Successful management of thrombotic thrombocytopenic purpura in a Jehovah's Witness without plasma exchange.

Thrombotic thrombocytopenic purpura (TTP) is a hematologic emergency characterized by microangiopathic hemolytic anemia and thrombocytopenia. Plasma exchange is the standard treatment. Treating TTP without plasma exchange is a challenge. Due to religious beliefs, Jehovah's Witnesses do not accept transfusions of blood products. We report a case of successful treatment of TTP in a Jehovah's Witness using plasma exchange with albumin replacement.

Dipeptidyl peptidase 2 apoptosis assay determines the B-cell activation stage and predicts prognosis in chronic lymphocytic leukemia.

OBJECTIVE: Dipeptidyl peptidase 2 (DPP2/DPP7) is a regulator of quiescence as inhibition of DPP2 results in apoptosis of resting, but not activated lymphocytes. The purpose of the present study was to investigate the prognostic value of DPP2 inhibition and the role of DPP2 in cell cycle in chronic lymphocytic leukemia (CLL). MATERIALS AND METHODS: We screened 152 peripheral blood samples from patients with CLL in an apoptosis assay with AX8819, a DPP2-specific inhibitor. The apoptotic response was correlated with B-cell receptor signaling and cell cycle and molecular prognostic factors. RESULTS: We categorized CLL into two prognostic subgroups. Inhibition of DPP2 induced apoptosis in 60% of CLL, while 40% were resistant to apoptosis. Resistance to apoptosis correlated with unmutated IgV(H) and increased ZAP-70 expression and was associated with unfavorable clinical outcomes. Sensitive CLL B cells expressed high p27, low c-Myc protein levels and decreased Syk phosphorylation, indicative of a resting phenotype. DPP2 inhibition in those cells resulted in apoptosis accompanied by enhanced phosphorylation of Syk, degradation of p27 and p130, and upregulation of c-Myc, indicative of activation and inappropriate cell cycle entry. Resistant CLL demonstrated baseline low p27 and high c-Myc protein levels and increased pSyk, indicative of an activated phenotype. Inhibition of heat shock protein 90 in this subset of CLL partially reversed apoptosis resistance. CONCLUSIONS: The DPP2 apoptosis assay provides a reliable prognostic factor in CLL. CLL B cells sensitive to DPP2 inhibition are in true G(0), while resistant CLL B-cells are partially activated. DPP2 inhibition alone or with concomitant inhibition of heat shock protein 90 warrants investigation as a therapeutic modality in CLL.

Variable contribution of monoclonal antibodies to ADCC in patients with chronic lymphocytic leukemia.

Monoclonal antibodies (mAbs) are increasingly used in treatment protocols for chronic lymphocytic leukemia (CLL). Here we determined (i) the extent of antibody-dependent cellular cytotoxicity (ADCC) of four different mAbs against primary CLL cells, (ii) whether ADCC correlates with antigen density on CLL cells, and (iii) whether allogeneic natural killer (NK) cells display superior ADCC than autologous. Effector cells for ADCC were (i) NK-92 cells not expressing FcR, (ii) NK-92 cells transfected with a high-affinity Fc receptor, (iii) autologous NK cells from patients with CLL, (iv) allogeneic NK cells. Results suggest that ADCC contributes to killing of CLL cells by anti-CD20 antibodies (rituximab and veltuzumab), whereas mAbs against CD22 (epratuzumab) and CD23 (lumiliximab) showed minimal ADCC. The magnitude of anti-CD20 mediated ADCC did not correlate with antigen density of CD20. ADCC was not influenced by the FcR genotype expressed by autologous NK cells. Allogeneic NK cells were superior to autologous NK cells in killing primary CLL cells.

Severe neutropenia in CHOP occurs most frequently in cycle 1: a predictive model.

Chemotherapy used to treat lymphoma can cause severe neutropenia. Risk models have identified factors that predict neutropenia across all chemotherapy cycles. We used clinical information obtained during pretreatment evaluation to develop a predictive model for severe neutropenia in the first cycle of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy. This case series study included lymphoma patients receiving CHOP chemotherapy with or without rituximab who did not receive pre-emptive hematopoietic growth factor. Risk factors for neutropenia were identified from previously published models and included age >or=65 years, hypoalbuminemia, renal/cardiovascular disease, anemia, abnormal bone marrow and increased lactate dehydrogenase (LDH). A composite score equal to the number of pretreatment risk factors was used to predict severe neutropenia in cycle 1. Fifty-three percent of patients (47 of 89) had severe neutropenia, with 70% of first episodes occurring during cycle 1. Eighty-two percent of first-cycle, severe neutropenia events occurred in patients >or=65-years-old. In univariate analysis, age >or=65 years and increased baseline LDH were significantly associated with increased risk for severe neutropenia in cycle 1. In logistic regression modeling, the probability of severe neutropenia in cycle 1 increased as the number of pretreatment risk factors increased, with a one-unit increase in risk score resulting in a 2.3-fold increase in severe neutropenia. The study results suggest that data obtained before initiating CHOP-based chemotherapy can be used to identify those patients who are at risk for severe neutropenia in cycle 1. If validated, our model could be used to identify patients who would benefit from early use of growth factors.