The 2017 WHO update on mature T- and natural killer (NK) cell neoplasms.

Over the last decade, there has been a significant body of information regarding the biology of the lymphoid neoplasms. This clearly supports the need for updating the 2008 WHO (World Health Organization) classification of haematopoietic and lymphoid tumours. The 2017 WHO classification is not a new edition but an update and revision of the 4th edition. New provisional entities but not new definitive entities are included, and novel molecular data in most of the entities and changes in the nomenclature in few of them have been incorporated. In the context of the mature T- and NK-cell neoplasms, the most relevant updates concern to: 1-dysregulation of the JAK/STAT pathway due to gene mutations which are common to various aggressive and indolent neoplasms; 2-incorporation of new molecular players that are relevant to the pathogenesis of these neoplasms and/or have prognostic implications; 3-inclusion of new provisional entities within the subgroups of anaplastic, primarily intestinal and cutaneous lymphomas such as breast implant-associated anaplastic large cell lymphoma, indolent T-cell lymphoproliferative disorder of the gastrointestinal tract and primary cutaneous acral CD8+ T-cell lymphoma; 4-identification of poor prognostic subtypes of peripheral T-cell lymphomas not otherwise specified (PTCL, NOS) characterized by overexpression of certain genes and of a subgroup PTCL, NOS with a T follicular phenotype that now is included together with angioimmunoblastic T-cell lymphoma under the umbrella of lymphomas with a T follicular helper phenotype; and 5-refinement on the designation and definition of already established entities. A review of the major changes will be outlined.

Novel and emerging drugs for rarer chronic lymphoid leukaemias.

Rarer chronic lymphoid leukaemias represent a challenge to the clinicians due to the limited information on their pathogenesis, difficulties on setting up prospective clinical trials and to their refractoriness to drugs used in the most common form of chronic lymphocytic leukaemia (CLL). In this review all these issues are addressed in three B-cell leukaemias: B-cell prolymphocytic leukaemia (B-PLL), hairy cell leukaemia (HCL) and HCL-variant and three T-cell leukaemias: T-cell prolymphocytic leukaemia (T-PLL), T-cell large granular lymphocytic leukaemia (T-cell LGLL) and adult T-cell leukaemia lymphoma (ATLL). Data will be presented on the natural history, current therapies and emerging drugs potentially useful in the treatment of patients with these leukaemias. Emphasis is made on: 1- the novel agents targeting a variety of B and T-cell antigens expressed on the surface of the leukaemic cells; these are either unconjugated monoclonal antibodies (McAb) such as Rituximab (anti-CD20), the second and third generation of anti-CD20 McAbs, Alemtuzumab (anti-CD52), Siplizumab (anti-CD2), Daclizumab (anti-CD25) and KW-0761, an anti-chemokine receptor 4 (CCR4) or McAbs conjugated to toxins such as CD22 linked to the pseudomonas exotoxin or radiolabelled McAb; 2- the use of new purine nucleosides such as nelarabine and 3- agents targeting deregulated genes in the leukaemic cells from these diseases such as the Poly (ADP-ribose) polymerase (PARP) Olarapib in T-PLL with deregulation of the ataxia telangiectasia mutated (ATM) gene. Data of phase I and II clinical studies with these agents as well as the potential and current use of other drugs are outlined.

Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications.

We performed an immunogenetic analysis of 345 IGHV-IGHD-IGHJ rearrangements from 337 cases with primary splenic small B-cell lymphomas of marginal-zone origin. Three immunoglobulin (IG) heavy variable (IGHV) genes accounted for 45.8% of the cases (IGHV1-2, 24.9%; IGHV4-34, 12.8%; IGHV3-23, 8.1%). Particularly for the IGHV1-2 gene, strong biases were evident regarding utilization of different alleles, with 79/86 rearrangements (92%) using allele (*)04. Among cases more stringently classified as splenic marginal-zone lymphoma (SMZL) thanks to the availability of splenic histopathological specimens, the frequency of IGHV1-2(*)04 peaked at 31%. The IGHV1-2(*)04 rearrangements carried significantly longer complementarity-determining region-3 (CDR3) than all other cases and showed biased IGHD gene usage, leading to CDR3s with common motifs. The great majority of analyzed rearrangements (299/345, 86.7%) carried IGHV genes with some impact of somatic hypermutation, from minimal to pronounced. Noticeably, 75/79 (95%) IGHV1-2(*)04 rearrangements were mutated; however, they mostly (56/75 cases; 74.6%) carried few mutations (97-99.9% germline identity) of conservative nature and restricted distribution. These distinctive features of the IG receptors indicate selection by (super)antigenic element(s) in the pathogenesis of SMZL. Furthermore, they raise the possibility that certain SMZL subtypes could derive from progenitor populations adapted to particular antigenic challenges through selection of VH domain specificities, in particular the IGHV1-2(*)04 allele.

Immunophenotyping of acute leukemia and lymphoproliferative disorders: a consensus proposal of the European LeukemiaNet Work Package 10.

The European LeukemiaNet (ELN), workpackage 10 (WP10) was designed to deal with diagnosis matters using morphology and immunophenotyping. This group aimed at establishing a consensus on the required reagents for proper immunophenotyping of acute leukemia and lymphoproliferative disorders. Animated discussions within WP10, together with the application of the Delphi method of proposals circulation, quickly led to post-consensual immunophenotyping panels for disorders on the ELN website. In this report, we established a comprehensive description of these panels, both mandatory and complementary, for both types of clinical conditions. The reason for using each marker, sustained by relevant literature information, is provided in detail. With the constant development of immunophenotyping techniques in flow cytometry and related software, this work aims at providing useful guidelines to perform the most pertinent exploration at diagnosis and for follow-up, with the best cost benefit in diseases, the treatment of which has a strong impact on health systems.

High-grade transformation in splenic marginal zone lymphoma with circulating villous lymphocytes: the site of transformation influences response to therapy and prognosis.

In a series of 48 patients with splenic marginal zone lymphoma (SMZL) with circulating villous lymphocytes, we describe the clinical and laboratory features of nine cases that transformed to high-grade B-cell lymphoma. These patients had a significantly greater incidence of peripheral lymph node involvement at diagnosis when compared to SMZL patients who did not transform (P < 0.03). While transformation in the bone marrow is frequently refractory to therapy and associated with poor outcome in SMZL, lymph node transformation responds well to chemotherapy with durable progression-free and overall survival.

Prolymphocytic leukaemia of B- and T-cell subtype: a state-of-the-art paper.

Prolymphocytic leukaemias of B and T cell subtype are rare diseases. Despite recent advances in immunophenotyping and molecular cytogenetics, leading to a better understanding of the underlying cell biology of the prolymphocytic leukaemias, prognosis for these patients remains poor. Purine analogues and monoclonal antibodies have shown efficacy in B-cell prolymphocytic leukaemia although further studies are warranted. Monoclonal antibody therapy with alemtuzumab has significantly improved outcome in T-cell prolymphocytic leukaemia (T-PLL) but responses are still transient and further disease progression is inevitable. While allogeneic stem cell transplant is an attractive option, due to the older age group of T-PLL patients the morbidity and mortality associated with the procedure is significant.

Splenic marginal zone lymphoma proposals for a revision of diagnostic, staging and therapeutic criteria.

Since the initial description of splenic marginal zone lymphoma (SMZL) in 1992, an increasing number of publications have dealt with multiple aspects of SMZL diagnosis, molecular pathogenesis and treatment. This process has identified multiple inconsistencies in the diagnostic criteria and lack of clear guidelines for the staging and treatment. The authors of this review have held several meetings and exchanged series of cases with the objective of agreeing on the main diagnostic, staging and therapeutic guidelines for patients with this condition. Specific working groups were created for diagnostic criteria, immunophenotype, staging and treatment. As results of this work, guidelines are proposed for diagnosis, differential diagnosis, staging, prognostic factors, treatment and response criteria. The guidelines proposed here are intended to contribute to the standardization of the diagnosis and treatment of these patients, and should facilitate the future development of clinical trials that could define more precisely predictive markers for histological progression or lack of response, and evaluate new drugs or treatments.

Adult T-cell leukaemia/lymphoma.

Adult T-cell leukaemia/lymphoma (ATLL) is a mature T-cell neoplasm of post-thymic lymphocytes aetiologically linked to the human T-cell lymphotropic virus, HTLV-I, and with a distinct geographical distribution. The disease manifests with leukaemia in greater than two thirds of patients, while the remaining patients have a lymphomatous form. According to the disease manifestations, various forms which differ in clinical course and prognosis have been recognised: acute, chronic, smouldering and lymphoma. Organomegaly, skin involvement, circulating atypical lymphocytes ("flower" cells) with a CD4+ CD25+ phenotype and hypercalcaemia are the most common disease features. The diagnosis should be based on a constellation of clinical features and laboratory investigations. The latter comprise: lymphocyte morphology, immunophenotype, histology of the tissues affected in the pure lymphoma forms and serology or DNA analysis for HTLV-I. The differential diagnosis of ATLL includes other mature T-cell neoplasms such as T-cell prolymphocytic leukaemia (T-PLL), Sézary syndrome (SS), peripheral T-cell lymphomas and occasionally healthy carriers of the virus or Hodgkin disease. The clinical course is aggressive with a median survival of less than 12 months in the acute and lymphoma forms. Despite major advances in understanding the pathogenesis of the disease, management of these patients remains a challenge for clinicians as they do not respond or achieve only transient responses to therapies used in high-grade lymphomas. The use of antiretroviral agents such as zidovudine in combination with interferon-alpha, with or without concomitant chemotherapy, has shown activity in this disease with improvement in survival and response rate. Consolidation with high dose therapy and autologous or allogeneic stem-cell transplantation should be considered in young patients.

Microsatellite instability indicative of defects in the major mismatch repair genes is rare in patients with B-cell chronic lymphocytic leukemia: Evaluation with disease stage and family history.

A possible role for DNA mismatch repair defects and microsatellite instability (MSI) in the pathogenesis of a number of B-cell lymphoproliferative disorders has recently been debated. To gain further insight into the impact of MSI on B-CLL, we evaluated samples from a series of 982 patients using the mono-satellite markers BAT25 and BAT26, which are highly sensitive in demonstrating classical mismatch repair (MMR) deficiency. Only 1% of cases displayed MSI and this was not correlated with stage of disease or family history of B-CLL. A sub-polymorphic germline variant of BAT25 was identified in one familial case, which was also detected in the patient's affected brother. In conclusion, our study demonstrates that MSI does not have a prominent role in the pathogenesis of B-CLL.

Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial.

BACKGROUND: Previous studies of patients with chronic lymphocytic leukaemia reported high response rates to fludarabine combined with cyclophosphamide. We aimed to establish whether this treatment combination provided greater survival benefit than did chlorambucil or fludarabine. METHODS: 777 patients with chronic lymphocytic leukaemia requiring treatment were randomly assigned to fludarabine (n=194) or fludarabine plus cyclophosphamide (196) for six courses, or chlorambucil (387) for 12 courses. The primary endpoint was overall survival, with secondary endpoints of response rates, progression-free survival, toxic effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number NCT 58585610. FINDINGS: There was no significant difference in overall survival between patients given fludarabine plus cyclophosphamide, fludarabine, or chlorambucil. Complete and overall response rates were better with fludarabine plus cyclophosphamide than with fludarabine (complete response rate 38%vs 15%, respectively; overall response rate 94%vs 80%, respectively; p<0.0001 for both comparisons), which were in turn better than with chlorambucil (complete response rate 7%, overall response rate 72%; p=0.006 and 0.04, respectively). Progression-free survival at 5 years was significantly better with fludarabine plus cyclophosphamide (36%) than with fludarabine (10%) or chlorambucil (10%; p<0.00005). Fludarabine plus cyclophosphamide was the best combination for all ages, including patients older than 70 years, and in prognostic groups defined by immunoglobulin heavy chain gene (V(H)) mutation status and cytogenetics, which were tested in 533 and 579 cases, respectively. Patients had more neutropenia and days in hospital with fludarabine plus cyclophosphamide, or fludarabine, than with chlorambucil. There was less haemolytic anaemia with fludarabine plus cyclophosphamide (5%) than with fludarabine (11%) or chlorambucil (12%). Quality of life was better for responders, but preliminary analyses showed no significant difference between treatments. A meta-analysis of these data and those of two published phase III trials showed a consistent benefit for the fludarabine plus cyclophosphamide regimen in terms of progression-free survival. INTERPRETATION: Fludarabine plus cyclophosphamide should now become the standard treatment for chronic lymphocytic leukaemia and the basis for new protocols that incorporate monoclonal antibodies.

Cytogenetic abnormalities additional to t(11;14) correlate with clinical features in leukaemic presentation of mantle cell lymphoma, and may influence prognosis: a study of 60 cases by FISH.

Mantle cell lymphoma (MCL), characterised by t(11;14)(q13;q32), has a poor prognosis. Many cases have additional cytogenetic abnormalities, and often have a complex karyotype. Fluorescence in situ hybridisation (FISH) was used to study 60 cases with leukaemic presentation of MCL, to determine the frequency, clinical correlations and prognostic impact of a panel of molecular cytogenetic abnormalities: 17p13 (TP53 locus), 13q14, 12 p11.1-q11 (centromere), 6q21 and 11q23. CD38 expression, of prognostic value in chronic lymphocytic leukaemia (CLL), was also studied, and correlations with clinical and cytogenetic abnormalities sought. Eighty per cent of cases had at least one abnormality in addition to t(11;14). Deletions at 17p13 (TP53) and 13q14 were most frequent and involved the majority of the leukaemic clone. Cases with TP53 deletion were more likely to have splenomegaly and marked leucocytosis (>30 x 10(9)/l), and less likely to have lymphadenopathy than those without deletion. Deletions at 11q23 and 6q21 were associated with extranodal disease. 13q14 and 11q23 deletions showed a trend towards worse prognosis by univariate analysis. In multivariate analysis, deletions at 13q14 and 6q21 were independent predictors of poor outcome. Deletion at 17p13 did not show prognostic impact in this series. CD38, positive in two-thirds of cases, was associated with male gender and nodal disease but not with any cytogenetic abnormality, or with survival.

Characteristic appearances of the bone marrow in T-cell large granular lymphocyte leukaemia.

AIMS: To augment the limited literature on bone marrow (BM) appearances in T-cell large granular lymphocyte (LGL) leukaemia and to identify a histological signature to aid in diagnosis of this condition. METHODS AND RESULTS: A descriptive analysis of the histology of the BM in T-cell LGL leukaemia was performed (n = 38). Antibodies against CD3, CD4, CD5, CD8, CD16, CD56, CD57 and CD20 or CD79a were employed. Antibodies against CD68 (macrophages) and CD34 (sinusoids) were also included. BM was normocellular or hypercellular in the majority of cases, with interstitial lymphoid infiltration in 97%. Lymphoid nodules were present in 55% and intrasinusoidal permeation in 58%. Apoptotic figures and haemosiderin deposition were common. All cases showed trilinear haematopoiesis with normal or increased megakaryopoiesis and erythropoiesis, but normal/reduced myelopoiesis. Reticulin was increased (Grade II-III). Immunohistochemistry revealed interstitial infiltration in all cases and helped to identify lymphoid nodules in two-thirds of cases. Preferential localization of CD8+ T lymphocytes to the interstitium and CD4+ T lymphocytes to the periphery of CD20+ B-cell nodules was seen in almost 90% of cases. CONCLUSIONS: Nodules with non-clonal B-cell centres surrounded by CD4+ cells, with interstitial CD8+ cells, are a characteristic finding in T-cell LGL leukaemia and may represent a histological signature for this condition.