A therapeutic effect of Forodesine for CNS relapsed primary testicular T cell lymphoma after allogeneic transplantation

Abstract

Most primary testicular malignant lymphomas are derived from B-cell, with only a few cases of T-cell origin (primary testicular T cell lymphoma; PTTCL). In this report, we present a case of PTTCL who relapsed simultaneously in the central nervous system (CNS) and peripheral nerves, which was managed by allogeneic hematopoietic stem cell transplantation, but recurred again in the CNS. Treatment with the purine nucleotide phosphorylase inhibitor Forodesine achieved a therapeutic response. This finding suggests that Forodesine might be useful as a treatment option for CNS relapse in heavily treated T-cell lymphoma.

INTRODUCTION

Peripheral T cell lymphoma (PTCL) accounts for 5–10% of all non-Hodgkin’s lymphomas (NHL).¹ The prognosis of PTCL is unfavorable. Currently, 5-year disease-free survival for PTCL after conventional first-line chemotherapy is ~30%.²

Primary testicular lymphoma (PTL) is an uncommon disease accounting for 1% of NHL. The most common histological type of PTL is diffuse large B-cell lymphoma.³ Meanwhile, primary testicular T cell lymphoma (PTTCL) has also been reported, but the number of cases is limited.⁴

Primary testicular B-cell lymphoma (PTBCL) is known to be more likely to relapse in the central nervous system (CNS) in about 20–30% of cases,⁵ although this is prophylactically managed with intrathecal chemotherapy injections. NHL may also complicate in peripheral nerve, which causes symptoms such as painful peripheral neuropathy.⁶

In this report, we describe a case of PTTCL with simultaneous CNS and peripheral nerve relapse. After allogenic hematopoietic stem cell transplantation (allo-HSCT), the patient achieved complete response (CR). However, he recurred again in the CNS and treatment with Forodesine showed a certain therapeutic effect.

CASE PRESENTATION

A 34-year-old man had been referred to our hematology team for management of a PTTCL, with a history of painless left scrotal swelling during the past two months and weight loss (Figure 1). Orchiectomy was performed as a diagnostic and initial therapy. Positron emission tomography-computed tomography (PET-CT) demonstrated the disseminated ¹⁸F-fluorodeoxyglucose (FDG) uptake including multiple regions of bone, such as clavicle, sacrum, femur and tibia (Figure 2A). A complete biological assessment including renal and liver functions, serum electrolytes, serum lactate dehydrogenase levels were normal.

Fig. 1.

Computed tomography (CT) images of primary left testicular T cell lymphoma. Axial (A) and coronal image (B).

Fig. 2.

(A) Initial image at presentation. Whole body three-dimensional positron emission tomography-computed tomography (PET-CT) revealed the several hot spots of hypermetabolism. (B) Follow up image after 6 cycles of CHOP (Cyclophosphamide, Doxorubicin, Vincristine, and Prednisolone). (C, D, E) Re-analyzed images at 1 month after the last course of CHOP. Axial cross-sections of PET-CT revealed the masses of left cervical lymph node (C), axillary brachial plexus (D) and pelvic bone/muscle (E).

Microscopic examination of the testicular mass showed a diffuse infiltration by large lymphoid cells. The immunostaining showed positivity for intracytoplasmic CD3 and CD5, in association with positive immune-reactivity to CD56 and CD4. Granzyme B, T cell intracellular antigen-1, Epstein-Barr virus encoded small RNA in situ hybridization (EBER) and CD30 were negative (Figure 3). The pathological diagnosis was peripheral T-Cell lymphoma-not otherwise specified (PTCL-NOS). The patient received the first line chemotherapy with seven courses of CHOP (Cyclophosphamide, Doxorubicin, Vincristine, and Prednisolone) regimen with four cycles of intrathecal Methotrexate (MTX) + Cytarabine (Ara-C). Course eight of CHOP was skipped due to COVID19 infection. PET-CT at the end of the sixth course showed that initial lesion had disappeared (Figure 2B).

Fig. 3.

Histological and immunohistochemical feature. (A) Diffuse and polymorphous infiltration of small-to medium-sized lymphocytes (HE x 200). (B, C, D) Immunohistochemical analysis. The tumor cells were positive for CD3 (B: CD3 x 200), CD4 (C: CD4 x 200) and CD5 (D: CD5 x 200).

One month after the last course of CHOP therapy, the patient suffered the progressive limb pain and right facial nerve palsy. Initially, he was diagnosed as Guillain-Barre syndrome and received immunoglobulin with little improvement. After re-evaluation of PET-CT scan, he had diffusely increased FDG uptake in the bilateral axillary brachial plexus, bone and muscle. (Figure 2C, D, E). Cerebrospinal fluid (CSF) examination indicated the infiltration of lymphoma into CNS.

He underwent re-biopsy from the mass of lower leg and was diagnosed as the relapse of PTTCL with concurrent involvement of CNS and peripheral nervous system. He was administered ICE (Ifosfamide + Carboplatin + Etoposide) regimen but failed to alleviate his symptoms. He was changed to combination of IVAC (Ifosfamide + Etopiside + Ara-C) / DHAP (Dexamethasone + Ara-C + Cisplatin) + high dose MTX (HDMTX) regimen and achieved CR after two cycles. He received allo-HSCT from related human leukocyte antigen (HLA)-matched donor. Pre-transplant conditioning included Cyclophosphamide (120 mg/kg), total body irradiation (12Gy). Cyclosporin (CsA) and MTX were used as graft versus host disease (GVHD) prophylaxis. He developed organizing pneumonia successfully treated by corticosteroid therapy. Six weeks post transplantation, a >95% donor chimerism was found. He was discharged 125 days post-transplant.

Six months after transplantation, he relapsed in bilateral nipple and lower limb diagnosed by PET-CT with FDG intake (Figure 4A). He was discontinued CsA and confirmed CR by re-evaluation of PET-CT at 12 months of post-transplantation (Figure 4B).

Fig. 4.

Follow up image after 6 months post-transplant. Whole body three-dimensional positron emission tomography-computed tomography revealed the several hot spots of hypermetabolism located at the bilateral nipples (red arrow) and along the lower limb (green arrow). (B) Re-analyzed image after 12 months post-transplant. All the accumulated sites were diminished.

Around 300 days after transplantation, vision loss in the right eye gradually began to appear, and the patient was diagnosed with Toxoplasmosis. He received Sulfamethoxazole-Trimethoprim and Atovaquone, and his symptoms gradually improved. However, on the 400 days after transplantation, a sudden decrease in vision in his left eye appeared. At first, we suspected Cytomegalovirus infection or Toxoplasmosis, and administered antibiotics including Foscarnet and Atovaquone, but there was no improvement in his symptoms. No marked change in fundus findings, and contrast-enhanced magnetic resonance imaging (MRI) of the head revealed hyperintense lesions in the parietal lobe and other areas (Figure 5A). CSF examination showed negative bacterial and fungal cultures, and the diagnosis of CNS relapse of the PTTCL was made based on the elevated CSF cell count and class V (conclusive for malignancy) on CSF cytology (Figure 5E).

Fig. 5.

Brain magnetic resonance imaging (MRI) findings of axial T1-weighted gadolinium-enhanced imaging (A, B, C, D). Hyperintense region (red circle) was diminished after Forodesine treatment (A, B). Disappearance of hyperintense lesions centered on the fourth ventricle of the cerebellum (yellow circle, C) after re-challenging of Forodesine (C, D). Cerebrospinal fluid (CSF) cell counts and Total protein level. White and black circle indicate positive and negative CSF cytology. Respectively (E). TP; total protein.

At the time of diagnosis, he had transfusion-dependent pancytopenia with uncertain etiologies, and based on the treatment history, it was considered difficult to use cytotoxic anti-neoplasm agents. Then, he received 300 mg of Forodesine as a single agent. After the start of treatment, vision in the left eye gradually improved, and a CSF examination showed a decrease in cell count and cytology became negative 2 weeks after treatment (Figure 5E). The lesions initially seen had also disappeared (Figure 5B). However, because of the worsening thrombocytopenia and upper gastrointestinal breeding, the treatment was terminated on the 28th day of treatment with Forodesine.

The patient was followed up on an outpatient basis, but on day 530 of transplantation, vision loss deteriorated again. Contrast-enhanced MRI of the head showed the appearance of hyperintense lesions centered in the fourth ventricle of the cerebellum (Figure 4C). CSF cell count increased and cytology changed to class V again (Figure 5E). Based on these findings, the patient was concluded to have a relapse of the CNS lesion. Since the myelosuppression was still severe at the time of the first dose, the patient was restarted on 100 mg of Forodesine, and the intracranial lesions disappeared again (Figure 5D), and the CSF cell count decreased and cytology cleared negative (Figure 5E), confirming the efficacy of the Forodesine treatment.

However, sepsis induced a deterioration of his general condition, and he succumbed to disease 600 days after transplantation.

DISCUSSION

We report a case of a patient with PTTCL who relapsed CNS and peripheral nerve lesions simultaneously. He underwent allo-HSCT, obtained CR and then relapsed again in the CNS. Forodesine achieved a certain degree of control of the recurrent lesions.

In the present, only about 20 cases of PTTCL have been reported,⁴ and many of them survived less than one year. Our case survived for about 3 years from the time of initial diagnosis, which might be the longest survival period to our knowledge.

The CNS relapse rate of PTBCL has been reported to be as high as 20–30%.^5,7 Similarly, in PTCL, besides testicular involvement, presence of extra-nodal site, soft tissue involvement and the presence of B symptoms have been reported to be associated with the risk of CNS relapse.^8,9 Our patient had all of these risk factors and was expected to be at high risk for CNS relapse.

Meanwhile, invasion of NHL into peripheral nerves, nerve roots or plexus is described as neurolymphomatosis (NL), which is a rare complication with a frequency of about 0.2%.¹⁰

The median overall survival (OS) for CNS relapse of PTCL patient is reported to be 3 months.^8,9,11–16 In addition, the median OS for NL regardless of histological type is reported to be around 10 months.¹⁷ Therefore, we expected that the prognosis of our patient would be poor.

In general, intrathecal chemotherapy injections are used to prevent CNS relapse in patients with PTL.

Recently, it has been reported that the risk of CNS relapse in PTBCL could be reduced by combining liposomal Ara-C infusion with Rituximab (R)+CHOP and HDMTX after 6 cycles of infusion.¹⁸ Therefore, we should consider appropriate prophylaxis for CNS relapse in PTCL including PTTCL as in the present case, where the risk of CNS relapse is expected to be high.

The treatment strategy for CNS relapse in PTCL has not been established. HDMTX therapy is mainly used, taking into account CNS penetration, and sometimes autologous stem cell transplantation or allo-HCT is also performed. However, there are a number of cases that are not eligible for intense chemotherapy due to advanced age or poor performance status at the time of relapse. In this case, although it was difficult to continue intensive therapy due to pancytopenia and treatment history of Ara-C and HDMTX, Forodesine was effective for the CNS lesions. In addition, the patient was responsive to re-challenge of Forodesine after discontinuation.

There have previously reported that the efficacy of Forodesine had been seen in patient with CNS relapse of PTCL.¹⁹ In that report, it was demonstrated that Forodesine was maintained in stable concentrations in the CSF as well as in the blood and had presumably transferred to the CNS in the present case as well. However, the clinical usefulness of Forodesine in our case was considered valuable in that it was effective in a circumstance that was expected to be refractory, namely, post-transplant relapse.

CONCLUSION

We report a case of PTTCL with simultaneous recurrence in the CNS and peripheral nerves, treated with allo-HSCT, followed by relapse in the CNS and subsequent management with Forodesine. The efficacy of Forodesine in CNS lesions awaits further studies.

AVAILABILITY OF DATA AND MATERIALS

The data used to support the findings of this study are included within the article.