COOLEY'S ANEMIA
`SEVENTH SYMPOSIUM
`
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`1 of 15
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`Taro Pharmaceuticals, Ltd.
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`Copyright 0 1998 by the Nen York Academy of Sciences. All rights reserwd. U11der the provi·
`sions of the United States Copyright Act of 1976, individual rt!aders of the Annals af"f! permiNed to
`makL fair 11Se of the maierial in them for teaching or Tl!search. Pem1issio11 is granted to quote from
`the Annals provided that the customary acluwwledgment is made of the source. Material m the
`Annals may be rt!pub/ished only by permission of the Academ~'. Addrt!SS inquiries to the Ext'cuth'e
`Editor aJ tht' New York Acathmy of Scrt'nces.
`Copying fees: For t'ach copy of an articlt' madt' beyond the free copying permillt'd wider Sution
`107 or 108 of the 1976 Copyright Act, a fu should bt' paid throu.11h the Copyright Clearance Center,
`222 Rosewood Drivt', Danvers, MA 01923. The fee for copying a11 article is $3.00 for nonacademic
`use; 1£.r use in the classroom, it is $().07 per page.
`~The paper used in this publication meets the minimwn Tl!Qllirtments of Americmr Nariona/
`Standard for Information Sciences-Pem1m1ence of Paper for Prinred Library Materials, ANSJ
`z.39.48-1984.
`
`CoyEJ! ART Exprrsnon of globm geMs. The fluw of geMric mformatum from the D.'IA seq..,,nu ro the final pro(cid:173)
`tein producr IJfl.'01"es sewral di$crete steps. First. the codmg strand is copied 11110 RNA b)· a proee.u c-alled tran(cid:173)
`scription. Ptoeeslflng of the RNA species mcludes 1rwdijico110ns of tlie S' en4. rr/erred to as copping, addition of
`odenoslltes on the J' en4, and splicing to remo•e i111ron uqumus. 17te final mRNA species is transported ro 1he
`cytoplasm ,.·here it is 1ronslo1ed inro protein. The a- and P·like chains assemble spontaneously to form hmwgle>(cid:173)
`bm molecvks. M utarrons that couse thala.wmua mov ur1etfere ,..,,h on) one of 1hese ma;or proee1ses, namely
`rronscnp/UJtl, proeessmg, transport. or rrons/011011. (From No11onal Heart. Lung, and Blcod lnsnrute/NIH rrport.
`Cooley's Anemia: Progress in Biology and Med1c111e · /99S) Spacecraft photograph Most of Africa and portions
`of Europe and Asia can be SCCll in thu spcctacUlar photograph l&kcn from the Apollo n spacecraft during its
`translunar coast roward the moon. Apollo II, with Astronauts Neil A. Annstrong, Mlcbael Collins. and &!v.~n E.
`Aldrin. Jr. aboard, was already 98.000 nautical miles from Earth l'hcn lhls picture was taken (councsy of NASA).
`
`Library of Congress Cataloging-lo-Publication Data
`Cuoley':. ane1nia : sevenlh :.ympo:.ium / ediu:d by Alan R . Cohen .
`p. cm. -
`(Annals of the New York Academy of Sciences, ISSN
`0077-8923 ; v. 850)
`"Seventh Cooley's Anemia Symposium . . . held in Cambridge,
`Massachusetts on May 30-June 2, 1997" - Conlents p.
`ISBN 1-57331-121-9 (cloth : alk. paper}. -
`ISBN 1-5733 1-122-7
`(paper : alk. paper)
`I. Thalassemia--Congresses. I. Cohen, Alan, 1946-
`II. Cooley's Anemia Symposium (7th : 1997 : Cambridge, Mass.)
`ill. Series.
`[DNLM: 1. beta-Thalassemia congresses. 2. Fetal Hemoglobin
`congresses. WH 170 C774 1998]
`Ql J .NS vol. 850
`[RC641.7.T5]
`500 s--dc2 1
`[6 16. 1'52]
`DNLM/DLC
`for Library of Congress
`
`98- 1779 1
`CIP
`
`CDP/PCP
`Printed in the United States of America
`ISBN 1-57331-121-9 (cloth)
`ISBN 1-57331-122-7 (paper)
`ISSN 0077-8923
`
`
`2 of 15
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`Taro Pharmaceuticals, Ltd.
`Exhibit 1027
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`ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
`
`Volume 850
`June 30, 1998
`
`COOLEY'S ANEMIA
`Seventh Symposium0
`
`Editor an.d Symposium Chairman
`ALAN R. COHE..""
`
`Organizing Committee
`ARn!UR BANK, FRANK G. GROSVELD. Guroo LUCARELLI, DAVID G. NATHAN,
`ARn!UR W. NIENHUIS. NAACY F. 0LIV1ERI, AND GEORGE STAMATOYA."INOPOULOS
`
`CONTENTS
`
`Preface. By A. R. COHEN .......................................... .xiii
`
`Thalassemia in the Next Millennium: Keynote Address.
`By D. J. WEATHERALL .......................................... I
`
`Part I. Globin Gene Expression and ReguJation
`A. Cis Control
`Developrnemal Control of£· and Y· Globin Genes.
`By G. STAMATOYANJliOPOULOS .................................... I 0
`
`The Dynamics of jl-Globin Gene Transcription. By F. F. GROSVELD, E. DE BOER,
`J. GRIBNAU, T. TRIMBORN, M. WUGERDE., and P. FRASER ................ 18
`
`j3-YAC Transgenic Mice for Studying LCR Function. By K. R. PETERSON,
`P. A. NAVAS, and G. STAMATOYANNOPOULOS ......................... 28
`
`Molecular Basis of Hereditary Persistence of Fetal Hemoglobin.
`By B. G. FORGET ............................................. 38
`
`Reduced ~ -Olobin Gene Expression in Aduh Mice Containing Deletions of
`Locus Control Region 5' HS·2 or 5' HS-3. By T. J. LEY, B. HUG.
`S. FlERING, E. EP~. M. A. BE."'lDER, and M. GROUDINE ............... 45
`
`Expression and Developmental Control of lhe Human a-Globin Gene Cluster.
`Bys. A. LO:BHAtll:J( and J. E. Russi:;LL ........•.....•.............. 54
`
`'Th.is volume is the result of a conference enulled Seventh Cooley's Anemia Symposium spon(cid:173)
`sored jointly by the New York Academy of Sciences and the Cooley's Anemia Foundation. held in
`Cambridge, Massachusetts on May 30-Junc 2, 1997.
`
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`B. Transcriptional Control
`Transcnpuonal Factors for Specific Globin Genes.
`By J. J. BIEKER ............................................... 64
`
`Silencing and Activation of Embryonic Globin Gene Expression. By G. D.
`Grl'.1>ER, R . SrNCAL.., J. A. LITT'LE, N . Oet.tPSEY, R. Fl?RRJS, and S. Z. WANO .• 70
`
`C. Pharmacologic Induction of Fetal Hemoglobin
`Hemoglobin Switching Protocols in Thalassemfa: Experience wilh Sodium
`Phenylbutyrale and Hydroxyurea. By G. J. DoVER . . . . . . . . . . . . . . . . . . . . 80
`
`Cellular and Molecular EffectS of a Pulse Butyrate Regimen and New Inducers
`of Globin Gene Expression and Hematopoiesis. By T. IKUTA. G. ATWEJi,
`V. BOOSALIS. G. L. \VHITE, S. DA FONSECA, M . BOOSALIS. 0. V. FAU..ER.
`and S. P. PERRINE ..............................••...........•. 87
`
`Elimination of Transfusions through Induction of Fetal Hemoglobin Synlhesis in
`Cooley's Anemia .. By N. F. OLIVIERI, 0 . C. REES, G. 0 . Gn-.'DER, S. L. TuEIN,
`J. S. WAYE, L. CHANG, G. M. BRJTIENHAM, and D. J. WEATHERALL ...... 100
`
`Butyrate Trials. By M . D. CAPPELLINI, G. GRAZIADEI. L. CrcERJ. A. COMINO,
`P. BIANCHI, M. POMATI, and G. FloRELU .......................... I I 0
`
`Hydroxyurea Therapy m Thalassemia. By D. LolJKOPOULOS, E. VOSKAR.IDOIJ, A.
`STA."10ULAKATOU, Y. PAPASSO'TlRIOU. v. l<ALOTYCHOU, A. LoUTRADI, G. COZMA,
`H . TSIARTA, and N. PAVLIDES ................................... 120
`
`The Role of Recombinant Human Erythroporetin in I.he Treatment of
`Thalassemia. By E. A. RACHMD..J:WITZ and M . AKER .................. 129
`
`Part II. Gene Transfer
`Improved Amphotropic Retrovirus-mediated Gene Transfer into Hematopoietic
`Stem Cells. By D. M. BootNE, C. E. DUNBAR, L. J. GIRARD, N. E. SEIDEL,
`A. P. CLINE, R. E. DoNAHIJE, and D. ORUc ........................ 139
`
`Retroviral Vectors Aimed at I.he Gene Therapy of Human ~Globin Gene Disdrders.
`By R. PAWUUK, T. BACHELOT, H. RAFroPOULOS. c. KALBERER, R. K. HUMPHRIES,
`A. BANK, and P. LEBOULCH .................................... 151
`
`Targeted Integration of a Recombinant Adeno-Associated Viral Globin Gene
`Vector into Human Chromosome 19. By 1. BERTRAN, Y.YANG, P. HARGROVE.
`E. F. VANIN, and A. W. NIENHUlS ................................ 163
`
`High-Level Transfer and Long-Tenn Expression of the Human 13-Globin Gene in a
`.178
`Mouse Transplant Model. By H. R AF'l'OPOlJl.OS, M. WARn, nnd A. RA"l)(
`
`Part m. Clinical Management of Cooley's Anemia and Its Complications
`Palhophysiology of Iron Overload. By C. HERsHKo, G. LINK, and
`r. CABM'TCHIK •...•••...•••...••••.•••••...•••..•...•..••••. 191
`
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`The Ongin of lhe Differences an IR)- and (S)-Desmcthyldesferrith1ocin : Iron
`Clearing Properties. B\ R J BERC.1:.Ro-.. J. WlEGA."\D, K. R.~n 11F·THOMPSO...,.
`• .•••••••. 202
`• • • • • . . . . . . . . • . . . .
`and W. R. WEL\IAR •
`
`Long-tenn Tnals of Deferiprone in Cooley'<, Anemia.. By N. F. Ou\ 11 RI and
`G. M. BRJTIE. ... HAM
`• • • • •
`. . . . . . . . . . . .
`• • • . • • • • • • •
`
`. .2 17
`
`A Mulu-Center Safety Trial of the Oral Iron Chelator Dcferiprone. By A. CoHE.,,
`R. GALANELLO, A PlGA, and C. VULLO ......•....•.•••.••••...•.. 223 )(
`
`,
`I
`
`Survival and Disease Complications in Thalassemia Major. B)' C. BORGNA-PtGNAm.
`S. RuGOLOTI'O, P. OE Sn+ANO. A. Pie.A, F. Dr GREGORIO, M. R. GAMBERINI,
`V. SABATO, C. Mr.uvENDI, M. D. CAPPELUJ'o.1, and G. VERLATO
`. •.•. 227
`.
`
`Nev. Approaches to the Management of Hepauus and Endocrine Disorders in
`Cooley's Anemia. By B. Wo,KE, A. V. HOFFBRAND. P. BOULOUX. C. JE..'iSE. .....
`and P. TELFER • • . • • • • . • • • • • . • • • . • . • . . • . • • . • • • • • • • • • . • • • • • • • .23 2
`
`Diagnosis and Management of Iron-induced Heart Disease in Cooley·, Anemia.
`By M. JESSUP and C S MAN'iO • • •• ................• ••..••.••••. 242
`
`Global Ep1dem1ology of Hemoglobin Disorders By M. ANGASTINIOTIS
`. . . . . . . . . . . . . . . . . • . . . . . . . . . .
`and B. MooELL . . • . . . . • . . . . . .
`
`.251
`
`Part JV. Transplantation for Tbalassemia
`Bone Marrow Transplnntntion in Thalo..~'>emia: The Experience of Pe~aro
`B_v G. LucARELLI. M. GALIMBERTI. C. G1ARDlNI. P. POl..CHJ. E. A'iGELUCCl.
`D. BARONCIA.''1, B. ERl:R. and 0 GA.ZJ.EV . . . . . . • . . . • • • . . . • • . . • . .
`
`270
`
`Current and Future Preparauve Regimens for Bone Marrow Transplantation in
`Thalassemia.. By R. STORB. c Yu. H. J DEEG, G. GEORGES. H -P. KIEM.
`P A. McSwEE.'iEY, R A NASH. B M SANDSf.AIER. K. M. Suu.1vA!'O,
`• . ... .... .276
`. . . . . . . . . . . . . . . . . .
`J L. WAG!'."ER, and M. C WALTERS
`
`Treatment of lron Overload an the "Ex-Thalasscmic'': Report from the Phlebotomy
`Program. By E. ANGl:.LUCCI, P. MliRETTO. G. LUCARELLI, M. RIPAl.TI,
`D. BAROS~B . EluR, M. GALIMBE.R11, M. M"NIBAU. c GIARDL'll.
`. • • • . •
`D. GAZIEV, S. RAPA, and P PoiCHI . . . . . . . . . . • . .
`
`288
`
`Late Effects of Bone Marrov. Tran,plantation for Tbalasscmia. By A. PICA.
`F. LoSGO, V. Vot, S. FACELl.O. R . MISIERO, and 8 . 0R.ESOW • • ... • ...• • . 294
`
`In Utt'ro Transplantauon for Thala\\Cmia. B\· A. W. f'LAxE and
`• ...•....•....•...•••••.•...•. 300
`E. D. l.ANJANI
`• • . . • • . •
`
`Unrelated and HLA-Nomdenucal Related Donor Marrow Transplantatton for
`Thalasscmia and Leukemia A Combined Report from the Seattle Marrow
`Transplant Team and the International Bone Marrow Transplant Registry.
`Bv K. M. SULLIVAN, c ANASP1Tl, M. HOROWITZ. P.A. Row1 INGS, E. w.
`f>ETERsDORF. P. J. MARTIN. R. A Curr, M. c. WALTERS, T. GOOLEY. J. S!EAAA.
`J E. A1''DERSON, J. BJERKE. M SIADl\K. M. E. D. Fl.OWC:RS, R A NASH. J E.
`..•...••.. 312
`SANDERS, F. R. APPELBAUM. R. STORB, and J. A. HASSIN
`
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`Part V. T balassemia lotermedia
`Relationship between Genotype and Phenotype: ThaJassemia Intennedia.
`By R. GM.ANELLO and A. CAO ......................... . ........ 325
`
`The Hemoglobin E Syndromes. By D. C. REES, L. STYLES, E. P. VJCHINSKY,
`J. B . CLEGG, and D. J. WE.ATHERAU.. .............................. 334
`
`The Morbidity of Bone Disease in Thalassemia. By E. P. VICHINSKY .......... 344
`
`Pa rt VI. Psychosocial Aspects of Th alassemia
`The Psychosocial Impact of Chronic Disease. By C. PoLms ................ 349
`
`Psychosocial Integration of Adolescents and Young Adults with Thalassemia
`Major. By A. DI PALMA, c. VULLO. B. ZANI, and A. FACCHINI .......... 355
`
`Future Orientation and Life Expectations of Adolescents and Young Adults with
`Thalassemia Major. Bys. BUSH, F. s. MANDEL, and P.-J. GIARDINA ...... 361
`
`Patient Psychosocial Perspectives. By G. POTENZA and R. CAZZ£1TA .......... 370
`+
`Summary of the Seventh Cooley's Anemia Symposium. By D. G. NAlliAN ..... 374
`
`Molecula r Biology
`
`Poster P resentations
`
`5' HS 1 and the Distal 13-Globin Promoter Functionally Interact in Single Copy
`j3-Globin Transgenic Mice. By P. PASCERI, D. PANNELL, x. Wu,
`and J. ELus ............................................... 377
`
`An m Vitro Model of Human Erythropoiesis for the Study of
`Hemoglobinopathies. By P. MAux, L. W. BARSKY, and T. C. FlsHER ..... 382
`
`Full Developmental Silencing of the Embryonic ~-Globm Gene Reflects
`Instability of Its mRNA. By J.E. RUSSELL, A. E. LU,
`and S. A. LIEBHABER .....••.. .. •.......•••.........•.••..••.• 386
`
`Red Blood Cells
`
`RBC Adhesion to Cremaster Endothelium in Mice with Abnormal Hemoglobin
`Is Increased by Topical Endotoxin. By X-W. Liu, S.S. PlERANGEU, J. BARKER,
`T. M. W1CK, and L. L. Hsu .................................... 391
`
`Enhancement by Ubiquitin Aldehyde of Proteolysis of Hemoglobin a-Subunits
`in J'S-Thalassemic Hemolysates. By J. R. SHA.£FFER and R. E. COHEN ..... 394
`
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`Genotype/Phenotype. Screening, and Diagnostic Considerations
`
`An a-2 Globin Gene Initiation Codon Mutation in a Vietnamese Patient with
`Hb H Disea~e. By F. KuTLAR, T. V. ADAMKffiWlCZ. R. B. MARKOWITZ,
`L. HOLI..EY, and A. KUTI.AR .................................... 398
`
`The Montreal Thalassemia Screening Program: Response of the High School
`Students. By A. CAPUA ........................................ 401
`
`Spectrum of 13-Thalassemia Mutations in Oman. By S. DAAR, H. M. HUSSEIN,
`T. MERGHOUB, and R. KR1SHNAMOOIUHY .... ... ...... . ............ 404
`
`Molecular Basis of 13-Thalassernia in Bahrain: An Epicenter for a Middle East
`Specific Mutation. By N. JASSIM, T. MERGHOUB, o. PASCAUD,
`H. AL MUJGIARRAQ, R. DUCROCQ. D. LABIE., J. ELION. R. KR1SHNAMOORTHY,
`and s. AL ARRAYED .......................................... 407
`
`Hemoglobin Elj3 Thalassemia: The Canadian Experience. By M. FoULAm,
`M. L. MACMIU.AN, E. NISBET-BROW"!, N. KLEIN, J. BARLAS, J. S. WAYE,
`and N. F. OLIVIERI ........................................... 410
`
`a- And 13-Thalassernia in Thailand. Bys. F'cCHAROEN, P. WINICHAGOON,
`N. SIRITANARATKUL. J. CHOWTHAWORN, and P. POOTRAKUL ............ .412
`
`Homozygous Hemoglobin Constant Spring with Normal Electrophoresis:
`A Possible Cause for Under Diagnosis. By L. KRISHNAMURTI
`nnd J. A. LnTLE ............................................ .415
`
`Audit of Prenatal Diagnosis for Hemoglobin Disorders in the United Kingdom:
`The First Twenty Years. By B. MODELL, M. PETRou. M. LAYTON, L. VARNAVIDES,
`C. MOISELY, R. H. T. WARD, C. RODECK, K. NICOLAIDES, A. FITCHES,
`}('
`and J. OLD ................................................. 420
`
`Spectrum of j3-Thalassernia Mutations in Guadeloupe (French West Indies) and
`Interactions with Other Hemoglobinopathies. By M. Rot.tANA, L. KEcLARD,
`A. FROGER, C. BERCHEL, and G. MtRAULT ........................ .423
`
`a-Globin Mutations and Rearrangements in Israel: PCR-Based Analysis Reveals
`Ethnic Diversity. By D. RUND, v. 0RON-KARN1, D. FTLON,
`and A. OPPENHEIM .......................................... .426
`
`Correlation of ~-Globin ELISA with PCR for (--"""')Deletion and Clinical
`Diagnosis for a-Thal-I Trait. By R. A. SrMKINS, K.-A. THAN, B. SCHAPIRO,
`E. S. CHOI, and P. R. DAOUST ........ . ......................... .429
`
`The Diverse Molecular Basis and Mild Clinical Picture of HbH Disease in Israel.
`By H. TAMARY, G. KLINGER, L. SHAL'<ION, H. KlRSCHMANN, A. KORE.'I,
`M. BENNET, and R. ZAizov ................................... .432
`
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`Phenotypic Prediction in j3-ThaJassemia. By P. J. Ho. G. W. HALL,
`L. Y. Luo, D. J. WEATKERALL, ands. L. THEIN . . . . . . . . . . . . . . • • . . . . • .436
`
`The Impact of Asian Immigration on Thala.~semia in California.
`By F. LOREY and G. CUNNINGHA..,I ............................... 442
`
`Feta l H emoglobin
`
`Detection of Fetal Hemoglobin in Erythrocy1es by Flow Cy1ometry. By
`T. A. CAMPBELL, R. E. WARE, and M. MASON ...................... 446
`
`Hydroxyurea and Hemin Affec1 Both the Transcriptional and Pos1-Transcriptional
`Mechanisms of Some Globin Genes in Human Adul1 Erythroid Cells.
`By P. KOLLIA, E. FtBACH, M. POUTOU. C. T. NOGUCHJ, A. N. SCHECHTER,
`. ....................... 449
`and D. LouKOPOULOs
`. . . . . . . . . . . . . . .
`
`Treatment of Two Infants with Cooley's Anemia with Sodium Phenylbutyrate.
`By M. L. MACMlll.AN, M. FOULADI, E. NISBET-BROV.'N. J. S. WAYE, and
`N. F. OLIVIERI .............................................. 452
`
`Erythropoietin Level and Effect of rHuEPO in 13-Thalassemic Mice. By R. A. POPP,
`S. G. SHTNPOCK, D. M. POPP, G. K. CLEMONS. and 0. B. VAJ-1 WYCK .... .455
`
`Increase in Hemoglobin Concentration during Therapy with Hydroxyurea in
`Cooley's Anemia. By B. R. SAXON. J. S. WAYE. and N. F. OuvlERJ ...... 459
`
`Preliminary Repon: Hydroxyurea Produces Significant Clinical Response in
`Thalassemia lntermedia. By L. STYLES. B. LE\\-1S, D. Foore, L. CUDA,
`and E. VtCHINSKY ............................................ 461
`
`C linical Issues
`
`Iron Overload and Antioxidant Status in Patients with f3-Thalassemia Major.
`By K. RELLER, B. DRESOW, M. COLL.ELL, R. FISCHER, R. E.'llGELHARDT, P. NIELSEN.
`M. DO'RKEN, C. POLITIS, and A. PlGA ............................. 463
`
`Effect of Iron Chelator LI on Iron Absorption in Man. B> B. DRESOW, R. FISCHER,
`P. NIELSEN, E. E. GABBE, and A. PlGA ............................ 466
`
`Survival and Morbidiry in Transfusion-dependent Thalassemic Patients on
`Subcutaneous Desferrioxamine Chelation: Nearly Two Decades of
`Experience. By E. M. CAU...EJA, J. Y. CHEN, M. LEssER, R. W. GRADY,
`M. I. NEW, and P. J. GIARDINA .................................. 469
`
`Regulation of Glucose Disturbances with Glibenclarnide in Patients with
`Thalassemia. By v. LAOIS, c. THEOOORJDES. F. PALAMIOOU, s. FRISS£RAS.
`H. BEROOUSl, and C. KATTAMJS ................................. 471
`
`Bone Metabolism in Thalassemia. By F. GAROFALO. A. PlGA, R. LALA. S. CHIABOTI"O,
`M. Dr STEFANO, and G. c. lSAJA ................................. 475
`
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`Selective Loss of Anterior Pituitary Volume with Severe Pituitary-Gonadal
`Insufficiency in Poorly Compliant Male Thalassemic Patients with
`Pubertal Arrest. By R. CHAITERJEE, M. KATZ, A. 0AnUoGE. G. M. BYDDER,
`and J.B. PORTER ........................................... .479
`
`A Trial to Investigate the Relationship between DFO Phannacokinecics and
`Metabolism and DFO-Related Toxicity. By J. B. PORTER
`and A. FAHERTY ............................................. 483
`...
`Deferoxamine Stability in lntravcnous Solution. By C. ROSE, C. CAMB~,
`G. FORZY, M. MAHtE.u, P. F'ENAux, and F. BAl!TERS ............. . .... 488
`
`Nontransfusional Iron Overload in Thalassemia: Association with Hereditary
`Hemochromatosis. By D. C. REEs. B. M. SINGH, L. Y. Luo,
`S. WICKRAMASlNGHE, and S. L. THEIN .......................•.... 490
`
`Stem Cell Tra nsplantation
`
`Mixed Chimerism after Bone Marrow Transplantation in Tha.lassemia. By
`S. NESCI. M. MANNA, G. LUCARELLI, P. TONUCCI, M. 0oNATI, 0. B~. F.
`AGOSTINELLI, and M. ANDREANI ..............................•.. 495
`
`Bone Marrow Transplantation for Homozygous 13-Thalassemia-The Memorial
`Sloan-Keuering Cancer Center Experience. By F. BoULAo, P. GIARDINA,
`A. GIU.IO, N. KERNAN, T. SMALL, J. BROCHSTEIN, K. VANSYCKLE, 0.
`GEORGE, P. SZABOLCS, and R. J. O'REILLY ......................... 498
`
`Booe Marrow Transplan1ation in Thalassemia: A Role for Radiation? By Y. S. LEE,
`K. M. KRtsTOVJCH, J. M. DucoRE, E. VtcHINSKY, V. L. CROUSE, B. E. GLADER,
`and M. 0. AMYL.ON .......................................... 503
`
`Psychosocial Issues and Health Care Delivery
`
`Patient-Oriented Research Facilitated through the Establishment of the Nurses
`Network for Cooley's Anemia (CANNA). By S. M. CARSON
`and L. QUILL ............................................... 506 X
`
`The Social Impact of Migration on Disease: Cooley's Anemia, Thalassemia, and
`New Asian Immigrants. By N. HEER, J. CHOY, and E. P. VtCHINSKY ...... 509
`
`The Psychosocial Burden of Cooley's Anemia in Affected Children and Their
`Parents. By N. KLEIN, A. SEN, J. RUSBY, s. RATIP, B. MODELL,
`and N. F. OuvtERJ ........................................... 5 12
`
`Outreach Strategies for Asian Pacific Island Communities. By J. CHov,
`R. C. YAMASHITA, 0. FOOTE, N. HEER. and E. P. V1CHJNSKY ............ 514 ><..
`
`Approaches co Working with Adult Thalassemia Patients in Pediaaic Settings.
`By L. WEISSMAN, M. TREADWELL, 0. FOOTE, N. HEER, and
`E. P. v ICHINSKY ............................................. 516
`
`
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`From a Distance: Using Information Technologies to Overcome Geographic
`Boundaries in Thalassenua Service Delivery. By R. C. YAMASHITA,
`K. QUIROLO, J. CHOY, and D. Foore ............................. .518
`
`Patient Cultures: Thalassem1a Service Delivery and Patient Compliance.
`By R . c. YAMASHITA, D. FOO'l"E, and L. WEISSMAN •••••••••••••••..•• 521
`
`Index of Conuibutors ............................................. 523
`
`Financial assistance was received from:
`
`Major Fwulers
`
`• NATIONAL HEART, LUNG, AND BLOOD INSTITUTE/NIH
`• NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY
`DISEASES/NIH
`
`Contributor
`
`• APOTEX RESEARCH, INC.
`• NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN
`DEVELOPMENT/NIH
`
`The New York Academy of Sciences believes it has a responsibility to provide
`an open forum for discussion of scientific questions. The positions taken by the
`participanlS in the reponcd conferences are their own and not necessarily those
`of the Academy. The Academy has no intent to influence legislation by provid(cid:173)
`ing such forums.
`
`
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`Survival and Disease Complications in
`Thalassemia Major
`
`CATERINA BORGNA-PIGNATTI,a,b SIMONE RUGOLOTTO,c PIERO
`DE STEFANO,d ANTONIO PIGA,e FELICIA DI GREGORIO,f
`MARIA RITA GAMBERINI,g VINCENZO SABATO,h CATERINA
`MELEVENDI,i MARIA DOMENICA CAPPELLINI,j AND
`GIUSEPPE VERLATOk
`bDepartment of Clinical and Experimental Medicine, University
`of Ferrara
`cDepartment of Pediatrics, University of Verona
`eDepartment of Pediatrics, IRCCS “San Matteo,” Pavia
`eDepartment of Pediatrics, University of Turin
`fDepartment of Pediatrics, University of Catania
`gAnnunziata Di Palma, Division of Pediatrics, Ospedale Sant’Anna;
`hDepartment of Pediatrics, University of Bari
`iDivision of Pediatrics, Ospedale Galliera, Genova
`jDepartment of Internal Medicine, University of Milan
`kInstitute of Medical Statistics, University of Verona
`
`ABSTRACT: We studied survival and disease complications in 1,146 patients with tha-
`lassemia major, born from January 1, 1960 to December 31, 1987. At last follow-up,
`in March 1997, probability of survival to age 20 years was 89% and to age 25 years
`was 82% for patients born in the years 1970–1974. Patients who died had a serum
`ferritin level, measured the year before death, significantly higher than those who
`survived. Diabetes was present in 5.4% of the patients; heart failure in 6.4%;
`arrhythmias in 5.0%, thrombosis in 1.1%, hypothyroidism in 11.6%, HIV infection
`in 1.8%. Hypogonadism was diagnosed in 55% of 578 patients who had reached
`pubertal age: 83.5% of hypogonadic females and 78.6% of males were receiving sub-
`stitutive hormonal therapy. In conclusion, the survival of patients with thalassemia
`major is good and improving, but the prevalence of severe complications is still high.
`
`Organ damage and early death used to be inevitable consequences of thalassemia major.
`
`The prognosis of the disease, however, has been improved by regular transfusions and
`iron chelation.
`In the last 14 years, as a part of a cooperative study, we followed a large number of
`patients with thalassemia major treated at seven Italian hospitals, and we confirmed that
`the survival of transfusion-dependent patients has been steadily and significantly increas-
`ing.1 Unfortunately, the prevalence of complications due to iron overload is still high.
`
`aAddress for correspondence: C. Borgna-Pignatti, Department of Clinical and Experimental
`Medicine, Pediatrics, University of Ferrara, Via Savonarola 9, 44100 Ferrara, Italy. Fax: 39-532-202
`103; E-mail: bre@dns.unife.it
`
`227
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`228
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`ANNALS NEW YORK ACADEMY OF SCIENCES
`
`PATIENTS AND METHODS
`
`Seven Italian teaching hospitals contributed their patients with thalassemia major to
`this study. Inclusion criteria required that the patients be born after January 1, 1960 and be
`alive at the time since when, at each center, clinical records were complete and reliable.
`The first data collection took place in 1983. Latest follow-up was March 1997.
`The patients notified by the participating centers were 1,146 (614 males and 532
`females). The distribution by calendar period of birth is shown in FIGURE 1.
`The Kaplan-Meier method2 and log-rank test3 were used to estimate and compare sur-
`vival and appearance of complications. Since, for older patients, no information could be
`drawn on mortality in the first decade of life, overall survival was evaluated only for
`patients born in or after 1970, while survival after the first decade of life was evaluated for
`all patients. In addition we collected, by means of specially prepared forms, data on com-
`plications potentially affecting the quality of life of the patients. Complications considered
`were: insulin-dependent diabetes, hypothyroidism requiring substitutive therapy, throm-
`bosis, heart failure or arrhythmias requiring therapy, absence of signs of puberty at age 15
`years for females and at age 17 for males, and HIV positivity. Mean yearly serum ferritin
`was available for the years 1991–1996. Since it was not normally distributed, a prelimi-
`nary logarithmic transformation was required for subsequent analysis. Comparison of fer-
`ritin levels between groups was performed by Student’s t test.
`
`RESULTS
`
`At last follow-up, 769 patients of 1,146 were alive with thalassemia, 26 had been lost
`to observation, and 248 had died. One hundred and three had undergone bone marrow
`transplantation; 13 of them had died as a consequence of the procedure. Crude death rates
`ranged from 67% for patients born before 1965 to 2.5% for those born after 1979.
`
`FIGURE 1. Distribution by cohort of birth of patients with thalassemia major who entered the study.
`
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`BORGNA-PIGNATTI et al.: SURVIVAL AND COMPLICATIONS
`
`229
`
`FIGURE 2. Probability of survival and of disease-free survival (excluding hypothyroidism and
`treated hypogonadism) of patients with thalassemia major born in 1970–1987.
`
`Survival and complications appearance were evaluated for the whole population born
`after 1970 (FIG. 2) and for the birth cohorts 1970–1974, 1975–1979, 1980–1984, and
`1985–1987. The probability of survival at different ages are presented in TABLE 1.
`The serum ferritin level of the year before death was, for patients who died between
`1991 and 1996, significantly higher than for patients who survived (3,314 ± 2,468 versus
`2,002 ± 1,455, p < 0.001).
`When data for males and females were analyzed separately, we found that females have
`a significantly better survival than males, both for the whole group born between
`1960–1974 ( p = 0.0242) and for the older patients (1960–1969) alone ( p = 0.039).
`Heart disease was the most frequent cause of death, being directly responsible for the
`death of 71% of the patients. Infection directly caused the death of 12% of the patients.
`Liver disease represented the third most frequent cause of death being directly responsible
`for the death of 6% of them. Other causes of death are reported in TABLE 2.
`The risk of developing complications was evaluated only for patients born after 1970
`(718). The prevalence of heart failure at age 15 was found to have decreased from 5% in
`patients from the cohort 1970–1974 to 2% in patients born in 1980–1984. Corresponding
`values for diabetes are 2.6% and zero. On the contrary, hypothyroidism is apparently
`becoming more frequent, being present, at age 15 years, in 4.8% of the patients born
`between 1970 and 1974, but in 8% of those born between 1980 and 1984. Overall, diabetes
`was present in 5.4%, heart failure 6.4%, arrhythmias 5.0%, thrombosis 1.1%, hypothy-
`roidism 11.6%, and HIV infection 1.8%. Hypogonadism was diagnosed in 55% of 578
`patients who had reached pubertal age: 83.5% of hypogonadic females and 78.6% of males
`were receiving substitutive hormonal therapy.
`
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`ANNALS NEW YORK ACADEMY OF SCIENCES
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`TABLE 1. Survival by Birth Cohort at Different Ages of Patients with Transfusion-
`Dependent Thalassemia
`Age (years)
`
`1980–1984
`
`1970–1974
`
`1975–1979
`
`10
`15
`20
`25
`
`98% (96–99)
`95% (92–97)
`89% (85–92)
`82% (77–86)
`
`98% (96–99)
`97% (94–98)
`96% (93–98)
`
`99% (95–100)
`98% (93–100)
`
`DISCUSSION
`
`In the last three decades, the treatment of thalassemia major has changed in many ways.
`Administration of deferoxamine by the intramuscular route became available to the major-
`ity of Italian patients in 1975, while regular subcutaneous infusion was started between
`1979 and 1981. In the same years the transfusion regimen evolved from correction of
`symptomatic anemia to the so-called hypertransfusion or supertransfusion regimens,
`aimed at maintaining a minimum hemoglobin level from 9–10 g/dl to above 12 g/dl. The
`impression that the supertransfusion regimen had increased the iron overload and its con-
`sequences has recently induced most centers to return to hypertransfusion. In addition, the
`early detection of complications has been actively pursued and their aggressive treatment
`has become the rule. A major pivotal point in the history of thalassemia treatment has been
`the introduction in 1981 of bone marrow transplantation from an HLA-identical sibling.4
`This progress has made information about survival and complications with conventional
`therapy particularly important.
`Not many data have been reported so far on survival of transfusion-dependent patients
`with thalassemia. Economidou reported in 19825 that at age 28 only 24% of Greek patients
`with thalassemia major and intermedia were alive. In 1982, Modell and coworkers6 found
`that the probability of reaching age 25 years was 25%. There is convincing evidence from
`several reports that iron chelation improves organ function,7–9 and that it is capable of pre-
`venting the development of cardiac disease.10 More recently, Brittenham and coworkers
`observed that the risk of dying and of developing diabetes and cardiac disease were
`decreased by the early use of deferoxamine.11 Data from Olivieri and coworkers, who studied
`97 patients born before 1976, demonstrate that after 15 years of chelation therapy, the
`probability of being free from cardiac disease is 91%, provided that less than one third of
`serum ferritin values exceeded 2,500 ng/ml.12 In our study we found that serum ferritin,
`and therefore, presumably, the iron burden, was higher in patients who died than in
`patients who survive.
`
`TABLE 2. Causes of Death Reported in Patients with Thalassemia, Born between 1960
`and 1984
`Cardiac causes
`Liver
`Endocrine
`Infections
`Thrombosis
`Anemia
`Tumors
`Unknown
`Other
`
`71%
`6%
`3%
`12%
`1%
`1%
`3%
`1%
`2%
`
`171
`15
`6
`28
`3
`2
`7
`3
`5
`
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`BORGNA-PIGNATTI et al.: SURVIVAL AND COMPLICATIONS
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`231
`
`We reported in 1989 the fatality rate and the causes of death in a group of patients with
`thalassemia major born since 1960.1 A remarkable improvement in life expectancy was
`observed when different birth cohorts were compared. This improvement was mainly due
`to the decrease in mortality for cardiac causes. Conversely, mortality due to causes other
`than heart disease had not decreased. The results have not changed at subsequent follow-
`ups. At the latest data collection the difference in survival between cohorts is still striking
`(TABLE 1). Moreover, the study of complications has confirmed that patients born in more
`recent years have a lower risk of developing heart disease, diabetes and hypogonadism,
`than patients born earlier. The trend is not so clear for hypothyroidism, which, in the past,
`was probably underdiagnosed.
`With modern therapy, complications and death should be unusual in the first ten years
`of life. This expectation is confirmed by our data. Only four patients out of 283 from the
`cohort 1970–1974, and none from the subsequent cohorts, have developed heart failure in
`the first decade of life. However, diabetes developed in the first decade of life in two chil-
`dren from the cohort 1975–1979.
`In conclus