Dear Editor,
Cutaneous T-cell lymphoma (CTCL) is a rare form of non-Hodgkin lymphoma caused by skin-homing T-cells. Mycosis fungoides (MF) and Sezary syndrome (SS), an aggressive CTCL variant characterized by blood involvement, are the major forms of CTCL. Black patients are known to have a higher incidence of CTCL, with estimates varying from 6 to 12 per million persons in Black patients compared to 4–10 per million persons in White patients [Citation1,Citation2]. Furthermore, some studies have reported an increased risk of aggressive disease and shorter disease-specific survival in Black patients [Citation3], although other studies have not identified these differences [Citation4].
Given these potential race-based differences in the presentation of CTCL, there is a need to better understand the treatment options in a diverse patient population. Little research has been done on the role of race in response to extracorporeal photopheresis (ECP), an established systemic therapy for CTCL. ECP is primarily used to treat MF/SS patients with erythroderma and peripheral blood involvement (stages IIIA, IIIB, and IVA1) [Citation5]. During ECP treatment, the patient’s blood is treated with photoactivated 8-methoxypsoralen and ultraviolet A using an extracorporeal leukapheresis procedure [Citation5]. This process results in apoptosis of malignant T-cells, which are then reinfused into the patient. It is thought that the apoptotic malignant T-cells release antigens that help generate an anti-tumor immune response [Citation5].
In this study, we evaluated response to ECP in a large and diverse cohort of patients with CTCL at Johns Hopkins Hospital. We studied patients with a best response of disease progression (hereafter referred to as ‘nonresponders with progression’) to investigate for factors related to their progression. We found that overall response rate and duration of response was similar between Black patients and White patients. However, the majority of patients who had disease progression on ECP were Black.
This study was approved by the Johns Hopkins University Institutional Review Board. We identified all patients older than 18 years with a diagnosis of MF or SS who were treated with ECP between 2009 and 2019 at the Johns Hopkins University Department of Dermatology. Patients who identified as either Black or White were evaluated for general characteristics including age, gender, and CTCL stage and type, as well as their ECP course including dates of treatment, concurrent treatments, and best response to ECP. Data was collected by retrospective chart review. Best response to ECP was evaluated according to the consensus criteria of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organization for Research and Treatment of Cancer [Citation6]. The overall response rate was defined as the percentage of patients with complete remission or partial response to ECP. Statistical analysis was conducted in SPSS.
Fifty-two percent (n = 24) patients were female and 47.6% were Black (n = 20) (). Black patients were younger (55.0 vs. 62.0 years; p = 0.14) and there were more female Black patients than female White patients (70.0% vs. 45.5%; p = 0.13). Most patients had advanced CTCL (stage IIB-IVB) at the start of ECP, including 85% of Black patients (n = 17) and 71.5% of White patients (n = 15; p = 0.45). Fifty percent of Black patients (n = 10) and 64% of White patients (n = 14) had B2 blood involvement at the start of ECP (p = 0.45). A few patients had received prior chemotherapy (n = 2, 5%) or immunotherapy (n = 6, 14%) before ECP.
Table 1. Demographic characteristics and response to extracorporeal photopheresis, stratified by race (n = 42).
Overall, the median time to start ECP after diagnosis was 10 months (range 0–185 months) and the overall response rate was 42.8% (). Median time to start ECP after diagnosis was 16.5 months for Black patients and 2.8 months for White patients (p = 0.16). Overall response rate was 35% for Black patients and 49.2% for White patients (p = 0.55). Median duration of response was 17 months for Black patients and 24 months for White patients (p = 0.18).
Seventy-five percent of Black patients and 82% of White patients received ECP in combination with other treatments (p = 0.71). The most common concurrent treatments were bexarotene (N = 23; 55%) and interferon-alpha (N = 22; 52%); fifteen patients received both interferon-alpha and bexarotene in combination with ECP. Less commonly, patients received concurrent methotrexate (N = 2; 5%) or an HDAC inhibitor (N = 5; 12%). There were no differences in the use of combination treatments in Black patients versus White patients (). There was no difference in the average number of prior systemic treatments in Black versus White patients (1 vs. 0.5; p = 0.16). There were no statistically significant differences in LDH, total WBCs, absolute eosinophil count, CD4 + CD7- cells, and CD4 + CD26- cells at ECP start.
Five of the six nonresponders with progression on ECP were Black (). One White female in her 60s with stage IVA1 Sezary syndrome progressed after six sessions of first-line ECP in combination with interferon-alpha and oral bexarotene and was then lost to follow-up. This patient had advanced Sezary syndrome at diagnosis, with 94% CD4 + CD26- cells on flow cytometry and an absolute lymphocyte count exceeding 20 × 103/uL. ECP was begun as first-line treatment and was likely insufficient to control the extent of blood involvement.
Table 2. Nonresponders with progression on ECP (n = 6).
The cohort of Black patients who progressed were young (average age 34.6 years; standard deviation 10.8 years), and four were female. Furthermore, all had an elevated BMI (average 31.5; range 26.2–41.7), compared to an average BMI of 26.4 (range 17.6–36.6; p = 0.06) in all other patients. Progression from early-stage disease at diagnosis to advanced-stage disease prior to extracorporeal photopheresis occurred in four of the five Black nonresponders with progression, compared to five of the thirty-six other patients (p = 0.006). Two Black nonresponders with progression had blood involvement detected by flow cytometry at ECP start (N = 1 B2, N = 1 B1); one patient with B0 disease by flow cytometry had positive TCRG clonality, while the two other patients had no evidence of blood involvement by flow cytometry or clonality assessment. Two patients had been lost to follow-up prior to ECP, which likely contributed to disease progression prior to ECP. All five patients began ECP as a second-line or later systemic therapy (range 2nd–8th line) and started ECP a median of 68.3 months (range 19.7–86.7 months) after diagnosis compared to 5.5 months (range 0–185 months) in patients who responded (p = 0.02).
Similar to the overall cohort, all nonresponders with progression were on an ECP combination therapy regimen with either both oral bexarotene and interferon-alpha (n = 3), interferon-alpha only (n = 1), bexarotene only (n = 1), and vorinostat only (n = 1). There was no significant difference in the average of the median household income based on zip code in nonresponders with progression compared to all other patients ($108,000 vs. $95,000, respectively; p = 0.4).
Black patients and White patients who responded to ECP had similar characteristics, including average age (60.7 vs. 62.0; p = 0.78), average BMI (27.2 vs. 27.4; p = 0.89), gender (66.7% vs. 42.9% female; p = 0.19), and median time to start ECP after diagnosis (10.3 vs. 3.1 months; p = 0.65). A high proportion of both groups received ECP as first-line therapy (Black: 66.7%, n = 10; vs. White: 71%, n = 15; p = 1). Rates of advanced-stage MF/SS at ECP start (n = 13, 86.7% vs. n = 14, 70%; p = 0.42) were also similar (n = 9, 40% vs. n = 7, 33.3%; p = 0.18).
Two Black patients had hypopigmented MF. Both these patients had a partial response to ECP. Both hypopigmented MF patients had blood involvement (n = 1 B1, n = 1 B2) at the time of ECP start. One patient received ECP monotherapy and the other patient received concurrent IFN-alpha.
ECP is a cornerstone of treatment in CTCL, and it is therefore essential to understand the efficacy of ECP in patients of all backgrounds. To our knowledge, this is the largest study to date of ECP outcomes in Black patients with CTCL. We found only one study that reported ECP outcomes in Black patients specifically (3 Black patients with early MF, stage IA-IIA; 1 progressed, 2 stable disease) [Citation7]. A prior study has shown decreased use of ECP and delayed start of ECP in Black patients but did not evaluate ECP outcomes in Black patients specifically [Citation8].
In this study, there were no statistically significant differences in overall response rate or duration of response between Black and White patients, indicating that in general ECP is likely a similarly effective treatment in both patient groups. Six patients had a best response of progression to ECP. While the underlying reasons for progression in these patients are unclear, several trends emerged. In terms of disease course, four of the six patients had progressed from early stage at diagnosis (defined as stage IA-IIA) to late-stage (defined as stage IIB-IVB) prior to ECP, and five of the six patients received ECP as a second-line or later treatment. Furthermore, Black patients with progression and failure to respond started ECP significantly later after diagnosis compared to patients who responded (median 68.3 months vs. 5.5 months; p = 0.02). First-line usage of ECP, ideally within two years of diagnosis, is known to improve the success rate for this treatment [Citation9]. Of note, responders and non-responders received similar ECP regimens, most commonly an established combination regimen of ECP and interferon-alpha and/or bexarotene.
In terms of demographic factors, five of the six patients identified as Black, four were young women, and all were overweight or obese. Potentially more aggressive behavior of CTCL has been reported in some young Black females but has not been definitively established. One analysis of 1,074 patients showed that Black women were more likely than White women to develop MF prior to the age of 40 (35% vs. 14.5%, p = 0.08) and to progress (OR 5.54, p = 0.0086) [Citation10]. Another study of 1,713 patients found that Black patients presented at a higher stage (OR 1.72, p = 0.02) and younger average age (51.5 vs. 59.2, p = 0.0001) [Citation1]. Other studies have not observed these associations [Citation4]. However, there is known heterogeneity in CTCL variants and outcomes within Black patients, as hypopigmented MF, a variant with an excellent prognosis, is more common in patients with skin of color. In our cohort, the two patients with hypopigmented MF responded favorably to ECP. There was also a trend that patients who progressed had a higher average BMI compared to all other patients (31.5 vs. 26.4; p = 0.06). Other larger-scale studies have not found an association between obesity and the severity of CTCL [Citation11]. However, in general, the role of obesity in outcomes of cancer is unclear, as described by the ‘obesity paradox’ [Citation12]. External challenges such as insurance issues or lack of treatment adherence also may have played a role in disease progression on ECP. Based on chart review, it was determined that two patients with progressive disease were lost to follow-up for several years before ECP could be started. However, full information regarding patients’ socioeconomic status and access to healthcare was not available by chart review. A limitation is that this is a retrospective study at a single institution; while this is one of the largest datasets regarding Black patients with CTCL on ECP, the statistical power is limited by the number of patients. A larger-scale and ideally prospective study is needed to tease out whether patients’ race, gender, and BMI are individually associated with increased likelihood of progression and failure to respond to ECP.
In conclusion, our results showed similar response rates and duration of response between Black patients and White patients. Young Black female patients with longstanding disease and prior disease progression comprised the majority of nonresponders with progression on ECP. Based on these findings, patients with known refractory MF/SS and progression prior to ECP, especially those who are young, Black, female, and/or have elevated BMI, should be monitored on ECP with increased caution, and alternative therapeutics should be considered promptly with signs of progression of disease.
IRB approval status
Reviewed and approved by the Johns Hopkins University Institutional Review Board (IRB00219125).
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
The data that support the findings of this study are available from the corresponding author, SR, upon reasonable request.
Additional information
Funding
References
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