SEARCH:   Advanced

Blood, 1 September 2004, Vol. 104, No. 5, pp. 1266-1269. Prepublished online as a Blood First Edition Paper on May 20, 2004; DOI 10.1182/blood-2003-12-4333. This Article Abstract Full Text (PDF) All Versions of this Article: 2003-12-4333v1 104/5/1266    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kuendgen, A. Articles by Gattermann, N. Search for Related Content PubMed PubMed Citation Articles by Kuendgen, A. Articles by Gattermann, N. Related Collections Neoplasia Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS Brief report Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid Andrea Kuendgen, Corinna Strupp, Manuel Aivado, Alf Bernhardt, Barbara Hildebrandt, Rainer Haas, Ulrich Germing, and Norbert Gattermann From the Department of Hematology, Oncology, and Clinical Immunology and the Institute of Genetics, Heinrich-Heine-University, Düsseldorf, Germany.    Abstract Top Abstract Introduction Study design Results and discussion References   Valproic acid (VPA) has been shown to inhibit histone deacetylase activity and to synergize with all-trans retinoic acid (ATRA) in the differentiation induction of acute myelogenous leukemia (AML) blasts in vitro. We treated 18 patients with myelodysplastic syndromes (MDS) and AML secondary to MDS (sAML/MDS) with VPA monotherapy (serum concentrations 346-693 µM [50-100 µg/mL]). Five patients received VPA and ATRA (80 mg/m2/d, days 1-7, every other week). Response according to international working group (IWG) criteria was observed in 8 patients (44%) on VPA monotherapy, including 1 partial remission. Median response duration was 4 months (range, 3-9 months). Four of 5 patients relapsing were treated with VPA + ATRA, 2 of them responding again. Among 5 patients receiving VPA + ATRA from the start, none responded according to IWG criteria, but 1 patient with sAML/MDS achieved a marked reduction in peripheral and marrow blasts. Thus, VPA is of therapeutic benefit for patients with MDS, and ATRA may be effective when added later.    Introduction Top Abstract Introduction Study design Results and discussion References   Valproic acid (VPA) is a short-chain fatty acid (SCFA) that has been used as an anticonvulsant for 30 years. Recently, the drug has been discovered to have additional properties. There is growing evidence that VPA, like other SCFAs, affects the growth and differentiation of a variety of malignant cells in vitro.1,2 Tumor cell differentiation induced by VPA is coupled with its capability to inhibit histone deacetylation.3,4 Histone acetylation status, which is controlled by histone acetylases (HATs) and deacetylases (HDACs), plays a key role in the regulation of gene transcription. Aberrant activity of HDACs in malignant cells leads to decreased histone acetylation and, in turn, silencing of tumor suppressor genes. This is because highly charged hypoacetylated histones bind tightly to DNA, preventing transcription factors from gaining access to the affected genes. Acetylation instead neutralizes the positive charge and generates an open, easily accessible DNA conformation, facilitating re-expression of the tumor suppressor genes.5-8 VPA is capable of inducing differentiation as well as apoptosis in leukemic cell lines in vitro, and this differentiating effect is enhanced by all-trans retinoic acid (ATRA).3,9-12 Because VPA is orally applicable, reaches stable serum concentrations, and has a low toxicity profile, we tried to harness its differentiation-promoting effects for the treatment of patients with myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) secondary to MDS (sAML/MDS).    Study design Top Abstract Introduction Study design Results and discussion References   Between February 2002, and August 2003, 23 patients with MDS and sAML/MDS were treated after written informed consent had been obtained. The study protocol was approved by the ethics committee of the Medical Faculty of Heinrich-Heine-University, Düsseldorf, Germany. Clinical characteristics of the patients are given in Table 1. View this table: [in this window] [in a new window]   Table 1.. Clinical and hematologic characteristics of patients with MDS/sAML treated with VPA ± ATRA   VPA was administered to reach serum concentrations between 346 and 693 µM (50 and 100 µg/mL), which is the therapeutic range for treatment of seizures. These concentrations have been shown to inhibit histone deacetylase activity in vitro3,4 and to exert an effect on fetal hemoglobin synthesis in vivo, indicating HDAC inhibition.15 Hematologic toxicities of VPA are mainly observed at serum valproate levels greater than 693 µM (100 µg/mL).16,17 ATRA was given at a dosage of 80 mg/m2/d in 2 divided doses, days 1 to 7, every other week.18 If neither significant side effects nor disease progression occurred, treatment was continued. Eighteen patients were started on VPA monotherapy, with addition of ATRA planned for patients who did not respond or who relapsed. In an attempt to enhance responses, 5 patients were treated with VPA + ATRA from the start, using the same dosages. Serum VPA concentrations were measured with a commercially available fluorescence polarization immunoassay (Abbott, Wiesbaden, Germany). Treatment response was assessed according to international working group (IWG) criteria.19    Results and discussion Top Abstract Introduction Study design Results and discussion References   Median treatment duration was 6 months (range, 2-23 months) for VPA and 3 months (range, 1-18 months) for ATRA. All patients had serum VPA concentrations within the target range and completed at least 2 months of treatment. Median dosage was 1250 mg (range, 900-2550 mg). According to IWG criteria, 8 patients (44%) on VPA monotherapy responded to treatment (nos. 3, 10, 11, 13, 14, 16, 21, 23), with a median time to response of 30 days (range, 14-38 days). We observed hematologic improvement in 7 patients, namely 2 major erythroid (MaR-E), 2 minor erythroid (MiR-E), 1 major neutrophil (MaR-N), and 2 major platelet responses (MaR-P; Figure 1), as well as partial remission (PR) in 1 patient (Figure 1). Among the responding patients, 3 have ongoing responses (4, 4, and 9 months, respectively). Five patients relapsed after a median of 4 months (range, 3-5 months), and 4 of these patients were switched to VPA + ATRA, with 2 responding for another 11 and 16 months, respectively, at the time of this writing. View larger version (23K): [in this window] [in a new window]   Figure 1.. Response of patient no. 16. Hematologic response (MaR-P) of a patient who initially presented with pancytopenia (white blood cell count [WBC], 2.6 = 109/L [2600/µL]; hemoglobin [Hgb], 69 g/L [6.9 g/dL]; platelets, 15 = 109/L [15 000/µL]) and a normocellular bone marrow. He was diagnosed as RCMD. He responded to immunosuppressive treatment with antithymocyte globulin but remained thrombocytopenic (around 40 = 109/L [40 000/µL]). Two years later, when his thrombocytopenia deteriorated, he received valproic acid monotherapy and responded for 5 months. After relapse he responded again to addition of ATRA. indicates 2 units of platelets were transfused.   Four patients showed stable disease, with a median duration of treatment of 5 months. Six patients had progressive disease. Of the nonresponding patients, 6 (2 SD, 4 PD) were changed to VPA + ATRA, without success. In the group of 5 patients treated with VPA + ATRA from the start, we observed no response according to IWG criteria. Still, 1 patient (no. 12) with sAML/MDS showed clearance of peripheral blasts (27%), and a decrease in bone marrow blasts (45% to 10%). Another patient had stable disease for 3 months, while 3 cases were classified as progressive disease. Regarding prognostic groups, all 3 patients belonging to the low-risk category according to the International Prognostic Scoring System (IPSS)14 showed a major response. In contrast, only one of the high-risk patients had a (minor) response. Still, among 9 patients with elevated blast count in the marrow, 3 (33%) achieved a significant reduction of peripheral and marrow blasts. Looking for other variables with prognostic relevance, we found that the frequency of red cell transfusions prior to VPA treatment was significantly lower in responders than in nonresponders (P = .026). Response to VPA was not associated with age (P = .397), sex (P = .278), pretreatment platelet count (P = .244), bone marrow blast count (P = .453), or dosage of VPA (P = .624). The frequency of chromosomal aberrations was not different (P = .879), but 3 of 4 responders with cytogenetic abnormalities had a low-risk karyotype (–Y). None of the patients with complex karyotype responded. Considering potential confounding factors, it is noteworthy that 2 responders had concomitant erythropoietin treatment. They had been receiving Epo for 7 and 18 months, respectively, making a late response to Epo unlikely. However, a synergism, perhaps by inhibition of apoptosis, cannot be excluded. In 2 patients who had been receiving thalidomide for 2.5 and 4 months, respectively, before starting VPA, a delayed thalidomide response cannot be excluded, although only one such case among 83 patients has been reported by Raza et al.20 Response to VPA monotherapy was better than response to first-line combination with ATRA. A possible explanation might be that HDAC inhibition is needed to relieve repression of retinoic acid signaling pathways.21 Therefore, pretreatment with VPA may be necessary for a synergistic effect of both drugs. Side effects were mild. Only one patient discontinued VPA because of vertigo and tremor. A few patients had fatigue ( grade 2). Thrombocytopenia (< 50% of initial platelet count) occurred in 8 patients and appeared to be attributable to study medication in 2 patients (nos. 10 and 4). Both patients had received VPA + ATRA, and platelet counts normalized when treatment was discontinued. In all other patients thrombocytopenia was more likely a result of progressive disease. Intermittent ATRA treatment was well tolerated. Grades 1 to 2 hyperkeratosis and cheilitis were observed in 2 patients. To our knowledge, this is the first report on valproic acid alone or in combination with ATRA for the treatment of MDS. Gore et al22,23 conducted 2 trials of the structurally related HDAC inhibitor phenylbutyrate in patients with MDS and AML, achieving responses in 4 of 27 and 2 of 23 patients, respectively. Of interest, plasma concentrations of phenylbutyrate, achieved at the maximum tolerated dose level, were lower than targeted on the basis of in vitro studies. On the basis of the relatively small numbers of patients treated, response to phenylbutyrate appears to be less frequent than response to VPA. Although VPA must be considered a first-generation HDAC inhibitor, it has the advantage of oral applicability, stable serum concentrations, and a low toxicity profile. From our study we conclude that oral treatment with valproic acid is well tolerated and achieves a response rate of approximately 40% in patients with MDS. Because VPA is also a promising drug for combination regimens with cytotoxic or demethylating agents,24 future studies may concentrate on using such combinations to increase the rate and duration of responses.    Acknowledgements   We thank Prof Aul, Duisburg, Germany, for providing clinical data.    Footnotes   Submitted December 22, 2003; accepted April 3, 2004. Prepublished online as Blood First Edition Paper, May 20, 2004; DOI 10.1182/blood-2003-12-4333. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: Andrea Kündgen, Department of Hematology, Oncology, and Clinical Immunology, Heinrich-Heine-University, Moorenstr 5, D-40225 Düsseldorf, Germany; e-mail: andrea{at}ta2000.de.    References Top Abstract Introduction Study design Results and discussion References   Cinatl J, Cinatl J, Driever PH, et al. Sodium valproate inhibits in vivo growth of human neuroblastoma cells. Anticancer Drugs. 1997;8: 958-963.[Medline] [Order article via Infotrieve] Werling U, Siehler S, Litfin M, Nau H, Gottlicher M. Induction of differentiation in F9 cells and activation of peroxisome proliferator-activated receptor delta by valproic acid and its teratogenic derivatives. Mol Pharmacol. 2001;59: 1269-1276.[Abstract/Free Full Text] Gottlicher M, Minucci S, Zhu P, et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 2001;20: 6969-6978.[CrossRef][Medline] [Order article via Infotrieve] Phiel CJ, Zhang F, Huang EY, et al. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem. 2001;276: 36734-36741.[Abstract/Free Full Text] Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med. 2003;349: 2042-2054.[Free Full Text] Marks PA, Richon VM, Rifkind RA. Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. J Natl Cancer Inst. 2000;92: 1210-1216.[Abstract/Free Full Text] Melnick A, Licht JD. Histone deacetylases as therapeutic targets in hematologic malignancies. Curr Opin Hematol. 2002;9: 322-332.[CrossRef][Medline] [Order article via Infotrieve] Vigushin DM, Coombes RC. Histone deacetylase inhibitors in cancer treatment. Anticancer Drugs. 2002;13: 1-13.[CrossRef][Medline] [Order article via Infotrieve] Drescher B, Ganser A, Krauter J. Effect of the histone deacetylase inhibitor valproic acid on t(15;17) positive leukemic cells [abstract]. Blood. 2003;102: 620a. Guel H, Wassmann B, Romanski A. Effect of the histone deacetylase inhibitor valproic acid in combination with all-trans retinoic acid on normal and malignant hematopiesis [abstract]. Blood. 2003;102: 626a. Kawagoe R, Kawagoe H, Sano K. Valproic acid induces apoptosis in human leukemia cells by stimulating both caspase-dependent and -independent apoptotic signaling pathways. Leuk Res. 2002;26: 495-502.[CrossRef][Medline] [Order article via Infotrieve] Jiemjit A, Trujillo M, Gore S. Induction of reexpression of silenced genes in acute leucemia by valproic acid [abstract]. Blood. 2002;100: 540a. Harris NL, Jaffe ES, Diebold J, et al. The World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues. Report of the Clinical Advisory Committee meeting, Airlie House, Virginia, November, 1997. Ann Oncol. 1999;10: 1419-1432.[Abstract/Free Full Text] Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89: 2079-2088.[Abstract/Free Full Text] Kieslich M, Schwabe D, Cinatl J Jr, Driever PH. Increase of fetal hemoglobin synthesis indicating differentiation induction in children receiving valproic acid. Pediatr Hematol Oncol. 2003;20: 15-22.[Medline] [Order article via Infotrieve] Acharya S, Bussel JB. Hematologic toxicity of sodium valproate. J Pediatr Hematol Oncol. 2000;22: 62-65.[CrossRef][Medline] [Order article via Infotrieve] Gesundheit B, Kirby M, Lau W, Koren G, Abdelhaleem M. Thrombocytopenia and megakaryocyte dysplasia: an adverse effect of valproic acid treatment. J Pediatr Hematol Oncol. 2002;24: 589-590.[CrossRef][Medline] [Order article via Infotrieve] Stasi R, Brunetti M, Terzoli E, Amadori S. Sustained response to recombinant human erythropoietin and intermittent all-trans retinoic acid in patients with myelodysplastic syndromes. Blood. 2002;99: 1578-1584.[Abstract/Free Full Text] Cheson BD, Bennett JM, Kantarjian H, et al. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood. 2000;96: 3671-3674.[Abstract/Free Full Text] Raza A, Meyer P, Dutt D, et al. Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes. Blood. 2001;98: 958-965.[Abstract/Free Full Text] Ferrara FF, Fazi F, Bianchini A, et al. Histone deacetylase-targeted treatment restores retinoic acid signaling and differentiation in acute myeloid leukemia. Cancer Res. 2001;61: 2-7.[Abstract/Free Full Text] Gore SD, Weng LJ, Zhai S, et al. Impact of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia. Clin Cancer Res. 2001;7: 2330-2339.[Abstract/Free Full Text] Gore SD, Weng LJ, Figg WD, et al. Impact of prolonged infusions of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia. Clin Cancer Res. 2002;8: 963-970.[Abstract/Free Full Text] Yang H, Hoshino K, Canalli AA, et al. Preclinical studies of the combination of the hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) and the histone deacetylase inhibitor (HDI) valproic acid (VPA) in leucemic cell systems [abstract]. Blood. 2003;102: 622a. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. M. Prince, M. J. Bishton, and S. J. Harrison Clinical Studies of Histone Deacetylase Inhibitors Clin. Cancer Res., June 15, 2009; 15(12): 3958 - 3969. [Abstract] [Full Text] [PDF] L. Stimson, V. Wood, O. Khan, S. Fotheringham, and N. B. La Thangue HDAC inhibitor-based therapies and haematological malignancy Ann. Onc., June 10, 2009; (2009) mdn792v1. [Abstract] [Full Text] [PDF] M. Dokmanovic, C. Clarke, and P. A. Marks Histone Deacetylase Inhibitors: Overview and Perspectives Mol. Cancer Res., October 1, 2007; 5(10): 981 - 989. [Abstract] [Full Text] [PDF] A. O. Soriano, H. Yang, S. Faderl, Z. Estrov, F. Giles, F. Ravandi, J. Cortes, W. G. Wierda, S. Ouzounian, A. Quezada, et al. Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome Blood, October 1, 2007; 110(7): 2302 - 2308. [Abstract] [Full Text] [PDF] W. Blum, R. B. Klisovic, B. Hackanson, Z. Liu, S. Liu, H. Devine, T. Vukosavljevic, L. Huynh, G. Lozanski, C. Kefauver, et al. Phase I Study of Decitabine Alone or in Combination With Valproic Acid in Acute Myeloid Leukemia J. Clin. Oncol., September 1, 2007; 25(25): 3884 - 3891. [Abstract] [Full Text] [PDF] T. Siitonen, T. Timonen, E. Juvonen, V. Terava, A. Kutila, T. Honkanen, M. Mikkola, H. Hallman, M. Kauppila, P. Nylanden, et al. Valproic acid combined with 13-cis retinoic acid and 1,25-dihydroxyvitamin D3 in the treatment of patients with myelodysplastic syndromes Haematologica, August 1, 2007; 92(8): 1119 - 1122. [Abstract] [Full Text] [PDF] I. Gojo, A. Jiemjit, J. B. Trepel, A. Sparreboom, W. D. Figg, S. Rollins, M. L. Tidwell, J. Greer, E. J. Chung, M.-J. Lee, et al. Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias Blood, April 1, 2007; 109(7): 2781 - 2790. [Abstract] [Full Text] [PDF] G. Garcia-Manero Modifying the Epigenome as a Therapeutic Strategy in Myelodysplasia Hematology, January 1, 2007; 2007(1): 405 - 411. [Abstract] [Full Text] [PDF] D. Dingli and F. Michor Successful Therapy Must Eradicate Cancer Stem Cells Stem Cells, December 1, 2006; 24(12): 2603 - 2610. [Abstract] [Full Text] [PDF] G. Garcia-Manero, H. M. Kantarjian, B. Sanchez-Gonzalez, H. Yang, G. Rosner, S. Verstovsek, M. Rytting, W. G. Wierda, F. Ravandi, C. Koller, et al. Phase 1/2 study of the combination of 5-aza-2'-deoxycytidine with valproic acid in patients with leukemia Blood, November 15, 2006; 108(10): 3271 - 3279. [Abstract] [Full Text] [PDF] G. Cimino, F. Lo-Coco, S. Fenu, L. Travaglini, E. Finolezzi, M. Mancini, M. Nanni, A. Careddu, F. Fazi, F. Padula, et al. Sequential Valproic Acid/All-trans Retinoic Acid Treatment Reprograms Differentiation in Refractory and High-Risk Acute Myeloid Leukemia. Cancer Res., September 1, 2006; 66(17): 8903 - 8911. [Abstract] [Full Text] [PDF] B. Sanchez-Gonzalez, H. Yang, C. Bueso-Ramos, K. Hoshino, A. Quintas-Cardama, V. M. Richon, and G. Garcia-Manero Antileukemia activity of the combination of an anthracycline with a histone deacetylase inhibitor Blood, August 15, 2006; 108(4): 1174 - 1182. [Abstract] [Full Text] [PDF] B. D. Cheson, P. L. Greenberg, J. M. Bennett, B. Lowenberg, P. W. Wijermans, S. D. Nimer, A. Pinto, M. Beran, T. M. de Witte, R. M. Stone, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia Blood, July 15, 2006; 108(2): 419 - 425. [Abstract] [Full Text] [PDF] E. H. Estey Statistical Considerations in Trials of Targeted Therapy: Acute Myelogenous Leukemia as an Example Am. Assoc. Cancer Res. Educ. Book, April 1, 2006; 2006(1): 289 - 292. [Full Text] [PDF] D. Cai, Y. Wang, O. G. Ottmann, P. J. Barth, A. Neubauer, and A. Burchert FLT3-ITD-, but not BCR/ABL-transformed cells require concurrent Akt/mTor blockage to undergo apoptosis after histone deacetylase inhibitor treatment Blood, March 1, 2006; 107(5): 2094 - 2097. [Abstract] [Full Text] [PDF] R. L. Bevins and S. G. Zimmer It's About Time: Scheduling Alters Effect of Histone Deacetylase Inhibitors on Camptothecin-Treated Cells Cancer Res., August 1, 2005; 65(15): 6957 - 6966. [Abstract] [Full Text] [PDF] K. N. Bhalla Epigenetic and Chromatin Modifiers As Targeted Therapy of Hematologic Malignancies J. Clin. Oncol., June 10, 2005; 23(17): 3971 - 3993. [Abstract] [Full Text] [PDF] N. P. Mongan and L. J. Gudas Valproic acid, in combination with all-trans retinoic acid and 5-aza-2'-deoxycytidine, restores expression of silenced RAR{beta}2 in breast cancer cells Mol. Cancer Ther., March 1, 2005; 4(3): 477 - 486. [Abstract] [Full Text] [PDF] L. De Felice, C. Tatarelli, M. G. Mascolo, C. Gregorj, F. Agostini, R. Fiorini, V. Gelmetti, S. Pascale, F. Padula, M. T. Petrucci, et al. Histone Deacetylase Inhibitor Valproic Acid Enhances the Cytokine-Induced Expansion of Human Hematopoietic Stem Cells Cancer Res., February 15, 2005; 65(4): 1505 - 1513. [Abstract] [Full Text] [PDF] G. Singh, P. H. Driever, and J. W. Sander Cancer risk in people with epilepsy: the role of antiepileptic drugs Brain, January 1, 2005; 128(1): 7 - 17. [Abstract] [Full Text] [PDF] J. D. Licht and D. W. Sternberg The Molecular Pathology of Acute Myeloid Leukemia Hematology, January 1, 2005; 2005(1): 137 - 142. [Abstract] [Full Text] [PDF] E. Hellstrom-Lindberg Update on Supportive Care and New Therapies: Immunomodulatory Drugs, Growth Factors and Epigenetic-Acting Agents Hematology, January 1, 2005; 2005(1): 161 - 166. [Abstract] [Full Text] [PDF] This Article Abstract Full Text (PDF) All Versions of this Article: 2003-12-4333v1 104/5/1266    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kuendgen, A. Articles by Gattermann, N. Search for Related Content PubMed PubMed Citation Articles by Kuendgen, A. Articles by Gattermann, N. Related Collections Neoplasia Clinical Trials and Observations Social Bookmarking                   What's this?

	Copyright © 2004 by American Society of Hematology         Online ISSN: 1528-0020