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.

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.

HTLV-I positive progressive spastic paraparesis (TSP) associated with a lymphoid disorder in three Chilean patients.

We describe the clinical and laboratory features in three Caucasian Chilean patients with tropical spastic paraparesis (TSP) associated with/or preceded by a lymphoproliferative disorder involving cutaneous lesions and localised lymphadenopathy. The neurological symptoms and signs were characteristic of TSP and CSF examination revealed the presence of oligoclonal bands. All three patients had a moderate leucocytosis (10-14 x 10(9)/l) with eosinophilia and a minority (2-4%) of circulating atypical polylobed or ATLL-like lymphocytes. Lymph node histology showed a diffuse pattern of infiltration (1 case) and marked expansion of the paracortical zone with convoluted lymphocytes and immunoblasts (2 cases). Skin biopsy demonstrated a dermal lymphoid infiltration with epidermotropism. Antibodies to HTLV-I were detected in the serum and CSF in the three patients and Southern blot analysis of peripheral blood mononuclear cells showed a monoclonal integration of HTLV-I proviral DNA in one case whereas in the two others the pattern was indicative of low level polyclonal integration. All three patients were treated with prednisolone and one with PUVA with transient partial response on the skin and neurological manifestations. Two patients died months to 5 years from presentation and the other is alive 12 years from diagnosis with active neurological and skin disease. The simultaneous occurrence of HTLV-I associated TSP with smouldering ATLL and a cutaneous ATLL or pre-leukaemic form is discussed.

Purification of haemopoietic progenitor cells from patients with chronic granulocytic leukaemia using percoll density gradients and elutriation.

Purification of haemopoietic progenitor cells from chronic granulocytic leukaemia buffy coat preparations requires a multistep approach using complementary cell separation techniques. In this study Percoll density gradient centrifugation and centrifugal elutriation were used to isolate large numbers of immature progenitor cells. Percoll density gradients were valuable as a first separation step: CFU-GM and CFU-GEMM could be enriched 75-fold in a light density fraction of d less than 1.056 g/ml and the technique could be adapted to cope with more than 10(10) buffy coat leucocytes. Progenitors cells were concentrated 3-fold by elutriation used as single method to separate buffy coat cells or when used to purify further light density Percoll fractions. When Percoll gradients and elutriation were used sequentially, undifferentiated mononuclear cells were enriched to more than 90% purity and between 5% and 40% of these cells formed CFU-GM or BFU-E colonies consisting of more than 40 cells. The enriched fractions were further characterized with monoclonal antibodies. The density and elutriation profiles of these colony forming cells resembled corresponding profiles of cells that reacted with the monoclonal antibody BI-3C5, which recognizes an antigen on primitive haemopoietic progenitor cells. Physical separation methods are a valuable first stage in the attempt to procure relatively pure myeloid progenitor cell populations, whose characteristics can then be further studied at a cellular or molecular level.