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.     

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.     

Factors predicting survival in peripheral T‐cell lymphoma in the USA: a population‐based analysis of 8802 patients in the modern era

Current prognostic models for peripheral T‐cell lymphoma (PTCL) have multiple limitations, and questions exist regarding applicability to current patients. We utilized the Surveillance Epidemiology and End Results (SEER)‐18 database to evaluate factors affecting overall survival (OS) of PTCL in the modern era and identified 8802 patients between 2000–2010. Most subtypes of PTCL increased in incidence during the study period. In univariate analyses, age >55 years, black race, advanced stage, absence of extra‐nodal disease, omission of radiation therapy (RT) and high‐risk histology each predicted inferior OS (P < 0·0001). Multivariate analysis (MVA) demonstrated that hepatosplenic, enteropathy‐associated and extra‐nodal Natural Killer/T cell histologies, each had hazard ratios >1·5 (P ≤ 0·0001) for death. Further, age ≥55 years, black race and advanced stage maintained their significance in the MVA (P < 0·0001 each). Based on the significant factors, a prognostic model was constructed and subsequently validated in an independent cohort. The new model incorporated age, stage, histology and race, with an OS ranging from 9 months (highest risk group) to 120 months (lowest risk group). In summary, this is the largest study of PTCL patients in the modern era that provides risk stratification utilizing a new prognostic model that can be incorporated into future prospective clinical trials.     

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.     

Adult T‐cell leukemia/lymphoma in a 21‐year‐old man

Adult T‐cell leukemia/lymphoma (ATL) is malignancy of mature T cells that caused by infection with human T‐cell leukemia virus type I (HTLV‐I). Leukemogenesis of ATL cells considered to involve a multistep oncogenic process, resulting in a very long latency period. But, we report here the case of a 21‐year‐old man having suffered from recurrent stomatititis who has already developed acute‐type ATL. ATL generally occurs after a long latency period, and the present case in a young man is thus very rare.     

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.     

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 .     

VcR-CVAD induction chemotherapy followed by maintenance rituximab in mantle cell lymphoma: a Wisconsin Oncology Network study

Intensive chemotherapy regimens are not feasible in many adults with mantle cell lymphoma (MCL). We sought to build upon our previous experience with a non-intensive regimen, modified R-hyperCVAD chemotherapy (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) with maintenance rituximab (MR), by the incorporation of bortezomib (VcR-CVAD) and the extension of MR beyond 2 years. Patients with previously untreated MCL received VcR-CVAD chemotherapy every 21 d for six cycles. Patients achieving at least a partial response to induction chemotherapy received rituximab consolidation (375 mg/m(2) × 4 weekly doses) and MR (375 mg/m(2) every 12 weeks × 20 doses). The primary end points were overall and complete response (CR), and secondary endpoints were progression-free (PFS) and overall survival (OS). Thirty patients were enrolled, with a median age of 61 years. All patients had advanced stage disease, and 60% had medium/high MCL International Prognostic Index risk factors. A CR or unconfirmed CR was achieved in 77% of patients. After a median follow-up of 42 months, the 3-year PFS and OS were 63% and 86%, respectively. The observed 3-year PFS and OS with VcR-CVAD in MCL were comparable to reported outcomes with more intensive regimens. A cooperative group trial (E1405) is attempting to replicate these promising results.     

Derangement of the T‐cell repertoire in patients with B‐cell non‐Hodgkin's lymphoma

Although a number of studies suggest that different immune pathways may play a role in the pathogenesis of non‐Hodgkin's lymphomas (NHL), the shape of the T‐cell compartment has been only superficially explored in these patients. In our study, we analyzed the peripheral T‐cell receptor (TCR) repertoire and the distribution of different T‐cell subsets – including regulatory T cells (Treg) – in 30 patients with NHL, by combining flow cytometry and spectratyping. We first demonstrated by flow cytometry an increased frequency of expanded T‐cell subpopulations expressing the same TCR beta variable (BV) subfamilies in CD8+ cells from NHL patients when compared with healthy controls, beside a higher frequency of Treg. Moreover, NHL patients were characterized by a higher percentage of BVs showing a skewed CDR3 profile both in CD4+ and CD8+ cells when analyzed by spectratyping. Our data suggest that the T‐cell branch of the immune system of patients with B‐cell NHL is deeply deranged, as witnessed by the increased degree of activation and skewing of their TCR repertoire along with the higher frequency of Treg.     

Prospective subgroup analyses of the randomized MCL‐002 (SPRINT) study: lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma

In the mantle cell lymphoma (MCL)‐002 study, lenalidomide demonstrated significantly improved median progression‐free survival (PFS) compared with investigator's choice (IC) in patients with relapsed/refractory MCL. Here we present the long‐term follow‐up data and results of preplanned subgroup exploratory analyses from MCL‐002 to evaluate the potential impact of demographic factors, baseline clinical characteristics and prior therapies on PFS. In MCL‐002, patients with relapsed/refractory MCL were randomized 2:1 to receive lenalidomide (25 mg/day orally on days 1–21; 28‐day cycles) or single‐agent IC therapy (rituximab, gemcitabine, fludarabine, chlorambucil or cytarabine). The intent‐to‐treat population comprised 254 patients (lenalidomide, n = 170; IC, n = 84). Subgroup analyses of PFS favoured lenalidomide over IC across most characteristics, including risk factors, such as high MCL International Prognostic Index score, age ≥65 years, high lactate dehydrogenase (LDH), stage III/IV disease, high tumour burden, and refractoriness to last prior therapy. By multivariate Cox regression analysis, factors associated with significantly longer PFS (other than lenalidomide treatment) included normal LDH levels (P < 0·001), nonbulky disease (P = 0·045), <3 prior antilymphoma treatments (P = 0·005), and ≥6 months since last prior treatment (P = 0·032). Overall, lenalidomide improved PFS versus single‐agent IC therapy in patients with relapsed/refractory MCL, irrespective of many demographic factors, disease characteristics and prior treatment history.     

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.     

Phase II study of HCVIDD/MA in patients with newly diagnosed peripheral T‐cell lymphoma

A phase II study was performed to evaluate the efficacy of hyper‐fractionated cyclophosphamide, vincristine, pegylated liposomal doxorubicin and dexamethasone alternating with methotrexate/cytarabine (HCVIDD/MA) in patients with newly diagnosed peripheral T‐cell lymphoma (PTCL), excluding ALK‐positive anaplastic large cell lymphoma. Fifty‐three patients were enrolled. Treatment was planned for up to 8 cycles but only 9% of patients received more than 6 cycles due primarily to disease progression (n = 13) or prolonged thrombocytopenia (n = 12). The overall response rate was 66% with a complete response rate of 57%. Median progression‐free survival (PFS) was 7·5 months. With a median follow‐up of 7·6 years, 5‐year PFS and overall survival (OS) were 21% and 48%, respectively. The patients with extranodal Natural Killer‐cell lymphoma had a shorter PFS (median, 2·4 months) than other subtypes. Grade 3/4 anaemia, neutropenia and thrombocytopenia were observed in 66%, 74% and 79% of patients, respectively. Of note, 23% of patients discontinued therapy due to prolonged thrombocytopenia. In conclusion, HCVIDD/MA for the first‐line treatment of PTCL patients is associated with significant myelosuppression leading to poor treatment adherence, and the response and survival outcomes with this regimen are similar to standard CHOP. This study was registered at www.clinicaltrials.gov as #NCT00290433.