Is Durability of Response Reported in Refractory CTCL: A Systematic Review

Introduction: Primary cutaneous T-cell lymphomas (CTCL) are a group of non-Hodgkin lymphomas derived from T-lymphocytes that infiltrate the skin. In refractory CTCL, treatments generally include systemic therapies in conjunction with skin-directed therapies. Numerous assessment criteria are used to evaluate the efficacy of different therapies administered to patients with CTCL. Robust treatment comparisons in CTCL are currently complicated by differences between studies in the efficacy outcomes reported. A systematic review (SR) was performed to summarise published evidence on the efficacy of treatments in patients with relapsed/refractory CTCL.

Methods: A SR was performed in January 2017 to identify clinical studies published in the last 10 years enrolling >20 patients treated for refractory CTCL.

Results: In total, 63 publications reporting on 54 unique studies and 21 different therapies for refractory CTCL were included in the SR. The majority of included studies (n=49) were single arm investigations. Five of the studies included were randomised controlled trials (RCT) comparing CTCL therapies. Two RCTs compared multiple doses of a single therapy (bexarotene or denileukin diftitox), two compared multiple therapies (interferon and methotrexate vs interferon and retinoids or brentuximab vs methotrexate or bexarotene), and one was a placebo-controlled trial of denileukin diftitox. Patient cohorts ranged in size from 21 to 216 patients and all patients had recurrent or refractory disease following ≥1 therapy for CTCL prior to the therapy for which data were extracted. The most frequently reported outcomes were objective response rate (ORR) reported in 82% of studies, complete response rate (80%), progression-free survival (52%), duration of response (48%), overall survival (24%) and time to tumour progression (20%) (Table 1). However, not all outcomes were reported for all therapies, outcome assessment criteria were not reported in all studies, and durable responses were rarely reported. In addition, there was substantial heterogeneity between studies in terms of patient characteristics, outcome assessment criteria, study design, and follow-up time. As such, a robust comparison of relative efficacy is not feasible. ORR was the most consistently reported outcome across studies and was reported for 19 different therapies in 44 different studies. The assessment criteria for ORR was reported in 15 studies. ORR is a useful measure of efficacy as it is directly attributable to drug effect and can be assessed in single-arm studies; however, as the time-point for assessment of ORR or the definition of ORR differed between studies or was not reported, the durability of response was difficult to interpret. The novel outcomes, objective global responses lasting at least 4 (ORR4) and 6 months (ORR6), were reported in three and two trials investigating the efficacy of brentuximab vedotin, respectively. ORR4 and ORR6 capture both the proportion of patients achieving a response and response duration as a single measurement and were 51-56% and 34%, respectively, following treatment with brentuximab vedotin. Health-related quality of life was investigated in only one study in which key endpoints, such as Skindex-29 symptom domains, were reported. Adverse events were reported following treatment with all therapies for refractory CTCL. However, there was a lack of consistency in the definition of the severity of adverse events reported.

Conclusion: Although progress has been made towards the standardisation of response criteria in CTCL, the evaluation of durability of response to treatment remains inconsistent. The routine use of clearly defined efficacy outcomes in clinical trials is required to enable robust comparisons of therapeutic efficacy.

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