http://orcid.org/0000-0002-8971-4565
Abstract
Cutaneous T-cell lymphomas (CTCL) are a group of non-Hodgkin lymphomas that typically present in the skin but can progress to systemic involvement. The optimal treatment for patients who relapse from or are refractory to systemic chemotherapy remains unclear. Romidepsin is a potent, class-I selective histone deacetylase inhibitor approved for the treatment of patients with CTCL who have had ≥1 prior systemic therapy. Here, we present a subanalysis of two phase-2 trials (NCT00106431, NCT00007345) of romidepsin in patients with CTCL who had prior treatment with systemic chemotherapy. Patients with prior chemotherapy were able to achieve durable responses to romidepsin, and response rates were similar to those in patients who were chemotherapy naïve. Overall, no new safety signals emerged in patients who had received prior chemotherapy. The data presented here suggest that romidepsin is safe and effective in patients with CTCL who received prior systemic chemotherapy.
Introduction
Cutaneous T-cell lymphomas (CTCL) are a relatively rare, heterogeneous group of non-Hodgkin lymphomas characterized by the clonal proliferation of skin-homing memory T cells [Citation1–5]. The most common forms of CTCL are mycosis fungoides (MF), and an aggressive, leukemic variant, Sézary syndrome (SS) [Citation6,Citation7]. CTCL is sometimes referred to interchangeably as MF/SS [Citation8,Citation9]. Although early-stage CTCL arises in the skin and is primarily indolent, it can progress to systemic disease (blood, lymph nodes, bone marrow) and is characterized by an aggressive behavior in advanced stages [Citation9,Citation10]. The median overall survival of patients with early-stage (IA–IIA) disease is 16–36 years, compared with 1–5 years for patients with advanced-stage (IIB–IVB) disease [Citation11,Citation12]. Most patients with CTCL experience pruritus (itching), which can significantly impact quality of life [Citation13–16].
Although there are a number of available treatments for patients with CTCL, there is no well-defined treatment algorithm [Citation8]. Patients with early-stage CTCL are typically treated with skin-directed therapies (e.g. phototherapy and topical agents) [Citation8,Citation10]. For patients with systemic disease, targeted therapies and biological response modifiers are preferred over chemotherapy [Citation8,Citation10]. Multiagent chemotherapy (e.g. CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone]) is typically reserved for patients with aggressive disease or those with nodal or visceral involvement [Citation8,Citation10]. Although most patients with CTCL respond to multiagent chemotherapy, durable responses are rare [Citation10,Citation17]. The use of multiagent chemotherapy also increases the risk of immunosuppression in a patient population already susceptible to infections and frequently colonized by Staphylococcus aureus [Citation18–21]. Infections are a major cause of death for patients with CTCL [Citation20,Citation21]. The lack of durable responses to treatment with chemotherapy suggests that additional systemic therapies are needed following relapse. However, the optimal systemic therapies for patients with CTCL who relapse or are refractory to chemotherapy are not known.
The epigenetic modifying agent romidepsin is a structurally unique, potent, bicyclic, class-I selective histone deacetylase inhibitor [Citation22–24]. However, while changes in histone acetylation are observed upon treatment with romidepsin, no characteristic HDAC signature has been found to date. Data from the National Cancer Institute 1312 (NCI 1312) trial suggest that romidepsin-mediated cell death is not the result of epigenetic modification. Instead, global acetylation may activate the intrinsic cellular apoptotic pathway. The resulting DNA damage may be the key contributor to the clinical effects of romidepsin [Citation25]. Romidepsin has been approved by the United States Food and Drug Administration for the treatment of patients with CTCL who have had at least one prior systemic therapy and for patients with peripheral T-cell lymphoma (PTCL) who have had at least one prior therapy [Citation26]. Approval of romidepsin for patients with CTCL was based on two phase-2 studies in which romidepsin produced rapid and durable responses [Citation25,Citation27,Citation28]. Patients in the pivotal study (GPI-004-0001; NCT00106431) had an overall response rate (ORR) of 34% (33/96), including 6% (6/96) with complete response (CR), and a median duration of response (DOR) of 15 months [Citation27]. In the NCI 1312 trial (NCT00007345), patients had an ORR of 33% (28/84), including 6% (5/84) with CR, and a median DOR of 13.8 months [Citation25,Citation28].
The optimal systemic treatments for patients with CTCL after relapse with chemotherapy remain unclear. Understanding the clinical profile of romidepsin in patients with CTCL who had received prior treatment with chemotherapy (single agent or multiagent) may contribute to defining a robust treatment algorithm. Here, we present a retrospective analysis of the efficacy and safety of romidepsin in patients with CTCL and prior treatment with systemic chemotherapy using data from the pivotal and NCI trials.
Methods
The details for the two multicenter, single-arm, open-label, phase-2 studies have been reported previously [Citation25,Citation27,Citation28]. The pivotal study included 96 adult patients with stage-IB to IVA CTCL who received ≥1 prior systemic therapy with adequate organ function, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 and had no known significant cardiac abnormalities. Romidepsin was administered intravenously at 14 mg/m2 on days 1, 8 and 15 of a 28-day cycle for up to six cycles; dosing could be reduced to 10 mg/m2 in response to adverse events (AEs). Patients could continue on treatment past the planned six cycles in the event of response or stable disease (SD). The primary endpoint in the pivotal trial was ORR as determined by a composite assessment of response in skin, lymph nodes and blood. Severity weighted assessment tool and erythroderma scores were used to assess response in the skin [Citation29–32]. Response Evaluation Criteria In Solid Tumors (RECIST) was used to assess response in the lymph nodes and was measured by computed tomography, magnetic resonance imaging or clinical measurement where appropriate [Citation33]. The presence of malignant T cells in the peripheral blood was measured by flow cytometry or, rarely, by morphology. Key secondary endpoints included DOR, time to response and time to progression. Reduction in pruritus was measured monthly using a patient-assessed 100-mm visual analog scale (VAS), which ranged from no itching (VAS score of 0) to unbearable itching (VAS score of 100) [Citation31,Citation32,Citation34]. Patients with a baseline VAS scores of 30–69 and 70–100 were considered to have moderate and severe pruritus, respectively. Clinically meaningful reduction in pruritus was defined as a ≥30 mm reduction in VAS score or a VAS score of 0 for at least two consecutive cycles. AEs were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events grading system version 3 and tabulated by the Medical Dictionary for Regulatory Activities system organ class.
In the NCI study, adult patients with relapsed or refractory CTCL stage-IA to IVB and an ECOG performance status of 0–2 were included. Patients with stage-IA to IIA CTCL were eligible only if they were refractory to, intolerant of, or reached a 6-month or longer response plateau on ≥2 prior CTCL therapies. The NCI study recruited an initial cohort of patients who had received ≤2 prior systemic chemotherapy regimens. Subsequently, the protocol was amended to eliminate this restriction. Romidepsin was initially administered intravenously at 18.5 mg/m2 on days 1 and 5. After three patients were treated, the dosage was amended to 14 mg/m2 on days 1, 8 and 15 of a 28-day cycle, and it could be reduced to 10.5 mg/m2 and then to 8.0 mg/m2 in response to hematological AEs or escalated to 17.5 mg/m2 in the absence of toxicity. Response to treatment was assessed by a composite assessment of response in the skin, lymph nodes, viscera and blood. RECIST was used to assess response in skin or viscera [Citation33]. Nodal response was assessed using International Working Group guidelines [Citation35]. Bone marrow involvement (International Working Group criteria), blood involvement (flow cytometry), and generalized erythroderma were all scored as present or absent [Citation35]. Key endpoints included ORR, DOR, time to response and time to progression. AEs were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events grading system version 2 (subsequently converted to version 4). The current analysis used a later cutoff date for AE data than those for previous analyzes [Citation25,Citation28]. All abnormalities were reported as AEs regardless of clinical significance.
Patients from both trials who had received prior chemotherapy were tabulated into one of two groups: patients who had received prior treatment with systemic chemotherapy regimens that were exclusively single-agent and those who had received prior systemic treatment with at least one multiagent regimen.
Results
Baseline characteristics and demographics
Of 96 patients in the pivotal trial, 73 (76%) received prior systemic chemotherapy; 33 of these 73 (45%) were treated with systemic chemotherapy regimens that were exclusively single agent and 39 (53%) received ≥1 multiagent regimen. One patient in the pivotal trial who received prior systemic chemotherapy was excluded from analyses of single agent and multiagent chemotherapy because the type of regimen was not recorded. Of 84 patients in the NCI trial, 52 (62%), received prior systemic chemotherapy. Of these 52 patients, 25 (48%) received only single-agent regimens and 27 (52%) received ≥1 multiagent chemotherapy regimen.
Baseline characteristics of sex, age, ECOG performance status and disease stage in the single-agent and multiagent populations of each study were comparable; no differences in the respective categories were statistically significant ().
Table 1. Baseline characteristics.
Efficacy
In both trials, patients with prior systemic chemotherapy had rapid responses to treatment with romidepsin (). In the pivotal trial, the ORR was 34% for patients with prior chemotherapy; the ORR for patients naïve to chemotherapy was 35%. Likewise, in the NCI trial, the ORRs were 35% and 31% for patients with and without prior chemotherapy. In the pivotal and NCI trials, there were no statistically significant differences in the ORR and rate of CR between the single-agent and multiagent populations. A majority of patients with prior chemotherapy (pivotal trial: 65.8%; NCI trial: 65.4%) had a response or SD for ≥90 days (SD90), and the percentages of patients in the single-agent and multiagent groups in each trial who had a response or SD90 were similar.
Table 2. Response to treatment with romidepsin in patients with prior chemotherapy.
Romidepsin was able to induce durable responses in patients with prior chemotherapy in both studies. In the pivotal trial, patients who received any prior chemotherapy (single agent or multiagent) had a median DOR of 15.0 months; in patients who received only single-agent chemotherapy, the median DOR was 15.0 months, while in patients who received multiagent chemotherapy, the median DOR to romidepsin was 3.6 months (log-rank p=.024; ). In the NCI trial, the median DOR in patients with any prior chemotherapy (single agent or multiagent) was 23.0 months; in patients treated only with single-agent chemotherapy, the median DOR was 19.3 months and among patients with multiagent chemotherapy, the median DOR was not estimable (log-rank p = .131; ).
Figure 1. Kaplan–Meier plot of duration of response for patients with prior chemotherapy (A) in the pivotal and (B) NCI trials. Two patients are not shown on the NCI Kaplan–Meier curve due to space constraints. One patient received prior multiagent chemotherapy and was censored at 103.2 months; one patient received no prior chemotherapy and was censored at 126.7 months.
In the pivotal trial, 50 of 73 of patients (68%) with prior chemotherapy had moderate to severe pruritus (VAS score ≥30 mm) at baseline, of whom 24 (48%) had a clinically meaningful reduction in pruritus (reduction of ≥30 mm; ). The proportion of patients with a clinically meaningful reduction in pruritus was similar in the single-agent and multiagent groups (57% vs. 42%; p = .396). Pruritus data were not recorded for all patients in the NCI trial.
Table 3. Change in pruritus among patients with prior chemotherapy treated with romidepsin in the pivotal trial.
Safety
In the pivotal trial, the percentage of patients who experienced a treatment-emergent adverse event (TEAE) or a drug-related AE of any grade was slightly lower in those who had prior chemotherapy than in those with no prior chemotherapy (TEAE: 95.9% prior vs. 100% no prior; drug-related AE: 90.4% prior vs. 95.7% no prior). In the NCI trial, the percentages of AEs were similar in both patient populations (TEAE: 100% prior and 100% no prior; drug-related AE: 96.2% prior and 96.9% no prior). In both studies, the proportion of patients who reported a grade ≥ 3 AE was higher in patients who had prior chemotherapy (). Among common grade ≥3 AEs, incidences of grade ≥3 asthenic conditions and anemia (treatment emergent and drug related) occurred at a higher rate in patients with prior chemotherapy in both trials, and grade ≥3 thrombocytopenia (treatment emergent and drug related) was higher in patients with prior chemotherapy in the NCI trial (). Although there were some differences between the rates of grade ≥3 AEs in patients who received single-agent regimens and those who received multiagent chemotherapy, no discernable pattern emerged (Supplementary Table 1).
Table 4. Grade ≥3 (A) treatment-emergent adverse events and (B) drug-related adverse events in patients with and without prior chemotherapy.
Discussion
In the pivotal and the NCI trials, patients with prior systemic chemotherapy had a similar ORR with romidepsin as patients who were chemotherapy naïve. Median DOR to romidepsin in patients with prior chemotherapy was 15.0 months and 23.0 months, respectively, in the pivotal and NCI trial, which compares favorably to the overall study population of each trial [Citation25,Citation27]. Among patients in the pivotal trial with prior systemic chemotherapy and moderate to severe pruritus at baseline, 48% experienced a clinically meaningful reduction in pruritus (reduction of ≥30 mm). Although analysis of AEs showed an increase of grade ≥3 AEs in patients with prior chemotherapy, there were no new safety signals. Taken together, these data suggest that romidepsin is safe and effective in patients who have had prior treatment with systemic chemotherapy.
Other than broad categories of drugs by stage proposed by NCCN guidelines, there is no currently accepted treatment algorithm for patients with CTCL, and questions about the optimal course of treatments remain. Chemotherapy should be reserved for advanced disease or until biological therapies have been exhausted [Citation8,Citation10]. A retrospective analysis comparing systemic treatments in patients with CTCL (N = 198) showed that systemic chemotherapy provided less durable disease control, as measured by time to next therapy, when compared with a histone deacetylase inhibitor, although the difference in time to next therapy was modest (3.9 vs. 4.5 months) [Citation17]. Supporting an argument for earlier introduction of romidepsin are safety results from real-world use [Citation36] and observed safety in elderly patients who, like patients with CTCL, often have impaired performance status (our unpublished data). Indeed, a retrospective analysis performed by investigators at Northwestern University identified a 61% response rate, with a median DOR of 13 months, in patients with CTCL [Citation36].
The retrospective nature of these analyses make it difficult to definitively assess an ideal sequencing of available therapeutics for CTCL patients. The clinician’s decision regarding choice of therapy will need to take into account the specifics of the patient’s clinical presentation (erythrodermic vs. patch, plaque or tumor-stage lesions) as well as differences in the treatment schedule that may be of importance to individual patients. Determining a treatment strategy for patients with CTCL that involves multiagent chemotherapy requires particular care. Published studies in patients with CTCL have demonstrated good response rates with multiagent chemotherapy, but poor durability [Citation10,Citation17]. Furthermore, efficacy must be weighed against the immunosuppressive properties of multiagent chemotherapy regimens in a patient population that is already susceptible to infection; single-agent regimens may be preferred in certain situations [Citation10,Citation12,Citation19–21]. In our analysis, patients treated exclusively with single-agent regimens and patients who received ≥1 multiagent chemotherapy regimen had statistically similar ORRs (pivotal trial: p = .129; NCI trial: p = 1.000). However, patients in the pivotal trial who had prior treatment exclusively with single-agent chemotherapy had a longer DOR with romidepsin than patients who had received multiagent chemotherapy (log-rank p = .024). This would seem to support the preference for single-agent chemotherapies over multiagent regimens in the context of subsequent treatment with romidepsin. However, a similar analysis of the NCI trial data showed no significant difference in median DOR in the single-agent and multiagent groups (log-rank p = .131). The differences in median DOR between pivotal and NCI studies may be due to differences in study design, and/or the post hoc nature of the subpopulation statistical analysis. It should also be noted that the analyses populations in this group (responders who had single vs. multiagent chemotherapy) were relatively small; further investigation is needed to clarify the potential differences in outcomes with romidepsin in patients previously treated with single-agent or multiagent chemotherapy.
Due to the lack of durable responses to chemotherapy in patients with CTCL, there is a need for additional therapies following relapse. The data presented here suggest that romidepsin is safe and effective for patients with CTCL who have had prior treatment with systemic chemotherapy. Future directions include the development of combination therapies utilizing novel agents with romidepsin or other HDAC inhibitors, and approaches to identify subsets of patients who benefit the most from HDAC inhibitor therapy.
Potential conflict of interest
Disclosure forms provided by the authors are available with the full text of this article online at https://doi.org/10.1080/10428194.2017.1361022.
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The authors would like to acknowledge Maureen Edgerly. The authors take full responsibility for the content of this manuscript, but thank William Ho, PhD (MediTech Media, Ltd), for providing medical editorial assistance. Financial support for medical editorial assistance was provided by Celgene Corporation.
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References
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