematologic AEs. No treatment‐related deaths were observed. The study showed chidamide‐included regimen could be an option for R/R DLBCL patients ineligible for intensive chemotherapies. Current data showed favorable efficiency and moderate safety profile. Further study is warranted for better illustration of efficacy and usage in combination therapies.


| INTRODUCTION
Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma in adults and is biologically aggressive. 1 The 5 year disease-free survival (DFS) rate is ∼60% when patients are treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). 2 Unfortunately, after an initial response to first-line treatment, one-third of patients relapse or experience refractory disease and require subsequent treatments, 3,4 of whom outcomes are generally poor, particularly for patients who are ineligible for intensive chemotherapy regimens and subsequent transplant treatment due to their advanced age, severe comorbidities, or unwillingness to receive intensive treatment. 5,6 Although there are lots of new drugs emerging now, the overall response rate (ORR) of refractory/relapsed DLBCL (R/R DLBCL) retains generally below 50.0% with a short survival time. 7 In 2013 Mounier N et al reported that rituximab plus gemcitabine and oxaliplatin (R-GemOx) regimen was effective for these ineligible patients with a 65% ORR, while the 5 year overall survival (OS) and progression-free survival (PFS) rates were 13.9% and 12.8%, respectively. 8 Moreover, patients with primary refractory disease or who experience relapse within 12 months after the first-line treatment have a dismal outcome with a median OS of approximately 5-6 months. [9][10][11] Therefore, there is a substantial unmet need for novel treatments for R/R DLBCL. Exploration of a therapy with acceptable toxicities as well as maximal output may be a pivotal point for these group of patients.
Chidamide is a novel orally active benzamide-type histone deacetylase inhibitor (HDACi) that can induce growth arrest and apoptosis in blood and lymphoid-derived tumor cells. 12 In a phase II study, 79 relapsed/refractory peripheral T-cell lymphoma (R/R PTCL) patients treated by chidamide achieved a 35% ORR (14% complete remission [CR]). Chidamide thus has been approved by the China Food and Drug Administration (CFDA) as a treatment for R/R PTCL. 13 Pasqualucci et al reported that CREBBP/EP300 mutations were a major pathogenetic mechanism in most B-cell non-Hodgkin's lymphomas, which indicated that the use of drugs targeting acetylation/deacetylation mechanisms is a promising strategy. 14 Recently, several kinds of HDACis were evaluated in clinical trials for B-cell non-Hodgkin's lymphoma (NHL). In a phase 2 study, mocetinostat, an isotype-selective HDACi, achieved an 18.9% ORR in 41 R/R DLBCL patients, and nearly 1/3 got a stable disease state. 15 Consequently, our single-center retrospective analysis evaluated the efficacy and toxicity of chidamide plus prednisone, etoposide and lenalidomide with or without rituximab (CPEL+/-R) for elderly and frail R/R DLBCL patients over a 2 year period.

| Patients
We conducted a retrospective, single-center, off-label, cohort study of all adult patients who had received chidamide for R/R

| Definition and criteria
Refractory disease was defined as stable disease (SD) or progressive disease (PD) in response to the immediate prior treatment and disease that relapsed within 12 months following a previously documented response (PR or CR), according to SCHOLAR-1 study. 9 Response to therapy was evaluated using the Lugano response criteria by Cheson 2014. 17 Clinical response would be assessed every 2 cycles of regimen and we defined assessment after 4 and 8 cycles as interim and final response, respectively. For patients who experienced SD or PD and refused further treatment, evaluation after 2 or 3 cycle was included as interim and final response. Toxicity was reported according to the National Cancer Institute's Common Criteria for Adverse Events 4.0.
The primary objective of the study was to evaluate the activity of CPEL+/-R in terms of the ORR and CR rate. The 618secondary objective was to evaluate the safety of CPEL+/-R in terms of adverse events (AEs) and survival outcomes in terms of PFS and OS.

| Statistics methods
PFS was calculated as the time from the first dose of CPEL+/-R to the first documentation of disease progression or death. OS was calculated from the start of CPEL+/-R treatment to the date of last follow-up or death from any cause. Statistical analysis was performed using the software package IBM SPSS (v.19.0; IBM Corp). Measurement data with non-normal distribution was expressed as median (range), while enumeration data was expressed as number of cases (%) and tested by X 2 method or Fisher exact test. Survival analysis were performed using the Kaplan-Meier curves and log-rank tests were performed to compare the pairs of subgroups in regard to the PFS and OS rate.
Statistical significance was set at p < 0.05.

| Patient characteristics
Thirty-four patients with R/R DLBCL treated by CPEL+/-R between 1 June 2018 and 1 June 2020 at our hospital were included in the study. Their clinical characteristic features are listed in Table 1

| Response
All patients were evaluable for response. In an intention-to-treat for OS and PFS, respectively)( Figure 4).
The regimen containing BR as a consolidated therapy produced better overall survival and progression-free survival rates and the difference was statistically significant by the means of the K-M logrank test, but appeared to have no significant difference by means of the Cox regression analysis (details not list).

| Toxicity
Sixty   inspiring us a lot. Although CAR-T therapy offer a promising ORR ranging from 52.0%-82.0% for the R/R DLBCL patients, [25][26][27] achieving adequate disease control and remission periods that allow enough time to manufacture and process viable CAR products is an unmet clinical need. It suggested that CPEL+/-R regimen may be act as a bridge to CAR-T cell therapy for the frail patients.

| DISCUSSION
One limitation to our study is the small sample size of patients.
Larger sample size and well-designed clinical trials are needed before a clear conclusion can be drawn. Another limitation of the cohort is the heterogeneity of regimen used in patients. While such condition happens in the real-world studies, where choices need to be made and adjusted on every single case's basis, these data do provide useful information and reference for physicians and investigators to design further study and regimen.

| CONCLUSION
In summary, the study illustrated the efficacy and safety of the CPEL +/-R regimen for R/R DLBCL patients who were ineligible for intensive chemotherapy and ASCT. Future studies are needed to define the optimal schedule.