Background
Peripheral T-cell lymphoma (PTCL) is an aggressive, uncommon form of non-Hodgkin lymphoma (NHL) that is typically associated with a poor prognosis [
1‐
3]. PTCL comprises many subtypes that vary in morphology, biology, and prognosis [
1,
2]. The most common subtypes globally are PTCL–not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large cell lymphoma (ALCL) [
2]. In western countries, PTCL accounts for 15% to 20% of aggressive lymphomas and 5% to 10% of NHL diagnoses. The prevalence is higher in Asia, with approximately 15% to 20% of all lymphomas classified as PTCL or natural killer/T-cell lymphoma [
2,
4‐
6]. Some of this variation may be a result of exposure or genetic susceptibility to pathogenic agents such as human T-lymphotropic virus-1 and Epstein-Barr virus in Asia [
2,
5,
7].
There is no current standard of care for patients with most subtypes of PTCL, and no agents have been approved specifically for use as first-line treatment of PTCL [
3,
8]. In the first line, most patients receive induction chemotherapy regimens derived from studies of B-cell lymphomas, most commonly anthracycline-containing regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) [
1‐
3,
8‐
11]. Although most patients achieve a response with induction chemotherapy, responses are typically brief and many patients experience relapse or become refractory to treatment [
1‐
3,
9,
10]. The role of stem cell transplantation (SCT) for patients with PTCL is yet to be clearly determined and, currently, only a minority (< 20%) of patients undergo SCT [
9‐
11]. Many patients with PTCL who receive SCT experience disease relapse after transplantation [
12].
Romidepsin—a structurally unique, potent, bicyclic class 1 selective histone deacetylase inhibitor [
13‐
15]—is approved for the treatment of both patients with cutaneous T-cell lymphoma who have received ≥ 1 prior systemic therapy and patients with PTCL who have received ≥ 1 prior therapy [
16]. Approval in PTCL was primarily based on results from a phase 2, single-arm, open-label study in relapsed/refractory PTCL (GPI-06-0002) [
17].
For romidepsin, data from GPI-06-0002 (n = 130) based on an October 2010 cutoff (median follow-up, 13.4 months) were presented in the package insert [
16] and published manuscript [
17] and include a 25% objective response rate (ORR), 15% confirmed/unconfirmed complete response (CR/CRu) rate, and median duration of response (DOR) of 17 months [
17]. As of the October 2010 data cutoff, 17 of 19 patients who had experienced CR/CRu had not progressed [
17]. The objective of this manuscript is to present updated GPI-06-0002 efficacy data and characteristics of patients who achieved long-term responses (≥ 12 months) based on a more recent Independent Review Committee (IRC) assessment (data cutoff, December 31, 2011; median follow-up, 22.3 months).
Discussion
Since 2009, 3 agents have been approved in the United States for patients with relapsed/refractory PTCL [
16,
18,
19]. Pralatrexate, a folate analogue, is approved for the treatment of patients with relapsed or refractory PTCL [
18] based on a single-arm phase 2 study showing 29% ORR, including 11% CR (n = 109) and a median DOR of 10.1 months [
20]. Brentuximab vedotin, a CD30-directed antibody-drug conjugate, is approved for the treatment of patients with systemic ALCL after failure of ≥ 1 prior multiagent chemotherapy regimen [
19]. ALCL is a common subtype of PTCL (approximately 25% of cases in North America) that is uniformly CD30+ [
2,
21]. Approval was based on an 86% ORR, including a 57% CR (n = 58) [
21] and a median DOR of 13.2 months [
22]. In patients with relapsed/refractory PTCL, romidepsin demonstrated a 25% ORR, including 15% CR/CRu and a median DOR of 28 months for all responders. Responses were rapid with a median time to objective response of 1.8 months. Long-lasting responses occurred across all major PTCL subtypes and in patients refractory to their last prior therapy.
Romidepsin has demonstrated comparable efficacy across the 3 most common PTCL subtypes. Although pralatrexate has general approval for the treatment of PTCL, based on results from the pivotal study in relapsed/refractory PTCL [
20], National Comprehensive Cancer Network guidelines report that pralatrexate has demonstrated limited activity in AITL [
8]. Brentuximab vedotin has demonstrated considerable activity in ALCL [
21], and responses have also been seen in CD30+ cases of other NHL subtypes (including AITL) [
23]; however, its utility in non-CD30+ PTCLs is unknown.
More than one-half of the patients with relapsed/refractory PTCL who achieved CR/CRu on romidepsin experienced long-term responses (≥ 12 months). Complete responses were achieved in patients with typically poor prognostic factors, and none of the examined patient or disease characteristics predicted failure to achieve long-term remission. Achievement of CR/CRu was associated with prolonged survival, and achievement of SD90 led to survival rates similar to the achievement of PR.
Amendments to the study protocol allowed for maintenance with 2 romidepsin doses per cycle for patients who received ≥ 12 treatment cycles and with 1 dose per cycle for patients who received ≥ 24 treatment cycles and had received 2 doses for ≥ 6 treatment cycles.
Extended dosing of romidepsin was tolerated; the most grade ≥ 3 AEs were observed in the first 2 cycles of treatment. ECG abnormalities were uncommon, and no clinically significant changes were observed across treatment cycles [
17]. An early analysis of a post-marketing QT study demonstrated that romidepsin does not have a concentration-dependent effect on the QTc interval (including at exposures more than 2-fold the approved dosing), and while clinically insignificant changes in QTc were reported, these changes were attributable to antiemetic premedication [
24]. Romidepsin was associated with a delayed concentration-dependent increase in heart rate with a maximum mean increase of 20 beats per minute 6 hours after the start of a 4-hour romidepsin infusion [
16]. Publication of the final analysis of the QT study is ongoing.
A SEER (Surveillance and Epidemiology End Results) database analysis from 1992 to 2009 showed that, with the exception of ALCL, the incidence of common PTCL subtypes has greatly increased over the past few decades (the combined rate more than tripled from 1992 to 2009) [
25]. However, over this same time period, survival times did not increase [
25] as they have for patients with B-cell lymphoma [
26]. Despite poor outcomes, anthracycline-based regimens continue to be commonly used for the treatment of PTCL [
1‐
3,
8‐
11]. With the approval of 3 novel agents since 2009 [
16,
18,
19], it is hoped that a trend toward improved survival will begin to emerge. Current studies are evaluating the combination of these newly approved agents with chemotherapeutic regimens. Preliminary results from a phase 1B study of romidepsin in combination with CHOP for the first-line treatment of patients with PTCL (14 evaluable patients) demonstrated an ORR of 78%, including 57% CR [
27], and a phase 2 extension study is ongoing. A separate phase 3 study of romidepsin + CHOP vs CHOP alone in frontline PTCL is also ongoing [
28]. Preliminary results from a phase 1 study of brentuximab vedotin with CH-P (CHOP minus vincristine) for the first-line treatment of patients with higher-risk systemic ALCL and other CD30+ mature natural killer/T-cell lymphomas (n = 26) demonstrated an ORR of 100%, including 88% CR [
29]. A phase 2 study of CEOP (cyclophosphamide, etoposide, vincristine, prednisone) alternating with pralatrexate for the first-line treatment of PTCL is underway [
30], and a separate phase 3 study will investigate pralatrexate vs observation maintenance therapy following CHOP-based induction in patients with PTCL [
31]. Long-term follow-up of these combination trials is essential to determine whether any of these combinations leads to durable responses.
Conclusions
The results presented herein demonstrate that treatment with single-agent romidepsin leads to highly durable responses in patients with relapsed/refractory PTCL, including patients with the 3 major PTCL subtypes, patients who received several prior systemic therapies, patients with advanced disease, and, importantly, patients refractory to their last prior therapy. Patients with long-term responses to romidepsin can successfully continue on romidepsin, with or without reducing dose frequency, to maintain response at the discretion of the investigator. Whether combining romidepsin with regimens that induce higher initial response rates (eg, CHOP) will enhance the durability of these responses and lead to prolonged survival, both in relapsed/refractory patients and in those with newly diagnosed disease, warrants further investigation. Additionally, the potential for use of romidepsin as maintenance therapy after chemotherapy induction or after consolidation with high-dose chemotherapy followed by SCT should be examined, because long-term tolerability has been demonstrated.
Competing interests
BC: Celgene Corporation. BP; honoraria: Celgene Corporation. HMP; research grant funding. FF; advisory board: Celgene Corporation. LS; consultancy, speakers bureau: Celgene Corporation; research funding: Gloucester. FM; honoraria: Celgene Corporation. LPB; consultancy: Celgene Corporation. SPI; consultancy: Celgene Corporation. AS; research funding, consultancy, honoraria: Celgene Corporation. TN; employee: Celgene Corporation. JN; employee Jan 2010 – Jul 2012: Celgene Corporation. BB; consultancy: Celgene Corporation. SH; consultancy and grant support: Celgene Corporation. CC, MG, MW, JW; The authors declare that they have no competing interests.
Authors’ contributions
BC interpreted the data, drafted the paper, and approved all versions including the final version. BB and JW acquired and analyzed the data, critically revised the paper, and approval all versions including the final version. BP, HMP, FF, LS, FM, LPB, SPI, AS, TN, JN, SH, CC, MG, MW interpreted the data, critically revised the paper and approved all versions including the final version. All authors are responsible for the accuracy and integrity of all aspects of the manuscript.