B-cell prolymphocytic leukemia: an enduring bona fide entity.

B-cell prolymphocytic leukemia (B-PLL) was recognized as a distinct entity in the fourth edition of the World Health Organization (WHO) classification for hematolymphoid neoplasms (WHO-HAEM4); however, its de novo presentation has been removed from the upcoming 5th edition classification (WHO-HAEM5). We present a case of a 65-year-old man with leukocytosis, fatigue, and no organomegaly by imaging. Bone marrow examination showed a prolymphocytoid population comprising 78% of the marrow elements. After thorough exclusion of other entities by clinical parameters and ancillary methods, we concluded that this case represents a de novo case of B-PLL.

B-prolymphocytic leukemia: Is it time to retire this entity?

B-prolymphocytic leukemia (B-PLL) is included as a distinct entity in the current World Health Organization classification of hematolymphoid neoplasms. However, the diagnosis of B-PLL has presented several challenges since its conception, and over the past decades investigations of B-PLL have revealed substantial biologic and molecular heterogeneity. These data have shown that many B-PLL cases present many similarities with other types of small B-cell lymphomas, and that small B-cell lymphomas can undergo prolymphocytoid transformation. As a result, the frequency of B-PLL has markedly decreased, and currently B-PLL is a very rare entity. Most recent studies focused on B-PLL cases have been conducted on limited cohorts, precluding robust conclusions. In this article, we provide a concise historical review of B-PLL and describe the diagnostic and clinical challenges associated with establishing this diagnosis. We also argue that cases currently classified as B-PLL are unlikely to be a unique biologic entity, but rather represent a state of morphologic transformation characterized by many prolymphocytes that is shared by various types of small B-cell lymphoma.

B and T cell prolymphocytic leukaemia.

Prolymphocytic leukaemias B-PLL and T-PLL are rare disorders, typically with an aggressive clinical course and poor prognosis. Combining morphology, immunophenotyping, cytogenetic and molecular diagnostics reliably separates B-PLL and T-PLL from one another and other disorders. In T-PLL discovery of frequent mutations in the JAK-STAT pathway have increased understanding of disease pathogenesis. Alemtuzumab (anti-CD52) produces excellent response rates but long-term remissions are only achieved in a minority following consolidation with allogeneic stem cell transplant. Molecular abnormalities in B-PLL are less understood. Disruption of TP53 is a key finding, conveying chemotherapy resistance requiring novel therapies such as B-cell receptor inhibitors (BCRi). Both conditions require improved pathobiological knowledge to identify new treatment targets and guide therapy with novel pathway inhibitors.

In vitro antileukemic activity of novel adenosine derivatives bearing boron cluster modification.

A series of adenosine derivatives bearing a boron cluster were synthesized and evaluated for their cytotoxicity against primary peripheral mononuclear cells from the blood of 17 patients with leukemias (16 CLL and 1 very rare PLL), as well as from 5 healthy donors used as a control. Among the tested agents, two, i.e., compounds 1 and 2, displayed high in vitro cytotoxicity and proapoptotic potential on leukemic cells, with only scarce activity being seen against control cells. Biological tests related to apoptosis revealed the activation of the main execution apoptotic enzyme, procaspase-3, in CLL and PLL cells exposed to compounds 1 and 2. Moreover, the above compounds indicated high activity in the proteolysis of the apoptotic markers PARP-1 and lamin B1, fragmentation of DNA, and the induction of some changes in the expression of the Mcl-1, protein apoptosis regulator in comparison with control cells.

Clinical features and diagnosis of hairy cell leukemia.

Significant advances in the diagnosis and treatment of hairy cell leukemia (HCL) have recently been made. Improved distinction of HCL from its mimics though clinical presentations, morphologic and immunophenotypic features, and more recently molecular biology, has highlighted marked differences in treatment response and overall prognosis between these disorders. As our understanding of the unique pathobiology of HCL has grown, exciting new avenues of treatment as well as insight into immune function have been obtained. This review provides an overview of the clinical features and diagnostic attributes of HCL, with contrast to other mature B cell lymphoproliferative disorders with overlapping features.

Auer Rod-Like Inclusions in Prolymphocytic Leukemia.

BACKGROUND: Prolymphocytic leukemia (PLL) is a generalized malignancy of the lymphoid tissue, usually of B cell type. Auer rod-like inclusions in prolymphocytic leukemia cells are an extremely rare event; the inclusions are very similar to the Auer rods morphologically. METHODS: We describe a case of B-cell PLL presenting with Auer rod-like inclusions. The diagnosis was eventually proven by the morphology, cytochemical staining, immunophenotypes, and electron microscopy. RESULTS: Auer rod-like inclusions are pathological changes of mitochondria with increasing density of matrix and disappearing internal instructure seen through a scanning electronic microscope. CONCLUSIONS: Auer rod-like inclusions can present in pathologically changed prolymphocytic leukemia cells.

Aberrations of MYC are a common event in B-cell prolymphocytic leukemia.

OBJECTIVES: B-cell prolymphocytic leukemia (B-PLL) remains a controversial entity, and its molecular pathogenesis is largely unknown. Patients are older, typically having marked lymphocytosis and splenomegaly in the absence of lymphadenopathy. It is defined as a mature B-cell leukemia with more than 55% circulating prolymphocytes. Leukemic mantle cell lymphoma and chronic lymphocytic leukemia in prolymphocytic transformation must be excluded. METHODS: Case archives were retrospectively reviewed for B-PLL in patients without a previous diagnosis of chronic lymphocytic leukemia or other B-cell neoplasm. RESULTS: We identified six cases of B-PLL with available cytogenetic data, five of which showed evidence of aberrations in MYC. Three cases showed additional signals for the MYC gene by fluorescence in situ hybridization (FISH), and two cases demonstrated t(8;14)MYC/IGH by karyotyping or FISH. High levels of MYC protein expression were detected in all cases tested with MYC aberrations. CONCLUSIONS: These results suggest that deregulation of MYC plays an important role in the pathogenesis of B-PLL and expands the spectrum of B-cell neoplasms associated with aberrations of MYC.

Mononeuritis multiplex in a patient with B-cell prolymphocytic leukaemia: a diagnostic challenge.

B-cell prolymphocytic leukaemia (BPLL) is a haematological malignancy defined as lymphocytosis and splenomegaly with >55% circulating cells being clonal prolymphocytes of B-cell origin. The evolution of this disease is more aggressive than chronic lymphocytic leukaemia. We reported a case of a 62-year-old man with BPLL who, on treatment, attained cytological, immunophenotypic and complete cytogenetic remission. He subsequently developed an asymmetric sensorimotor neurological disorder, suggestive of lymphomatous infiltration (neurolymphocytosis). Repetition of the MRI and the electromyography was essential for diagnosis. Progressive mononeuritis multiplex in B-cell leukaemias/lymphomas is rare and may be the only presenting symptom of relapsed or progressive disease. Repeat imaging studies based on judicious evaluation of the clinical scenario for exclusion of other causes of neurological symptoms is necessary. This can be challenging in patients with long-standing malignancies who have received multiple courses of chemotherapy and/or radiotherapy.

Omega 3 fatty acids increase the chemo-sensitivity of B-CLL-derived cell lines EHEB and MEC-2 and of B-PLL-derived cell line JVM-2 to anti-cancer drugs doxorubicin, vincristine and fludarabine.

BACKGROUND: B-Cell chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the United States. Clinical treatment of CLL is often limited due to drug resistance and severe therapy-induced toxicities. We hypothesized that the omega 3 (n-3) fatty acids, eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA), would increase the sensitivity of malignant B-lymphocytes to anti-cancer drugs doxorubicin, vincristine and/or fludarabine in vitro and that increased sensitivity is achieved by alterations in cell-cycle progression leading to growth inhibition and/or enhanced cell death. We further postulate that enhanced sensitivity is dependent on the formation of lipid peroxides and to the generation of reactive oxygen species (ROS). METHODS: In the present study, B-CLL-derived leukemic cell lines EHEB and MEC-2 and the B-Prolymphocytic leukemic-derived (PLL) cell line JVM-2 were tested for in vitro sensitivity against doxorubicin, vincristine or fludarabine in the presence or absence of vehicle, arachidonic acid (omega 6), EPA or DHA. Cell cycle analysis and Annexin-V assays were performed to determine cell cycle progression and % apoptotic cells, respectively. Assays for malondialdehyde, a measure of lipid peroxidation, and DCF fluorescence assays, a measure of intracellular ROS, were performed to determine if enhanced sensitivity of cells to the drugs by n-3 was dependent on the formation of ROS. RESULTS: Our results indicated that: 1) EPA and DHA differentially sensitized B-leukemic cell lines EHEB, JVM-2 and MEC-2 to doxorubicin, vincristine and fludarabine in vitro; 2) n-3 alone and with drug treatment increased cell death and induced G2/M arrest in a cell-type specific manner; 3) lipid peroxidation increased in the presence of n-3; 4) there was higher lipid peroxidation in MEC-2 cells in presence of DHA and doxorubicin than with either alone; 5) n-3 increased generation of ROS in MEC-2, and 6) the addition of vitamin-E abrogated the increase in ROS generation and chemo-sensitivity of MEC-2 to doxorubicin by DHA. CONCLUSION: N-3's are promising chemo-sensitizing agents for the treatment of CLL. Selective enhancement of chemo-sensitivity of EHEB, JVM-2 and MEC-2 to drugs by n-3 that is not dependent on increased lipid peroxidation and ROS generation indicates alternative mechanisms by which n-3 enhances chemo-sensitivity.

Splenic B-cell lymphomas with more than 55% prolymphocytes in blood: evidence for prolymphocytoid transformation.

We describe 4 patients aged 62 to 79 years with splenomegaly and bone marrow involvement by splenic B-cell lymphoma who developed more than 55% prolymphocytes in blood. The diagnosis of B-cell prolymphocytic leukemia was considered clinically based on a markedly elevated leukocyte (up to 131.5×10(9)/L) or prolymphocyte (up to 86%) count. Splenectomy was performed in all patients, and spleen weight ranged from 1500 to 2380 g. In 3 patients, the neoplasms were classified as splenic marginal zone lymphoma, and in 1 patient, the neoplasm was classified as splenic diffuse red pulp small B-cell lymphoma. In 2 patients, splenectomy preceded a B-cell prolymphocytic leukemia-like picture, and the spleen showed splenic marginal zone lymphoma or splenic diffuse red pulp small B-cell lymphoma with increased (10%-20%) nucleolated cells consistent with prolymphocytes. In the other 2 patients, a B-cell prolymphocytic leukemia-like picture prompted splenectomy. Initial examination of bone marrow in these patients suggested splenic marginal zone lymphoma. The spleen specimens showed extensive involvement by splenic marginal zone lymphoma with numerous prolymphocytes. Flow cytometry immunophenotyping in all cases showed lymphocytes positive for monotypic surface immunoglobulin (bright), pan-B-cell antigens, CD11c, CD22, and FMC7. Immunohistochemical analysis in all patients showed moderate to bright p53 expression in the spleen (n=3) or bone marrow (n=2). Annexin A1 and cyclin D1 were negative in all cases. Conventional cytogenetic analysis showed del(7q) in 3 patients. We conclude that splenic B-cell lymphoma of various types can undergo prolymphocytoid transformation with more than 55% prolymphocytes in the blood mimicking B-cell prolymphocytic leukemia.