Effective remission of Chidamide on treatment of advanced mycosis fungoides:An unusual case report

Each author’s full name, their degrees (M.D., etc.), and their institutions:
Yuxuan Che,Xiaolei Ding,Jincheng Song,Xian Zhang,Xiuhua Sun,Liye Xu,
The degrees of all the authors are M.D.and the institutional address for all the authors is the medical oncology of the second affiliated hospital of Dalian Medical University. The full contact information of the corresponding author:
Liye Xu, M.D. Email:[email protected] Telephone:+8617709873656
Key words: mycosis fungoides,cutaneous changes,chidamide, treatment
A running short title: chidamide on mycosis fungoides
No conflict of interest.

Effective remission of Chidamide on treatment of advanced mycosis fungoides:An unusual case report

Abstract
Mycosis fungoides(MF) and Sézary syndrome(SS) are the most common types of primary cutaneous T-cell lymphoma(CTCL),which primarily involves skin without curative treatment.We report a case of a 29-year-old female Chinese patient,who developed multiple cutaneous lesions gradually for 5 years.However,the patient could not tolerate pruritus and ulceration of cutaneous lesions,so she was admitted to hospital and diagnosed with advanced MF based on clinical manifestation,laboratory and image results.Then she received four cycles of COPE regimen(cyclophosphamide,vincristine,prednisolone and etoposide).Though the skin lesions shrinked and sense of pruritus alleviated quickly after the chemotherapy,the effective remisson duration was not satisfactory.Therefore, the patient received gemcitabine and thalidomide for three cycles subsequently.Still the remission duration was not long-lasting.After that,she took chidamide orally 2 times a week.By the time of 7 weeks,the patches almost diminished and the patient did not feel itching for almost 6 months. And she did not have any adverse effect and had a better quality of life than the period of chemotherapy.
Key words: mycosis fungoides,cutaneous changes,chidamide, treatment
Introduction
Mycosis fungoides(MF) and Sézary syndrome(SS) are the most common types of primary cutaneous T-cell lymphoma(CTCL).The incidence of CTCLs has been gradually increasing(Weinstock,1988)with 7-8 people per million a year(Sokolowska-Wojdylo,2015).The clinical manifestation of MF is characterized by erythematous patches, plaques, or tumors on the skin and sometimes lymph nodes,blood and viscera can be involved.The stage system for MF from 2007(Olsen,2007)classifies disease presentation into TNMB stages,which includes skin(T),lymph nodes(N),viscera(M), and blood(B).Through the TNMB classification,patients with MF can be stratified into early-stage(stage IA to IIA) or advanced stage(stage IIB to IVB).As there is no curative treatment for MF and SS,the purpose of treatment aims to alleviate clinical symptoms and improve quality of life on the basis of age,ECOG score,disease burden and progression,prior treatments(Wilcox,2017).According to clinical trials,IFN-α and IFN-γ,toll-like receptor(TLR)agonists,histone deacetylase inhibitors(HDACi),brentuximab vedotin(BV) and mogamulizumab have been reported to exert effective results.And although chemotherapy can be used for systemic therapy,multiple chemotherapy induces immunosuppression that leads to infections and poor tolerance(Akilov,2011).Moreover,chemotherapy can shorten the median time

until the next treatment in patients with MF/SS(Diamandidou,1996).In this report,we presented a case of MF in a young Chinese woman,who was diagnosed five years after symptoms began.Even though she received multiple chemotherapy at first,the symptoms were not controlled well.However,she achieved long-lasting remission after taking chidamide orally,a drug of ,histone deacetylase inhibitor. Written informed consent was obtained from the patient.
Case Report
A 29-year-old female Chinese patient who used to be healthy developed a brown patch with the diameter of 3cm beneath the breast after the delivery in 2012.Though she felt itchy,she did not go to the hospital for further therapy because she can tolerate.However,the patches increased in number and spread to the limbs in 2014.Moreover,the sense of pruritus aggravated gradually.Then she received hormone orally according to the advice of a local dermatologist.The number of patches decreased and the sense of pruritus alleviated.In early 2017,the patches infiltrated into the chest,abdomen and back with intolerant itching.What’s more,there were numbers of nodules and some of which had been ulcerated.Then she was admitted to the second affiliated hospital of Dalian Medical University.Skin examination revealed multiple patches and nodules mainly in the trunk and limbs which covered more than 90% of her whole skin(Panel A).Skin biopsies of patches on the right leg demonstrated that among the papillary layer of dermis and superficial dermis,numerous small and medium lymphocytes with irregular cell nucleus can be seen and part of which were gyrus-like. Immunohistochemical (IHC) analysis revealed that the lymphocytes were positive for CD2, CD3, CD4, CD5, CD7.CD8 was weakly focally positive and Ki-67 index was approximatelly 20%.Laboratory investigations showed that lactate dehydrogenase was above normal,and complete blood count,and erythrocyte sedimentation rate were all normal.HIV and hepatitis test panels were negative.Computed tomography(CT) showed that there were multiple enlarged lymph nodes with the maximal size of 4.0×1.4cm in the left neck,bilateral axillas and groins.Based on the clinical manifestation, laboratory and image results, particularly the specific gyrus-like lymphocytes,diagnosis of advanced mycosis fungoides was made.The patient was started on COPE regimen(cyclophosphamide, vincristine,prednisolone and etoposide) for four cycles.After the first cycle,the patches and nodules of the patient shrinked and sense of pruritus apparently alleviated(Panel B).However,after the fourth cycle,the skin lesions aggravated and multiple enlarged lymph nodes increased in size and numbers based on CT images.Then the patient received gemcitabine and thalidomide for three cycles.But the skin lesions did not become better.After that,the patient took chidamide orally 2 times a week.By the time of 7 weeks,the patches almost diminished and the patient did not feel itching(Panel C). And she did not have any adverse effect and had a better quality of life than the period of chemotherapy for 6 months.
Discussion
The onset of MF is often insidious and cutaneous symptoms at early stage can mimic
non-malignant inflammatory skin diseases,such as dermatits.Therefore,the median duration from the initial appearance of skin changes to a diagnosis of MF/SS is almost 6

years(Diamandidou,1996).In this case,the duration from the initial skin symptoms to the diagnosis of MF was around 5 years.She had received hormone therapy and multiple chemotherapy,but the skin symptoms aggravated gradually from skin patches to numerous tumour lesions.Moreover,the patient had severe gastrointestinal toxicity after the multiple chemotherapy.Chidamide,an orally novel benzamide-type HDACi,was found to be a low nanomolar inhibitor of HDAC1,2,3 and 10 through blocking the catalytic pocket of class I HDACs(Xie,2004& Ning,2012). According to the previous results,chidamide can enhance the cytotoxic effect,activate NK cell functions and antigen-specific CD8+cytotoxic T-lymphocyte-mediated cellular antitumor immunity (Ning,2012&Yao,2013).Furthermore,chidamide can upregulate the expression of genes involved in immune cell-mediated antitumor activity(Ning,2012).Phase I study demonstrated that orally chidamide was well tolerated with favorable pharmacology and effective histone acetylation.In this clinical trial,one heavily pretreated patient with stage IVa CTCL took chidamide orally and achieved partial remission(PR) and got a total response duration of 133 days (Mei,2012).The pivotal phase II study was an open-label, single-arm, multicenter investigation of chidamide monotherapy in peripheral T-cell lymphomas that had relapsed from or were refractory to one or more systemic therapies. The overall response rate was 28% (complete remission/complete remission unconfirmed: 14%; partial remission: 14%).The median duration of response was 9.9(1.1-40.8)months.The main adverse event(AE) that occurred were thrombocytopenia(51%), leucopenia(40%),neutropenia(22%)and fatigue(10%),and most AEs were tolerable.Hematological adverse events occurred mostly in the first 6 weeks of treatment.
Based on a large data set of 1275 patients with MF/SS from 29 international sites,four
factors(stage IV, age＞60 years, large-cell transformation, and increased lactate dehydrogenase) were independent prognostic markers for a poor survival(Julia,2015).In our case,the patient was diagnosed with advanced stage and increased lactate dehydrogenase.And with effective therapy,the lactate dehydrogenase declined.At the same time,we detected immunoglobulinE(IgE) and it turned out that the trend of IgE was as same as the lactate dehydrogenase.According to the previous research,non-malignant Th1 cells and CD8+ tumor infiltrating T cells composed the microenvironment in early-stage of MF,which advanced-stage of MF and SS are considered Th-2 diseases accompanied by high serum level of IgE(Kazuyasu,2018).Therefore,IgE might also be a prognostic factor for MF as lactate dehydrogenase.
There is no standard therapy for advanced MF.Though chemotherapy could be a method,the remission duration was not satisfactory.Chidamide,an orally novel benzamide-type HDACi produced in China,showed effective and long remission in the patient with advanced MF.Therefore,chidamide might be a new approach for treatment of advanced MF and the mechanism needs to be more explored.
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Panel A Multiple patches and nodules in the trunk
Panel B After first cycle of chemotherapy,the patches and nodules in the trunk shrinked Panel C The patches in the limbs diminished by the Chidamide time of 7 weeks taking chidamide