CD30+ Cutaneous T Cell Lymphoma: Response to Rotational Total Skin Electron Irradiation

Cutaneous T cell lymphoma (CTCL) is a rare group of lymphoproliferative disorders characterized by localization of T lymphocytes to the skin with an overall incidence of 10.2 cases per million person-years [1]. It is becoming increasingly recognized that CTCL is heterogeneous, with multiple variants that have unique clinical presentations, histologic features, and therapeutic considerations [2]. The most common subtype of CTCL is mycosis fungoides (MF), which typically presents with pruritic patches and plaques in areas of skin not commonly exposed to sun, and may evolve to cutaneous tumors or erythroderma [3]. Demographic features including African-American race, male gender, and age have been found to be risk factors for CTCL, while extent of skin involvement, overall disease stage, and age are prognostic indicators [2, 3]. The prognostic significance of lymphocytic CD30 positivity in CTCL prognosis remains controversial: some have reported it as a favorable prognostic factor, [4] while others have shown it to be associated with advanced disease and independently associated with poorer survival [5].

Total skin electron irradiation (TSEI) has been shown to be an effective palliative treatment for CTCL, even following failure with previous treatment modalities. This has been demonstrated in multiple retrospective reviews showing that conventional dose (≥30 Gy) TSEI achieves high clinical response rates [3, 6‐11] typically using large-field/modified Stanford technique (discontinuous irradiation). However, more recent clinical series using dual-field rotational TSEI (RTSEI) technique, where a patient is rotated at a constant speed about the vertical axis while being irradiated with continuous dual-field irradiation (providing a theoretical advantage in dose homogeneity compared to its large-field/modified Stanford counterpart), showed promising results [12, 13]. Given that there have been no previous studies that have examined the response of CD30+ CTCL to RTSEI, we investigated the effect of CD30 status on treatment response and survival in our cohort of patients with CTCL treated with conventional dose RTSEI.

At present there in no long-term curative treatment for CTCL. Management is difficult as there are no standardized treatment regimens, there is prognostic heterogeneity even within group stages, and high-quality trials are lacking due to disease rarity. There is an urgent need to identify patients at high or low risk for disease progression or mortality to aid in clinical decisions about treatment including escalation/de-escalation of radiation dose or initiation/holding of systemic agents. Since treatment for CTCL, especially advanced-stage disease, is palliative, improved prognostication would help avoid treatment toxicity in cases at low risk for progression. Recently, the prognostic Cutaneous Lymphoma International Prognostic index (CLIPi) was developed for early- and late-stage MF using a cohort of 1502 UK patients and validated in a set of 1221 patients treated at MD Anderson Cancer Center (MDACC; Houston, TX, USA); however, this has yet to be validated in a prospective manner [15‐17]. The Cutaneous Lymphoma International Consortium (CLIC) developed a prognostic score for advanced MF stage IIB to IV and Sezary syndrome (SS) with 1394 patients from 29 centers worldwide including the following factors: stage IV disease, age greater than 60 years, large cell transformation, and elevated serum lactate dehydrogenase [18].

CD30 is a member of the tumor necrosis receptor family, and is found on activated T and B cells. A recent study of 47 non-transformed MF cases from the University of Pittsburgh (Pittsburgh, PA, USA) reported that patients were found to have worse survival, higher stage at diagnosis, and higher maximum stage if dermal cells are CD30+ (>4.7%) [5]. A study of 51 patients with large cell transformation of MF at Memorial Sloan Kettering Cancer Center (New York, NY, USA) reported that predominance of CD30 in the epidermis rather than dermis was associated with poorer survival [19]. However, a retrospective analysis of 100 patients with transformed MF from the Netherlands showed that CD30 negativity was associated with multivariate analysis with reduced disease-specific survival (DSS) and OS [4]. In a long-term outcomes study, CD30 was found to have no significant effect on OS, DSS, and progression-free survival (PFS) in 1263 MF SS patients at MDACC [17]. The CLIC reported that when CD30 is scored positive above 10% of tumoral cells, it is not statistically significant for OS but is associated with worse OS in the subset of patients with T3 disease [18]. Finally, CD30 is also targetable with brentuximab vedotin, a monoclonal chimeric antibody conjugated to antitubulin agent monomethyl auristatin E. A recent phase 2 study found that brentuximab vedotin has significant objective global response 70% (21/30) in treatment patients with refractory or advanced MF/SS who have a range of CD30 expression levels [20]. Similarly, another phase 2 trial found overall response of 73% (35/48) in patients with CD30+ lymphoproliferative disorders treated with brentuximab vedotin [21].

Additionally, CD30+ patients may benefit from the addition of novel targeted agents such as Brentuximab vedotin to radiation, perhaps concurrently or sequentially. Recently, the concept of combined radiation and immunotherapy to enhance clinical outcomes has advanced. To date there is no trial of the safety of brentuximab vedotin with radiation. We feel prospective trial development of combined brentuximab vedotin and radiation for CTCL should proceed based on the results of recent phase 2 trials.

Our analysis is limited by small sample size; however, this is the largest report of CD30+ patients, and their response to radiotherapy. More specifically, the small sample size precluded us from examining in more detail the role of maintenance systemic and dermatologic agents. In addition, if a patient did not follow up or did not have a recorded clinical response at the specified time points without record of recurrence by other providers, they were excluded from CCR analysis which further decreased patient numbers in the present analysis. Additionally, as this was a retrospective review, many patients had incomplete clinicopathological information, information from outside hospitals, or were lost to follow-up. Incomplete data regarding CD30 status increases confounding as patients deemed by clinicians to have aggressive disease or transformation often have more thorough workup. Strengths of our study included documentation of clinical response across multiple post-treatment time points, single institution experience with standardized RTSEI delivery and dosing, and all CD30+ cases were reviewed by a hematopathologist to confirm CD30 status.

In this retrospective study, RTSEI for CTCL resulted in excellent CCR at 6 weeks, with a median RFS of 11 months. This is consistent with and improves upon treatment results reported previously. CD30+ patients receiving RTSEI were found to have higher T stage and trended towards decreased CCR at 6 months post-RTSEI compared with the CD30− patients. Maintenance therapy including topical, systemic antineoplastic, systemic dermatologic, and phototherapies failed to show any significant improvement in RFS in the CD30+ group. Future work should examine quality of life metrics, the role of maintenance systemic or targeted treatments, and combination RTSEI and brentuximab vedotin in CD30+ patients with CTCL.