Relapsed , refractory peripheral T-cell lymphoma not otherwise specified successfully treated with allogeneic haematopoietic stem cell transplantation

Peripheral T-cell lymphoma (PTCL) is a rare haematological malignancy accounting for 3.7% of all lymphomas and 10-15% of all non-Hodgkin lymphomas (NHL) [1,2]. Peripheral T-cell lymphoma not otherwise specified (PTCL, NOS) is the commonest subtype of PTCL. However, its’ prevalence is lower in Asia than in the West [3]. Only 11 cases of T-cell lymphoma, NOS were reported in Sri Lanka in 2010 [4]. However, PTCL, NOS subtype is not mentioned in this report. PTCL, NOS is a highly aggressive lymphoma notorious for chemo-refractoriness and frequent relapses. High-dose chemotherapy with autologous stem cell transplantation is incorporated in to primary therapy for young fit patients but remains ineffective for most and has not been tested in a randomized study [5]. Allogeneic haematopoietic stem cell transplantation (allo-HSCT) may offer a potential cure for these patients though the optimal type and timing of transplantation remain to be defined [6].


Introduction
Peripheral T-cell lymphoma (PTCL) is a rare haematological malignancy accounting for 3.7% of all lymphomas and 10-15% of all non-Hodgkin lymphomas (NHL) [1,2].Peripheral T-cell lymphoma not otherwise specified (PTCL, NOS) is the commonest subtype of PTCL.However, its' prevalence is lower in Asia than in the West [3].Only 11 cases of T-cell lymphoma, NOS were reported in Sri Lanka in 2010 [4].However, PTCL, NOS subtype is not mentioned in this report.PTCL, NOS is a highly aggressive lymphoma notorious for chemo-refractoriness and frequent relapses.High-dose chemotherapy with autologous stem cell transplantation is incorporated in to primary therapy for young fit patients but remains ineffective for most and has not been tested in a randomized study [5].Allogeneic haematopoietic stem cell transplantation (allo-HSCT) may offer a potential cure for these patients though the optimal type and timing of transplantation remain to be defined [6].
We report a case of relapsed chemo-refractory PTCL, NOS in a young Sri Lankan man who responded to an allo-HSCT performed for the first time in Sri Lanka.

Case report
A 37-year old previously healthy man from Sabaragamuwa province in Sri Lanka presented with a productive cough and progressive loss of appetite and weight over 2 months.Examination showed generalized lymphadenopathy without any skin lesions or hepatosplenomegaly.

Histology of cervical lymph node biopsy showed, infiltration by intermediate sized lymphocytes with
Ceylon Medical Journal 2018; 63: 78-79 DOI: http://doi.org/10.4038/cmj.v63i2.8672 irregular nuclei, open chromatin and nucleoli with moderate cytoplasm.Immunohistochemistry showed CD4, CD5, CD3 and CD20 positivity and negative for CD7, CD8, CD10, CD15, CD23, CD30, CD138, ALK1, PAX5, PD-1 and CXCL13.Ki67 was 90%.A few cells resembling Reed Sternberg (RS) cells positive for CD30, PAX5, Epstein-Bar virus were present.Conclusion was PTCL, NOS with CD20 expression.CD20, a marker of B-cell lineage, is an unusual finding in PTCL, NOS as reported in the literature.Haematological and biochemical investigations were normal.PET/CT scan revealed hypermetabolic lymphadenopathy above and below the diaphragm including bilateral cervical, supraclavicular, axillary, hilar, mediastinal, gastrohepatic and gastrosplenic regions and involvement of lungs.Final diagnosis was PTCL, NOS stage IV.Following 6 cycles of cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) chemotherapy he went in to remission by PET/CT.Within 2 months he relapsed with generalized lymphadenopathy and constitutional symptoms.Relapsed PTCL, NOS was confirmed on a repeat lymph node biopsy.Salvage chemotherapy with gemcitabine, cisplatin and dexamethasone was given without a significant response.PET/CT scan confirmed rapidly progressive disease post 2 cycles of chemotherapy.
HLA typing of siblings revealed a 10/10 match with his younger brother.Matched sibling allo-HSCT was done at Asiri Central hospital, Colombo with reduced intensity conditioning (RIC) using Fludarabine, Melphalan and antithymocyte globulin.RIC was selected anticipating disease eradication and achieving a graft versus lymphoma (GVL) Case report effect.Cyclosporine was given for graft versus host disease (GVHD) prophylaxis.Peripheral blood stem cells from his brother (dose=9×10 6 /kg CD34+ cells) were infused on day 0. It was well tolerated with only grade 2 mucositis.Neutrophil and platelet engraftment was seen on post-transplant day+9 and +10 respectively.Chimerism testing on days+15, +60, +98 revealed >98% donor DNA.
In the absence of graft versus host disease, cyclosporine was discontinued after day+100.PET/CT scan 4 months' post HSCT showed a complete metabolic response.He is not on any medication and remains well 7 months after HSCT.

Discussion
PTCL, NOS is diagnosed when other specific entities of mature T-cell lymphomas have been excluded [7].It is a highly aggressive disease with a 5-year overall survival of 20-30% and poor response to therapy [7].Median age of presentation is 60-years.Male predominance.Most present with peripheral lymphadenopathy.Extranodal involvement is common in skin and gastro-intestinal tract.Many, like our patient, present in advanced stages.PTCL, NOS has heterogeneous morphological, immunohistochemistry and molecular features [3].Reed Sternberg cells are seen in some with Epstein-Bar virus positivity, as in our patient.Cases of PTCL with Epstein-Bar virus positive Reed Sternberg like cells are uncommon [8].As in our patient, CD20 positivity in PTCL, NOS is also rarely reported and is associated with a more aggressive clinical course [9].CHOP is the standard first line treatment for primary disease.Consolidation with auto-HSCT may provide a survival benefit, however limited by early relapses and frequent chemo-refractoriness [3].Aberrant CD20 expression may need further evaluation for Rituximab use.
Reported cases of PTCL, NOS treated with allo-HSCT are extremely rare and it's been suggested that outcomes are better if performed early in relapse [3], as was done in our patient.

Conclusion
This report adds to the literature the role of allo-HSCT in PTCL, NOS and highlights the importance of timely provision of this treatment modality to suitable patients.