Pitfalls of vaccinations with WT1-, Proteinase3- and MUC1-derived peptides in combination with MontanideISA51 and CpG7909

Cancer Immunology, Immunotherapy

Volumn 60, Issue 2, 2011, Pages 161-171

  Kuball, Jürgen ^a   De Boer, Karin ^a   Wagner, Eva ^d   Wattad, Mohammed ^e   Antunes, Edite ^d   Weeratna, Risini D ^b   Vicari, Alain P ^b,c   Lotz, Carina ^a   Van Dorp, Suzanne ^a   Hol, Samantha ^a   Greenberg, Philip D ^f,g   Heit, Wolfgang ^e   Davis, Heather L ^b   Theobald, Matthias ^d  

^a UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

^b PFIZER INC   (United States)

^c MERCK SERONO S A   (Switzerland)

^d JOHANNES GUTENBERG UNIVERSITY   (Germany)

^e Eye Hospital   (Germany)

^f Fred Hutchinson Cancer Research Center   (United States)

^g UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE   (United States)

Author keywords

AML; CpG; MM; T cell; Vaccination; WT1

Indexed keywords

AGATOLIMOD; CD4 ANTIGEN; CD8 ANTIGEN; EPITOPE; HLA A ANTIGEN; HLA DR ANTIGEN; INTERLEUKIN 2; MONTANIDE ISA 51; MUCIN 1; MYELOBLASTIN; TUMOR NECROSIS FACTOR ALPHA; WT1 PROTEIN;

ACUTE GRANULOCYTIC LEUKEMIA; ADJUVANT THERAPY; ADULT; ARTICLE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL EXPANSION; CLINICAL ARTICLE; CONTROLLED CLINICAL TRIAL; CYTOKINE PRODUCTION; DELAYED HYPERSENSITIVITY; DRUG SAFETY; FATIGUE; FEMALE; FEVER; HELPER CELL; HUMAN; IMMUNOGENICITY; INJECTION SITE INFLAMMATION; LYMPHOCYTE COUNT; LYMPHOCYTE DEPLETION; MALE; MULTICENTER STUDY; MULTIPLE MYELOMA; OPEN STUDY; PRIORITY JOURNAL; TREATMENT OUTCOME;

ADOLESCENT; ANTIGENS, NEOPLASM; CANCER VACCINES; CD4-POSITIVE T-LYMPHOCYTES; CD8-POSITIVE T-LYMPHOCYTES; FEMALE; HUMANS; LEUKEMIA, MYELOID, ACUTE; MALE; MANNITOL; MUCIN-1; MULTIPLE MYELOMA; MYELOBLASTIN; NEOPLASM STAGING; NEOPLASM, RESIDUAL; OLEIC ACIDS; OLIGODEOXYRIBONUCLEOTIDES; PEPTIDES; PILOT PROJECTS; TREATMENT OUTCOME; WT1 PROTEINS;

EID: 79151471698     PISSN: 03407004     EISSN: 14320851     Source Type: Journal    
DOI: 10.1007/s00262-010-0929-7     Document Type: Article

References (53)

1. J Molldrem S Dermime K Parker YZ Jiang D Mavroudis N Hensel P Fukushima AJ Barrett 1996 Targeted T-cell therapy for human leukemia: cytotoxic T lymphocytes specific for a peptide derived from proteinase 3 preferentially lyse human myeloid leukemia cells Blood 88 2450 2457 1:CAS:528:DyaK28XmtFSjtbs%3D 8839835
2. JJ Molldrem E Clave YZ Jiang D Mavroudis A Raptis N Hensel V Agarwala AJ Barrett 1997 Cytotoxic T lymphocytes specific for a nonpolymorphic proteinase 3 peptide preferentially inhibit chronic myeloid leukemia colony-forming units Blood 90 2529 2534 1:CAS:528:DyaK2sXmtlegtro%3D 9326217
3. I Bellantuono L Gao S Parry S Marley F Dazzi J Apperley JM Goldman HJ Stauss 2002 Two distinct HLA-A0201-presented epitopes of the Wilms tumor antigen 1 can function as targets for leukemia-reactive CTL Blood 100 3835 3837 1:CAS:528:DC%2BD38XoslKls7o%3D 10.1182/blood.V100.10.3835 12411326
4. J Kuball ML Dossett M Wolfl WY Ho RH Voss C Fowler PD Greenberg 2007 Facilitating matched pairing and expression of TCR chains introduced into human T cells Blood 109 2331 2338 1:CAS:528:DC%2BD2sXnslygsrk%3D 10.1182/blood-2006- 05-023069 17082316
5. M Wolfl J Kuball WY Ho H Nguyen TJ Manley M Bleakley PD Greenberg 2007 Activation-induced expression of CD137 permits detection, isolation, and expansion of the full repertoire of CD8+ T cells responding to antigen without requiring knowledge of epitope specificities Blood 110 201 210 1:CAS:528:DC%2BD2sXnsVaisLc%3D 10.1182/blood-2006-11-056168 17371945
6. Y Oka A Tsuboi T Taguchi T Osaki T Kyo H Nakajima OA Elisseeva Y Oji M Kawakami K Ikegame N Hosen S Yoshihara F Wu F Fujiki M Murakami T Masuda S Nishida T Shirakata S Nakatsuka A Sasaki K Udaka H Dohy K Aozasa S Noguchi I Kawase H Sugiyama 2004 Induction of WT1 (Wilms' tumor gene)-specific cytotoxic T lymphocytes by WT1 peptide vaccine and the resultant cancer regression Proc Natl Acad Sci USA 101 13885 13890 1:CAS:528:DC%2BD2cXotVygtbY%3D 10.1073/pnas.0405884101 15365188
7. U Keilholz A Letsch A Busse AM Asemissen S Bauer IW Blau WK Hofmann L Uharek E Thiel C Scheibenbogen 2009 A clinical and immunologic phase 2 trial of Wilms tumor gene product 1 (WT1) peptide vaccination in patients with AML and MDS Blood 113 6541 6548 1:CAS:528:DC%2BD1MXotlWrurk%3D 10.1182/blood-2009-02- 202598 19389880
8. K Rezvani AS Yong S Mielke BN Savani L Musse J Superata B Jafarpour C Boss AJ Barrett 2008 Leukemia-associated antigen-specific T-cell responses following combined PR1 and WT1 peptide vaccination in patients with myeloid malignancies Blood 111 236 242 1:CAS:528:DC%2BD1cXjtVKiug%3D%3D 10.1182/blood-2007-08-108241 17875804
9. EM Hiltbold P Ciborowski OJ Finn 1998 Naturally processed class II epitope from the tumor antigen MUC1 primes human CD4 + T cells Cancer Res 58 5066 5070 1:CAS:528:DyaK1cXnsFSmt74%3D 9823312
10. N Domenech RA Henderson OJ Finn 1995 Identification of an HLA-A11-restricted epitope from the tandem repeat domain of the epithelial tumor antigen mucin J Immunol 155 4766 4774 1:CAS:528:DyaK2MXptlejsrs%3D 7594478
11. P Brossart S Wirths G Stuhler VL Reichardt L Kanz W Brugger 2000 Induction of cytotoxic T-lymphocyte responses in vivo after vaccinations with peptide-pulsed dendritic cells Blood 96 3102 3108 1:CAS:528:DC%2BD3cXnslGnt7w%3D 11049990
12. P Brossart A Schneider P Dill T Schammann F Grunebach S Wirths L Kanz HJ Buhring W Brugger 2001 The epithelial tumor antigen MUC1 is expressed in hematological malignancies and is recognized by MUC1-specific cytotoxic T-lymphocytes Cancer Res 61 6846 6850 1:CAS:528:DC%2BD3MXntFaisbk%3D 11559560
13. JL Gulley PM Arlen KY Tsang J Yokokawa C Palena DJ Poole C Remondo V Cereda JL Jones MP Pazdur JP Higgins JW Hodge SM Steinberg H Kotz WL Dahut J Schlom 2008 Pilot study of vaccination with recombinant CEA-MUC-1-TRICOM poxviral-based vaccines in patients with metastatic carcinoma Clin Cancer Res 14 3060 3069 1:CAS:528:DC%2BD1cXmtVCmtbo%3D 10.1158/1078-0432.CCR-08-0126 18483372
14. JW Smith EB Walker BA Fox D Haley KP Wisner T Doran B Fisher L Justice W Wood J Vetto H Maecker A Dols S Meijer HM Hu P Romero WG Alvord WJ Urba 2003 Adjuvant immunization of HLA-A2-positive melanoma patients with a modified gp100 peptide induces peptide-specific CD8+ T-cell responses J Clin Oncol 21 1562 1573 1:CAS:528:DC%2BD2cXptlCksLs%3D 10.1200/JCO.2003.09.020 12697882
15. WJ van Driel ME Ressing GG Kenter RM Brandt EJ Krul AB van Rossum E Schuuring R Offringa T Bauknecht A Tamm-Hermelink PA van Dam GJ Fleuren WM Kast CJ Melief JB Trimbos 1999 Vaccination with HPV16 peptides of patients with advanced cervical carcinoma: clinical evaluation of a phase I-II trial Eur J Cancer 35 946 952 10.1016/S0959-8049(99)00048-9 10533477
16. SA Rosenberg JC Yang DJ Schwartzentruber P Hwu FM Marincola SL Topalian NP Restifo ME Dudley SL Schwarz PJ Spiess JR Wunderlich MR Parkhurst Y Kawakami CA Seipp JH Einhorn DE White 1998 Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma Nat Med 4 321 327 1:CAS:528:DyaK1cXhs1Kju7c%3D 10.1038/nm0398-321 9500606
17. DE Speiser D Lienard N Rufer V Rubio-Godoy D Rimoldi F Lejeune AM Krieg JC Cerottini P Romero 2005 Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909 J Clin Invest 115 739 746 1:CAS:528:DC%2BD2MXit1emt7o%3D 15696196
18. M Pashenkov G Goess C Wagner M Hormann T Jandl A Moser CM Britten J Smolle S Koller C Mauch I Tantcheva-Poor S Grabbe C Loquai S Esser T Franckson A Schneeberger C Haarmann AM Krieg G Stingl SN Wagner 2006 Phase II trial of a toll-like receptor 9-activating oligonucleotide in patients with metastatic melanoma J Clin Oncol 24 5716 5724 1:CAS:528:DC%2BD2sXhtVChsL8%3D 10.1200/JCO.2006.07.9129 17179105
19. D Valmori NE Souleimanian V Tosello N Bhardwaj S Adams D O'Neill A Pavlick JB Escalon CM Cruz A Angiulli F Angiulli G Mears SM Vogel L Pan AA Jungbluth EW Hoffmann R Venhaus G Ritter LJ Old M Ayyoub 2007 Vaccination with NY-ESO-1 protein and CpG in Montanide induces integrated antibody/Th1 responses and CD8 T cells through cross-priming Proc Natl Acad Sci USA 104 8947 8952 1:CAS:528:DC%2BD2sXmt1Wntb0%3D 10.1073/pnas.0703395104 17517626
20. DE Speiser P Baumgaertner V Voelter E Devevre C Barbey N Rufer P Romero 2008 Unmodified self antigen triggers human CD8 T cells with stronger tumor reactivity than altered antigen Proc Natl Acad Sci USA 105 3849 3854 1:CAS:528:DC%2BD1cXjs1Ohsrk%3D 10.1073/pnas.0800080105 18319339
21. BG Molenkamp BJ Sluijter PA van Leeuwen SJ Santegoets S Meijer PG Wijnands JB Haanen AJ van den Eertwegh RJ Scheper TD de Gruijl 2008 Local administration of PF-3512676 CpG-B instigates tumor-specific CD8+ T-cell reactivity in melanoma patients Clin Cancer Res 14 4532 4542 1:CAS:528:DC%2BD1cXosFGitLk%3D 10.1158/1078-0432.CCR-07-4711 18628468
22. C Huber N Bobek J Kuball S Thaler S Hoffarth C Huber M Theobald M Schuler 2005 Inhibitors of apoptosis confer resistance to tumour suppression by adoptively transplanted cytotoxic T-lymphocytes in vitro and in vivo Cell Death Differ 12 317 325 1:CAS:528:DC%2BD2MXitlCmsLw%3D 10.1038/sj.cdd.4401563 15678149
23. WY Ho HN Nguyen M Wolfl J Kuball PD Greenberg 2006 In vitro methods for generating CD8(+) T-cell clones for immunotherapy from the naive repertoire J Immunol Methods 310 40 52 1:CAS:528:DC%2BD28Xit1Ogsbw%3D 10.1016/j.jim.2005.11. 023 16469329
24. S Pepperl-Klindworth K Besold N Frankenberg M Farkas J Kuball M Theobald B Plachter 2006 Cytomegalovirus interleukin-10 expression in infected cells does not impair MHC class I restricted Peptide presentation on bystanding antigen-presenting cells Viral Immunol 19 92 101 1:CAS:528:DC%2BD28Xis1Grtr0%3D 10.1089/vim.2006.19.92 16553554
25. J Alexander J Fikes S Hoffman E Franke J Sacci E Appella FV Chisari LG Guidotti RW Chesnut B Livingston A Sette 1998 The optimization of helper T lymphocyte (HTL) function in vaccine development Immunol Res 18 79 92 1:CAS:528:DyaK1cXotVGgu7Y%3D 10.1007/BF02788751 9844827
26. J Alexander J Sidney S Southwood J Ruppert C Oseroff A Maewal K Snoke HM Serra RT Kubo A Sette, et al. 1994 Development of high potency universal DR-restricted helper epitopes by modification of high affinity DR-blocking peptides Immunity 1 751 761 1:CAS:528:DyaK2MXislWktL4%3D 10.1016/S1074-7613(94) 80017-0 7895164
27. BD Cheson JM Bennett KJ Kopecky T Buchner CL Willman EH Estey CA Schiffer H Doehner MS Tallman TA Lister F Lo-Coco R Willemze A Biondi W Hiddemann RA Larson B Lowenberg MA Sanz DR Head R Ohno CD Bloomfield 2003 Revised recommendations of the international working group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia J Clin Oncol 21 4642 4649 10.1200/JCO.2003.04.036 14673054
28. J Blade D Samson D Reece J Apperley B Bjorkstrand G Gahrton M Gertz S Giralt S Jagannath D Vesole 1998 Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant Br J Haematol 102 1115 1123 1:STN:280:DyaK1cvitl2mtw%3D%3D 10.1046/j.1365-2141.1998.00930.x 9753033
29. DL Barber EJ Wherry D Masopust B Zhu JP Allison AH Sharpe GJ Freeman R Ahmed 2006 Restoring function in exhausted CD8 T cells during chronic viral infection Nature 439 682 687 1:CAS:528:DC%2BD28XhtFyktL0%3D 10.1038/nature04444 16382236
30. RM Teague BD Sather JA Sacks MZ Huang ML Dossett J Morimoto X Tan SE Sutton MP Cooke C Ohlen PD Greenberg 2006 Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors Nat Med 12 335 341 1:CAS:528:DC%2BD28XitVGnt7w%3D 10.1038/nm1359 16474399
31. EA Moseman X Liang AJ Dawson A Panoskaltsis-Mortari AM Krieg YJ Liu BR Blazar W Chen 2004 Human plasmacytoid dendritic cells activated by CpG oligodeoxynucleotides induce the generation of CD4+ CD25+ regulatory T cells J Immunol 173 4433 4442 1:CAS:528:DC%2BD2cXnslWmtr0%3D 15383574
32. AG Jarnicki H Conroy C Brereton G Donnelly D Toomey K Walsh C Sweeney O Leavy J Fletcher EC Lavelle P Dunne KH Mills 2008 Attenuating regulatory T cell induction by TLR agonists through inhibition of p38 MAPK signaling in dendritic cells enhances their efficacy as vaccine adjuvants and cancer immunotherapeutics J Immunol 180 3797 3806 1:CAS:528:DC%2BD1cXisl2js7w%3D 18322186
33. S Gnjatic NK Altorki DN Tang SM Tu V Kundra G Ritter LJ Old CJ Logothetis P Sharma 2009 NY-ESO-1 DNA vaccine induces T-cell responses that are suppressed by regulatory T cells Clin Cancer Res 15 2130 2139 1:CAS:528: DC%2BD1MXjtF2rur0%3D 10.1158/1078-0432.CCR-08-2632 19276258
34. BG Molenkamp PA van Leeuwen S Meijer BJ Sluijter PG Wijnands A Baars AJ van den Eertwegh RJ Scheper TD de Gruijl 2007 Intradermal CpG-B activates both plasmacytoid and myeloid dendritic cells in the sentinel lymph node of melanoma patients Clin Cancer Res 13 2961 2969 1:CAS:528:DC%2BD2sXlt1Krsbk%3D 10.1158/1078-0432.CCR-07-0050 17504997
35. A Dzionek Y Inagaki K Okawa J Nagafune J Rock Y Sohma G Winkels M Zysk Y Yamaguchi J Schmitz 2002 Plasmacytoid dendritic cells: from specific surface markers to specific cellular functions Hum Immunol 63 1133 1148 1:CAS:528:DC%2BD38XptlWntL8%3D 10.1016/S0198-8859(02)00752-8 12480257
36. PG Maslak T Dao LM Krug S Chanel T Korontsvit V Zakhaleva R Zhang JD Wolchok J Yuan J Pinilla-Ibarz E Berman M Weiss J Jurcic MG Frattini DA Scheinberg 2010 Vaccination with synthetic analog peptides derived from WT1 oncoprotein induces T-cell responses in patients with complete remission from acute myeloid leukemia Blood 116 171 179 1:CAS:528:DC%2BC3cXpslSmsb8%3D 10.1182/blood-2009-10-250993 20400682
37. VF Van Tendeloo CJ Van De Velde A Van Driessche N Cools S Anguille K Ladell E Gostick K Vermeulen K Pieters G Nijs B Stein EL Smits WA Schroyens AP Gadisseur I Vrelust PG Jorens H Goossens I de Vries DA Price Y Oji Y Oka H Sugiyama ZN Berneman 2010 Induction of complete and molecular remissions in acute myeloid leukemia by Wilms' tumor 1 antigen-targeted dendritic cell vaccination Proc Natl Acad Sci USA 107 13824 13829 10.1073/pnas.1008051107 20631300
38. C Choi M Witzens M Bucur M Feuerer N Sommerfeldt A Trojan A Ho V Schirrmacher H Goldschmidt P Beckhove 2005 Enrichment of functional CD8 memory T cells specific for MUC1 in bone marrow of patients with multiple myeloma Blood 105 2132 2134 1:CAS:528:DC%2BD2MXitVOntrg%3D 10.1182/blood-2004-01-0366 15561890
39. TF Gajewski Y Meng C Blank I Brown A Kacha J Kline H Harlin 2006 Immune resistance orchestrated by the tumor microenvironment Immunol Rev 213 131 145 1:CAS:528:DC%2BD28XhtF2lsrbL 10.1111/j.1600-065X.2006.00442.x 16972901
40. P Aichele K Brduscha-Riem RM Zinkernagel H Hengartner H Pircher 1995 T cell priming versus T cell tolerance induced by synthetic peptides J Exp Med 182 261 266 1:CAS:528:DyaK2MXmsVCksbs%3D 10.1084/jem.182.1.261 7540654
41. RE Toes RJ Blom R Offringa WM Kast CJ Melief 1996 Enhanced tumor outgrowth after peptide vaccination. Functional deletion of tumor-specific CTL induced by peptide vaccination can lead to the inability to reject tumors J Immunol 156 3911 3918 1:CAS:528:DyaK28XivVamsLs%3D 8621930
42. L Bonifaz D Bonnyay K Mahnke M Rivera MC Nussenzweig RM Steinman 2002 Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance J Exp Med 196 1627 1638 1:CAS:528:DC%2BD38XpslWlu7o%3D 10.1084/jem.20021598 12486105
43. JK Orleans-Lindsay LD Barber HG Prentice MW Lowdell 2001 Acute myeloid leukaemia cells secrete a soluble factor that inhibits T and NK cell proliferation but not cytolytic function-implications for the adoptive immunotherapy of leukaemia Clin Exp Immunol 126 403 411 1:CAS:528: DC%2BD38XltVejtQ%3D%3D 10.1046/j.1365-2249.2001.01692.x 11737054
44. ME Chamuleau AA van de Loosdrecht CJ Hess JJ Janssen A Zevenbergen R Delwel PJ Valk B Lowenberg GJ Ossenkoppele 2008 High INDO (indoleamine 2, 3-dioxygenase) mRNA level in blasts of acute myeloid leukemic patients predicts poor clinical outcome Haematologica 93 1894 1898 1:CAS:528:DC%2BD1MXhtFyntbk%3D 10.3324/haematol.13112 19050070
45. RM Kedl WA Rees DA Hildeman B Schaefer T Mitchell J Kappler P Marrack 2000 T cells compete for access to antigen-bearing antigen-presenting cells J Exp Med 192 1105 1113 1:CAS:528:DC%2BD3cXnsVaru7c%3D 10.1084/jem.192.8.1105 11034600
46. RA Seder PA Darrah M Roederer 2008 T-cell quality in memory and protection: implications for vaccine design Nat Rev Immunol 8 247 258 1:CAS:528:DC%2BD1cXjs1antLk%3D 10.1038/nri2274 18323851
47. D Kim A Monie L He YC Tsai CF Hung TC Wu 2008 Role of IL-2 secreted by PADRE-specific CD4+ T cells in enhancing E7-specific CD8+ T-cell immune responses Gene Ther 15 677 687 1:CAS:528:DC%2BD1cXks12kt7g%3D 10.1038/sj.gt.3303102 18273057
48. AM Krieg 2007 Development of TLR9 agonists for cancer therapy J Clin Invest 117 1184 1194 1:CAS:528:DC%2BD2sXlt1OmtrY%3D 10.1172/JCI31414 17476348
49. D Karan AM Krieg DM Lubaroff 2007 Paradoxical enhancement of CD8 T cell-dependent anti-tumor protection despite reduced CD8 T cell responses with addition of a TLR9 agonist to a tumor vaccine Int J Cancer 121 1520 1528 1:CAS:528:DC%2BD2sXhtVSns7%2FJ 10.1002/ijc.22873 17565748
50. T Nicholaou LM Ebert ID Davis GA McArthur H Jackson N Dimopoulos B Tan E Maraskovsky L Miloradovic W Hopkins L Pan R Venhaus EW Hoffman W Chen J Cebon 2009 Regulatory T-cell-mediated attenuation of T-cell responses to the NY-ESO-1 ISCOMATRIX vaccine in patients with advanced malignant melanoma Clin Cancer Res 15 2166 2173 1:CAS:528:DC%2BD1MXjtF2ru70%3D 10.1158/1078-0432.CCR-08-2484 19276262
51. SY Kordasti W Ingram J Hayden D Darling L Barber B Afzali G Lombardi MW Wlodarski JP Maciejewski F Farzaneh GJ Mufti 2007 CD4+ CD25high Foxp3 + regulatory T cells in myelodysplastic syndrome (MDS) Blood 110 847 850 1:CAS:528:DC%2BD2sXos1CqsL8%3D 10.1182/blood-2007-01-067546 17412885
52. K Giannopoulos A Dmoszynska M Kowal J Rolinski E Gostick DA Price J Greiner M Rojewski S Stilgenbauer H Dohner M Schmitt 2010 Peptide vaccination elicits leukemia-associated antigen-specific cytotoxic CD8+ T-cell responses in patients with chronic lymphocytic leukemia Leukemia 24 798 805 1:CAS:528:DC%2BC3cXks1Kmu7k%3D 10.1038/leu.2010.29 20220777
53. J Greiner A Schmitt K Giannopoulos MT Rojewski M Gotz I Funk M Ringhoffer D Bunjes S Hofmann G Ritter H Dohner M Schmitt 2010 High-dose RHAMM-R3 peptide vaccination for patients with acute myeloid leukemia, myelodysplastic syndrome and multiple myeloma Haematologica 95 1191 1197 1:CAS:528:DC%2BC3cXhtlWjsLvO 10.3324/haematol.2009.014704 20081055