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Cladribine (2-chlorodeoxyadenosine, 2-CdA) treatment-associated infections may shorten potentially long-term survival in hairy cell leukemia (HCL). In search of the optimal mode of 2-CdA administration, 132 patients with untreated HCL were randomized to receive either standard 5-day 2-CdA protocol or a novel schedule of 6 weekly 2-CdA infusions suggested to be less toxic. Analysis of treatment response confirmed similar complete remission rates, overall response rates, progressionfree survival, and overall survival in both 2-CdA protocols. However, we did not observe lower toxicity in the weekly schedule. Of special interest, no significant differences were found in the rate of grade 3/4 infections (18% for daily and 26% for weekly protocol, difference ؊8.2%; 95% confidence interval [CI] ؊23.2% to 6.9%; P ‫؍‬ .28) and the rate of septic deaths (3% for daily and 2% for weekly protocol, difference 1.4%; 95% CI ؊4.3% to 7.0%; P ‫؍‬ .64). In conclusion, HCL treatment with weekly 2-CdA infusions is equally effective but no safer than the standard 5-day 2-CdA protocol. IntroductionCladribine (2-chlorodeoxyadenosine, 2-CdA) belongs to standard therapeutic options for hairy cell leukemia (HCL). In chemotherapy-naive HCL, one course of 2-CdA induces complete response (CR) and long-term survival in the vast majority of patients. [1][2][3][4][5] Given this considerable clinical efficacy, the major challenge regarding 2-CdA therapy is reduction of side effects, especially severe infections that may lead to septic death. Lauria et al 6 suggested that a novel schedule based on 6 weekly 2-hour 2-CdA infusions could be as effective as the standard 7-day and 5-day protocols but associated with less neutropenia and fewer life-threatening infections. To test the potential clinical benefit of the weekly schedule, in 1998 the Polish Adult Leukemia Group (PALG) initiated a prospective multicenter, randomized comparison with 5-day 2-CdA infusion that is the standard treatment of active HCL in Poland. Patients, materials, and methodsThe study was carried out at 14 hematology centers, with central randomization and data management performed in the Department of Hematology at the Medical University of Lodz. The study was approved by the ethics committee of the Medical University of Lodz, and all patients gave informed consent in accordance with the Declaration of Helsinki. Eligibility criteriaPatients with untreated, active HCL, World Health Organization (WHO) scale performance status better than grade 4, normal liver and renal function, without secondary neoplasm, and age 18 years or older were considered eligible. The diagnosis of HCL and the criteria of activity of disease were defined as previously reported. Preliminary results of this study were presented at 46th annual meeting of the American Society of Hematology, San Diego, CA, December 4-7, 2004, 17 and at the 48th annual meeting of the American Society of Hematology, Orlando, FL, December 9-12, 2006. 18 The publication costs of this article were defrayed in part by page...

Neurosteroids are important regulators of central nervous system function and may be involved in processes of neuronal cell survival. This study was undertaken to test the effect of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), pregnenolone (PGL), pregnenolone sulfate (PGLS), and allopregnanolone (Allo) on hydrogen peroxide- and staurosporine-induced toxicity in SH-SY5Y cells. It has been found that DHEAS inhibited the hydrogen peroxide toxicity in a concentration-dependent manner, whereas DHEA was active only at higher doses. PGL and PGLS showed neuroprotective effects only at the lowest concentration. Allo had no significant effect on hydrogen peroxide-evoked lactate dehydrogenase release and at the highest concentration aggravated its toxic effects. Next part of this study evaluated neurosteroid effects on staurosporine-induced apoptosis. DHEAS, DHEA, and PGL significantly antagonized effects of staurosporine on both caspase-3 activity and mitochondrial membrane potential. PGLS and Allo inhibited the staurosporine-induced changes in both apoptotic parameters only at the lowest concentration. Antiapoptotic properties of neurosteroids were positively verified by Hoechst staining. Furthermore, as shown by calcein assay, DHEA, DHEAS, and PGL increased viability of staurosporine-treated cells, and these effects were attenuated by specific inhibitors of phosphatidylinositol 3-kinase (PI3-K) and extracellular signal-regulated protein kinase (ERK)-mitogen activated protein kinase (MAPK). These data indicate that neurosteroids prevent SH-SY5Y cell damage related to oxidative processes and activation of mitochondrial apoptotic pathway. Moreover, neuroprotective effects of DHEA, DHEAS seem to depend on PI3-K and ERK/MAPK signaling pathways. It can be suggested that, at physiological concentrations, all studied neurosteroids participate in the inhibition of neuronal apoptosis, but with various potencies.

The objective of the study was to determine the effectiveness and the toxicity of a combined chemotherapy consisting of cladribine (2-CdA), mitoxantrone and cyclophosphamide (CMC regimen) in the treatment of previously untreated B cell chronic lymphocytic leukemia (B-CLL). From August 1998 to December 2000 2-CdA was administered at a dosage of 0.12 mg/kg for 3 (CMC3) or 5 (CMC5) consecutive days, mitoxantrone at 10 mg/m 2 on day 1 and cyclophosphamide at 650 mg/m 2 on day 1 to 62 patients with advanced or progressive B-CLL. The cycles were repeated at 4 week intervals or longer if severe myelosuppression occurred. Twenty patients received CMC5 and 42 patients CMC3. Within the analyzed group an overall response (OR) rate (CR+PR) of 64.5% (95% CI: 52.7-76.3%) was reported, including 29.0% CR. There was no difference in the CR rate between the patients treated with CMC5 (30%) and CMC3 (28.6%) (P = 0.9), nor in the OR rate (55.0% and 69.0%, respectively, P = 0.3). Residual disease was identified in seven out of 18 (38.9%) patients who were in CR, including two treated with CMC5 and five treated with CMC3 protocols. CMC-induced grade III or IV thrombocytopenia occurred in 12 (19.4%) of patients, including four (20%) CMC5-treated and eight (19%) CMC3-treated patients (P = 0.8). Neutropenia grade III or IV was observed in seven (35%) and 11 (26.2%) patients, respectively (P = 0.8). Severe infections, including pneumonia and sepsis, occurred more frequently after CMC5 (11 patients, 55.0%) than CMC3 (10 patients, 28.6%) (P = 0.03) Fourteen patients died, including six treated with CMC5 and eight treated with CMC3 (30% and 19%, respectively). Infections were the cause of death in nine patients, including four in the CMC5 group and five in the CMC3 group. In conclusion, our results indicate that the CMC programme is an active combined regimen in previously untreated B-CLL patients; its efficiency seems to be similar to that observed earlier in B-CLL patients treated with 2-CdA as a single agent. However, toxicity, especially after CMC5 administration, is significant. Therefore, we recommend the CMC3 but not the CMC5 programme for further evaluation. Leukemia (2001Leukemia ( ) 15, 1510Leukemia ( -1516

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