How I manage peripheral T‐cell lymphoma,not otherwise specified and angioimmunoblastic T‐cell lymphoma: current practice and a glimpse into the future

Peripheral T‐cell lymphoma (PTCL ), not otherwise specified (NOS ) and angioimmunoblastic T‐cell lymphoma (AITL ) are the most frequent of more than 20 mature PTCL entities featuring a broad spectrum of morphological, immunophenotypic, molecular and clinical characteristics. Unfortunately, recent progress in understanding the (epi)genetic background of PTCL has not been met with similar advances in treatment. Thus, CHO (E)P [cyclophosphamide, doxorubicin, vincristine, and prednisone (plus etoposide)] remains standard first‐line therapy. Patients without comorbidities achieving complete or partial remission proceed to autologous stem cell transplantation. With this approach about 50% of patients survive long‐term. Patients relapsing after or progressing during first‐line therapy have a dismal prognosis. They receive salvage gemcitabine‐therapy followed by allogeneic transplantation whenever possible. After allografting, approximately half of the patients survive long‐term; any other treatment is palliative. New drugs investigated in phase II studies achieved response rates between 10% and 30%; long‐term remissions are the exception to the rule. While most new drugs are not licensed and not readily available, a plethora of other innovative drugs targeting (epi‐)genetic abnormalities are in early development. These, together with combinations of new and old drugs, will hopefully increase response to first‐line therapy, bridge more patients to transplantation, and finally improve prognosis for all patients with PTCL .     

Concomitant angioimmunoblastic T‐cell lymphoma and low grade B‐cell lymphoproliferative disorder

The presence of a rearranged immunoglobulin gene, in addition to the expected T‐cell receptor gene rearrangement, is a frequent, albeit poorly understood, finding in the setting of angioimmunoblastic lymphadenopathy. A case of an angioimmunoblastic T‐cell lymphoma is presented, where this apparently paradoxical dual gene rearrangement could be ascribed to the coexistence of an occult B‐cell lymphoproliferative disorder.     

Therapy refractory angioimmunoblastic T‐cell lymphoma in complete remission with lenalidomide

The prognosis of therapy refractory angioimmunoblastic lymphoma (AITL) is very poor. In this report we describe a patient with AITL refractory to 2 lines of chemotherapy. He was treated with lenalidomide 15 mg continuously and prednisone. After 2 yr follow‐up, the patient has no detectable disease. Lenalidomide was well tolerated without side‐effects. Lenalidomide even in lower dosed combined with steroids can induce complete responses in patients with refractory AITL.     

THP‐COP regimen for the treatment of peripheral T‐cell lymphoma and adult T‐cell leukemia/lymphoma: a multicenter phase II study

Objective: The efficacy of pirarubicin (THP)‐COP was previously compared with cyclophophamide + doxorubicin + vincristine + prednisolone (CHOP) in elderly patients with lymphoma. The subset analysis showed that T‐cell lymphoma had a significantly better response with THP‐COP, whereas no such difference was observed in B‐cell lymphoma. The aim of this study is to confirm the efficacy of THP‐COP in the treatment of T‐cell lymphoma. Methods: We underwent a multicenter phase II study of THP‐COP as a first‐line treatment for T‐cell lymphoma. The overall response rate, survival period, and toxicity were analyzed. Results: Fifty‐three patients were enrolled in this study. Seventeen patients had peripheral T‐cell lymphoma (PTCL), including nine of PTCL not otherwise specified (PTCL‐NOS) and eight of angioimmunoblastic T‐cell lymphoma (AITL). Thirty‐six patients had adult T‐cell leukemia/lymphoma (ATLL), including 20 of acute type and 16 of lymphoma type. A treatment response was obtained in 35 (66%) patients, including 17 (32%) complete responses. Median overall survival (OS) and progression‐free survival (PFS) times were 14.3 months and 5.2 months, respectively. Patients with ATLL showed a tendency to obtain low response rate (61% vs. 77%, P = 0.27) and had a significantly inferior OS (13.3 vs. 28.6 months, P = 0.04) and PFS (4.6 vs. 8.1 months, P = 0.01) in comparison with PTCL. Grade 3 to 4 neutropenia, anemia, and thrombocytopenia occurred in 72%, 34%, and 58% of the patients, respectively. Febrile neutropenia was observed in 51% and grade 3 non‐hematological toxicities in 2–9% of the patients. Conclusion: The efficacy of THP‐COP is equivalent to that of CHOP for the first‐line therapy in T‐cell lymphoma.     

The survival outcome of patients with relapsed/refractory peripheral T‐cell lymphoma‐not otherwise specified and angioimmunoblastic T‐cell lymphoma

Survival outcome of patients with peripheral T‐cell lymphoma‐not otherwise specified (PTCL ‐NOS ) and angioimmunoblastic T‐cell lymphoma (AITL ) who experience disease progression/relapse remains very poor. A total of 321 patients, newly diagnosed with PTCL ‐NOS (n  = 180) or AITL (n  = 141) between 1999 and 2015, were analysed. Failure‐free survival (FFS ) and overall survival (OS ) were calculated from the time of first disease progression (FFS 1, OS 1), from second disease progression (FFS 2, OS 2) and from third progression (FFS 3, OS 3). With a median follow‐up duration of 52 months, 240 patients (135 PTCL ‐NOS , 105 AITL ) experienced progression/relapse. In patients with PTCL ‐NOS , the median durations of FFS 1, FFS 2 and FFS 3 were 3·1, 2·5 and 2·1 months, respectively. In patients with AITL , they were 5·5, 2·9 and 2·3 months, respectively. There was no improvement in FFS 1 and OS 1 by the time of recurrence during this period (1999–2004, 2005–2009 and 2010–2015). The median FFS after pralatrexate and romidepsin was only 3·0 and 2·5 months, respectively. The 5‐year OS rates after salvage autologous and allogeneic transplant were 32% and 52%, respectively; while the 5‐year OS rates for patients who did not undergo transplant was 10%. Further research for novel therapeutic approaches with higher efficacy and better safety profile are needed.     

Pulmonary manifestations of peripheral T‐cell lymphoma: case report and review of the literature

Introduction: Peripheral T‐cell lymphomas (PTCL) represent approximately 10% of non‐Hodgkin's lymphomas. Pulmonary involvement is an uncommon manifestation of this heterogeneous group of malignancies. Methods: Report of a case. Results: This case report describes a 75‐year‐old man with fever, weight loss, anemia, enlargement of spleen and liver, atypical lymphocytes and pulmonary nodules. Lung biopsy showed lymphocytic infiltration of the lung parenchyma. T‐cell receptor gamma gene rearrangement by polymerase chain reaction confirmed the diagnosis of peripheral T‐cell lymphoma. Unfortunately, the patient died because of refractory and aggressive disease. Conclusion: Pulmonary and pleural involvement are seen in patients with PTCL and usually carry a poor prognosis. The subject of pulmonary involvement in peripheral T‐cell lymphoma is discussed. Please cite this paper as: Vahid B, Machare‐Delgado E and Marik PB. Pulmonary manifestations of peripheral T‐cell lymphoma: case report and review of the literature. The Clinical Respiratory Journal 2007; 1:114–117.     

Peripheral T‐cell lymphoma gene expression profiling and potential therapeutic exploitations

Peripheral T‐cell lymphomas constitute a heterogeneous group with regard to diagnosis, treatment and prognosis. Efforts have been made to combine novel techniques with cytology and immunochemistry in order to more precisely define these entities. Molecular profiling has contributed to novel insights in the biology of T‐cell lymphoma. Regarding anaplastic large cell lymphoma, low expression T‐cell receptor signalling and high STAT3 target signatures have been associated with the ALK‐positive subgroup. Gene expression profiling differentiates angioblastic T‐cell lymphoma from other T‐cell malignancies, suggests that the normal counterpart of lymphoma cells are follicular helper T cells, and supports the involvement of vascular endothelial growth factor deregulation in its physiopathology. In peripheral T‐cell lymphoma unspecified, gene profiling suggests the normal counterpart of tumour cells are activated CD4⁺ or CD8⁺ T‐lymphocytes, delineates prognostic groups depending on the proliferative signature, and suggests therapeutic options aimed at regulating nuclear factor‐κB and platelet‐derived growth factor receptor‐α phosphorylation. Gene expression profiling of primary cutaneous T cell lymphomas highlighted the importance of abnormal methylation patterns, suggested a pivotal role for JUNB/AP‐1, and defined a predictive model for response to interferon‐α. In conclusion, gene expression profiling is beginning to change the pathological classification, the prognosis profiles and the therapeutic approach in T‐cell lymphomas.     

Follicular helper T‐cells: expanding roles in T‐cell lymphoma and targets for treatment

Follicular helper T‐cells (Tfh cells) are a subset of CD4⁺ T‐cells that are essential for normal production of high affinity antibodies. Tfh cells characteristically produce IL21 and IL4 and show high expression of surface markers CXCR5, ICOS, PDCD1 (PD‐1) and the chemokine CXCL13. In this review we will focus on the emerging links between Tfh cells and subtypes of T‐cell non‐Hodgkin lymphoma: angioimmunoblastic T‐cell lymphoma (AITL) and ~20% of peripheral T‐cell lymphoma not otherwise specified (PTCL‐NOS) have surface marker features of Tfh cells and share a spectrum of genetic abnormalities. The recurrent genetic abnormalities associated with AITL include mutations in epigenetic modifiers such as TET2 and DNMT3A and the motility and adhesion gene, RHOA, is mutated in up to 70% of cases. ~20% of PTCL‐NOS demonstrate RHOA mutations and have other characteristics suggesting an origin in Tfh cells. The recognition that specific genetic and surface markers are associated with malignant Tfh cells suggests that the next few years will bring major changes in diagnostic and treatment possibilities. For example, antibodies against IL21, PDCD1 and ICOS are already in clinical trials for autoimmune disease or other malignancies and antibodies against CXCL13 are in pre‐clinical development.     

Non‐anaplastic peripheral T‐cell lymphoma in children and adolescents – a retrospective analysis of the NHL‐BFM study group

Mature (peripheral) T‐cell lymphoma (PTCL) other than anaplastic large cell lymphoma is a heterogeneous group of diseases and exceedingly rare in children and adolescents. Survival rates range between 46% and 85%. This study reports the disease characteristics, treatment and outcome of all patients with the diagnosis of mature TCL registered in the Berlin‐Frankfurt‐Munster non‐Hodgkin lymphoma database between 1986 and 2012. All diagnoses were centrally reviewed and revised by clinico‐pathological correlation according to the criteria of the current World Health Organization classification. Of the 69 patients originally registered as having PTCL, the diagnosis was confirmed in 38 of them. Most patients were treated with an anaplastic large cell lymphoma (ALCL)‐like therapy regimen. Patients with PTCL‐not otherwise specified comprised the largest group and showed a 5‐year event‐free survival rate of 61 ± 11%. Patients suffering from Natural Killer/T‐cell‐ and hepatosplenic TCL had the poorest outcome. Our results suggest that the outcomes of children with mature TCL other than ALCL depend on the subtype and are worse than in all other paediatric lymphomas. The clinical experience presented in this largest study on paediatric mature TCL may serve as basis for future collaborative international prospective clinical trials.     

Phase II trial of zanolimumab (HuMax‐CD4) in relapsed or refractory non‐cutaneous peripheral T cell lymphoma

The efficacy and safety of zanolimumab (HuMax‐CD4) in patients with relapsed or refractory peripheral T Cell lymphoma (PTCL) was evaluated. Twenty‐one adult patients with relapsed or refractory CD4⁺ PTCL of non‐cutaneous type (angioimmunoblastic T cell lymphoma (AITL) n = 9, PTCL‐not otherwise specified (NOS) n = 7, anaplastic large cell lymphoma (ALCL) n = 4 and enteropathy type T cell lymphoma n = 1) were treated in a single‐arm multi‐centre study, with weekly intravenous infusions of zanolimumab 980 mg for 12 weeks. Median age was 69 years (range 26–85). Seventeen of the patients had advanced stage disease (Ann Arbor stages III–IV). Objective tumour responses were obtained in 24% of the patients with two complete responses unconfirmed (CRu) and three partial responses (PR). One of the CRus lasted more than 252 d. Responses were obtained in different PTCL entities: AITL (n = 3), ALCL (n = 1) and PTCL‐NOS (n = 1). In general, the trial drug was well tolerated with no major toxicity. Zanolimumab at a dose of 980 mg weekly demonstrated clinical activity and an acceptable safety profile in this poor‐prognosis patient population, suggesting that the potential benefit combining zanolimumab with standard chemotherapy in the treatment of PTCL should be investigated.     

Peripheral T‐cell lymphoma presenting as myelofibrosis with the expression of basic fibroblast growth factor

Myelofibrosis is often observed in chronic myeloproliferative disorders (CMPD), but non‐Hodgkin's lymphoma with diffuse myelofibrosis is rare. We describe an elderly case with peripheral T‐cell lymphoma‐unspecified (PTCL) presenting as diffuse myelofibrosis. Bone marrow biopsy revealed infiltration of atypical lymphocytes and diffuse myelofibrosis without any increase in megakaryocytes. To discuss the pathogenesis of fibrosis, we examined cytokines relative to fibrosis using immunostaining. The expression of basic fibroblast growth factor (bFGF) was diffusely detected in the area of extracellular matrix of bone marrow. In addition, in situ hybridization revealed that infiltrating lymphoma cells expressed bFGF mRNA. Basic FGF, originally identified based on its mitogenicity for fibroblasts, has multiple potential, influencing neoangiogenesis, bone marrow fibrosis and the proliferation of tumor cells. Basic FGF might play an important role in the pathogenesis of myelofibrosis in the present case.     

An audit of patients with mature T‐cell non‐Hodgkin lymphoma by transplant status in Tasmania

This retrospective audit of patients diagnosed with mature T‐cell lymphoma across a 10‐year period provides contemporary information on the outcomes and treatment patterns of an Australian cohort. Forty‐two patients diagnosed with mature T‐cell lymphoma were identified from the Tasmanian Cancer Registry and analysed using medical records and simple statistical analysis. The demographics and outcomes of patients in this cohort were comparable to large international studies with treatment patterns in line with the best available evidence.