T-cell chronic lymphocytic leukemia. T-cell function and lymphokine secretion.

The leukemic T-cells of the six patients with T-cell chronic lymphocytic leukemia (T-CLL), four with CD4 and CD45R-positive (CD4+ CD45R*) T-CLL and two with CD8 and CD45R-positive (CD8+ CD45R+) T-CLL phenotype were studied for detailed immunologic phenotypic and functional characteristics. The levels of soluble interleukin-2 receptors were elevated significantly in the serum of all four patients with CD4+ CD45R+ T-CLL. Moreover, the CD4+ CD45R+ T-CLL patients' T-cells, after in vitro stimulation with phytohemagglutinin and concanavalin A, expressed elevated percentages of interleukin-2 receptors on cells and secreted high interleukin-2 activity. The B-cell growth factor (BCGF) activity from three patients with CD4+ CD45R+ T-CLL was enhanced, but B-cell differentiation factor (BCDF) activity of the all T-CLL patients was decreased. Reduced BCGF and BCDF activity of the leukemic T-cells was one possible mechanism of hypogammaglobulinemia detected in two patients with T-CLL. All T-CLL patients' leukemic T-cells had diminished immunoregulatory functional activity in allogeneic mixed lymphocyte reactions. These observations suggest that leukemic T-cells from T-CLL patients have many immunologic functional defects that may be important in their proliferative potential.     

Bruton tyrosine kinase inhibition in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia and remains incurable outside of the setting of allogeneic stem cell transplant. While the standard therapy for both initial and relapsed CLL has traditionally included monoclonal antibody therapy in combination with chemotherapy, there are patients with high-risk disease features including unmutated IgVH, del(11q22) and del(17p13) that are associated with poor overall responses to these therapies with short time to relapse and shortened overall survival. Additionally, many of these therapies have a high rate of infectious toxicity in a population already at increased risk. Targeting the B-cell receptor (BCR) signaling pathway has emerged as a promising therapeutic advance in a variety of B-cell malignancies, including CLL. Bruton agammaglobulinemia tyrosine kinase (Btk) is a tyrosine kinase in the BCR pathway critical to the survival of both normal and malignant B cells and inhibition of this kinase has shown to block the progression of CLL. Ibrutinib, a first in class oral inhibitor of Btk, has shown promise as a very effective agent in the treatment of CLL—in both relapsed and upfront therapy, alone and in combination with other therapies, and in patients of all-risk disease—which has led to its approval in relapsed CLL and as frontline therapy in patients with the high-risk del(17p13) disease. Several studies are ongoing to evaluate the efficacy and safety of ibrutinib in combination with chemotherapy as frontline treatment for CLL and investigation into newer-generation Btk inhibitors is also underway.     

Short communication: bendamustine-related hemolytic anemia in chronic lymphocytic leukemia

Purpose

Immune hemolytic anemia (IHA) may complicate the course of chronic lymphocytic leukemia (CLL), especially in patients with advanced disease, and as a complication of treatment with chlorambucil or fludarabine. Bendamustine, a novel agent with both alkylating and purine-analog properties, was approved in the USA for use in CLL in 2008. Since then, clinical data on its adverse events are accumulating. IHA related to bendamustine was seldom described and is thus reported and reviewed.

Methods

We assessed five cases of CLL patients complicated by IHA, out of 31 treated with bendamustine for a relapse of their disease. Also reviewed are previous case reports in the literature.

Results and conclusions

Bendamustine-related IHA is more common than suspected (16 %). No such cases were found in non-CLL patients. Personal history of fludarabine-triggered AIHA may be a risk factor for this complication (recorded in 4/5 patients, 80 %). The mechanism is thought to be related to the loss of T cell regulatory control as described for other agents. Physicians using bendamustine for the treatment for CLL should be aware of this complication.     

Fludarabine-associated autoimmune hemolytic anemia occurring in B-cell chronic lymphocytic leukemia

Autoimmune phenomena are reported to occur frequently in B-cell chronic leukemia (B-CLL). Fludarabine, one of the most effective chemotherapeutic agents for CLL, may increase the risk of these phenomena and may be life-threatening. Here we present a case of an 80-year-old man with B-CLL who developed autoimmune hemolytic anemia (AIHA), associated with one cycle of fludarabine treatment, and who was successfully treated with rituximab and prednisolone.     

Immunotoxin-mediated inhibition of chronic lymphocytic leukemia cell proliferation in humans

We evaluated the cytotoxicity of the immunotoxin OKT1-SAP on fresh B-chronic lymphocytic leukemia (B-CLL) cells from 31 consecutive patients. OKT1-SAP comprised the OKT1 (CD5) monoclonal antibody disulfide linked to saporin-6 (SAP) ribosome-inactivating protein from the plant Saponaria officinalis. The effect of OKT1-SAP on target CD5-positive B-CLL cells was estimated using an in vitro proliferation inhibition assay in which control or OKT1-SAP-treated B-CLL cells were induced to proliferate by sequential stimulation with insolubilized anti-C3b receptor CB04 (CD35) antibody and low molecular weight B-cell growth factor. In 90% of patients, OKT1-SAP specifically suppressed B-CLL cell proliferation in a dose-related manner (50% inhibitory concentration, 4.0-6.8 nM). Taken together the findings reported in this article provide information relevant to the clinical development of immunotoxins because: (a) the in vitro conditions under which B-CLL cell proliferation is inhibited by OKT1-SAP are achievable in vivo without nonspecific toxicity according to our previous toxicology and pharmacokinetics studies in primates; and (b) the B-CLL cell proliferation inhibition assay described here provides a basis for future comparative studies.     

Humoral immunodeficiency in T-cell chronic lymphocytic leukemia. An immunologic assessment

The humoral antibody immunodeficiency in two patients with T-cell chronic lymphocytic leukemia (T-CLL) appeared to be the result of immunoregulatory abnormalities in the leukemic T-cell populations. Both patients had CD4+ CD45R+ "virgin" or suppressor-inducer T-CLL, but Patient 1 had hypogammaglobulinemia and Patient 2, immunoglobulin (Ig) M hypergammaglobulinemia. Although, CD25+ interleukin-2 (IL-2) receptors were present on leukemic T-cells of both patient, OKT9+ (CD71) transferrin receptors and OKT10 (CD38) activation antigens were found only on Patient 2's cells. Highly elevated amounts of IL-2 was secreted from phytohemagglutinin-stimulated and concanavalin A-stimulated T-cells in both patients. In Patient 1 with hypogammaglobulinemia, immune defects involve T-cells, first an intense suppressor activity on B-cell-induced IgM and IgG synthesis and, second, deficient production of B-cell growth factor (BCGF) and B-cell differentiation factor (BCDF). In Patient 2, highly elevated BCGF and IgM-specific BCDF was secreted by T-cells, a mechanism leading to IgM hypergammaglobulinemia in this patient. These studies stress the importance of BCGF and BCDF activity of leukemic T-cells in humoral antibody immunodeficiency disorders in T-CLL cases.     

Abnormalities in T-cell associated rearrangement of T-cell receptor gamma chain genes in B-cell chronic lymphocytic leukemia

Non-random rearrangement of genes encoding the gamma chain of the T-cell antigen receptor is known to occur in a developmentally regulated fashion during thymocyte differentiation. We show here that peripheral blood T lymphocytes from patients with B-cell chronic lymphocytic leukemia display marked abnormalities in the spectrum of gamma variable region gene rearrangements compared with normal peripheral blood. Of seven patients studied, all displayed a reduction of rearrangements into V9 (subgroup V II), while two cases had, in addition, over-representation of specific rearrangements involving subgroup V I; one V 2/4, the other V 5. These observations have a number of implications relevant to mechanisms of disease pathogenesis, and may provide new insight into the basis of T-cell dysfunction that is frequently associated with this condition.     

Hemophagocytic syndrome associated with CD8 positive T-cell chronic lymphocytic leukemia

We describe a case of hemophagocytic syndrome (HPS) associated with CD8-positive T-cell chronic lymphocytic leukemia (CD8 + T-CLL). A 68-year-old man with CD8 + T-CLL presented with fever, progressive pancytopenia, and lymphadenopathy. Laboratory findings showed a hyper-ferritinemia, abnormalities of coagulation tests, and liver and renal dysfunction with hypoproteinemia. He did not respond to any treatments and died of respiratory failure 10 days after the admission and 14 months after the onset of CD8 + T-CLL. Pathological findings of the autopsy demonstrated infiltration of CD8 + T-CLL cells in multiple organs along with the increase of histiocytes with prominent hemophagocytosis. Serum concentration levels of IL-6, soluble IL-2 receptor and VEGF were all elevated at admission. These findings revealed that he had a secondary HPS. It was suggested that HPS should be considered in patients with an unexplained cytopenia and a fever during the clinical course of CD8 + T-CLL.     

Progress in BCL2 inhibition for patients with chronic lymphocytic leukemia

The prosurvival protein BCL2 is uniformly expressed in chronic lymphocytic leukemia (CLL), and enables leukemia cell survival in the face of cytotoxic treatment and increasing genomic, metabolic, and oxidative stresses. The therapeutic potential of BCL2 inhibition was first observed in the clinic following BCL2 antisense therapy. Subsequently, a number of small molecule inhibitors were developed to mimic the function of the pro-apoptotic BH3-only proteins (BH3-mimetics). These molecules are now in late-phase clinical trials and demonstrate potent activity, including the occurrence of acute tumor lysis syndrome in subjects with multiply relapsed, chemorefractory CLL. In this review, we discuss the history and summarize current knowledge regarding BCL2 inhibition as therapy of CLL.     

Poorly expressed CD2 antigen on the leukemic cells of adult T-cell leukemia and chronic lymphocytic leukemia of T-cell lineage

Adult T-cell leukemia (ATL) and T-cell chronic lymphocytic leukemia (T-CLL) are hematologic neoplasms in differentiated stages of peripheral mature T cells. This is suggested by the presence of CD2 (E rosette receptor) and mature and/or pan-T cell membrane surface antigens on their leukemic cells. We recently encountered one patient with ATL and another with T-CLL; their leukemic cells poorly expressed CD2 antigens, but clinical presentation, morphology of the leukemic cells and other marker studies were characteristic of either ATL or CLL. The clinical significance of the poor expression of CD2 remains to be further studied. The two patients reported here died of severe complications 4 and 9 weeks after diagnosis. The poor expression of CD2 in the peripheral T cells in these neoplasms is likely to indicate an aggressive nature of the disease.     

Rituximab-based chemotherapy for steroid-refractory autoimmune hemolytic anemia of chronic lymphocytic leukemia.

Autoimmune hemolytic anemia (AIHA) is a well known complication of chronic lymphocytic leukemia (CLL). Steroids are the first line of treatment and there are limited effective treatment options for steroid refractory AIHA of CLL. Rituximab, an active agent against B cell malignancies, has also been noted to be active in certain autoimmune hematologic disorders. We used a combination of rituximab, cyclophosphamide and dexamethasone (RCD) in eight CLL patients with steroid refractory AIHA. Rituximab was given at a dose of 375 mg/m(2) i.v. on day 1 (D-1). Cyclophosphamide was given at a dose of 750 mg/m(2) on D-2. Twelve mg of dexamethasone was given i.v. on D-1, D-2 and orally from D-3 to D-7. Cycles were repeated every 4 weeks till the best response. Response in AIHA was evaluated by frequent blood counts and Coombs test. All eight patients achieved a remission of their AIHA. Median pretreatment hemoglobin was 8.3 g/dl and post-treatment hemoglobin was 14.3 g/dl. Five patients converted to Coombs negative after RCD. Median duration of response was 13 months (7-23+). Retreatment with RCD was also effective in achieving a response on relapse of AIHA. Our results indicate that a rituximab-based combination regimen (RCD) is highly effective in treating steroid refractory AIHA of CLL.     

Coexistence of chronic myelogenous leukemia and chronic lymphocytic leukemia

A 55-year-old man is reported who initially developed chronic lymphocytic leukemia. Seven years later, after chemotherapy with chlorambucil, chronic myelogenous leukemia was diagnosed in addition to the chronic lymphocytic leukemia. Four previously reported cases with the same sequence of events are reviewed as well as cases of chronic myelogenous leukemia following chemotherapy alone.     

T-cell function in chronic lymphocytic leukaemia

According to the immune-surveillance hypothesis, cancer cells evolve strategies to evade or suppress the immune system as part of the development of this disease. The malignant B-cells of chronic lymphocytic leukaemia are prime examples of this premise, having been shown to generate a variety of ways of suppressing T-cell anti-tumour immune responses and these are summarized here. These mechanisms range from impairment of antigen presentation by the tumour cells themselves, to suppression of the immune microenvironment by contact dependent pathways and alterations in the cytokine milieu. By understanding these defects, novel targeted therapies can be developed with the aim of restoring T-cell function. Indeed, some of the recent advances in the treatment of chronic lymphocytic leukaemia have been demonstrated to have profound immunomodulatory effects, repairing these defects in T-cell function.     

Alemtuzumab to treat refractory autoimmune hemolytic anemia or thrombocytopenia in chronic lymphocytic leukemia

Autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP) are recognized complications of chronic lymphocytic leukemia (CLL) that can be life-threatening if not managed appropriately. Conventional therapies for these autoimmune disorders, such as corticosteroids, splenectomy, and immunosuppressive agents, may not induce complete resolution in all patients, and relapses are common. In recent years, monoclonal antibodies such as alemtuzumab and rituximab, already used successfully for the management of lymphoproliferative disorders, have been shown to be effective in the treatment of a range of autoimmune disorders. The potent antitumor activity of alemtuzumab, in combination with its profound immunosuppressive activity, prompted investigation of its use in patients with severe CLL-related AIHA and ITP. Results from a range of reports confirm the efficacy of alemtuzumab for the treatment of severe, CLL-related autoimmune cytopenias that have failed to respond to conventional therapies and may even be rituximab-refractory.