Abstract
Extracorporeal photopheresis (ECP) is an established, safe, and effective treatment for cutaneous T-cell lymphoma (CTCL). There is no published literature reviewing the clinical efficacy of ECP at varying frequencies or the ideal duration of therapy. The SARS-CoV-2 pandemic necessitated a reduced frequency of ECP for patients with CTCL at our center. We performed a retrospective chart review of patients with CTCL receiving ECP at the Penn Dermatology Photopheresis Service (PDPS) on March 1, 2020, and followed up their course until January 31, 2021. Our retrospective cohort study suggests that one day of ECP with extending duration between treatments can be considered an alternative maintenance regimen in appropriate patients with stable disease on concomitant multimodality immunomodulatory therapy.
1. Introduction
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of rare lymphoproliferative disorders. Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma, with malignant lymphocytes residing in the skin. Sezary syndrome (SS) is considered a leukemic variant of cutaneous T-cell lymphoma, and diagnosis requires demonstration of a circulating malignant clone in the skin and blood [1]. The median overall survival in patients with stage IVA1 disease is 3.8 years [2].
Extracorporeal photopheresis (ECP) is an established, safe, and effective leukapheresis-based therapy for advanced CTCL. The original study of ECP in patients with treatment-resistant CTCL reported a response in 27 of 37 patients, with 9 having a complete response [3]. A complete response was seen in 30% of patients (n = 29), and a significant clinical improvement was achieved in 75% of patients with multimodality therapy in our case series of CTCL patients treated with ECP and 1 or more systemic immunomodulatory agents for at least three months [4]. ECP is well tolerated with no reports of grade III/IV adverse effects following treatment [5]. ECP is now mostly performed in the outpatient setting, and treatment duration ranges from 1.5 to three hours. The THERAKOS CELLEX photopheresis system is only available at selected institutions, and the protocol requires highly skilled staff, thereby making it often inaccessible geographically and demanding of time.
Remarkably, current treatment intervals remain identical today to regimens published by Dr. Edelson in 1987 [3]. There is no published literature reviewing the clinical efficacy of ECP at varying frequencies or the ideal duration of therapy. Furthermore, there are no data published, to our knowledge, regarding frequency of disease flare/progression on ECP monotherapy at the standard regimen. Current consensus guidelines recommend one cycle on two consecutive days every 2–4 weeks with the option for more frequent cycles in symptomatic patients and those with a high tumor burden [5]. Tapering of ECP is also highly ambiguous. An update from the UK Photopheresis Society proposes indefinitely continuing ECP treatment in patients with complete, partial, or minimal clinical response due to its safety profile, synergy with other immunomodulatory medications, and a paucity of other efficacious treatment options for advanced disease [6]. With our current understanding of the immunologic mechanism of ECP, the optimal frequency of therapy remains unclear.
The standard starting regimen at the Penn Dermatology Photopheresis Service (PDPS) is 2 consecutive days every four weeks. Treatment with ECP is most often layered with other immunomodulatory modalities [4]. Typically, once a patient has achieved a durable response, tapering ECP begins by decreasing the frequency by one week between cycles, while continuing two consecutive treatment days for each cycle, at a frequency of every 12 weeks.
At the onset of the SARS-CoV-2 pandemic, due to the uncertainty regarding the risk of transmission and mortality of COVID-19, ECP treatments were temporarily halted for 8 weeks (March 15–May 13, 2020) and then resumed with reduced patient volume to create COVID-safe pathways in concordance with national recommendations (issued prior to the development of effective COVID-19-specific therapies and vaccines) [7]. Clinically stable patients were decreased from two consecutive days of ECP per cycle to one day only.
2. Methods
We performed a retrospective chart review of patients with CTCL receiving ECP at the PDPS on March 1, 2020, and followed up their course until January 31, 2021 (Table 1). All patients on multimodality immunotherapy with ECP as a pillar of their treatment were included in the study. Patients were followed up for eight months after ECP was restarted following the first wave of the pandemic, and outcomes were recorded. Progression of disease was defined based on accepted clinical endpoints and response criteria [8, 9]. We defined a flare of disease as any worsening of the disease that did not meet the criteria for progression, including a change in symptoms such as pruritus.
3. Results
Our patient cohort (n = 31) consisted of 12 women and 19 men, 10 Black and 21 White, with an average age of 67.8 years. There were 12 patients with SS and 19 with MF. Histologically, three patients had large cell transformation, and four had folliculotropism. All patients were on multimodality immunomodulatory therapy, which included interferon, retinoids, and skin-directed therapy. There were two patients on methotrexate and one on dupilumab. The median number of months on ECP prior to March 1, 2020, was 35. Twenty-six out of 31 patients decreased the frequency of ECP after pausing during the first wave of the pandemic from 2 consecutive days per treatment cycle to one day per cycle to mitigate the risks of COVID-19 in concordance with national cutaneous lymphoma pandemic guidelines [7]. All of these patients had stable disease and demonstrated a durable response to treatment prior to making this shift.
At the first assessment following the two-month hiatus from ECP, one patient had a subjective flare with increased pruritus but had stable examination and blood staging, and one patient had progressive disease with erythroderma and lymphadenopathy (remaining B0). Notably, this patient also had an interruption of their systemic regimen. Eight months after each patient resumed ECP (at the reduced one day per cycle frequency), one additional patient had a disease flare with increased body surface area involvement prompting initiation of phototherapy. None of the patients went off ECP multimodality therapy.
4. Discussion/Conclusion
In CTCL, there is an accumulating body of evidence to show that there is a complex interplay between the host immune system and the immune response incited by 8-methoxypsoralen and UVA-treated cells. Interestingly, in patients with Sezary syndrome, who have demonstrated a complete response in blood, consensus guidelines generally recommend continuing ECP treatment [6]. The exact immunomodulatory effects of ECP have yet to be uncovered. There have been no randomized controlled trials validating ECP compared to conventional treatment modalities for CTCL or has the optimal frequency of ECP, and the necessity for two consecutive treatment days per cycle has been studied in controlled trials. In the original literature, the duration of ECP was decided by technology as the rate of infusion was such that, to receive the therapeutic regimen, patients needed two consecutive days [3]. The COVID-19 pandemic initially necessitated reduced ECP regimens at our center in order to ensure the health and safety of patients and staff, and our decision to reduce ECP frequency was informed by national guidelines [7]. We determined that all patients with CTCL receiving ECP as part of multimodality therapy, who were clinically and biochemically stable, would decrease the frequency of ECP to one day per cycle primarily to mitigate the risks of COVID-19. Twenty-five of the twenty-six patients with the reduced ECP frequency did not develop disease flare or progression up to 8 months following the change in regimens. Our retrospective cohort study suggests that one day of ECP with extending duration between treatments can be considered an alternative maintenance regimen in appropriate patients with stable disease on concomitant multimodality immunomodulatory therapy. However, this conclusion should be further studied in multicenter prospective controlled trials evaluating optimal ECP regimens. It is our hope that, with reduced intensity regimens, ECP might become more accessible to patients who live outside ECP center catchment areas and further create availability for a scarce and demanding resource at a given institution.
Data Availability
The clinical data used to support the findings of this study are included within the article.
Conflicts of Interest
Dr. A Rook works at TLR Biosciences Consultant, Soligenix Advisory Board.