doi:10.1182/blood-2013-06-5061542013 122: 859-860   

 David G. Nathan Hemoglobin disorders: a look to the future

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oxygen-carrying capacity, and chronictransfusions are effective in both primarystroke prevention in children with abnormaltranscranial Doppler cerebral blood flowvelocities and secondary stroke prophylaxisfollowing overt cerebrovascular events.3 Evenas the indications for transfusions continueto expand, serious hazards of transfusionssuch as alloimmunization can create almostinsurmountable challenges for some patients.Strategies to avoid or manage this risk aredesperately needed.

Studies have demonstrated that antibodiesagainst C, E, and Kell antigens account for.50% of alloantibodies identified in patientswith SCD and that extended antigen matchingto include C, E, and Kell can decrease thedevelopment of new antibodies in thispopulation by 40% to 90%.2,4 Althoughacademic medical centers are more likely toprovide extended antigen matching,5 a recentNorth American survey indicated two-thirds ofinstitutions continue to only match for ABOand D in nonalloimmunized patients withSCD.6 There are also significant globalvariations in transfusion practices in SCD.7,8

To date, this is the largest cohort of SCDpatients who have been supported over anextended period almost exclusively with bloodcollected from self-identified African-American donors. Ethnic disparity has oftenbeen cited as the major contributor toallosensitization in SCD throughout Europeand North America, where the donorpopulation is predominantly nonblack.Diversity of the blood supply in anincreasingly global, multiethnic nation isimportant, whether planning for nationaldisasters or insuring safe and adequateresources for routine procedures.9 AfricanAmericans, in particular, continue to beunderrepresented in community blooddonation programs. Strategies to enhancematching by focused recruitment of African-American blood donors or establishingdirected donor programs for children withSCD have long been advocated as potentialsolutions to this very serious transfusion-related complication.

The incorporation of DNA-based methodsinto standard transfusion practices fordetermining RBC genotype is becoming morefeasible, particularly for polymorphic antigens inmost blood group systems.8 The Rh system,however, has been a notable exception, primarilydue to its complexities as demonstrated by Chou

et al. The wide diversity of Rh variants amongtheir patients (and presumably their donors)suggests that additional or alternate approachesmay be needed to improve matching and reducealloimmunization.

The authors identify a very relevantconcern for hematologists and for patientswith sickle cell disease. Racial differencesalone do not explain the increased propensityof patients with SCD to develop allo- andautoantibodies. Patientswith hemoglobinopathiesand most non-European ethnic groups areamong the populations that pose exceptionalchallenges in blood banking as identifiedby the 2007 National Heart, Lung, and BloodInstitute Working Group on TransfusionsEpidemiology and Recipient OutcomesResearch and in whom more research isneeded.10 The paper by Chou et al providessome very critical insights to a problem forwhich as yet there does not appear to be aneasy solution.Conflict-of-interest disclosure:The author declares

no competing financial interests. n

REFERENCES1. Chou ST, Jackson T, Vege S, Smith-Whitley K,Friedman DF, Westhoff CM. High prevalence of redblood cell alloimmunization in sickle cell disease despitetransfusion from Rh-matched minority donors. Blood.2013;122(6):1062-1071.

2. Vichinsky EP, Luban NL, Wright E, et al; StrokePrevention Trail in Sickle Cell Anemia. Prospective RBC

phenotype matching in a stroke-prevention trial in sicklecell anemia: a multicenter transfusion trial. Transfusion.2001;41(9):1086-1092.

3. Smith-Whitley K, Thompson AA. Indications andcomplications of transfusions in sickle cell disease. PediatrBlood Cancer. 2012;59(2):358-364.

4. Lasalle-Williams M, Nuss R, Le T, et al. Extended redblood cell antigen matching for transfusions in sickle celldisease: a review of a 14-year experience from a singlecenter (CME). Transfusion. 2011;51(8):1732-1739.

5. Afenyi-Annan A, Willis MS, Konrad TR, LottenbergR. Blood bank management of sickle cell patients atcomprehensive sickle cell centers. Transfusion. 2007;47(11):2089-2097.

6. Osby M, Shulman IA. Phenotype matching of donorred blood cell units for nonalloimmunized sickle celldisease patients: a survey of 1182 North Americanlaboratories. Arch Pathol Lab Med. 2005;129(2):190-193.

7. Vichinsky EP, Ohene-Frempong K, Thein SL, et al.Transfusion and chelation practices in sickle cell disease:a regional perspective. Pediatr Hematol Oncol. 2011;28(2):124-133.

8. Anstee DJ. Red cell genotyping and the future ofpretransfusion testing. Blood. 2009;114(2):248-256.

9. Kleinman S, King MR, Busch MP, et al. The NationalHeart, Lung, and Blood Institute retrovirus epidemiologydonor studies (Retrovirus Epidemiology Donor Studyand Retrovirus Epidemiology Donor Study-II): twentyyears of research to advance blood product safety andavailability. Transfus Med Rev. 2012;26(4):281-304.

10. Hillyer CD, Blumberg N, Glynn SA, Ness PM;NHLBI Working Group in Transfusion RecipientEpidemiology and Outcomes Research. Transfusionrecipient epidemiology and outcomes research:possibilities for the future. Transfusion. 2008;48(8):1530-1537.

© 2013 by The American Society of Hematology

l l l TRANSPLANTATION

Comment on Locatelli et al, page 1072

Hemoglobin disorders:a look to the future-----------------------------------------------------------------------------------------------------

David G. Nathan1,2,3 1DANA-FARBER CANCER INSTITUTE, 2BOSTON CHILDREN’S HOSPITAL, AND 3HARVARD MEDICAL SCHOOL

In this issue of Blood, Locatelli et al compare the results of histocompatible familydonor bone marrow and cord blood transplants (BMT and CBT) for severe bthalassemia (SBT) and sickle cell disease (SCD) as experienced by the Eurocordand European Blood and Marrow Transplantation group and collaborating centersin the United States, Hong Kong, and Israel between 1994 and 2005.1 Obviously,many changes in medical care and particularly MHC typing occurred over thatdecade, so this retrospective represents a moving target, but some firm points can bemade for which we are indebted to this excellent group.

In 1984, Thomas and Storb and theircolleagues reported on the first 4 patients

with SBT who were treated with

histocompatible BMT in Seattle.2 Two yearslater, Johnson and Billings and their associatesreported a successful transplant of a child

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with leukemia and SCD who was apparentlycured of both disorders,3 and Lucarelli andcolleagues reported a much larger experience ofthe treatment of SBT with histocompatiblefamily donors in their specialized unit inPesaro, Italy.4 Their results were very goodfor that time and they have considerablyimproved.5 A few years later, the Belgian groupled by Vermylen and colleagues reportedastonishingly good results, first in 12 and thenin 24 African patients with SCD.6 ThisstimulatedMarkWalters (then in Seattle) andhis coworkers to carry out a BMT trialfor SCD in the United States. The trialevoked a very thoughtful editorial by Plattand Guinan,7 who pointed out the greatdifficulty faced by families of SCD patients ifthey roll the dice in favor of histocompatiblefamily donor BMT.

The issue is highly complex. Conservativemedical care is expensive and not curative butis steadily improving for patients with SCDand BMT. Though the future course ofpatients with SBT can usually be determinedin the first year of life, patients with SCDare highly variable. Their futures cannot besecurely predicted in the first years of life.Yet it is clear that decisions to move to apotentially curative transplant should be madeearly, before the organ-damaging effects ofthe diseases increase the risk of the transplantprocedure. And the risks are significant.Though only 5% died in the Locatelli et alexperience, another 10% or more developedsevere chronic graft-versus-host disease.A surgical procedure with 5% mortalitywould receive very close scrutiny.

These dilemmas are further complicatedby the comparison of BMT and CBTattempted by Locatelli et al. The CBT groupwas much smaller in number and size andconsiderably younger. Their doses of cordblood cells were much lower; they receivedthiotepa more often and less busulfan/cyclophosphamide, antithymocyte globulin,and methotrexate. It is very difficult tocompare these groups, but the results speakfor themselves. In the hands of this group,

CBT patients did as well as one could hopefor at this time.

Can we predict the future of managementof SBT and SCD? BMT will surely be inthe therapeutic arsenal. With better typing,more closely matched donors will be found.But unless we can conquer graft rejection andthe dread chronic graft-versus-host disease,the detection of better donors will inevitablyreduce the donor pool. Whether CBT willstay in use in the long term is questionable,because the low dose of repopulating cellsin a CBT creates a very long period ofsusceptibility to infection. In contrast,encouraging BMT and even peripheral bloodtransplant results are being accumulated inseveral centers using adult haploidenticalfamily donors.8 While CBT has been a usefulstop gap, it may become unnecessary.

The key to less invasive and dangeroustreatment of SBT and SCD may lie inreplacement gene therapy or, more likely, inmanipulation of the fetal switch. Gene therapyapproaches have been proposed and actuallycarried out. Progress in that area is slow butdemonstrable. Gene-editing efforts are alsounder close study. Perhaps the most promisingidea is to suppress the fetal switch, an approachrecently reviewed by Sankaran and Orkin.9

If successful, this method of therapy wouldcure both SBT and SCD.

The clinical application of these novel ideaslies in the future, but that future seems assured.Meanwhile, safer red cell transfusions,improved orally active iron chelators, controlof infection (particularly in the newbornperiod), attacks on the inflammatory responsein SCD, and far better psychosocial supportwill produce a much better quality of life forpatients who are fortunate enough to be caredfor in resource-rich environments.

Our greatest challenge is the hard fact thatSBT and particularly SCD are scourges ofpoor countries. Can we really propose highlysophisticated and very expensive care inthose settings? Perhaps a cheap and nontoxicpill will be found that reverses the fetal switch,but that nirvana seems quite distant.

Therefore, despite our cultural and religiousdifferences, we must face the fact that thesediseases are preventable. We will soon becapable of prenatal diagnosis of the majorhemoglobin mutations from samples ofmaternal blood and can do so now routinelyfrom chorionic villous biopsy specimens.Central laboratories can be established by theWorld Health Organization to provide thedata, and local medical workers trained tounderstand the data can give the properadvice. These opportunities create difficultand contentious questions, but the task ofmodern medicine is to do the best we can forthe most we can. To meet that challenge, wewill have to consider the impact of ourresearch in a world larger than our own.Conflict-of-interest disclosure:The author declares

no competing financial interests. n

REFERENCES1. Locatelli F, Kabbara N, Ruggeri A, et al. Outcome ofpatients with hemoglobinopathies given either cord bloodor bone marrow transplantation from an HLA-identicalsibling. Blood. 2013;122(6):1072-1078.

2. Thomas ED, Buckner CD, Sanders JE, et al. Marrowtransplantation for thalassaemia. Lancet. 1982;2(8292):227-229.

3. Johnson FL, Look AT, Gockerman J, Ruggiero MR,Dalla-Pozza L, Billings FT III. Bone-marrowtransplantation in a patient with sickle-cell anemia. N EnglJ Med. 1984;311(12):780-783.

4. Lucarelli G, Polchi P, Izzi T, et al. Allogeneic marrowtransplantation for thalassemia. Exp Hematol. 1984;12(8):676-681.

5. Lucarelli G, Isgro A, Sodani P, Gaziev J. Hematopoieticstem cell transplantation in thalassemia and sickle cellanemia. Cold Spring Harb Perspect Med. 2012;2:a011825.

6. Vermylen C, Cornu G, Ferster A, Ninane J, Sariban E.Bone marrow transplantation in sickle cell disease: theBelgian experience. Bone Marrow Transplant. 1993;12(Suppl 1):116-117.

7. Platt OS, Guinan EC. Bone marrow transplantation insickle cell anemia—the dilemma of choice. N Engl J Med.1996;335(6):426-428.

8. Bolaños-Meade J, Fuchs EJ, Luznik L, Lanzkron SM,Gamper CJ, Jones RJ, Brodsky RA. HLA-haploidenticalbone marrow transplantation with posttransplantcyclophosphamide expands the donor pool for patients withsickle cell disease. Blood. 2012;120(22):4285-4291.

9. Sankaran VG, Orkin SH. The switch from fetal toadult hemoglobin. Cold Spring Harb Perspect Med. 2013;3:a011643.

© 2013 by The American Society of Hematology

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