https://orcid.org/0000-0003-1887-9343
Abstract
Background
Response rates of approved systemic therapies for cutaneous T-cell lymphoma (CTCL) hover near 30%, suggesting unmet need. This study describes real-world treatment patterns and response rates of extracorporeal photopheresis (ECP) in CTCL patients.
Methods
A chart review was conducted in the United States of adults with CTCL who initiated ECP between January 1, 2017, and February 28, 2019, and received at least three months of ECP treatment as monotherapy or concomitant therapy. Clinical outcomes were collected quarterly for up to 18 months.
Results
The 52 patients were predominantly Caucasian. Half were male; median age was 69 years. Most patients had Sézary syndrome (50%) or mycosis fungoides (36.5%). Nearly 40% of patients had stage IV disease; 33% had lymph node involvement. Nineteen patients (36.5%) achieved response (>50% reduction in BSA affected); median time to response was 6.5 months. The percentage of patients rated as at least minimally improved was 59.5% at 6 months (N = 22), 75.0% at 9 months (N = 24), and 60.0% at 12 months (N = 15) after ECP initiation.
Conclusions
Despite the ECP treated population in this study being older and having more advanced-stage disease than recent trials, response rates were comparable. These real-world findings support ECP as an effective treatment option for CTCL patients.
Introduction
Cutaneous T-cell lymphomas (CTCL) are a group of rare lymphoproliferative disorders that result from the accumulation of malignant T-cells that lead to itchy plaques, nodular lesions, and/or tumors (Citation1). Incidence is less than 1 per 100,000 in the US (Citation2). Initial diagnosis can be challenging as symptoms are similar to benign conditions (Citation2), with disease often progressing for several years prior to diagnosis and initiation of treatment. The two most common subtypes of CTCL are Sézary syndrome (SS) and mycosis fungoides (MF), representing more than two-thirds of cases of CTCL, as estimated by a meta-analysis of registries worldwide (Citation3). Pruritus associated with CTCL can have a substantial impact on health-related quality of life (Citation4, Citation5), as can being a caregiver for someone with CTCL (Citation6).
Treatment for CTCL is highly dependent on staging, with treatments ranging from skin-directed therapies (e.g., topical corticosteroids, topical retinoids, topical nitrogen mustard gel, phototherapy) for early-stage (ISLC stages IA and IB) disease to radiotherapy and systemically administered agents (e.g., therapeutic antibody therapies, histone deacetylase inhibitors, oral retinoids, chemotherapies) and skin-directed radiotherapy for more advanced stage disease (Citation2). For patients who are unresponsive to other treatments, extracorporeal photopheresis (ECP), an immunomodulatory therapy that has been used for more than 35 years in the treatment of cutaneous T-cell lymphoma (CTCL), is indicated (Citation7). ECP is a procedure in which a leukocyte-enriched blood fraction is combined with 8-methoxypsoralen and exposed to an ultraviolet A (UVA) light source. Its mechanism of action includes induction of apoptosis of malignant T cells, monocyte to dendritic cell differentiation, and cytokine profile alterations (Citation8). Clinical trials of ECP in CTCL reported response rates (defined as a 25% improvement in Body Area Severity Score maintained for four weeks) ranging from 28% to 54% at six months (Citation9).
Current NCCN guidelines recommend ECP as a preferred systemic therapy for patients across all disease stages, with combination therapy with interferon and/or retinoid in patients with advanced disease (Citation10). In CTCL, ECP is associated with a 31-86% overall response rate (including complete and partial response), depending on subtype, stage, and concomitant therapies (Citation7, Citation11, Citation12).
The goal of this study was to describe real-world use of ECP in CTCL patients, including treatment patterns and clinical response. Specific aims were to (1) describe clinical and demographic characteristics of CTCL patients who initiated ECP treatment; (2) describe ECP treatment patterns and utilization; (3) determine the proportion of CTCL patients who respond to ECP treatment in the early treatment period (first six months) and longer-term treatment (longer than six months); and (4) identify patient and disease characteristics associated with early response.
Materials and methods
Study design
A retrospective medical chart review was conducted, and de-identified, patient-level data were abstracted from the electronic medical records (EMRs) of patients with CTCL treated with ECP. Study investigators were responsible for identifying eligible CTCL patients and EMR data from diagnosis to up to 18 months after initiation of ECP were abstracted. The study protocol was reviewed and approved by institutional review boards as required by each site. Informed consent was not required given the nature of the study.
Physician selection and recruitment
Physicians were recruited from a list of medical centers in the United States with THERAKOS® CELLEX® Photopheresis systems. One physician per center was recruited for the study. Each physician was expected to provide data for up to 20 patients with CTCL. Physicians and/or their designees were instructed to assign a unique identifier for each randomly selected patient enrolled in the study to facilitate follow-up on data queries and for data validation.
Patient inclusion/exclusion criteria
Patients were eligible if they were diagnosed with CTCL and initiated ECP between January 1, 2017, and February 28, 2019; had received ECP treatment at age ≥18 years with no ECP treatment received in the year prior to data collection; and had response data documented in their chart.
Data collection
Data abstracted included sociodemographic and clinical characteristics, clinical outcomes, and treatment characteristics. Data were collected via the Medrio electronic data capture (EDC) platform, a CFR Part 11 compliant system. The Medrio database build process included definition of data elements, question wording and response options; design of data entry screens consistent with agreed upon data elements; programming of automatic data validation checks to ensure data quality; user acceptance testing; creation of case report form completion guidelines, with screen shots for use at local sites; pilot testing and programming of data listings/reports for routine status updates.
Study measures
Patient demographics collected included age at diagnosis of CTCL, age at ECP initiation, sex, race, insurance coverage, body mass index and Charlson comorbidity index. Clinical characteristics included disease stage, subtype, extent of body surface area (BSA) affected at diagnosis, Severity Weighted Assessment Tool (SWAT) scores at ECP initiation, transplant details, laboratory findings, NIH disease severity scores and Karnofsky performance score.
ECP treatment patterns were described in terms of number and duration of ECP sessions, prior or concomitant therapy and proportions of patients with mono or combination therapy. We also examined systemic therapy regimens received prior to ECP initiation and their duration of treatment. Time to ECP initiation was defined as time from CTCL diagnosis to ECP initiation. Duration was calculated as time between the start of the first and the end of the last ECP treatment. Time to response was defined as the time between the date of ECP initiation and date response was achieved. Patients receiving combination therapy with ECP were defined as patients with at least a 30-day overlap between ECP and phototherapy, radiation therapy, retinoid, interferon, or other medications for CTCL treatment. Patients receiving ECP monotherapy were defined as patients who received ECP without a 30-day overlap with other CTCL treatments. Key clinical outcomes examined were BSA affected, appearance of new skin lesions, and the physician-rated Clinical Global Impression–Improvement (CGI-I) scores. Response to ECP was defined as >50% reduction in BSA affected at any point during the follow-up period, consisting of the time from ECP initiation through the end of data collection.
Statistical analyses
Descriptive statistics were calculated for baseline characteristics, treatment patterns and clinical outcomes of interest. Measures of centrality (mean, median) and spread (standard deviation [SD], range/interquartile range [IQR]) are reported for continuous variables and frequency counts and proportions are reported for categorical variables. All statistical analyses were performed using SAS v 9.4 (SAS Institute Inc., Cary, NC).
Ethics and IRB approval
Prior to data abstraction, the research protocol and CRF were submitted to an independent, central institutional review board (WGC IRB), which determined that this study met the criteria for a waiver of authorization for use and disclosure of protected health information and was exempt from IRB oversight. All study procedures were conducted in accordance with the Declaration of Helsinki. Furthermore, the study was conducted in accordance with legal and regulatory requirements, as well as with scientific purpose, value, and rigor, and followed generally accepted research practices such as Good Pharmacoepidemiology Practices (GPP) issued by the International Society for Pharmacoepidemiology (ISPE), the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) guidance, Pharmaceutical Research and Manufacturers of America (PhRMA) guidelines.
Results
Patient characteristics
Participating physicians abstracted data from the medical charts of 52 eligible patients; median duration of follow-up was 33.6 months. Half (50.0%) of the study patients were female; median age at ECP initiation was 69 years; most (84.6%) were Caucasian and 53.8% had Medicare coverage. Most patients were diagnosed with Sézary syndrome (50%) or mycosis fungoides (36.5%) Median BSA involvement with plaques/patches at diagnosis was 80%. shows the demographics, disease, and clinical characteristics of the study cohort.
Table 1. Patient demographics and baseline clinical characteristics.
Treatment characteristics
Median duration of CTCL treatment initiation prior to ECP therapy was 17.1 months (IQR: 8.2, 31.5) among this patient cohort (). Most patients received ECP in combination with other prior treatments; only 8 patients received ECP monotherapy. The median time to ECP initiation after CTCL diagnosis was 2 months (IQR: 0.9, 10) where median duration of therapy was 9.6 months. The majority (62.0%) of patients received 1 ECP treatment, 26% received 2 treatments and 12% received 3 treatments. Median duration of regimen 1 was 7.6 months, regimen 2 was 7.3 months, and 1.9 months for regimen 3. A total of 44 patients discontinued therapy during the study period and the most common primary reason for ECP treatment discontinuation was disease progression (n = 16, 36.4%). Median time to death after ECP initiation was 15.5 months (IQR: 6.3, 38.7).
Clinical outcomes
In the ECP treated patients, a 51% reduction in BSA was seen in 36.5% of patients. The median time to response was 6.5 months (IQR: 2.9, 9.6) (). Among those with available data, the percentage of patients rated as minimally improved, much improved, or very much improved on the CGI-I improved from 52.9% at 3 months (n = 51) to 80% at 18 months (n = 22), as shown in . After 18 months of treatment, 60% of patients (n = 20) had a reduction of at least 50% in BSA involved. Twenty five percent (n = 13) of patients had appearance of new lesions at a median time of 5.9 months (IQR: 3.6, 10.1). Improvement in peripheral blood involvement was also observed over time as percent change in CD4 + CD7-neg cell counts, CD4 + CD26-neg cells, CD4 + CD26 cells, CD4/CD8 ratio and absolute abnormal T cell counts, as shown in . The absolute median CD4/CD8 ratio decreased from 7.5 (IQR: 3.9, 22.8) at ECP initiation to 5.4 (IQR: 3.4, 15.0) at 6 months after treatment. In terms of percent change, after 9 months of treatment, patients experienced median reductions in CD4/CD8 ratio of 17.8%, total abnormal T-cells of 58.1%, CD4 + CD7- cell counts of 26.3% and a 22.8% median reduction in CD4 + CD26- cell counts.
Table 2. Response during ECP treatment.
Table 3. Clinical outcomes during ECP treatment.
Table 4. Laboratory outcomes during ECP treatment.
Discussion
In this retrospective observational study of patients with CTCL who were treated with ECP, clinical responses were seen as early as three months following ECP initiation, with more than 60% of patients being rated as having at least minimal improvement at six months. The median duration of ECP treatment in this study was 9.6 months, with most patients receiving ECP in combination with other agents, such as retinoids and cytokines. Other studies reported longer duration of response (Citation13) although the length of this chart review was not sufficient to fully explore duration of response in these patients. A growing body of evidence on the duration of response might support longer courses of ECP treatment.
A variety of assessment measures have been used to determine effectiveness of ECP for treatment of CTCL, including clinician-rated global assessments, changes in body surface area affected using various thresholds, and the SWAT or mSWAT (Citation14), making it difficult to compare results among studies. Further, inter-rater reliability in real world studies remains a confounding factor as it is unreasonable to assume that the same physician provided assessments across all data that are being abstracted (Citation14). Nevertheless, the patterns emerging across studies show that ECP remains an effective treatment for patients with CTCL and that most responses occur early in the course of treatment. Published studies have not typically reported the proportion of responses by specified thresholds although response at six to eight months following ECP was shown to be a predictor of long-term outcomes for patients with CTCL in a small study (Citation15). The UK Photopheresis Society identified studies of ECP in CTCL patients; complete response rates ranged from 0 to 62% and partial response rates ranged from 15 to 72% (Citation16). Our study, while small, provides unique insight on treatment and response patterns for current treatments.
Chart review studies have certain inherent limitations and strengths. Patient treatment patterns and clinical characteristics represent the practices of physicians who agree to participate in this study, and may vary from non-responding physicians, e.g., those who refuse study participation, or fail to complete the study requirements on time and are excluded from the study, or who are unresponsive to the screening invitation. Further, clinical characteristics such as skin scores, BSA affected, and flow cytometry readings may be underreported/under-documented in a routine clinical setting as compared to what would be expected from a prospective clinical trial. Though efforts are made to ensure physician/patient inclusion criteria are based on random selection, there are, nevertheless, risks of selection bias. Retrospective chart review studies, including this study, offer a strength compared to clinical trials in that the patients in chart reviews typically represent a more heterogenous population than in randomized trials; however, there is often missing data due to the nature of these studies without a clear understanding of the reason for missingness.
Another limitation of this study is the low representation of non-Caucasians in the dataset. It is unclear if these percentages are representative of the population demographics in the participating centers or represent under-utilization of ECP in non-Caucasian patients. A recent study of outcomes in CTCL based on racial and ethnic backgrounds reported higher incidence in Blacks with similar outcomes. Future reviews of ECP could focus on enrollment in areas with higher numbers of patients in underrepresented groups.
In summary, this real-world review of ECP showed response rates similar to those reported in prospective trials in which most patients had less advanced disease. The findings in this real-world chart review study, in which almost all patients received ECP as concomitant therapy, showed response rates similar to clinical trials in which patient populations were younger and often had less advanced disease. The findings fill a gap in existing knowledge of treatment patterns and clinical outcomes about patients diagnosed with CTCL in the US.
Acknowledgements
We wish to thank Dr.Amy Johnson of University Hospitals Cleveland for her assistance.
Disclosure statement
Michael Girardi has performed consulting for Synthekine and Mallinckrodt, received research funding from Mallinckrodt, and is an inventor and equity holder for Transimmune AG.
Kacie Carlson has no conflicts to disclose.
Francine Foss has performed consulting for ASTEX, Citius, and Secura, been a speaker for Acrotech and Seagen, and been an investigator for Citius, CRISPR and Daiichi.
Xingyue Huang is an employee of Mallinckrodt Pharmaceuticals.
Shelby L Corman and Patrick Edmundson were employees of OPEN Health at the time the study was conducted.
Hrishikesh P. Kale was an employee of OPEN Health at the time the study was conducted. He is currently employed by Johnson and Johnson and is a stockholder of the company.
Jordana Schmier and Rutika Raina are current employees of OPEN Health, which received funding from Mallinckrodt Pharmaceuticals to conduct this research project.
Additional information
Funding
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