PD-1 Antibody Combined With Decitabine Is Effective in the Treatment of Refractory Peripheral T-cell Lymphoma Not Otherwise Specied: a Case Report

Background: Peripheral T-cell lymphoma not otherwise specied (PTCL-NOS) is a highly aggressive lymphoma with a poor response to chemotherapy, frequent relapses, low overall survival, and poor prognosis, and is the most common form of PTCL. For relapsed/refractory (R/R) PTCLs, the ecacy of traditional chemotherapy is even worse, so clinical trials and new drugs become their therapeutic hopes. Here, We report on a 43-year woman with refractory PTCL-NOS has a good response to PD-1 antibody combined with decitabine. Case presentation: A 43-year-old woman with refractory PTCL-NOS, who has a poor ecacy in the rst-line and second-line treatments, even the disease progresses after treatment with histone deacetylase inhibitors and proteasome inhibitors, however, has a good response to PD-1 antibody combined with decitabine. The patient got signicant tumor regression and some of the masses even disappeared. Conclusions: The PD-1 monoclonal antibody combined with decitabine may be a good choice to improve prognosis when used early if conventional rst- and second-line regimens, histone deacetylase inhibitors, and proteasome inhibitors are ineffective.


Background
Peripheral T-cell lymphoma, not otherwise speci ed (PTCL-NOS) is a group of highly heterogeneous and aggressive malignant tumors [1], accounting for approximately 30-50% of PTCLs [2], usually occurring in middle-aged and elderly patients, with a male-to-female ratio of 1.5-1.9:1.0 [3]. PTCL-NOS is characterized by systemic diseases with nodal or extranodal involvement, including lymph nodes, skin, liver, spleen, bone marrow, and peripheral blood. Nearly half of cases may have B symptoms at diagnosis, and may also encounter hemophagocytic syndrome characterized by fever, cytopenia, and spleen/liver enlargement [4]. There is no standard treatment regimen established for PTCL-NOS currently. The response to conventional chemotherapy is rather poor, and the 5-year median overall survival (OS) rate is usually less than 30% [5]. Besides, PTCL-NOS has no clear phenotype. Currently, the World Health Organization (WHO) classi cation of PTCL-NOS is based on its morphologic, immunophenotypic, cytogenetic and clinical features [6,7]. In summary, no standard therapeutic regimens for PTCL-NOS were reported in previous studies, and there is a long way to go before we can conquer this hard nut. Here, we report a case of refractory PTCL-NOS, which has a poor e cacy in the rst-line and second-line treatments, and even suffers disease progression with the treatment of histone deacetylase inhibitors and proteasome inhibitors. However, with the combined treatment of PD-1 antibody and decitabine, the patient got signi cant tumor regression and some of the masses even disappeared. Unfortunately, this patient developed IV degree of myelosuppression during remission and nally died of respiratory failure. In review of the previous studies of PTCL-NOS, we found that there existed no reports of such therapeutic strategy is effective in this disease. Therefore, we report this case for dissucssion and potential reference.
She admitted our hospital on November 7, 2018. Specialist examination: chronic illness, anemia, obvious pigmentation of the whole body, a large amount of scattered dandruff, super cial lymph nodes (submandibular, neck, armpit, trochle, groin, armpit) reaching the enlarged lymph nodes, which the texture is tough, xed, obvious pain of inguinal lymph nodes. Both hearing weaked, the double breast touched multiple masses, with no tenderness, toughness, clear borders, good mobility, and mild edema in both lower limbs. Bone marrow cytology showed that bone marrow hyperplasia was active and lymphocyte morphology was abnormal, considering Non-Hodgkin's lymphoma bone marrow image and iron de ciency anemia (NHL-BMI, IDA). Skin biopsy pathology showed that pre-neck V-zone skin consistent with peripheral T-cell lymphoma, tumor cell CD20-CD2 + CD3 + CD4 + CD5 + CD7 + CD8 + CD30-GranB-Ki-67 approximately 10% TCR recombinant+. As a result, combined with the patient history and examination, the diagnosis of refractory PTCL was established. So on November 9th and December 3rd, two courses of DEAD (doxorubicin liposome 20mg*3d, etoposide 150mg*3d, cytarabine 500mg*3d, dexamethasone 15mg*5d) were combined with Chidamide, which consciously the masses shrinked after chemotherapy, but the interval increased again. On December 18, the CLAG program (Cladribine 10 mg*5d, cytarabine 1g*4d, G-CSF 150ug*3d) was combined with thalidomide, and Simultaneously, the second generation gene sequencing showed: Notch1 and SOCS1 mutations.
At the beginning of January 2019, the patient's skin lesions, facial and limb edema were aggravated, and the nger joints were seen in the masses (Fig. 1), which the disease progression (PD) was evaluated. On January 14th, the PD regimen (bortezomib 2.27mg d1, 4, 8, 11 and dexamethasone 20mg d1-4, 8-11) was given, and edema slightly relieved on the 2nd day of treatment. But on January 18th, the whole body began ro appear a large number of scattered masses, with highlighting the leather surface, hard, no tenderness, and progressively enlarging, which the largest one is located in the lower abdomen, about 3cm*5cm (Fig. 2), and the whole body appeared edema again. Therefore, we added bcl-2 inhibitors -venetoclax, and the disease still progressed after the end of the treatment.
On January 29th we tried PD-1 antibody -Carellidizumab (SHR-1210, 200mg, every 3 weeks) (Suzhou Shengdia Biomedical Co., Ltd.) combined with decitabine (25mg*5d). After treatment, the body masses was signi cantly reduced (Fig. 3), some of the masses disappeared, edema subsided, and evaluation of partial remission (PR). Unfortunately, before receiving the second cycle, the patient developed IV° myelosuppression and severe pulmonary infection. Despite the step up of antibiotic therapy and the addition of corticosteroids, the patient worsened, and eventually died of respiratory failure (Table 1).  [11,12]. In addition, EBV and CCR4 positive are also poor prognostic factors [13,14]. This patient had an ECOG score of 1 point, elevated LDH, bone marrow involvement, skin and gastrointestinal involvement, and EBV positive.
The best treatment options for PTCL-NOS are still controversial, due to its heterogeneity, complex clinical manifestations, di cult diagnosis, and lack of randomized controlled studies. The rst-line chemotherapy regimen recommended by NCCN 2016 is CHOP, EPOCH, and Hyper-CVAD/MTX-Ara-C, and secondline options include DHAP, ESHAP, GDP, GND, GemOx, ICE, GVD, and new drugs such as pralatrexate, alemtuzumab, bortezomib, diltiazem, bendamustine, histone deacetylase inhibitor, PD-1/PDL-1 antibody, CD30 antibody -brentuximab vedotin, etc [15], or combined with chemotherapy [5]. Data on R/R PTCL will be presented separately, when available ( Table 2). The patient's previous rst-line and second-line treatment regimen was ineffective, even treated with the histone deacetylase inhibitor -Chidamide, the disease still progresses, which con rmed the diagnosis of relapsed/refractory PTCL-NOS, with stage IVb. In review with the patient's medical history and previous treatment regimens, different combinations of doxorubicin liposome, cladribine, bortezomib, thalidomide, etc. were had successively given, and the masses were progressively increased, which considering the treatment is ineffective.  In recent years, blocking immune checkpoints is considered an important breakthrough in cancer treatment, especially PD-1 inhibitors in anti-tumor therapy. The anti-PD-1 monoclonal antibody speci cally binds to the PD-1 molecule on the surface of T cells, thereby blocking the PD-1/Programmed Cell Death-1 (PD-L1) pathway, which leading to tumor immune tolerance, re-activating the anti-tumor activity of lymphocytes, thereby achieving the purpose of treating tumors [19]. As far as lymphoma is concerned, PD-1 antibody has a signi cant effect on classic Hodgkin's lymphoma [20]. Kwong et al. reported the results of 100% (7/7), and the CR rate was 71.4% (5/7) [21]. Barta SK,et al. have shown that PD-1 monoclonal antibody -Pembrolizumab exhibits modest single-agent activity in relapsed or refractory T-cell lymphoma, mainly through AKT inhibition of T-cell receptor-mediated signal transduction [22]. Several studies have also con rmed the presence of abnormally hypermethylation in T-cell lymphoma and their cell lines, often occurring in the promoter region of tumor suppressor genes (eg:P15INK4B, SHP-1, P53) and leading to silencing of the gene.
Recently, recurrent mutations in epigenetic modi ed genes have been found in PTCL-NOS. Importantly, studies by Ji MM, et al. provide clinical evidence that histone-modi ed gene mutations, particularly those involved in histone methylation and acetylation, which is signi cantly associated with tumor chemoresistance and disease progression in PTCL-NOS [23]. Decitabine is a nucleoside analogue. Phosphatiated decitabine is involved in DNA synthesis, and then covalently binds to DNA methyltransferase to inhibit its activity, resulting in hypomethylation of DNA and activation of tumor suppressor genes, thereby which cause cell differentiation or apoptosis [24,25].
It has been reported that DNA methylation of new organisms promotes T cell failure and limits anti-PD-1 immunotherapy, while methylation inhibition can enhance T cell regeneration mediated by PD-1 blockade [26,27]. Theoretically, decitabine and anti-PD-1 antibodies play a synergistic effect to restore immune surveillance. Nevertheless, in a small retrospective analysis, a high CR rate of PD-1 inhibitors was observed in several patients with relapsed/refractory cHL who had received epigenetic therapy [28]. Whether the combination of anti-PD-1 antibody and decitabine can enhance the anti-tumor T cell lymphoma effects has not been reported. Combined with the review of relevant literature, this patient still chooses decitabine combined with carrelizumab for treatment, and the effect is also de nite. The results had shown that the combination of decitabine and carrelizumab is safe, and the CR rate for patients with relapsed/refractory cHL is very high [29]. Since immune-based therapy requires appropriate immune activation, the epigenetic modi er decitabine can promote T cell activation and enhance the effectiveness and duration of the clinical response of anti-PD-1 antibodies.
The patient was found to be positive for PD-1 in immunohistochemistry, so we tried PD-1 antibody combined with decitabine. After treatment, the whole body mass was signi cantly reduced, and some of the masses disappeared, which was considered effective. By destroying the combination of PD-1 and PD-L1 on tumors or other immunosuppressive cells, PD-1 blockers can restore the activity of tired T cells. However, compared with effector and memory T cells, exhausted T cells have unique epigenetic properties and will not be remodeled by PD-1 blockade, which may limit the long-lasting anti-tumor ability of anti-PD-1 antibodies [30]. Low-dose decitabine may change the epigenetic status of tumors and immune cells. Although decitabine alone is not su cient to treat advanced solid tumors, low-dose decitabine can enhance T cell activity, promote the in ltration of CD8 + and CD4 + T cells, increase the sensitivity of chemotherapy drugs and broaden the T cell receptor library in peripheral blood [31,32]. Therefore, the enhanced anti-tumor response of decitabine combined with PD-1 blockers may be caused by multiple mechanisms. Although this patient's disease has been effectively relieved, we expect allogeneic hematopoietic stem cell transplantation after better control of the disease. Unfortunately, due to multiple strong chemotherapy, the patient developed IV degree of myelosuppression during the course of the disease and eventually died of respiratory failure.

Conclusion
In summary, this case report on the diagnosis of relapsed/refractory PTCL-NOS is rare. Survival outcomes in patients with progressed/relapsed PTCL-NOS were still poor, with no signi cant changes even with new treatment regimens. It is necessary to enter the clinical trial at an early stage and combinated the new drugs, which after the disease is controlled, allogeneic hematopoietic stem cell transplantation can be performed as soon as possible to improve survival. Reviewing the course of the patient, PD-1 monoclonal antibody combined with decitabine may be a good choice and improve prognosis with early using when

Declarations
All data generated or analyzed are included in this published article Ethics approval and consent to participate All data were collected anonymously and with patient's consent. All procedures in this study were approved by the Ethics Committee of the Second A liated Hospital of Army Medical University.

Consent for publication
Written informed consent was obtained from the patient for the publication of this case report and any accompanying images. Figure 1 skin lesions, facial and limb edema, and the nger joints were seen in the masses.