CEOP/IVE/GDP alternating regimen compared with CEOP as the first-line therapy for newly diagnosed patients with peripheral T cell lymphoma: results from a phase 2, multicenter, randomized, controlled clinical trial

Abstract

Background: Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)/CHOP-like chemotherapy is widely used in peripheral T cell lymphoma (PTCL). Here we conducted a phase 2, multicenter, randomized, controlled trial, comparing the efficacy and safety of CEOP/IVE/GDP alternating regimen with CEOP in newly diagnosed PTCL.

Methods: PTCL patients, except for anaplastic large cell lymphoma-anaplastic lymphoma kinase positive, were 1:1 randomly assigned to receive CEOP/IVE/GDP (CEOP, cyclophosphamide 750 mg/m2, epirubicin 70 mg/m2, vincristine 1.4 mg/m2 [maximum 2 mg] on day 1, and prednisone 60 mg/m2 [maximum 100 mg] on days 1-5 every 21 days, at the first and fourth cycle; IVE, ifosfamide 2000 mg/m2 on days 1-3, epirubicin 70 mg/m2 on day 1, and etoposide 100 mg/m2 on days 1-3 every 21 days, at the second and fifth cycle; and GDP, gemcitabine 1000 mg/m2 on days 1 and 8, cisplatin 25 mg/m2 on days 1-3, and dexamethasone 40 mg on days 1-4 every 21 days, at the third and sixth cycle) and CEOP (every 21 days for 6 cycles). Analysis of efficacy and safety was of the intent-to-treatment population. The primary endpoint was a complete response rate at the end of treatment. Meanwhile, whole exome sequencing and targeted sequencing were performed in 62 patients with available tumor samples to explore prognostic biomarkers in this cohort as an exploratory post hoc analysis.

Results: Among 106 patients, 53 each were enrolled to CEOP/IVE/GDP and CEOP. With 51 evaluable patients each in two groups, a complete response rate of the CEOP/IVE/GDP group was similar to that of the CEOP group (37.3% vs. 31.4%, p = 0.532). There was no difference in median progression-free survival (PFS; 15.4 months vs. 9.2 months, p = 0.122) or overall survival (OS; 24.3 months vs. 21.9 months, p = 0.178). Grade 3-4 hematological and non-hematological adverse events were comparable. Histone modification genes were most frequently mutated (25/62, 40.3%), namely KMT2D, KMT2A, SETD2, EP300, and CREBBP. Multivariate analysis indicated that CREBBP and IDH2 mutations were independent factors predicting poor PFS and OS (all p < 0.001), while KMT2D predicting poor PFS (p = 0.002).

Conclusions: CEOP/IVE/GDP alternating regimen showed no remission or survival advantage to standard chemotherapy. Future clinical trials should aim to develop alternative regimen targeting disease biology as demonstrated by recurrent mutations in epigenetic factors.

Trial registration: The study was registered on ClinicalTrial.gov (NCT02533700) on August 27, 2015.

Keywords: Alternating regimen; CHOP; Overall response rate; Peripheral T cell lymphoma; Prognosis; Prognostic biomarker.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1

CONSORT diagram of the study. CEOP = cyclophosphamide, epirubicin, vincristine, and prednisone. IVE = ifosmide, epirubicin, and etoposide. GDP = gemcitabine, cisplatin, and dexamethasone

Fig. 2

Gene Mutations in peripheral T cell lymphoma. a Gene mutations identified by whole exome sequencing and targeted sequencing in 62 patients. The percentage of patients with mutations was listed on the right. The mutations are classified into the categories indicated on the left. b Number and type of non-silent somatic mutations presented above, number and percentage of non-silent somatic single-nucleotide variants presented below. c Circos diagram presenting correlation between genes

Fig. 3

Treatment response and survival outcomes. Kaplan-Meier curves showed (a) progression-free survival and (b) overall survival of the CEOP/IVE/GDP group and of the CEOP group. HR = hazard ratio

Fig. 4

Subgroup analysis for complete response at end of treatment. LDH = lactate dehydrogenase, IPI = International Prognostic Index. *PTCL subtype includes PTCL-NOS and other types

Fig. 5

Gene mutations and treatment response/survival outcomes. a Relation between treatment response (including complete response, partial response, and no response) and gene mutation profile. b–d Kaplan-Meier curves showed progression-free survival (upper panel) and overall survival (lower panel) of PTCL patients, according to the mutation status of CREBBP (b), IDH2 (c), and KMT2D (d)