[Decitabine treatment in myelodysplastic syndromes--results of a compassionate patient program in Israel].

INTRODUCTION: Hypermethylation of tumor suppressor genes (TSG) has been recognized as an important factor in the pathogenesis of malignancies, including myelodysplastic syndromes (MDS). Decitabine (trade name Dacogen; 5-aza-2'-deoxycytidine) is a cytosine analog which inhibits the enzyme DNA methyltransferase (DNMT), inducing hypomethylation and activates TSG, leading to tumor cell growth inhibition. In clinical trials with hypomethylating agents in advanced MDS, a total response rate of 30-73% has been observed, with a complete response (CR) of 9-37%, partial response (PR] of similar rate and a hematologic improvement (HI] in 20-48% of the patients. AIM: We report the results of a national Israeli compassionate program of decitabine administration to patients with advanced MDS. PATIENTS AND METHODS: From July 2007 through August 2008, under the joint sponsorship of The Israel Society of Hematology and Blood Transfusions and Janssen, Israel, a compassionate program was conducted. Decitabine was administered to patients with advanced MDS who were not candidates for any other anti-MDS treatment, except for supportive care. The selected regimen was a 5-day intravenous administration of 20 mg/m/d, every 28 days. After the program had been completed, an approval of the institutional Helsinki committees was obtained, and the data were collected in an attempt to evaluate the results of this novel treatment. The standard response criteria, i.e. total response, CR, PR and HI were applied. Toxicity, survival and leukemic transformation rate were also analyzed. RESULTS: Twenty-four patients with advanced MDS participated in the program but evaluable information could be collected only on 17 patients. The median number of therapeutic cycles was two per patient. Twelve patients were transfusion-dependent at program onset, of whom 7 either benefited from reduced transfusion requirements or became transfusion-free. The overall response rate was 26%, with 23% PR and 13% HI. Two patients (13%) demonstrated leukemic transformation. The median overall survival was 17 months and the median event-free survival was 13 months. Nine out of 12 patients, who could be evaluated, experienced 3-4 degree bone marrow suppression. A single patient suffered from vocal cord paralysis, apparently, unrelated to the treatment. DISCUSSION AND CONCLUSIONS: The overall response rate was 26% in this national compassionate program of decitabine administration to patients with advanced MDS. Although somewhat low, this is similar to other reports. Possible reasons for the relatively low response rate include a small number of patients, the nature of a compassionate program, the limited number of therapeutic cycles, and the very advanced degree of the disease in most patients who had been on several treatment lines prior to the program. Nevertheless, understanding the role of epigenetics in the pathogenesis of neoplasms and MDS, which led to the introduction of hypomethylation agents such as decitabine into clinical practice, is an encouraging step towards better care of cancer, including MDS.

[The new anticoagulants].

Anticoagulant therapy is based on two veteran drugs, which have been in use for over 60 years: heparin and warfarin. Due to the limitations of these agents, new parenteral anticoagulants have been introduced, mainly the low molecular weight heparins, fondaparinux and direct thrombin inhibitors. The need to develop new drugs has led to major efforts by the pharmaceutical industry and many promising anticoagulant oral agents are being tested. Ximelgatran has been withdrawn from the market after several cases of hepatotoxicity have been observed. Two oral agents, dabigatran and rivaroxaban, have recently been approved in Europe. Dabigatran inhibits thrombin, while rivaroxaban is factor X inhibitor. Other drugs include apixaban, idraparinux and are in Phase III studies.

Chronic paraneoplastic cutaneous syndrome preceding an indolent variant of mantle cell lymphoma: favorable response to rituximab.

Mantle cell lymphoma (MCL) is an aggressive type of malignant lymphoma with short median survival despite conventional therapy. We describe the unusual case of a 66-year-old man with a chronic skin rash which preceded the occurrence of an indolent MCL by 2 years. Repeated skin biopsies did not show involvement by the lymphoma. Short therapy with rituximab resulted in the complete and lasting resolution of the cutaneous lesions.

Evaluation of arterial compliance in polycythemia vera patients: short and long-term influence of phlebotomy.

BACKGROUND: Thrombosis is a major cause of morbidity and mortality in polycythemia vera. Hypercoagulability is principally due to hyperviscosity of the whole blood, an exponential function of the hematocrit. PV is also associated with endothelial dysfunction that can predispose to arterial disease. Reduction of the red cell mass to a safe level by phlebotomy is the first principle of therapy in PV. This therapy may have some effect on the arterial compliance in PV patients. OBJECTIVES: To estimate the influence of phlebotomies on large artery (Cl) and small artery compliance (C2) in PV patients by using non-invasive methods. METHODS: Short-term hemodynamic effects of phlebotomy were studied by pulse wave analysis using the HDI-Pulse Wave CR2000 (Minneapolis, MN, USA) before and immediately after venesection (350-500 ml of blood). We repeated the evaluation after 1 month to measure the long-term effects. RESULTS: Seventeen PV patients were included in the study and 47 measurements of arterial compliance were performed: 37 for short-term effects and 10 for long-term effects. The mean large artery compliance (C1) before phlebotomy was 12.0 ml/mmHg x 10 (range 4.5-28.6), and 12.6 ml/mmHg x 10 (range 5.2-20.1) immediately after phlebotomy (NS). The mean small artery compliance (C2) before and immediately after phlebotomy were 4.4 mg/mmHg x 10 (range 1.2-14.3) and 5.5 mg/mmHg x 10 (range 1.2-15.6) respectively (delta C2-1.1, P < 0.001). No difference in these parameters could be demonstrated in the long-term arm. CONCLUSIONS: Phlebotomy immediately improves arterial compliance in small vessels of PV patients, but this effect is short lived.

Non-Hodgkin's lymphoma and residential proximity to toxic industrial waste in southern Israel.

Environmental exposure has been linked to non-Hodgkin's lymphoma (NHL). Toxic volatile compounds were found in groundwater downstream of an industrial site in southern Israel. The risk of NHL and clinical characteristics of NHL patients were analyzed in relation to their proximity to the site.

Complement profile in childhood immune thrombocytopenic purpura: a prospective pilot study.

Immune thrombocytopenic purpura (ITP) is a frequent, usually acute hematologic complication of viral diseases in children. Its evolution is usually benign with spontaneous resolution. Some authors have raised the hypothesis of a possible role of the complement system in the pathogenesis of ITP. In the present study, we measured the complement system components in 25 children with ITP. The complement system was abnormal in most patients with ITP as compared with the control group: 20 of the 25 patients had at least one low-component level. The most affected components were properdin, factor H (p=0.005 and p=0.001, respectively), C1q, C9, and factor B. Our results may indicate a possible role for the complement system in the pathogenesis of pediatric ITP.

Human CTL epitopes prostatic acid phosphatase-3 and six-transmembrane epithelial antigen of prostate-3 as candidates for prostate cancer immunotherapy.

Specific immunotherapy of prostate cancer may be an alternative or be complementary to other approaches for treatment of recurrent or metastasized disease. This study aims at identifying and characterizing prostate cancer-associated peptides capable of eliciting specific CTL responses in vivo. Evaluation of peptide-induced CTL activity in vitro was done following immunization of HLA-A2 transgenic (HHD) mice. An in vivo tumor rejection was tested by adoptive transfer of HHD immune lymphocytes to nude mice bearing human tumors. To confirm the existence of peptide-specific CTL precursors in human, lymphocytes from healthy and prostate cancer individuals were stimulated in vitro in the presence of these peptides and CTL activities were assayed. Two novel immunogenic peptides derived from overexpressed prostate antigens, prostatic acid phosphatase (PAP) and six-transmembrane epithelial antigen of prostate (STEAP), were identified; these peptides were designated PAP-3 and STEAP-3. Peptide-specific CTLs lysed HLA-A2.1+ LNCaP cells and inhibited tumor growth on adoptive immunotherapy. Furthermore, peptide-primed human lymphocytes derived from healthy and prostate cancer individuals lysed peptide-pulsed T2 cells and HLA-A2.1+ LNCaP cells. Based on the results presented herein, PAP-3 and STEAP-3 are naturally processed CTL epitopes possessing anti-prostate cancer reactivity in vivo and therefore may constitute vaccine candidates to be investigated in clinical trials.

Thrombotic thrombocytopenic purpura due to alcohol binge drinking.

Binge alcohol drinking is a pattern of alcohol abuse that is common among young males worldwide. It has been found to be associated with an increased likelihood of injury as a cause of death. Chronic alcohol abuse is known to cause some common hematological manifestations such as macrocytosis, thrombocytopenia, sideroblastic anemia, global marrow suppression, and folic acid deficiency anemia. We present a rare case involving an unusual and severe hematological manifestation of binge alcohol drinking: thrombotic thrombocytopenic purpura (TTP). The patient we present had severe and prolonged TTP necessitating prolonged treatment with plasmapheresis and plasma exchange. We discuss the relevant medical literature and the possible physiopathology of this complication.

Conventional dose fludarabine-based regimens are effective but have excessive toxicity in elderly patients with refractory chronic lymphocytic leukemia.

The best approach to elderly patients with relapsing chronic lymphocytic leukemia (CLL) or disease refractory to conventional therapy with alkylating agents has not yet been established. Fludarabine and its combination with mitoxantrone and/or cyclophosphamide, which is the most effective treatment in younger patients, has not been extensively utilized in the elderly CLL. Here we report our results with fludarabine-based chemotherapy in 32 previously treated patients over the age of 65 years. The overall response rate was 59% with no complete remission, 3 nodular partial remissions and 16 partial remissions. The median time to progression of disease was 7 months. Only 10 patients completed the entire treatment program, because of poor compliance due to toxicity. Eight patients developed neutropenic fever, 14 severe bacterial infections and 2 patients showed progressive encephalopathy. For comparison, in a younger group of patients with refractory CLL (< 65 years), 38 of 50 patients completed the treatment plan, and the ORR was 80% (10 CR, 11 PR-nodular, 19 PR) with a median response of 12 months. Neutropenic fever was diagnosed in 10 and severe bacterial infection in 4 patients. In conclusion, fludarabine-based chemotherapy is effective for refractory CLL, however, excessive toxicity such as severe infections and neurological complications, do not allow completion of treatment in the majority of the elderly patients. Because maintenance of a good quality of life should be the main goal in the elderly CLL population, dose reduction of fludarabine and the appropriate use of myeloid growth factors and prophylactic antibiotics appear mandatory in this group of patients.

Severe enoxaparin-induced thrombocytopenia complicated by pulmonary emboli.

Low molecular weight heparins (LMWH) have been widely used in the last decade, especially for prophylaxis of deep venous thrombophlebitis. Enoxaparin-induced thrombocytopenia is rarely encountered, in contrast to its high prevalence among patients treated with unfractionated heparin. We report a case of a patient who was admitted because of a pulmonary embolus due to proximal deep vein thrombophlebitis 2 weeks after surgery, despite prophylaxis with low-dose enoxaparin after prostatectomy. The patient's original normal platelet count (255,000/microl) dropped to 30,000/microl while on enoxaparin therapy. Testing for antibodies against heparin was positive. Warfarin was initiated and an inferior vena caval filter was inserted. Within a few days, platelet count increased to 100,000/microl, pulmonary status improved, and the patient was released in good clinical condition. Heparin-induced thrombocytopenia (HIT) is discussed, as are alternative treatments for unfractionated heparins and LMWH.

Novel role of 1,25(OH)(2)D(3) in induction of erythroid progenitor cell proliferation.

OBJECTIVE: Burst-forming unit erythroid and colony-forming unit erythroid growth in vitro is lower in studies of continuous ambulatory peritoneal dialysis patients than healthy controls. Burst-forming unit erythroid growth was potentiated by addition of 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and normalized by erythropoietin (Epo) therapy, suggesting an interaction between Epo and 1,25(OH)(2)D(3) at the stem cell level. The objective of this study was to determine the mechanism by which 1,25(OH)(2)D(3) enhances the stimulatory effect of Epo on the growth of erythroid precursor cells. MATERIALS AND METHODS: We examined the effect of 1,25(OH)(2)D(3) and Epo on stem cell proliferation. Proliferation of TF1 cells of erythroid origin was measured by the XTT method, 3[H] thymidine incorporation, and cell counting by trypan blue exclusion; cord blood (CB) stem cells were counted. Epo receptor (EpoR) quantitation was evaluated by 125I-Epo binding and Scatchard analysis, immunoprecipitation, and Western blotting. Expression of EpoR mRNA was measured by reverse transcriptase polymerase chain reaction. RESULTS: The stem cell factor-dependent CB stem cells and the TF1 cells responded to Epo and 1,25(OH)(2)D(3) by increased proliferation, while their simultaneous addition potentiated cell proliferation in a synergistic manner (25.67% +/- 4.8% of Epo proliferation at day 10 for CB cells; p < 0.005). 1,25(OH)(2)D(3) produced an up-regulation of EpoR number in TF1 cells and increased the expression of EpoR mRNA (p < 0.01). CONCLUSIONS: The increase in EpoR expression induced by 1,25(OH)(2)D(3) might explain the synergistic interaction between Epo and 1,25(OH)(2)D(3) in stem cells.