SECTION XXIII: NON-MALIGNANT DISORDERS

Hematopoietic Cell Transplantation for Nonmalignant Disorders Jakub Tolar,1 Parinda A. Mehta,2 Mark C. Walters3

Hereditary disorders that trace their origin to the hematopoietic stem cell have been targeted for allogeneic therapy and were among the first human diseases cured by successful hematopoietic cell transplantation (HCT). More recently, the possibility of treating nonhematopoietic hereditary disorders in which engraft- ment of hematopoietic cells might ameliorate tissue damage in target organs has also been investigated with encouraging results. As in the malignant hematological disorders, transplantation results have improved over the past 3 decades as a consequence of more refined donor selection and patient risk stratification with modifications to the conditioning regimen. The application of these principles is described in this update about HCT for hereditary marrow failure syndromes and hemoglobin disorders. In addition, a novel indica- tion of HCT for epidermolysis bullosa is presented. Together, these representative disorders illustrate the potential for an expanding role of HCT for nonmalignant disorders. Biol Blood Marrow Transplant 18: S166-S171 (2012) Ó 2012 Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation

HEMATOGENOUS CELLS FOR process that integrates the skin cells, skin extracellular EXTRACELLULAR MATRIX DEFICIENCY matrix, and systemic factors—mainly blood cells and EPIDERMOLYSIS BULLOSA cytokines—into dynamic tissue healing. Keratinocytes and dermal fibroblasts express adhesive proteins that One of the most fascinating and daunting chal- ensure the epidermis remains attached to the skin base- lenges of current transplantation biology is to harness ment membrane and to the papillary dermis. Congen- the potential of stem cells for tissue regeneration. ital deficiency of any of at least 15 such proteins results Adoptive transfer of hematopoietic stem cells can, of in a blistering condition called epidermolysis bullosa course, regenerate the lymphohematopoietic system (EB) [1]. Of the multiple forms of EB, the severest are: in the recipients of hematopoietic cell transplantation (HCT), but only recently have we and others obtained  recessive dystrophic EB (RDEB) caused by mutations evidence that bone marrow and cord blood transplan- in the collagen type VII (C7) gene (COL7A1), and tation can mediate tissue repair in the largest extrame-  junctional EB (JEB) caused by loss-of-function dullary organ—the skin. mutations in one of the three genes (LAMA3, The skin is constantly exposed to environmental in- LAMB3, and LAMC2) that encode one of three chains sults and requires effective repair tools to maintain its in the heterotrimeric protein laminin 332 (L332). protective function. Skin repair is a highly organized C7 and L332 deficiencies result in severe scarring, contractures, and, ultimately, shortened survival— most often because of infections and aggressive squa- From the 1Blood and Marrow Transplantation, University of 2 mous cell carcinoma. Even though suffering is difficult Minnesota Medical School, Minneapolis, Minnesota; Division of Bone Marrow Transplantation and Immune Deficiency, to measure objectively, the painful challenges that Cincinnati Children’s Hospital Medical Center, Cincinnati, individuals with EB endure are extraordinary. EB skin Ohio; and 3Jordan Family Director, Blood and Marrow Trans- can blister with a touch, and the resulting wounds heal plantation Program, Children’s Hospital & Research Center, with mutilating scarring. Their upper alimentary tract Oakland, California. can blister just as easily. Esophageal strictures develop Financial disclosure: See Acknowledgments on page S171. Correspondence and reprint requests: Mark C. Walters, MD, Jordan with aberrant tissue repair, and eating is painful. People Family Director, Blood and Marrow Transplantation Program, with EB are separated from many interactions with their Children’s Hospital & Research Center, Oakland, 747 52nd peers, as most common daily activities are impossible Street, Oakland, CA 94609 (e-mail: [email protected]). Ó for them. Every moment and aspect of their lives is con- 2012 Published by Elsevier Inc. on behalf of American Society for sumed by this debilitating genodermatosis [2]. Blood and Marrow Transplantation 1083-8791/$36.00 Remarkably, stem cell transplantation can amelio- doi:10.1016/j.bbmt.2011.10.023 rate the deficiency of this skin-specific structural

S166 Biol Blood Marrow Transplant 18:S166-S171, 2012 HCT for Nonmalignant Disorders S167 protein in an animal model of RDEB [3]. We found nate the early stages of aberrant skin formation in that donor cells at the dermal-epidermal junction pro- development and, in principle, provide an inex- duced C7 in the skin of the RDEB mice. Strikingly, haustible supply of EB patient-specific stem cells paw blisters healed and rudimentary homotrimers of that can be useful for future stem cell gene therapy C7, termed anchoring fibrils, were formed [4]. These strategies [10]. data were supported by the research of others, who Clinical trials in EB illustrate that: demonstrated the positive effect of in utero infusion of bone marrow cells in RDEB and postnatal infusions 1. Translation of laboratory observations in relevant in JEB [5,6]. animal models to a clinically meaningful intervention Based on these proof-of-concept studies in murine is possible within a short period of time (\2 years). models that show the replacement of missing C7 and 2. Further modifications in the use of stem cell trans- skin repair, a first in-human study was initiated in plantation as a durable source of extracellular ma- 2007. After this clinical trial of allogeneic HCT in trix proteins may make this regenerative medicine seven children with RDEB had shown that C7 can in- approach effective in other cutaneous and extra- crease and ameliorate many of the disease manifesta- cutaneous conditions. tions [7], we hypothesized that children with JEB 3. Only by performing the laboratory and clinical ex- could respond favorably to allogeneic transplantation perimentation that contributed to achievement of as well, and that both groups could benefit from coin- the original objectives do we learn about the nature fusion of hematopoietic and mesenchymal stem cells of ‘‘the growing frontier.’’ Thus, only in the context (MSCs) from allogeneic marrow. of new data do previously unanticipated questions To investigate this, we treated eight additional emerge, both biologic, for example, how robust children with RDEB and two children with JEB using must hematogenous engraftment be to significantly allogeneic cotransplantation of hematopoietic and contribute to skin repair?; and ethical, for example, MSCs. Altogether, 17 patients have been treated, how much preliminary data are enough to substan- with survival in 13 and clinical amelioration of the dis- tiate clinical trials in infants with severe phenotype ease in 11. Healthy donor cells from the hematopoietic versus adults with a mild form of the same disease? graft migrated to the injured skin. Simultaneously, In summary, significant biochemical and quality- there has been an increase in the production of C7 of-life benefits can be derived from allogeneic hemato- and L332 and increased skin integrity with reduced poietic and mesenchymal cell transplantation for tendency to blister formation. The results of these tri- RDEB and JEB, conditions characterized by severely als demonstrate that the infusion of allogeneic hemato- compromised wound healing because of the congenital poietic cells can result in substantial clinical benefit [8]. absence of skin structural proteins. These severe Laboratory investigations in EB show that: congenital mechanobullous disorders are unique in 1. Unique among proteins critical to skin integrity, their capacity to illuminate the mechanisms of cross- C7 function depends on extracellular polymeriza- correction of a structural protein deficiency in extracel- tion. This makes RDEB the ideal human skin lular matrix and regeneration of extramedullary tissues condition to explore, and thus illuminate, the by hematogenous cells in disease and injury states. mechanisms of cross-correction of structural pro- tein deficiency in extracellular matrix. 2. Depletion of cells with high proliferative potential HCT FOR CHROMOSOME SENSITIVITY from skin stem cell niches by hyperactive unpro- SYNDROMES ductive tissue repair in EB may facilitate high donor cell engraftment. The empty stem cell niches in EB DNA is continuously damaged by endogenous and skin that are depleted of their own stem cells by exogenous (eg, ionizing radiation) mutagens. Repair of repeated and futile attempts at skin regeneration, DNA damage (DNA double- and single-strand breaks) may serve as permissive ‘‘docking stations’’ for is a complex process carried out by an array of DNA donor cells. Such cells may, in turn, release factors repair pathways (eg, homologous recombination, non- that operate on the host or that may differentiate homologous end-joining). Defects in any of these into cells that directly participate in the wound- repair mechanisms or in telomere maintenance can healing process via release of C7, L332, or other tis- lead to chromosome instability syndromes. The chro- sue repair proteins. Simultaneously, this further mosome instability syndromes mainly manifest as con- supports the idea of EB as a unique model of skin genital bone marrow failure (BMF) syndromes (eg, tissue repair with donor regenerative cells [9]. Fanconi anemia, Shwachman-Diamond syndrome 3. The novel technology of reprogramming skin cells [SDS], dyskeratosis congenita [DC], Bloom syndrome, into pluripotent stem cells (iPSCs) by a combination and Nijmegen breakage syndrome and a variety of pri- of specific transcription factors can further illumi- mary immune deficiency disorders such as severe S168 J. Tolar et al. Biol Blood Marrow Transplant 18:S166-S171, 2012 combined immune deficiency syndromes–DNA ligase Over the last 3 decades, these regimens have been IV, Artemis, Cernunnos, etc.). modified significantly, with the goal of limiting toxicity Congenital BMF syndromes are associated with while maintaining engraftment and improving a range of congenital anomalies, impaired hematopoie- outcomes by decreasing GVHD. An additional impor- sis leading to progressive marrow failure, and cancer tant goal is to minimize the development of secondary predisposition. The typical clinical features of these dis- malignancies in these patients. Kapelushnik and orders are generally well known to practicing hematolo- colleagues [14] were the first to report use of gists, although they are sometimes overlooked in adult a fludarabine-based conditioning regimen for a child practice where they present less frequently. However, with FA in leukemic transformation. This highly immu- it is becoming increasingly apparent that patients lack- nosuppressive nucleoside analog is well tolerated by ing characteristic physical stigmata may still harbor patients with FA, as it does not cause direct DNA a congenital BMF syndrome. In addition, some patients damage and has allowed for the elimination of radiation present with clinical symptoms for the first time as an in a matched sibling donor setting with good results. adult. Sensitive and specific diagnostic tests, including Outcomes of unrelated donor (URD) HCT for FA identification of mutations in specific genes, are now have been inferior, primarily because of high risk of available for many of these disorders. This is particularly graft failure, aGVHD, and excessive regimen-related useful while evaluating patients with suspected marrow organ toxicity. Before the introduction of fludarabine failure syndrome, and it is essential for screening sibling in the FA-preparative regimen, survival for URD trans- donors,toensurethatanaffectedsiblingisnotusedas plants was approximately 30%. Three groups in the a stem cell donor. HCT remains the only potentially United States including Cincinnati Children’s Hospi- curative option for many of these disorders. However, tal, University of Minnesota, and Memorial Sloan- the inherent chemotherapy and radiation sensitivity Kettering Cancer Center have pioneered regimens makes transplantation for these disorders challenging. that include low-dose total-body irradiation (TBI), cyclophosphamide, ATG, and fludarabine followed by T cell-depleted marrow or peripheral blood stem FANCONI ANEMIA cell transplants [15-17]. All three centers have had promising results. However, with the small number Fanconi anemia (FA) is a genetic disorder character- of patients with FA who undergo allogeneic HCT, ized by congenital anomalies, progressive BMF, and results of single-center trials are difficult to interpret predisposition to malignancies. The cellular phenotype in terms of optimal cytoreductive regimens and dosing. of FA is characterized by an abnormally high level of Reported survival rates with fludarabine-containing baseline chromosomal breakage along with an in- preparative regimens range from 38% to 96%. In an creased sensitivity to DNA cross-linking or alkylating attempt to decrease late secondary malignancies and agents [11]. The earliest attempts at transplanting pa- improve immune recovery in this vulnerable popula- tients with FA (1970s and 1980s) used 50 mg/kg of cy- tion, the Minnesota group has shown that the TBI clophosphamide  4 days. These transplantations had dose can be reduced to 300 cGY. However, further re- high mortality and morbidity. This study provided the duction led to graft failure. first clinical evidence of a special sensitivity of FA cells Most recently with a similar goal, a multi- to alkylating chemotherapy agents. Such hypersensitiv- institutional study is ongoing at four centers, using ity was also observed in vitro when FA cells were a chemotherapy- only preparative regimen, containing incubated with alkylating agents. Gluckman and col- pharmacokinetically adjusted low-dose busulfan, leagues [12] were the first to investigate a markedly at- cyclophosphamide, fludarabine, and rabbit ATG. All tenuated conditioning regimen for patients with FA grafts are T cell depleted using the CliniMacs CD34 and successfully demonstrated that HCT could be columns (Miltenyi, Auburn, CA). So far, engraftment, safely performed using low-dose cyclophosphamide, early toxicity, and infection data appear to be similar to with long-term survival in 75% of patients. They also historical TBI-based protocols, with no graft failures confirmed the suspected increased radiosensitivity in after 15 of a planned 25 transplants. Overall, these the majority of patients with FA. Following these re- results appear promising, and future patients will likely sults, patients were conditioned with low-dose cyclo- not need radiation. phosphamide (20 mg/kg) in combination with 5 Gy thoracoabdominal irradiation. The addition of antithy- SDS mocyte globulin (ATG) to the Gluckman regimen was the next important milestone. The most recent of these HCT is the only known curative treatment for bone reports showed a 10-year actuarial survival rate of 89%, marrow failure associated with SDS. Similar to FA, chil- with a significant decrease in acute (23%) and chronic dren with SDS tend to have increased toxicity with (12%) graft-versus-host disease (aGVHD and intensive conditioning regimens. Various case reports/ cGVHD) in a matched sibling donor HCT setting [13]. series describe fatal congestive heart failure, neurologic Biol Blood Marrow Transplant 18:S166-S171, 2012 HCT for Nonmalignant Disorders S169 complications, pulmonary complications, and multior- were alive with full donor engraftment at a median gan failure with typical ablative regimens containing follow-up of 26.5 months [21]. At our center, we cyclophosphamide. In one review, more than 50% of have adopted RIC with Campath 1H, fludarabine, the patients succumbed to cardiopulmonary complica- and melphalan, with the melphalan dose reduced by tions in the early posttransplantation phase. Similarly, 50% to avoid excessive regimen-related toxicity and a review of the European experience with HCT in 26 mortality. One of these patients with DC and myelo- SDS patients [18], reported an overall treatment- dysplastic syndrome with monosomy 7 is 1 year post- related mortality of 35.5% at 1 year. Interestingly, they transplantation, with normal hematopoiesis and no found a significantly higher mortality rate in patients re- evidence of monosomy 7. Of note, this, patient did ceiving a TBI-containing conditioning regimen (67% not receive Campath to avoid risk of mixed chime- for TBI versus 20% for non-TBI-containing regimen; rism and potential relapse of myelodysplastic syn- P 5 .03). Recent efforts have thus focused on reduced- drome. However, long-term follow-up data are not intensity conditioning (RIC) regimens to ameliorate car- available, and it remains to be seen how these patients diac and pulmonary toxicities. Sauer and colleagues [19] ultimately fare. Regardless of the potential reduction used fludarabine, treosulfan, and melphalan, and we have in toxicity associated with these regimens, preexisting previously reported our experience with successful use of characteristics of DC (eg, pulmonary and liver dis- anRIC regimen consisting of Campath-1H,fludarabine, ease) may ultimately limit the effectiveness of HCT and melphalan. These data indicate that HCT with RIC in these patients. is feasible in patients with SDS and is associated with ex- In summary, progress in improving the outcomes cellent donor cell engraftment and modest morbidity. for children with chromosomal sensitivity syndromes has been limited by the rarity of these disorders, as DC well as disease-specific genetic, molecular, cellular, and clinical characteristics that increase the risks of DC is an inherited disorder that usually presents complications associated with HCT. However, recent with the clinical triad of abnormal skin pigmentation, progress has been made, as best evidenced by use of nail dystrophy, and mucosal leukoplakia. Noncutane- various RIC regimens with improved outcomes and ous manifestations include progressive liver cirrhosis by improved diagnostic testing. The rarity of these and pulmonary fibrosis. The availability of a simple diseases, coupled with the likely incremental im- diagnostic blood test measuring telomere length and provements that will result from ongoing research genetic testing that is positive in about 50% of patients will require prospective multicenter or even interna- has greatly increased recognition of this disorder. Out- tional clinical trials to improve the outcome for these comes of allogeneic HCT have been poor because of children. early and late complications. Langstone and colleagues [20] performed transplantation on eight patients with HCT FOR HEMOGLOBINOPATHIES DC and BMF. Six who underwent transplantation us- ing matched sibling donors were conditioned with cy- The hemoglobinopathies, which account for the clophosphamide (140-200 mg/kg) with or without most common hereditary disorders worldwide, are ATG, and two with matched URD received cyclo- curable by HCT. But unlike rarer hereditary disor- phosphamide (120 mg/kg) and TBI (1200 cGy). Three ders of childhood that often are rapidly fatal in the patients died from respiratory failure and pulmonary absence of HCT, expanded and improved supportive fibrosis at 70 days, 8 years, and 20 years posttransplan- therapies for hemoglobin disorders now routinely ex- tation. Three patients died early from invasive fungal tend the life span of affected individuals well into infections, one died from refractory aGVHD on day adulthood [22,23]. As a consequence, in regions of 44, and one patient was alive at 463 days, who under- the world where this healthcare is readily available, went surgical resection of a rectal carcinoma 14 HCT is pursued infrequently in children with these months post HCT. Other reports using myeloablative disorders because of a perception among families conditioning showed similar results. and their physicians that the risk-benefit balance has The presence of pulmonary disease in a significant shifted away from HCT [24]. More recently, how- proportion of DC patients before HCT may explain ever, there has emerged a growing consensus that the high incidence of fatal pulmonary complications survival into adulthood is accompanied by chronic in the HCT setting. More recent studies have used and life-threatening complications, and this new un- RIC with encouraging results for successful engraft- derstanding has caused many to reconsider the role ment with fewer complications, for both related and of HCT for these disorders, particularly in young unrelated allografts [25]. Tolar et al. recently pub- adult patients in whom the quality of life has declined lished their experience with a RIC regimen contain- [25]. Thus, transplantation investigators are now ing cyclophosphamide, fludarabine, alemtuzumab, challenged by how to make HCT successful in older and a single 200 cGy dose of TBI. Four patients individuals where risks of GVHD, graft rejection, and S170 J. Tolar et al. Biol Blood Marrow Transplant 18:S166-S171, 2012 impaired organ function are very likely to have a neg- mixed results. There are now several series that report ative impact on outcomes. In this brief review, we will only transient donor engraftment after nonmyeloabla- examine what has and has not been successful in elu- tive preparation following a minimal toxicity regimen, cidating a successful approach to HCT for hemoglo- and this strategy has been dropped for the most binopathies and speculate about the best future part [31]. There has been better success with engraft- prospects for expanding the role of HCT. ment after applying reduced-intensity regimens that The curative potential of HCT for hemoglobin- accomplish immunoablation by incorporating the use opathies was proved first in thalassemia major and of alemtuzumab. One recent trial in adults with sickle later in sickle cell disease, utilizing a myeloablative cell disease who also received sirolimus for postgrafting backbone of busulfan and cyclophosphamide before immunosuppression experienced stable donor-host HLA-identical (ID) sibling bone marrow transplanta- chimerism when postgrafting immunosuppression tion (reviewed in [26]). These initial studies showed was extended long term after HCT [32]. Several multi- a very high success rate, with failures caused either center clinical trials are being conducted to explore the by transplant-related deaths or more frequently, graft utility of a combination of alemtuzumab with melpha- rejection accompanied by autologous reconstitution lan and fludarabine in children with hemoglobinopa- and disease recurrence. The risk of disease recurrence thies based upon promising preliminary experience in thalassemia was highest in pediatric recipients who with this regimen in children with nonmalignant con- had poor-risk features such as hepatomegaly, hepatic ditions. The use of umbilical cord blood (UCB) as fibrosis, or poor adherence to regular iron chelation a source of donor cells has also been tested, as this therapy before HCT. In addition, transplant-related source of hematopoietic cells extends a lower risk of mortality in young adults with thalassemia ranged GVHD, a complication that carries no benefit in non- from 27% to 37% [27]. Together, these clinical series malignant conditions. Initial reports showed that UCB showed that it was possible to treat hemoglobinopa- from HLA-ID sibling donors, either alone or in combi- thies successfully by HCT and that patient selection nation with marrow from the same sibling donor, affected outcome. However, as most affected individ- showed results that were very similar to outcomes after uals lacked an HLA-ID sibling donor, the application bone marrow transplantation, with a reduced risk of of HCT for hemoglobinopathies was not broadly GVHD [33]. Attempts to extend these results by using expanded, and for the most part was restricted to unrelated UCB donors have been disappointing, due in children. large part to a high rate of graft rejection, particularly Several recent patient series show progress in how after nonmyeloablative preparation [34]. Thus, the fu- to tackle the problems of graft rejection and condi- ture use of UCB from unrelated donors for this indica- tioning regimen toxicity, and in so doing, should tion is uncertain today. help expand HCT beyond the realm of HLA-ID sib- In summary, the investigations and clinical expe- ling bone marrow transplantation. First, by extending rience reported to date indicate that there is an un- the duration and intensity of pretransplantation im- usually difficult barrier to allogeneic engraftment munosuppression by administering azathioprine and after HCT for hemoglobinopathies, which remains hydroxyurea 6 weeks before HCT and by adding flu- incompletely understood. Nonetheless, there is very darabine to the conditioning regimen, it was possible good empirical evidence that aggressive inhibition to improve transplantation outcomes in high-risk pe- of the host immune system is required for engraft- diatric thalassemia recipients [28]. Similarly, the re- ment, using either myeloablative or immunoablative placement of fludarabine for cyclophosphamide in therapy for pretransplant conditioning. This is partic- the conditioning regimen resulted in an acceptable ularly important in the setting of unrelated and HLA- toxicity profile and was sufficient for engraftment af- mismatched donor HCT. It is also very likely that ter unrelated donor bone marrow transplantation in donor availability will continue to create challenges, children and young adults [29]. The use of treosulfan especially in light of the poor results after unrelated in lieu of busulfan also appeared to generate excellent UCB transplantation that have diminished enthusi- results in the unrelated donor setting [30]. Thus, it asm for this source of hematopoietic cells. Thus, it appears that modulation of the conditioning regimen is possible that renewed effort will be focused on in such a manner that might amplify suppression of the use of HLA-mismatched and haploidentical re- the host-versus-graft rejection has served to make en- lated donors. Of course, this approach also carries graftment of donor cells more likely to occur, even a significant challenge of how to overcome the barrier after alternate-donor HCT. Similarly, the use of al- to engraftment, as was highlighted in a recent thalas- ternative and novel chemotherapeutic agents in the semia trial [35]. But improved methodologies, such as conditioning regimen might also improve the toxicity the use of postgrafting high-dose cyclophosphamide, profile. might provide a novel path to engraftment without Other obvious strategies to extend transplantation significant GVHD [36]. Additional investigations more safely and broadly have also been pursued, with into the causes of graft rejection and clinical trials Biol Blood Marrow Transplant 18:S166-S171, 2012 HCT for Nonmalignant Disorders S171 of novel transplantation designs that mitigate this risk 17. Chaudhury S, Auerbach AD, Kernan NA, et al. Fludarabine- will be needed to advance alternative donor trans- based cytoreductive regimen and T-cell-depleted grafts from alternative donors for the treatment of high-risk patients with plantation for hemoglobinopathies. Fanconi anaemia. Br J Haematol. 2008;140:644-655. 18. Cesaro S, Oneto R, Messina C, et al. Haematopoietic stem cell ACKNOWLEDGMENTS transplantation for Shwachman-Diamond disease: a study from the European Group for blood and marrow transplantation. Br J Haematol. 2005;131:231-236. Financial disclosure: JK and PM have nothing to 19. Bhatla D, Davies SM, Shenoy S, et al. Reduced-intensity condi- disclose. MCW is medical director of the ViaCord tioning is effective and safe for transplantation of patients with Processing Laboratory. Shwachman-Diamond syndrome. Bone Marrow Transplant. 2008; 42:159-165. 20. Langston AA, Sanders JE, Deeg HJ, et al. Allogeneic marrow REFERENCES transplantation for aplastic anaemia associated with dyskeratosis congenita. Br J Haematol. 1996;92:758-765. 1. Fine JD, Eady RA, Bauer EA, et al. The classification of 21. Dietz AC, Orchard PJ, Baker KS, Giller RH, Savage SA, inherited epidermolysis bullosa (EB): report of the Third Inter- Alter BP, et al. Disease-specific hematopoietic cell transplanta- national Consensus Meeting on Diagnosis and Classification of tion: nonmyeloablative conditioning regimen for dyskeratosis EB. J Am Acad Dermatol. 2008;58:931-950. congenita. Bone Marrow Transplant. 2011;46:98-104. 2. Bruckner-Tuderman L. Dystrophic epidermolysis bullosa: path- 22. Borgna-Pignatti C, Rugolotto S, De Stefano P, et al. Survival ogenesis and clinical features. Dermatol Clin. 2010;28:107-114. and complications in patients with thalassemia major treated 3. Heinonen S, Mannikko M, Klement JF, Whitaker-Menezes D, with transfusion and deferoxamine. Haematologica. 2004;89: Murphy GF, Uitto J. Targeted inactivation of the type VII col- 1187-1193. lagen gene (Col7a1) in mice results in severe blistering pheno- 23. Quinn CT, Rogers ZR, McCavit TL, Buchanan GR. Improved type: a model for recessive dystrophic epidermolysis bullosa. survival of children and adolescents with sickle cell disease. J Cell Sci. 1999;112(Pt 21):3641-3648. Blood. 2010;115:3447-3452. 4. Tolar J, Ishida-Yamamoto A, Riddle M, et al. Amelioration of 24. van Besien K, Koshy M, Anderson-Shaw L, et al. Allogeneic epidermolysis bullosa by transfer of wild-type bone marrow stem cell transplantation for sickle cell disease. A study of cells. Blood. 2009;113:1167-1174. patients’ decisions. Bone Marrow Transplant. 2001;28:545-549. 5. Chino T, Tamai K, Yamazaki T, et al. Bone marrow cell transfer 25. McClish DK, Penberthy LT, Bovbjerg VE, et al. Health related into fetal circulation can ameliorate genetic skin diseases by pro- quality of life in sickle cell patients: the PiSCES project. Health viding fibroblasts to the skin and inducing immune tolerance. Qual Life Outcomes. 2005;3:50. Am J Pathol. 2008;173:803-814. 26. Michlitsch JG, Walters MC. Recent advances in bone marrow 6. Fujita Y, Abe R, Inokuma D, et al. Bone marrow transplantation transplantation in hemoglobinopathies. Curr Mol Med. 2008;8: restores epidermal basement membrane protein expression and 675-689. rescues epidermolysis bullosa model mice. Proc Natl Acad Sci 27. Gaziev J, Sodani P, Polchi P, Andreani M, Lucarelli G. Bone USA. 2010;107:14345-14350. marrow transplantation in adults with thalassemia: treatment 7. Wagner JE, Ishida-Yamamoto A, McGrath JA, et al. Bone mar- and long-term follow-up. Ann N Y Acad Sci. 2005;1054:196-205. row transplantation for recessive dystrophic epidermolysis bul- 28. Sodani P, Gaziev D, Polchi P, et al. New approach for bone mar- losa. N Engl J Med. 2010;363:629-639. row transplantation in patients with class 3 thalassemia aged 8. Tolar J, Blazar BR, Wagner JE. Concise review: transplantation younger than 17 years. Blood. 2004;104:1201-1203. of human hematopoietic cells for extracellular matrix protein 29. La Nasa G, Littera R, Locatelli F, et al. Status of donor-recipient deficiency in epidermolysis bullosa. Stem Cells. 2011;29:900-906. HLA class I ligands and not the KIR genotype is predictive for 9. Petrova A, Ilic D, McGrath JA. Stem cell therapies for recessive the outcome of unrelated hematopoietic stem cell transplanta- dystrophic epidermolysis bullosa. Br J Dermatol. 2010;163: tion in beta-thalassemia patients. Biol Blood Marrow Transplant. 1149-1156. 2007;13:1358-1368. 10. Tolar J, Xia L, Riddle MJ, et al. Induced pluripotent stem cells 30. Bernardo ME, Zecca M, Piras E, et al. Treosulfan-based condi- from individuals with recessive dystrophic epidermolysis tioning regimen for allogeneic haematopoietic stem cell trans- bullosa. J Invest Dermatol. 2011;131:848-856. plantation in patients with thalassaemia major. Br J Haematol. 11. Auerbach AD, Wolman SR. Susceptibility of Fanconi’s anaemia 2008;143:548-551. fibroblasts to chromosome damage by carcinogens. Nature. 31. Iannone R, Casella JF, Fuchs EJ, et al. Results of minimally toxic 1976;261:494-496. nonmyeloablative transplantation in patients with sickle cell 12. Gluckman E. Bone marrow transplantation in Fanconi’s anemia. anemia and beta-thalassemia. Biol Blood Marrow Transplant. Stem Cells. 1993;11(suppl 2):180-183. 2003;9:519-528. 13. Farzin A, Davies SM, Smith FO, et al. Matched sibling donor 32. Hsieh MM, Kang EM, Fitzhugh CD, et al. Allogeneic hemato- haematopoietic stem cell transplantation in Fanconi anaemia: poietic stem-cell transplantation for sickle cell disease. N Engl J an update of the Cincinnati Children’s experience. Br J Haematol. Med. 2009;361:2309-2317. 2007;136:633-640. 33. Locatelli F, Rocha V, Reed W, et al. Related umbilical cord 14. Kapelushnik J, Or R, Slavin S, Nagler A. A fludarabine-based blood transplantation in patients with thalassemia and sickle protocol for bone marrow transplantation in Fanconi’s anemia. cell disease. Blood. 2003;101:2137-2143. Bone Marrow Transplant. 1997;20:1109-1110. 34. Ruggeri A, Eapen M, Scaravadou A, et al. Umbilical cord blood 15. Tan PL, Wagner JE, Auerbach AD, Defor TE, Slungaard A, transplantation for children with thalassemia and sickle cell dis- Macmillan ML. Successful engraftment without radiation after ease. Biol Blood Marrow Transplant. 2011;17:1375-1382. fludarabine-based regimen in Fanconi anemia patients undergo- 35. Sodani P, Isgro A, Gaziev J, et al. Purified T-depleted, CD341 ing genotypically identical donor hematopoietic cell transplan- peripheral blood and bone marrow cell transplantation from tation. Pediatr Blood Cancer. 2006;46:630-636. haploidentical mother to child with thalassemia. Blood. 2010; 16. Boyer MW, Gross TG, Loechelt B, Leemhuis T, Filipovich A, 115:1296-1302. Harris RE. Low risk of graft-versus-host disease with transplan- 36. Brodsky RA, Luznik L, Bolanos-Meade J, Leffell MS, Jones RJ, tation of CD34 selected peripheral blood progenitor cells from Fuchs EJ. Reduced intensity HLA-haploidentical BMT with alternative donors for Fanconi anemia. J Pediatr Hematol Oncol. post transplantation cyclophosphamide in nonmalignant hema- 2003;25:890-895. tologic diseases. Bone Marrow Transplant. 2008;42:523-527.