PTCLs are relatively rare lymphomas with mostly poor outcomes. In contrast to the progress made in the treatment of aggressive B-cell lymphoma, management of patients with PTCL is disappointing, with no major progress made over the past decades. Due to the rarity and geographic variation of the disease, randomized prospective trials are scarce and there is no consensus on the optimal therapy for PTCL patients. CHOP or CHOP-like regimens are the most widely used first-line therapy. The CR rates of around 50% have been reported. However, with the exception of ALK-positive ALCL, most types of PTCLs exhibited poor long-term survival. In China, a retrospective study included a total of 679 PTCL patients over two decades. The 5-year OS rate of 34.9% in AITL and 27.6% in PTCL, NOS were reported in this study, with no improvement of survival during the past two decades [5].
Given the poor outcomes associated with CHOP as first-line therapy, other more intensive chemotherapies have been investigated. High-dose CHOP alternating with ESHAP (etoposide, cisplatin, cytarabine and prednisone) followed by auto-SCT in young patients failed to overcome the poor prognosis of PTCL patients. The CR rate of 49% and 4- year PFS and OS rates of 30% and 39% were reported in this study [21]. In a retrospective study from MD Anderson Cancer Center, the CR rate of more intensive regimens, including hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) was not superior to CHOP regimen, with CR rate of 59% and 3-year OS rates of 49% [22]. Gemcitabine-based regimens also failed to show advantage over standard CHOP regimen. In a phase 2 multicentre randomized trial, the CR rate of GEM-P regimen (gemcitabine, cisplatin, and methylprednisolone) was inferior to CHOP regimen (46% vs. 62%), with 2-year PFS rates of 38% versus 37%, respectively [9]. The above studies suggested that the past usage of cytotoxic chemotherapy at varying intensity was not sufficient in the treatment of PTCL. There is a critical need for new treatment approaches.
Epigenetic dysregulation plays an important role in PTCL oncogenesis. In recent years, HDAC inhibitors have emerged as novel therapeutic agents for PTCL. Since 2006, three of the 7 new drugs approved by the US Food and Drug Administration (FDA) for the treatment of PTCL were HDAC inhibitors, including vorinostat, romidepsin and belinostat. In the phase 2 trial of romidepsin for patients with relapsed PTCL, an ORR of 38% was reported with median DOR of 8.9 months [11]. The BELIEF trial evaluated belinostat for patients with relapsed or refractory PTCL. An ORR of 25.8% and median DOR of 13.6 months were achieved [12]. The safety and efficacy of romidepsin combined with CHOP was assessed in previously untreated PTCL patients. A comparable CR rate (51%) and more favorable PFS and OS rates (41.0% and 70.7% at 30 months) compared with CHOP alone were achieved. However, this combination therapy was associated with severe toxicity, including 89% of grade 3–4 neutropenia, 78% of grade 3–4 thrombocytopenia, and 3 cases of acute cardiac toxicity [23].
In our study, combining chidamide with CHOEP chemotherapy proved to be effective, with CR rate of 55.9% and ORR of 82.4%. Several studies reported relatively high CR rate over 50% with CHOP or CHOEP therapy alone. In the study conducted by d'Amore F et al, CR rate of 51% and ORR of 82% were reported with CHOP/CHOEP regimen [24]. However, the time interval of CHOP/CHOEP was shorten to 2 weeks which is not feasible in elderly patients. In the phase 3 study evaluating brentuximab vedotin combined with chemotherapy for CD30-positive PTCL, CR rate of 56% and ORR of 72% were reported in the CHOP control group [25]. However, 22% of the enrolled patients in this study were ALK-positive ALCL with relatively good prognosis. Considering that the histologic subtypes were mainly AITL and PTCL, NOS with no ALK-positive ALCL included and more than 1/3 of patients were older than 60 years in our study, the response achieved with C-CHOEP regimen was satisfactory. The significantly higher CR rate compared with CHOEP therapy further confirmed the superiority of C-CHOEP therapy.
Although a fair number of PTCL patients are sensitive to chemotherapy, their response duration is often short with frequent relapse resulting in poor long-term survival. The relapse rate of 27–43% was reported in PTCL patients, generally higher than that of B-cell lymphoma [26–27]. In our study, the median DOR was not reached with a median follow-up time of 33 months. Patients in the C-CHOEP group showed much superior long-term survival (3-year PFS and OS rates of 46.8% and 73.5%) than the 30–40% long-term survival reported with CHOP regimen in previous studies. These results indicated a more durable response achieved with C-CHOEP induction and chidamide maintenance.
In general, chidamide monotherapy had a very favorable toxicity profile. In the real-world study of chidamide in relapsed or refractory PTCL, AEs of grade 3 or higher were mainly hematologic toxicities including thrombocytopenia (10%) and neutropenia (6%) [15]. In our study, combination of chidamide with CHOEP regimen was well tolerated with no additional hematologic toxicities and increased risk of infections compared to the CHOEP regimen. Chidamide maintenance was also feasible with mostly mild hematologic toxicities. In a pilot study evaluating romidepsin in patients with ENKTL, the trial was discontinued due to severe Epstein-Barr virus (EBV) reactivation in 3 of the 5 enrolled patients [28]. No EBV or HBV reactivation was observed either in the C-CHOEP induction phase or the chidamide maintenance phase in our study.
The limitations of our study also need to be acknowledged. Due to the relatively small number of PTCL patients in a single institution, conducting randomized controlled trial was relatively difficult and historic groups were used as controls in our study. The study results may be confounded by selection bias, unbalanced demographics, and time differences. However, clinical experience of our study may serve as reference for future multicentre phase 3 randomized controlled trials. Differences in responses and survivals of different histologic subtypes of PTCL could also be investigated in further large-scale studies.