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Curative therapy for hemoglobinopathies: an International Society for Cell & Gene Therapy Stem Cell Engineering Committee review comparing outcomes, accessibility and cost of ex vivo stem cell gene therapy versus allogeneic hematopoietic stem cell transplantation

Published:December 06, 2021DOI:https://doi.org/10.1016/j.jcyt.2021.09.003

      Abstract

      Thalassemia and sickle cell disease (SCD) are the most common monogenic diseases in the world and represent a growing global health burden. Management is limited by a paucity of disease-modifying therapies; however, allogeneic hematopoietic stem cell transplantation (HSCT) and autologous HSCT after genetic modification offer patients a curative option. Allogeneic HSCT is limited by donor selection, morbidity and mortality from transplant conditioning, graft-versus-host disease and graft rejection, whereas significant concerns regarding long-term safety, efficacy and cost limit the broad applicability of gene therapy. Here the authors review current outcomes in allogeneic and autologous HSCT for transfusion-dependent thalassemia and SCD and provide our perspective on issues surrounding accessibility and costs as barriers to offering curative therapy to patients with hereditary hemoglobinopathies.

      Key Words

      Introduction

      Thalassemia major and sickle cell disease (SCD) are the two most frequent hereditary hemoglobinopathies in the world. The annual birth rate is estimated to increase from the current 300 000 to over 400 000 births in the next several decades, 80% of which occur in low- or middle-income countries [
      • Piel FB
      • Hay SI
      • Gupta S
      • Weatherall DJ
      • Williams TN.
      Global burden of sickle cell anaemia in children under five, 2010–2050: modelling based on demographics, excess mortality, and interventions.
      ]. Thalassemia major and SCD therefore represent a growing global health burden, and treatment options that aim to reduce the burden of disease are needed.
      Despite a significant increase in survival for patients with thalassemia with regular blood transfusions, iron chelation therapy, evidence-based practice guidelines, splenectomy and antibiotic prophylaxis [

      Cappellini MD, Cohen A, Porter J, et al., editors. Guidelines for the Management of Transfusion Dependent Thalassaemia (TDT) [Internet]. 3rd edition. Nicosia (CY): Thalassaemia International Federation; 2014. Available from: https://www.ncbi.nlm.nih.gov/books/NBK269382/.

      ,
      • Telfer P.
      Update on survival in thalassemia major.
      ], complications directly from transfusion therapy or indirectly from iron overload and organ damage increase the medical burden of disease as much as 10–15% per patient [
      • Bonifazi F
      • Conte R
      • Baiardi P
      • Bonifazi D
      • Felisi M
      • Giordano P
      • et al.
      Pattern of complications and burden of disease in patients affected by beta thalassemia major.
      ,
      • Borgna-Pignatti C.
      The life of patients with thalassemia major.
      ,
      • Borgna-Pignatti C
      • Cappellini MD
      • De Stefano P
      • Del Vecchio GC
      • Forni GL
      • Gamberini MR
      • et al.
      Survival and complications in thalassemia.
      ]. Recently, luspatercept (previously called ACE-536) was approved by the Food and Drug Administration for the treatment of adults >18 years of age with transfusion-dependent thalassemia (TDT) as an agent that improves red blood cell (RBC) maturation by an incompletely understood mechanism.
      Hydroxyurea (HU) is efficacious in reducing SCD-related complications and is therefore a routine consideration as early as 9 months of age before protective fetal hemoglobin (HbF) levels fall and SCD-related complications begin to occur [
      • Steinberg MH
      • Barton F
      • Castro O
      • Pegelow CH
      • Ballas SK
      • Kutlar A
      • et al.
      Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment.
      ,
      • Wang WC
      • Ware RE
      • Miller ST
      • Iyer RV
      • Casella JF
      • Minniti CP
      • et al.
      Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG).
      ,
      • Ware RE.
      How I use hydroxyurea to treat young patients with sickle cell anemia.
      ,
      • Zimmerman SA
      • Schultz WH
      • Burgett S
      • Mortier NA
      • Ware RE
      Hydroxyurea therapy lowers transcranial Doppler flow velocities in children with sickle cell anemia.
      ]. HU must, however, be continued indefinitely with close monitoring, which may contribute to low uptake and adherence. Newer Food and Drug Administration-approved therapies include L-glutamine and crizanlizumab to reduce pain events and voxelotor to improve anemia; however, the role of these drugs in the management of patients with SCD remains unclear. In addition, the costs of these new drugs provide additional barriers to broad access. Similarly, chronic blood transfusion therapy requires a patient's time and commitment, carries the risk of iron overload and alloimmunization and does not fully eliminate the complications of the disease.
      Given the burden of disease and limitations of disease-modifying therapies currently available for SCD and TDT, curative strategies are needed. As RBC disorders, both SCD and TDT can be cured by hematopoietic stem cell transplantation (HSCT); however, the use of HSCT is limited in both conditions by a paucity of available HLA-identical sibling donors and well-matched unrelated donors (MUDs) [
      • Gragert L
      • Eapen M
      • Williams E
      • Freeman J
      • Spellman S
      • Baitty R
      • et al.
      HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry.
      ,
      • Walters MC
      • Patience M
      • Leisenring W
      • Eckman JR
      • Buchanan GR
      • Rogers ZR
      • et al.
      Barriers to bone marrow transplantation for sickle cell anemia.
      ]. Although allogeneic HSCT is limited by donor availability, morbidity and mortality from transplant conditioning, graft-versus-host disease (GVHD) and graft rejection, gene therapy, either by gene addition or gene modification, targeting autologous hematopoietic stem cells (HSCs) may become a universal cure for SCD and TDT that eliminates the major limitations of allogeneic transplantation. Here the authors review and provide perspectives on the outcomes, accessibility and cost of ex vivo stem cell gene therapy versus allogeneic HSCT in TDT and SCD.

      Indications for and Limitations of Allogeneic HSCT for TDT and SCD in the Current Era

      Transfusion dependence due to thalassemia is the principal indication for HSCT. Challenges of providing blood, chelation therapy, adequate monitoring and patient support, particularly in developing countries, hinder transfusion with chelation as an effective treatment modality [
      • Ladis V
      • Chouliaras G
      • Berdoukas V
      • Chatziliami A
      • Fragodimitri C
      • Karabatsos F
      • et al.
      Survival in a large cohort of Greek patients with transfusion-dependent beta thalassaemia and mortality ratios compared to the general population.
      ]. Children with TDT and a suitable, unaffected, HLA-identical sibling should be offered HSCT as early as possible to avoid complications associated with chronic transfusions and iron overload. Outcomes from HSCT correlate with severity of iron overload and duration of exposure; thus, outcomes are best in individuals in whom the risks of organ damage from excess iron stores have been minimized [
      • Angelucci E
      • Pilo F
      • Coates TD.
      Transplantation in thalassemia: Revisiting the Pesaro risk factors 25 years later.
      ].
      Clinical phenotypes of SCD are extremely variable, and there is no clear definition of symptomatic SCD; thus, unlike TDT, there are no universal, widely adopted indications for HSCT in SCD. The presence of central nervous system disease is generally acceptable for HSCT given the risk of second overt strokes or progressive cerebral infarcts despite adequate transfusion therapy [
      • Hulbert ML
      • McKinstry RC
      • Lacey JL
      • Moran CJ
      • Panepinto JA
      • Thompson AA
      • et al.
      Silent cerebral infarcts occur despite regular blood transfusion therapy after first strokes in children with sickle cell disease.
      ,
      • Scothorn DJ
      • Price C
      • Schwartz D
      • Terrill C
      • Buchanan GR
      • Shurney W
      • et al.
      Risk of recurrent stroke in children with sickle cell disease receiving blood transfusion therapy for at least five years after initial stroke.
      ]. Recurrent vaso-occlusive crisis (VOC) despite HU, recurrent acute chest syndrome, osteonecrosis, sickle nephropathy, red cell alloimmunization, pulmonary hypertension and recurrent splenic sequestration encompass other “severe” disease complications that may be considered indications for HSCT [
      • Kassim AA
      • Sharma D.
      Hematopoietic stem cell transplantation for sickle cell disease: The changing landscape.
      ], but most of these reflect expert opinion.
      HSCT for either TDT or SCD is limited by disease complications, the preparative regimen and the graft source, all of which contribute to peritransplant morbidity and mortality. Patients with both TDT and SCD exhibit ineffective erythropoiesis; therefore, mixed donor chimerism is sufficient in part because of the competitive advantage of donor RBCs [
      • Abraham A
      • Cluster A
      • Jacobsohn D
      • Delgado D
      • Hulbert ML
      • Kukadiya D
      • et al.
      Unrelated Umbilical Cord Blood Transplantation for Sickle Cell Disease Following Reduced-Intensity Conditioning: Results of a Phase I Trial.
      ,
      • Fitzhugh CD
      • Cordes S
      • Taylor T
      • Coles W
      • Roskom K
      • Link M
      • et al.
      At least 20% donor myeloid chimerism is necessary to reverse the sickle phenotype after allogeneic HSCT.
      ,
      • Alfred A
      • Vora AJ
      What is the minimum level of donor chimerism necessary to sustain transfusion independence in thalassaemia?.
      ]. Studies investigating reduced intensity conditioning (RIC) regimens have reported similar overall survival (OS) and event-free survival (EFS) with lower toxicity [
      • Anurathapan U
      • Pakakasama S
      • Mekjaruskul P
      • Sirachainan N
      • Songdej D
      • Chuansumrit A
      • et al.
      Outcomes of thalassemia patients undergoing hematopoietic stem cell transplantation by using a standard myeloablative versus a novel reduced-toxicity conditioning regimen according to a new risk stratification.
      ,
      • Hsieh MM
      • Fitzhugh CD
      • Weitzel RP
      • Link ME
      • Coles WA
      • Zhao X
      • et al.
      Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype.
      ,
      • Hsieh MM
      • Kang EM
      • Fitzhugh CD
      • Link MB
      • Bolan CD
      • Kurlander R
      • et al.
      Allogeneic hematopoietic stem-cell transplantation for sickle cell disease.
      ] compared with myeloablative regimens. However, standard preparative regimens currently utilize myeloablation to efficiently lower the barrier for engraftment and minimize graft rejection, and therefore some patients are excluded from HSCT based solely on the ability to tolerate myeloablation. Some modifications may be made in high-risk patients [
      • Li C
      • Wu X
      • Feng X
      • He Y
      • Liu H
      • Pei F
      • et al.
      A novel conditioning regimen improves outcomes in beta-thalassemia major patients using unrelated donor peripheral blood stem cell transplantation.
      ,
      • Mathews V
      • Savani BN
      Conditioning regimens in allo-SCT for thalassemia major.
      ,
      • Bernardo ME
      • Zecca M
      • Piras E
      • Vacca A
      • Giorgiani G
      • Cugno C
      • et al.
      Treosulfan-based conditioning regimen for allogeneic haematopoietic stem cell transplantation in patients with thalassaemia major.
      ,
      • Bernardo ME
      • Piras E
      • Vacca A
      • Giorgiani G
      • Zecca M
      • Bertaina A
      • et al.
      Allogeneic hematopoietic stem cell transplantation in thalassemia major: results of a reduced-toxicity conditioning regimen based on the use of treosulfan.
      ,
      • Gaziev J
      • Marziali M
      • Isgro A
      • Sodani P
      • Paciaroni K
      • Gallucci C
      • et al.
      Bone marrow transplantation for thalassemia from alternative related donors: improved outcomes with a new approach.
      ]; however, deviation from myeloablative therapy remains under investigation and is currently done under clinical trials. Furthermore, both TDT and SCD patients exhibit an intact immune system, and hyperinflammation specific to SCD, requiring sufficient immunosuppression for sustained engraftment. In general, patients with stable donor engraftment after HSCT do not experience sickle-related complications after HSCT in SCD, or require ongoing transfusion support in TDT, with stabilization or even improvement in end-organ pathology. However, this is balanced by a significant risk of infertility, which remains a major barrier and important concern for patients and families [
      • Hsieh MM
      • Fitzhugh CD
      • Weitzel RP
      • Link ME
      • Coles WA
      • Zhao X
      • et al.
      Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype.
      ,
      • Hsieh MM
      • Kang EM
      • Fitzhugh CD
      • Link MB
      • Bolan CD
      • Kurlander R
      • et al.
      Allogeneic hematopoietic stem-cell transplantation for sickle cell disease.
      ,
      • Bernaudin F
      • Socie G
      • Kuentz M
      • Chevret S
      • Duval M
      • Bertrand Y
      • et al.
      Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease.
      ,
      • Dedeken L
      • Le PQ
      • Azzi N
      • Brachet C
      • Heijmans C
      • Huybrechts S
      • et al.
      Haematopoietic stem cell transplantation for severe sickle cell disease in childhood: a single centre experience of 50 patients.
      ,
      • Walters MC
      • Hardy K
      • Edwards S
      • Adamkiewicz T
      • Barkovich J
      • Bernaudin F
      • et al.
      Pulmonary, gonadal, and central nervous system status after bone marrow transplantation for sickle cell disease.
      ,
      • Walters MC
      • Patience M
      • Leisenring W
      • Eckman JR
      • Scott JP
      • Mentzer WC
      • et al.
      Bone marrow transplantation for sickle cell disease.
      ].

      Outcomes: Allogeneic HSCT in TDT and SCD

      HLA-matched sibling donor HSCT

      The effectiveness of HSCT for TDT with HLA-matched sibling donor was established in the 1980s [
      • Thomas ED
      • Buckner CD
      • Sanders JE
      • Papayannopoulou T
      • Borgna-Pignatti C
      • De Stefano P
      • et al.
      Marrow transplantation for thalassaemia.
      ], with reported OS and disease-free survival (DFS) now approaching 91% and 83%, respectively, with bone marrow (BM) from HLA-identical siblings [
      • Angelucci E
      • Matthes-Martin S
      • Baronciani D
      • Bernaudin F
      • Bonanomi S
      • Cappellini MD
      • et al.
      Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel.
      ]. Similarly, proof of concept for cure of SCD after HSCT occurred in 1984 when a child with sickle cell anemia developed acute myelogenous leukemia (AML) and was cured of both her AML and SCD after HLA-matched sibling HSCT [
      • Johnson FL
      • Look AT
      • Gockerman J
      • Ruggiero MR
      • Dalla-Pozza L
      • Billings 3rd., FT
      Bone-marrow transplantation in a patient with sickle-cell anemia.
      ]. Since then, over 1000 patients with SCD have successfully undergone HSCT with an HLA-identical sibling donor, with greater than 90% of all patients cured of SCD [
      • Gluckman E
      • Cappelli B
      • Bernaudin F
      • Labopin M
      • Volt F
      • Carreras J
      • et al.
      Sickle cell disease: an international survey of results of HLA-identical sibling hematopoietic stem cell transplantation.
      ,
      • Eapen M
      • Brazauskas R
      • Walters MC
      • Bernaudin F
      • Bo-Subait K
      • Fitzhugh CD
      • et al.
      Effect of donor type and conditioning regimen intensity on allogeneic transplantation outcomes in patients with sickle cell disease: a retrospective multicentre, cohort study.
      ]. Table 1 is a partial summary of HLA-identical HSCT in TDT and SCD over the last 5 years.
      Table 1Allogeneic Transplant for TDT and SCD
      Matched Sibling Donors
      Author (reference)PublishedDiseaseNumberMyeloablationOSEFSaGVHD/cGVHD
      Saraf (44)2016SCD13No100%93%0/0
      Baronciani (39)2016TDT1061NR91%83%7%/5%
      Gaziev (41)2016TDT+37Yes92%92%28%/6%
      Gluckman (36)2017SCD1000Yes (n=873; 87%)92.9%91.4%14.8%/14.3%
      Eapen (37)2019SCD558Yes (n=348; 62%)96.2%90.7%11.6%/18.1%
      Li (40)2019TDT677Yes89%86%11.8%/8.3%
      Guilcher (43)2019SCD16No100%100%0/0
      Krishnamurti (45)2019SCD22
      Entire cohort (n=22) included 17 patients who received marrow from an HLA-identical sibling donor and 5 patients who received marrow from an 8/8 HLA-allele matched unrelated donor.
      No94%94%18%/29%
      Bernaudin (117)2020SCD234
      French series of 234 patients with SCD who received a matched-sibling-donor stem cell transplantation following standardized myeloablative conditioning between 1988 to 2012. ^Cohort (n=144) includes data on 70 unrelated adult donors (49%), six unrelated cord blood (4%), and 68 haploidentical donors
      Yes97%93.9%20.1%/10.5%
      Shin (47)2020TDT, SCD9(TDT);4(SCD)No91.7%91.7%20%/20%
      Swaminathan (53)2020TDT177Yes95%96%41%/17%
      Alzahrani (46)2021SCD122No93%87%1.6%/0
      Matched Unrelated/Mismatched Cord Blood Donors
      Shenoy (57)2016SCD29No79%69%28%/62%
      Abraham (18)2017SCD9No100%78%33%/33%
      Li (40)2019TDT252Yes87%82%21.5%/8.4%
      Sun (56)2019TDT48Yes100%100%8.3%/8.3%
      Gluckman (59)2020SCD71Yes88%62%23%/23%
      Gluckman (58)2020SCD144^Yes86%72%24%/24%
      Swaminathan (53)2020TDT58Yes87%84%60%/20%
      Feng (68)2021TDT10Yes90%80%44%/67%
      Haploidentical Donors
      Fitzhugh (73)2017TDT, SCD2(TDT);21(SCD)No87%50%0/0
      Gilman (83)2017SCD8No88%88%25%/13%
      Gaziev (82)2018TDT, SCD11(TDT);3(SCD)Yes84%69%28%/21%
      Pawlowska (75)2018SCD4Yes100%100%0/75%
      de la Fuente (77)2019SCD15No100%93%20%/6%
      Foell (81)2019SCD20No90%90%35%/30%
      Bolanos-Meade (72)2019TDT, SCD5(TDT);12(SCD)No100%94%24%/18%
      Cairo (78)2019SCD19Yes84%84%6.2%/6.7%
      Foell (85)2020SCD25Yes88%88%28%/16%
      Anurathapan (79)2020TDT83Yes96%96%42%/45%
      aGVHD: acute graft-vs-host-disease; cGVHD: chronic graft-vs-host-disease; NR: not reported; SCD: sickle cell disease; TDT: transfusion dependent thalassemia. + TDT class 3 recipients treated with a modified preparatory conditioning regimen.
      low asterisk Entire cohort (n=22) included 17 patients who received marrow from an HLA-identical sibling donor and 5 patients who received marrow from an 8/8 HLA-allele matched unrelated donor.
      low asterisklow asterisk French series of 234 patients with SCD who received a matched-sibling-donor stem cell transplantation following standardized myeloablative conditioning between 1988 to 2012. ^Cohort (n=144) includes data on 70 unrelated adult donors (49%), six unrelated cord blood (4%), and 68 haploidentical donors
      Initial experiences in matched sibling HSCT in TDT formalized three independent prognostic factors (Pesaro classification): hepatomegaly >2 cm, portal fibrosis and history of inadequate iron chelation therapy [
      • Lucarelli G
      • Galimberti M
      • Polchi P
      • Angelucci E
      • Baronciani D
      • Giardini C
      • et al.
      Bone marrow transplantation in patients with thalassemia.
      ]. DFS of 87%, 85% and 80% for Pesaro class I, II and III recipients, respectively, demonstrated that optimal lifelong transfusion and chelation therapy, preventing anemia and iron-related tissue damage, is critical for transplant success. Subsequently, age >14 years was established as an independent risk factor [
      • Baronciani D
      • Angelucci E
      • Potschger U
      • Gaziev J
      • Yesilipek A
      • Zecca M
      • et al.
      Hemopoietic stem cell transplantation in thalassemia: a report from the European Society for Blood and Bone Marrow Transplantation Hemoglobinopathy Registry, 2000-2010.
      ], though after adjusting for donor type and conditioning regimen, new data suggest the best outcome is in patients aged ≤6 years [
      • Li C
      • Mathews V
      • Kim S
      • George B
      • Hebert K
      • Jiang H
      • et al.
      Related and unrelated donor transplantation for β-thalassemia major: results of an international survey.
      ]. Modifications in conditioning with the addition of Thiotepa (TT) have improved outcomes for patients with Pesaro class III recipients [
      • Gaziev J
      • Isgro A
      • Sodani P
      • Marziali M
      • Paciaroni K
      • Gallucci C
      • et al.
      Optimal Outcomes in Young Class 3 Patients With Thalassemia Undergoing HLA-Identical Sibling Bone Marrow Transplantation.
      ].
      Similarly, the largest international survey of results of HLA-identical sibling HSCT in SCD identified several key factors associated with survival after transplantation: age, graft type and transplant period [
      • Gluckman E
      • Cappelli B
      • Bernaudin F
      • Labopin M
      • Volt F
      • Carreras J
      • et al.
      Sickle cell disease: an international survey of results of HLA-identical sibling hematopoietic stem cell transplantation.
      ]. The 5-year EFS and OS of over 1000 patients worldwide were 91.4% and 92.9%, respectively; there was no difference in EFS or OS based on preparative regimen (myeloablative versus non-myeloablative); EFS decreased with increasing age at transplantation; and EFS improved in patients transplanted after 2006 given improvements in supportive care and prevention and management of complications. The use of non-myeloablative or RIC regimens is more common in SCD than TDT, currently demonstrates an acceptable OS and EFS with very little morbidity or GVHD [
      • Hsieh MM
      • Fitzhugh CD
      • Weitzel RP
      • Link ME
      • Coles WA
      • Zhao X
      • et al.
      Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype.
      ,
      • Hsieh MM
      • Kang EM
      • Fitzhugh CD
      • Link MB
      • Bolan CD
      • Kurlander R
      • et al.
      Allogeneic hematopoietic stem-cell transplantation for sickle cell disease.
      ,
      • Aydogdu S
      • Toret E
      • Aksoy BA
      • Aydin MF
      • Cipe FE
      • Bozkurt C
      • et al.
      Comparison of Hematopoietic Stem Cell Transplantation Results in Patients with β-Thalassemia Major from Three Different Graft Types.
      ,
      • Guilcher GMT
      • Monagel DA
      • Nettel-Aguirre A
      • Truong TH
      • Desai SJ
      • Bruce A
      • et al.
      Nonmyeloablative Matched Sibling Donor Hematopoietic Cell Transplantation in Children and Adolescents with Sickle Cell Disease.
      ,
      • Saraf SL
      • Oh AL
      • Patel PR
      • Jalundhwala Y
      • Sweiss K
      • Koshy M
      • et al.
      Nonmyeloablative Stem Cell Transplantation with Alemtuzumab/Low-Dose Irradiation to Cure and Improve the Quality of Life of Adults with Sickle Cell Disease.
      ,
      • Krishnamurti L
      • Neuberg DS
      • Sullivan KM
      • Kamani NR
      • Abraham A
      • Campigotto F
      • et al.
      Bone marrow transplantation for adolescents and young adults with sickle cell disease: Results of a prospective multicenter pilot study.
      ,
      • Alzahrani M
      • Damlaj M
      • Jeffries N
      • Alahmari B
      • Singh A
      • Rondelli D
      • et al.
      Non-myeloablative human leukocyte antigen-matched related donor transplantation in sickle cell disease: outcomes from three independent centres.
      ] and is being trialed in patients with TDT [
      • Shin SH
      • Park SS
      • Park S
      • Jeon YW
      • Yoon JH
      • Yahng SA
      • et al.
      Non-myeloablative matched sibling stem cell transplantation with the optional reinforced stem cell infusion for patients with hemoglobinopathies.
      ]. By using reduced toxicity with immunomodulatory conditioning, engraftment is still achieved and allows older adults who have accumulated end-organ damage, those refractory to HU, and those who have developed severe alloimmunization to be eligible for curative therapy.
      Compared with BM as the source of HSCs, HLA-matched sibling cord blood (CB) is associated with similar OS and DFS but decreased rates of both acute GVHD (aGVHD) and chronic GVHD (cGVHD) in patients with hemoglobinopathies [
      • Locatelli F
      • Kabbara N
      • Ruggeri A
      • Ghavamzadeh A
      • Roberts I
      • Li CK
      • et al.
      Outcome of patients with hemoglobinopathies given either cord blood or bone marrow transplantation from an HLA-identical sibling.
      ]. Conversely, compared with BM, significantly higher rates of both aGVHD and cGVHD are reported when peripheral blood stem cells (PBSCs) are used in patients with TDT, despite similar 2-year OS and DFS [
      • Ghavamzadeh A
      • Iravani M
      • Ashouri A
      • Mousavi SA
      • Mahdavi N
      • Shamshiri A
      • et al.
      Peripheral blood versus bone marrow as a source of hematopoietic stem cells for allogeneic transplantation in children with class I and II beta thalassemia major.
      ]. In SCD, lower OS is demonstrated for PBSC transplanation recipients compared to those receiving BM as a stem cell source [
      • Gluckman E
      • Cappelli B
      • Bernaudin F
      • Labopin M
      • Volt F
      • Carreras J
      • et al.
      Sickle cell disease: an international survey of results of HLA-identical sibling hematopoietic stem cell transplantation.
      ].
      The authors agree with recommendations from the European Society for Blood and Marrow Transplantation working groups suggesting that young TDT patients with an available HLA-identical sibling should be offered HSCT as soon as possible before development of iron overload and iron-related tissue damage [
      • Piel FB
      • Hay SI
      • Gupta S
      • Weatherall DJ
      • Williams TN.
      Global burden of sickle cell anaemia in children under five, 2010–2050: modelling based on demographics, excess mortality, and interventions.
      ], transplant-related risk factors should be evaluated according to the Pesaro risk score [

      Cappellini MD, Cohen A, Porter J, et al., editors. Guidelines for the Management of Transfusion Dependent Thalassaemia (TDT) [Internet]. 3rd edition. Nicosia (CY): Thalassaemia International Federation; 2014. Available from: https://www.ncbi.nlm.nih.gov/books/NBK269382/.

      ], CB and BM from HLA-matched sibling donors are equally effective stem cell sources [
      • Telfer P.
      Update on survival in thalassemia major.
      ] and routine use of PBSC transplantation should be avoided because of the increased risk of cGVHD [
      • Bonifazi F
      • Conte R
      • Baiardi P
      • Bonifazi D
      • Felisi M
      • Giordano P
      • et al.
      Pattern of complications and burden of disease in patients affected by beta thalassemia major.
      ]. With regard to patients with SCD, young patients with symptomatic SCD who have an HLA-matched sibling donor should be transplanted as early as possible, preferably at pre-school age, with unmanipulated BM or CB [
      • Angelucci E
      • Matthes-Martin S
      • Baronciani D
      • Bernaudin F
      • Bonanomi S
      • Cappellini MD
      • et al.
      Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel.
      ].

      Alternative donor outcomes

      Despite some improvements in alternative donor outcomes, HSCT from a non-HLA-matched sibling donor should be considered an experimental approach and should be conducted in the context of well-designed trials. Table 1 is a partial summary of unrelated donor and haploidentical HSCT in TDT and SCD over the last 5 years.

      Unrelated donors

      MUD HSCT in TDT is limited by a high incidence of aGVHD and cGVHD and inferior OS and DFS compared with matched sibling HSCT [
      • La Nasa G
      • Giardini C
      • Argiolu F
      • Locatelli F
      • Arras M
      • De Stefano P
      • et al.
      Unrelated donor bone marrow transplantation for thalassemia: the effect of extended haplotypes.
      ,
      • La Nasa G
      • Caocci G
      • Argiolu F
      • Giardini C
      • Locatelli F
      • Vacca A
      • et al.
      Unrelated donor stem cell transplantation in adult patients with thalassemia.
      ,
      • Hongeng S
      • Pakakasama S
      • Chuansumrit A
      • Sirachainan N
      • Kitpoka P
      • Udomsubpayakul U
      • et al.
      Outcomes of transplantation with related- and unrelated-donor stem cells in children with severe thalassemia.
      ,
      • Swaminathan VV
      • Uppuluri R
      • Patel S
      • Ravichandran N
      • Ramanan KM
      • Vaidhyanathan L
      • et al.
      Matched Family versus Alternative Donor Hematopoietic Stem Cell Transplantation for Patients with Thalassemia Major: Experience from a Tertiary Referral Center in South India.
      ]. A higher risk of alloreactive reactions is noted with higher Pesaro risk class and older age, and improved results are reported with high-resolution molecular typing for both HLA class I and II molecules and according to stringent criteria of compatibility with the recipient [
      • Flomenberg N
      • Baxter-Lowe LA
      • Confer D
      • Fernandez-Vina M
      • Filipovich A
      • Horowitz M
      • et al.
      Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome.
      ,
      • Fleischhauer K
      • Locatelli F
      • Zecca M
      • Orofino MG
      • Giardini C
      • De Stefano P
      • et al.
      Graft rejection after unrelated donor hematopoietic stem cell transplantation for thalassemia is associated with nonpermissive HLA-DPB1 disparity in host-versus-graft direction.
      ]. In an attempt to improve outcomes, changes to preparative regimens have been trialed [
      • Li C
      • Wu X
      • Feng X
      • He Y
      • Liu H
      • Pei F
      • et al.
      A novel conditioning regimen improves outcomes in beta-thalassemia major patients using unrelated donor peripheral blood stem cell transplantation.
      ,
      • Sun L
      • Wang N
      • Chen Y
      • Tang L
      • Xing C
      • Lu N
      • et al.
      Unrelated Donor Peripheral Blood Stem Cell Transplantation for Patients with beta-Thalassemia Major Based on a Novel Conditioning Regimen.
      ]. TT and fludarabine were added to the classic preparative busulfan (Bu)/cyclophosphamide (Cy)-based regimen, reducing the Bu dose by one third to decrease lung and liver toxicity [
      • Li C
      • Wu X
      • Feng X
      • He Y
      • Liu H
      • Pei F
      • et al.
      A novel conditioning regimen improves outcomes in beta-thalassemia major patients using unrelated donor peripheral blood stem cell transplantation.
      ]. No statistically significant difference was observed between the matched sibling and MUD groups in terms of 3-year OS, treatment-free survival, treatment-related mortality, cumulative incidence of graft failure and grade III–IV aGVHD. Expert recommendations are if a well-MUD is available, allogeneic HSCT is a suitable option for a child with lifelong control of iron overload and absence of iron-related tissue complications. The unrelated donor must be selected using high-resolution molecular typing for both HLA class I and II loci and according to stringent criteria of compatibility with the recipient [
      • Angelucci E
      • Matthes-Martin S
      • Baronciani D
      • Bernaudin F
      • Bonanomi S
      • Cappellini MD
      • et al.
      Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel.
      ] and BM as stem cell source.
      The current experience with MUD HSCT for SCD is limited, with mixed results, and primarily restricted by high rates of GVHD and rejection [
      • Shenoy S
      • Eapen M
      • Panepinto JA
      • Logan BR
      • Wu J
      • Abraham A
      • et al.
      A trial of unrelated donor marrow transplantation for children with severe sickle cell disease.
      ,
      • Gluckman E
      • Cappelli B
      • Scigliuolo GM
      • De la Fuente J
      • Corbacioglu S.
      Alternative donor hematopoietic stem cell transplantation for sickle cell disease in Europe.
      ,
      • Gluckman E
      • Fuente J
      • Cappelli B
      • Scigliuolo GM
      • Volt F
      • Tozatto-Maio K
      • et al.
      The role of HLA matching in unrelated donor hematopoietic stem cell transplantation for sickle cell disease in Europe.
      ]. A reduced-toxicity regimen is now being tested in a comparative trial of HSCT and standard of care based on the availability of a suitable HLA-matched related or unrelated donor (BMT CTN 1503, NCT01565616).
      Unrelated umbilical CB HSCT is reported to have high rates of graft failure and delayed hematopoietic recovery secondary to low stem cell content [
      • Strocchio L
      • Romano M
      • Cefalo MG
      • Vinti L
      • Gaspari S
      • Locatelli F.
      Cord blood transplantation in children with hemoglobinopathies.
      ,
      • Ruggeri A
      • Eapen M
      • Scaravadou A
      • Cairo MS
      • Bhatia M
      • Kurtzberg J
      • et al.
      Umbilical cord blood transplantation for children with thalassemia and sickle cell disease.
      ]. In SCD, trials using unrelated CB are limited by small numbers and show high rates of graft rejection and infection [
      • Locatelli F
      • Kabbara N
      • Ruggeri A
      • Ghavamzadeh A
      • Roberts I
      • Li CK
      • et al.
      Outcome of patients with hemoglobinopathies given either cord blood or bone marrow transplantation from an HLA-identical sibling.
      ,
      • Ruggeri A
      • Eapen M
      • Scaravadou A
      • Cairo MS
      • Bhatia M
      • Kurtzberg J
      • et al.
      Umbilical cord blood transplantation for children with thalassemia and sickle cell disease.
      ,
      • Adamkiewicz TV
      • Szabolcs P
      • Haight A
      • Baker KS
      • Staba S
      • Kedar A
      • et al.
      Unrelated cord blood transplantation in children with sickle cell disease: review of four-center experience.
      ,
      • Kamani NR
      • Walters MC
      • Carter S
      • Aquino V
      • Brochstein JA
      • Chaudhury S
      • et al.
      Unrelated donor cord blood transplantation for children with severe sickle cell disease: results of one cohort from the phase II study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN).
      ,
      • Locatelli F
      • Rocha V
      • Reed W
      • Bernaudin F
      • Ertem M
      • Grafakos S
      • et al.
      Related umbilical cord blood transplantation in patients with thalassemia and sickle cell disease.
      ,
      • Radhakrishnan K
      • Bhatia M
      • Geyer MB
      • Del Toro G
      • Jin Z
      • Baker C
      • et al.
      Busulfan, fludarabine, and alemtuzumab conditioning and unrelated cord blood transplantation in children with sickle cell disease.
      ]. The umbilical CB arm of the sickle cell unrelated donor transplant trial of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0601) was suspended because of a high incidence of graft rejection and low DFS [
      • Kamani NR
      • Walters MC
      • Carter S
      • Aquino V
      • Brochstein JA
      • Chaudhury S
      • et al.
      Unrelated donor cord blood transplantation for children with severe sickle cell disease: results of one cohort from the phase II study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN).
      ]. The conditioning regimen has been modified to include HU and TT, with a reported DFS and OS in nine patients of 78% and 100%, respectively, with 33% GVHD (n = 3) at a median follow-up of 2 years [
      • Abraham A
      • Cluster A
      • Jacobsohn D
      • Delgado D
      • Hulbert ML
      • Kukadiya D
      • et al.
      Unrelated Umbilical Cord Blood Transplantation for Sickle Cell Disease Following Reduced-Intensity Conditioning: Results of a Phase I Trial.
      ]. When higher cell doses were used in TDT, the 5-year OS and EFS were 88.3% and 73.9%, respectively [
      • Jaing TH
      • Hung IJ
      • Yang CP
      • Chen SH
      • Chung HT
      • Tsay PK
      • et al.
      Unrelated cord blood transplantation for thalassaemia: a single-institution experience of 35 patients.
      ]. Strategies to improve outcomes in unrelated CB HSCT include the use of multiple CB units [
      • Sideri A
      • Neokleous N
      • Brunet De La Grange P
      • Guerton B
      • Le Bousse Kerdilles MC
      • Uzan G
      • et al.
      An overview of the progress on double umbilical cord blood transplantation.
      ,
      • Feng J
      • Lee V
      • Leung AWK
      • Lam GKS
      • Chow TTW
      • Cheng FWT
      • et al.
      Double-unit unrelated cord blood transplantation for thalassemia major: Comparison with HLA-identical sibling bone marrow transplantation.
      ]; combining CB with T-cell-depleted, HLA-haploidentical CD34+ HSCs [
      • Kwon M
      • Bautista G
      • Balsalobre P
      • Sanchez-Ortega I
      • Serrano D
      • Anguita J
      • et al.
      Haplo-cord transplantation using CD34+ cells from a third-party donor to speed engraftment in high-risk patients with hematologic disorders.
      ]; and ex vivo expansion of umbilical CB-derived stem and progenitor cells [
      • Delaney C
      • Heimfeld S
      • Brashem-Stein C
      • Voorhies H
      • Manger RL
      • Bernstein ID
      Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution.
      ,
      • Horwitz ME
      • Chao NJ
      • Rizzieri DA
      • Long GD
      • Sullivan KM
      • Gasparetto C
      • et al.
      Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment.
      ].

      Haploidentical donors

      The major challenge of HLA-haploidentical HSCT is bidirectional alloreactivity leading to a high incidence of graft rejection and GVHD. T-cell depletion strategies (i.e., in vivo post-transplant Cy [PTCy] or ex vivo CD34+ selection of donor grafts) reduce recipient T cells that recognize the disparate HLA of the haploidentical donor cells and cause graft rejection while also reducing donor T-cell-mediated GVHD. HLA-haploidentical transplantation with PTCy in patients with SCD and TDT demonstrates high OS, limited toxicity and effective reduction of aGVHD and cGVHD in most studies [
      • Bolanos-Meade J
      • Cooke KR
      • Gamper CJ
      • Ali SA
      • Ambinder RF
      • Borrello IM
      • et al.
      Effect of increased dose of total body irradiation on graft failure associated with HLA-haploidentical transplantation in patients with severe haemoglobinopathies: a prospective clinical trial.
      ,
      • Fitzhugh CD
      • Hsieh MM
      • Taylor T
      • Coles W
      • Roskom K
      • Wilson D
      • et al.
      Cyclophosphamide improves engraftment in patients with SCD and severe organ damage who undergo haploidentical PBSCT.
      ,
      • Frangoul H
      • Evans M
      • Isbell J
      • Bruce K
      • Domm J.
      Haploidentical hematopoietic stem cell transplant for patients with sickle cell disease using thiotepa, fludarabine, thymoglobulin, low dose cyclophosphamide, 200 cGy tbi and post transplant cyclophosphamide.
      ,
      • Pawlowska AB
      • Cheng JC
      • Karras NA
      • Sun W
      • Wang LD
      • Bell AD
      • et al.
      HLA Haploidentical Stem Cell Transplant with Pretransplant Immunosuppression for Patients with Sickle Cell Disease.
      ,
      • Wiebking V
      • Hutker S
      • Schmid I
      • Immler S
      • Feuchtinger T
      • Albert MH.
      Reduced toxicity, myeloablative HLA-haploidentical hematopoietic stem cell transplantation with post-transplantation cyclophosphamide for sickle cell disease.
      ,
      • de la Fuente J
      • Dhedin N
      • Koyama T
      • Bernaudin F
      • Kuentz M
      • Karnik L
      • et al.
      Haploidentical Bone Marrow Transplantation with Post-Transplantation Cyclophosphamide Plus Thiotepa Improves Donor Engraftment in Patients with Sickle Cell Anemia: Results of an International Learning Collaborative.
      ,
      • Cairo MS
      • Talano JA
      • Moore TB
      • Shi Q
      • Weinberg RS
      • Grossman B
      • et al.
      Familial Haploidentical Stem Cell Transplant in Children and Adolescents With High-Risk Sickle Cell Disease: A Phase 2 Clinical Trial.
      ]. Increasing total body irradiation to 400 cGy resulted in 100% OS and 94% EFS (SCD, n = 12, β-thalassemia, n = 5), resolution of all GVHD at last follow-up and independence from transfusion in five patients with TDT [
      • Bolanos-Meade J
      • Cooke KR
      • Gamper CJ
      • Ali SA
      • Ambinder RF
      • Borrello IM
      • et al.
      Effect of increased dose of total body irradiation on graft failure associated with HLA-haploidentical transplantation in patients with severe haemoglobinopathies: a prospective clinical trial.
      ]. The increase in total body irradiation to 400 cGy and addition of TT to the preparative regimen appear to improve engraftment and are being assessed in an ongoing multi-center trial for SCD (BMT CTN 1507, NCT03263559). In TDT, pre-transplant pharmacologic immunosuppression followed by a reduced-toxicity conditioning regimen resulted in a 3-year OS and EFS of >96% each, and 7% severe GVHD in a cohort of 83 patients [
      • Anurathapan U
      • Hongeng S
      • Pakakasama S
      • Songdej D
      • Sirachainan N
      • Pongphitcha P
      • et al.
      Hematopoietic Stem Cell Transplantation for Severe Thalassemia Patients from Haploidentical Donors Using a Novel Conditioning Regimen.
      ]. Reports of ex vivoαβ T-cell receptor/CD19+-depleted grafts or CD3+-depleted/CD34+-selected grafts are limited by small numbers of patients, investigating various conditioning and GVHD prophylactic regimens and reported generally lower EFS and OS and higher GVHD than the PTCy protocols [
      • Dallas MH
      • Triplett B
      • Shook DR
      • Hartford C
      • Srinivasan A
      • Laver J
      • et al.
      Long-term outcome and evaluation of organ function in pediatric patients undergoing haploidentical and matched related hematopoietic cell transplantation for sickle cell disease.
      ,
      • Foell J
      • Schulte JH
      • Pfirstinger B
      • Troeger A
      • Wolff D
      • Edinger M
      • et al.
      Haploidentical CD3 or α/β T-cell depleted HSCT in advanced stage sickle cell disease.
      ,
      • Gaziev J
      • Isgro A
      • Sodani P
      • Paciaroni K
      • De Angelis G
      • Marziali M
      • et al.
      Haploidentical HSCT for hemoglobinopathies: improved outcomes with TCRalphabeta(+)/CD19(+)-depleted grafts.
      ,
      • Gilman AL
      • Eckrich MJ
      • Epstein S
      • Barnhart C
      • Cannon M
      • Fukes T
      • et al.
      Alternative donor hematopoietic stem cell transplantation for sickle cell disease.
      ,
      • Marzollo A
      • Calore E
      • Tumino M
      • Pillon M
      • Gazzola MV
      • Destro R
      • et al.
      Treosulfan-Based Conditioning Regimen in Sibling and Alternative Donor Hematopoietic Stem Cell Transplantation for Children with Sickle Cell Disease.
      ,
      • Foell J
      • Kleinschmidt K
      • Jakob M
      • Troeger A
      • Corbacioglu S
      Alternative donor: alphass/CD19 T-cell-depleted haploidentical hematopoietic stem cell transplantation for sickle cell disease.
      ]. Infectious complications from delayed immune reconstitution and associated morbidity and mortality remain problematic with this overall strategy. Despite these overall improvements in haploidentical models, patient numbers remain small, and more study data are therefore needed to guide clinical practice.

      Outcomes: Gene Therapy in TDT and SCD

      Gene transfer outcomes in TDT

      A broad strategy in genetic modification for thalassemia includes insertion of a functional globin gene that sufficiently corrects the globin chain imbalance that is characteristic of thalassemia. This strategy offers wide applicability, given that there are more than 200 individual thalassemia mutations identified, and can be done using lentiviral (LV) transduction of a normally functioning β-globin gene into autologous HSCs that are then infused as autologous HSCT after myeloablative conditioning. Clinical trials investigating gene transfer for TDT are listed in Table 2.
      Table 2Clinical Trials in Gene Transfer for TDT and SCD
      Gene Transfer Clinical Trials
      ClinicalTrials.gov IdentifierStart DateTitleDiseaseStatusPhaseAgeNStudy ObjectiveLocation
      NCT016396902012ß-Thalassemia Major With Autologous CD34+ Hematopoietic Progenitor Cells Transduced With TNS9.3.55 a Lentiviral Vector Encoding the Normal Human ß-Globin GeneTDTActive, not recruiting1>1810To investigate safety and efficacy of treatment of beta thalassemia major with autologous CD34+ HPCs Transduced With TNS9.3.55 a Lentiviral Vector Encoding the Normal Human ß-Globin GeneNew York, USA
      NCT017451202013A Study Evaluating the Safety and Efficacy of the LentiGlobin BB305 Drug Product in β-Thalassemia Major ParticipantsTDTCompleted1/212-3519To evaluate the safety and efficacy of autologous HCT using LentiGlobin BB305 Drug Product [autologous CD34+ hematopoietic stem cells transduced with LentiGlobin BB305 lentiviral vector encoding the human βA-T87Q-globin gene]USA, multicenter; Sydney, Australia; Bangkok, Thailand
      NCT021515262013A Study Evaluating the Efficacy and Safety of LentiGlobin BB305 Drug Product in Beta-Thalassemia Major and SCDTDT, SCDCompleted1/25-357To evaluate safety and efficacy of the administration of LentiGlobin BB305 Drug Product to subjects with either beta-thalassemia major or severe SCDParis, France
      NCT021405542014A Study Evaluating the Safety and Efficacy of the LentiGlobin BB305 Drug Product in Severe SCDSCDSuspended1/212-5050To evaluate gene therapy by transplantation of autologous CD34+ stem cells transduced ex vivo with the LentiGlobin BB305 lentiviral vector in subjects with severe SCDUSA, multicenter
      NCT021864182014Gene Transfer for Patients With SCDSCDActive, not recruiting1/218-4510To determine whether transfer of a fetal hemoglobin gene using a Gamma Globin Lentivirus Vector into human blood making cells is safe and feasible in patients with SCDUSA, multicenter and Jamaica
      NCT022478432014Stem Cell Gene Therapy for SCDSCDActive, not recruiting1/2>186Assess the safety and initial evidence for efficacy of an autologous transplant of βAS3-FB vector transduced bone marrow CD34+ cells for adults with severe SCDUSA, California
      NCT024534772015Gene Therapy for Transfusion Dependent Beta-thalassemia (TIGET-BTHAL)TDTActive, not recruiting1/23-6410To evaluate safety and efficacy of autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene for the treatment of patients affected by TDTMilano, Italy
      NCT029062022016A Study Evaluating the Efficacy and Safety of the LentiGlobin® BB305 Drug Product in Subjects With Transfusion-Dependent β-Thalassemia, Who do Not Have a β0/β0 GenotypeTDTActive, not recruiting3<5023To evaluate the efficacy and safety of autologous HCT using LentiGlobin BB305 Drug Product.USA, multicenter; Marseille, France; Hannover, Germany; Rome, Italy; London, UK
      NCT032070092017A Study Evaluating the Efficacy and Safety of the LentiGlobin® BB305 Drug Product in Subjects With Transfusion-Dependent β-ThalassemiaTDTActive, not recruiting3<5018To evaluate the efficacy and safety of autologous HCT using LentiGlobin BB305 Drug ProductUSA, multicenter; Marseille, France; Germany, multicenter; Thessaloniki, Greece; Rome, Italy; London, UK
      NCT032826562018Gene Transfer for SCDSCDSuspended13-407To evaluate feasibility of HSC gene transfer for SCD using autologous BM derived CD34+ HSCs transduced with a lentiviral vector containing a short-hairpin RNA targeting BCL11aUSA, Massachusetts
      NCT040917372019CSL200 Gene Therapy in Adults With Severe SCDSCDActive, not recruiting118-453To evaluate the safety of the following: collection of CD34+ HPCs by apheresis after mobilization with plerixafor, reduced intensity conditioning with melphalan, and administration of CSL200 (Autologous Enriched CD34+ Cell Fraction That Contains CD34+ Cells Transduced With Lentiviral Vector Encoding Human γ-GlobinG16D and Short-Hairpin RNA734) in adult subjects with SCDUSA, California
      NCT039647922019Safety and Efficacy of Gene Therapy of SCD by Transplantation of an Autologous CD34+ Enriched Cell Fraction That Contains CD34+ Cells Transduced ex Vivo with the GLOBE1 Lentiviral Vector Expressing the βAS3 Globin Gene (DREPAGLOBE)SCDRecruiting1/25-3510To evaluate the Safety and Efficacy of Gene Therapy of SCD by Transplantation of an Autologous CD34+ enriched cell fraction that contains CD34+ cells transduced ex vivo with the GLOBE1 lentiviral vector expressing the βAS3 globin gene (GLOBE1 βAS3 Modified Autologous CD34+ Cells)Paris, France
      NCT042931852020A Study Evaluating Gene Therapy With BB305 Lentiviral Vector in SCDSCDSuspended32-5035To evaluate HSC transplantation with LentiGlobin BB305 Drug Product for SCDUSA, multicenter
      HCT: hematopoietic stem cell transplantation, HPC: hematopoietic progenitor cells, SCD: sickle cell disease, TDT: transfusion dependent thalassemia
      NCT01745120 and NCT02151526 reported data on 22 patients with TDT who underwent autologous HSCT after transduction with an anti-sickling variant of β-globin (βT87Q, LentiGlobin BB305) [
      • Thompson AA
      • Walters MC
      • Kwiatkowski J
      • Rasko JEJ
      • Ribeil JA
      • Hongeng S
      • et al.
      Gene Therapy in Patients with Transfusion-Dependent beta-Thalassemia.
      ]. At a median follow-up of 26 months (range, 15–42), all but one of the 13 patients who had a non-β0/β0 genotype stopped receiving red cell transfusions, and nine patients with a β0/β0 genotype or two copies of the IVS1-110 mutation had a median annualized transfusion volume reduction of 73%, with discontinuation of RBC transfusions in three (33%) patients. Levels of HbAT87Q ranged from 3.4 g/dL to 10.0 g/dL (total hemoglobin [Hb], 8.2–13.7 g/dL). Treatment-related adverse events were typical of those associated with myeloablative Bu. No clonal dominance related to vector integration was observed. This protocol is now being investigated in two phase 3 studies for patients with TDT (NCT03207009) and patients with TDT who do not have a β0/β0 genotype (NCT02906202). Based on the phase 1/2 results, the European Medicines Agency approved this LV product, which contains approximately 24–400 million autologous CD34+ cells transduced with HbAT87Q, in 2019 for individuals 12 years and older who have TDT with a non-β0/β0 genotype.
      NCT02453477 reported data on nine subjects with TDT after direct intra-bone injection of HSCs transduced with the GLOBE LV vector, which encodes a β-globin gene with a modified enhancer region [
      • Marktel S
      • Scaramuzza S
      • Cicalese MP
      • Giglio F
      • Galimberti S
      • Lidonnici MR
      • et al.
      Intrabone hematopoietic stem cell gene therapy for adult and pediatric patients affected by transfusion-dependent ss-thalassemia.
      ]. With a median follow-up of 18 months, transfusion requirement was eliminated in three of the four evaluable children and was reduced in three adults. Younger age and persistence of higher vector copy number in the repopulating HSCs were associated with better outcome. Adverse events were chemotherapy-related; there were no vector-related concerns. NCT01639690 is investigating transduction with TNS9.3.55, an LV vector encoding the normal β-globin gene; however, data have not yet been reported.

      Gene transfer outcomes in SCD

      Gene addition strategies in SCD involve the addition of an anti-sickling β-globin or γ-globin cassette that overcomes the impaired erythropoiesis associated with sickle Hb. Clinical trials investigating gene transfer for SCD are listed in Table 2. In general, participants undergo a period of transfusions prior to PBSC mobilization and apheresis with plerixafor followed by myeloablative conditioning and cell infusion. Protocols initially used BM harvest as a source of autologous HSCs; however, recent reports suggest higher CD34+ cells/kg yield after plerixafor mobilization, improved transduction efficiency and improved HSC quality compared with BM from subjects with SCD [
      • Boulad F
      • Shore T
      • van Besien K
      • Minniti C
      • Barbu-Stevanovic M
      • Fedus SW
      • et al.
      Safety and efficacy of plerixafor dose escalation for the mobilization of CD34(+) hematopoietic progenitor cells in patients with sickle cell disease: interim results.
      ,
      • Esrick EB
      • Manis JP
      • Daley H
      • Baricordi C
      • Trebeden-Negre H
      • Pierciey FJ
      • et al.
      Successful hematopoietic stem cell mobilization and apheresis collection using plerixafor alone in sickle cell patients.
      ,
      • Lagresle-Peyrou C
      • Lefrere F
      • Magrin E
      • Ribeil JA
      • Romano O
      • Weber L
      • et al.
      Plerixafor enables safe, rapid, efficient mobilization of hematopoietic stem cells in sickle cell disease patients after exchange transfusion.
      ,
      • Leonard A
      • Bonifacino A
      • Dominical VM
      • Luo M
      • Haro-Mora JJ
      • Demirci S
      • et al.
      Bone marrow characterization in sickle cell disease: inflammation and stress erythropoiesis lead to suboptimal CD34 recovery.
      ,
      • Tisdale JF
      • Pierciey FJ
      • Kamble R
      • Kanter J
      • Krishnamurti L
      • Kwiatkowski JL
      • et al.
      Successful Plerixafor-Mediated Mobilization, Apheresis, and Lentiviral Vector Transduction of Hematopoietic Stem Cells in Patients with Severe Sickle Cell Disease.
      ,
      • Uchida N
      • Leonard A
      • Stroncek D
      • Panch SR
      • West K
      • Molloy E
      • et al.
      Safe and efficient peripheral blood stem cell collection in patients with sickle cell disease using plerixafor.
      ].
      The largest current experience in gene therapy for SCD is the phase 1/2 study evaluating the safety and efficacy of autologous CD34+ HSCs transduced with βT87Q, LentiGlobin BB305 (NCT02140554) [
      • Kanter J
      • Tisdale JF
      • Mapara MY
      • Kwiatkowski JL
      • Krishnamurti L
      • Schmidt M
      • et al.
      Resolution of Sickle Cell Disease Manifestations in Patients Treated with Lentiglobin Gene Therapy: Updated Results from the Phase 1/2 Hgb-206 Group C Study.
      ,
      • Thompson AA
      • Walters MC
      • Mapara MY
      • Kwiatkowski JL
      • Krishnamurti L
      • Aygun B
      • et al.
      Resolution of Serious Vaso-Occlusive Pain Crises and Reduction in Patient-Reported Pain Intensity: Results from the Ongoing Phase 1/2 HGB-206 Group C Study of LentiGlobin for Sickle Cell Disease (bb1111) Gene Therapy.
      ,
      • Kanter J
      • Walters MC
      • Hsieh M
      • Krishnamurti L
      • Kwiatkowski JL
      • Kamble R
      • et al.
      Interim Results from a Phase 1/2 Clinical Study of Lentiglobin Gene Therapy for Severe Sickle Cell Disease.
      ,
      • Tisdale JF
      • Kanter J
      • Mapara MY
      • Kwiatkowski JL
      • Krishnamurti L
      • Schmidt M
      • et al.
      Current Results of Lentiglobin Gene Therapy in Patients with Severe Sickle Cell Disease Treated Under a Refined Protocol in the Phase 1 Hgb-206 Study.
      ]. This has evolved over three cohorts, and as of March 3, 2020, 40 Group C patients (age, 12–38 years) have initiated cell collection and 25 have been treated with the drug product (DP), with a follow-up period of 2.8–24.8 months [
      • Thompson AA
      • Walters MC
      • Mapara MY
      • Kwiatkowski JL
      • Krishnamurti L
      • Aygun B
      • et al.
      Resolution of Serious Vaso-Occlusive Pain Crises and Reduction in Patient-Reported Pain Intensity: Results from the Ongoing Phase 1/2 HGB-206 Group C Study of LentiGlobin for Sickle Cell Disease (bb1111) Gene Therapy.
      ]. In the 16 evaluable patients with ≥6 months of follow-up, total Hb has ranged from 9.6 g/dL to 16.2 g/dL, with an HbAT87Q contribution of 2.7–9.4 g/dL and median HbS ≤60% of total Hb. There is near pancellular expression of HbAT87Q ≥6 months post-treatment, with approximately 90% of RBCs containing βAT87Q by 18 months and reduction in sickling propensity comparable to sickle cell trait. At last visit post-treatment, key hemolysis markers were trending toward normalization, and no patients required RBC transfusions. Post-treatment, no acute chest syndrome or serious VOCs were observed, and participants reported clinically meaningful improvements in pain reduction at 12 months post-treatment (n = 5).
      On February 16, 2021, NCT02140554 and NCT04293185 were placed on a temporary suspension because of a reported suspected unexpected serious adverse reaction (SUSAR) of AML [
      bluebird bio Announces Temporary Suspension on Phase 1/2 and Phase 3 Studies of LentiGlobin Gene Therapy for Sickle Cell Disease (bb1111) [press release].
      ]. A patient from the initial Group A of NCT02140554 developed AML 5 years after gene therapy, and the trial was halted to determine if there was any relationship to the use of the LV vector. Additionally, a second SUSAR of myelodysplastic syndrome in a patient from Group C of NCT02140554 is currently being investigated. Prior to suspension, there was one death in Group A related to Bu conditioning and unrelated to LV therapy [
      • Hsieh MM
      • Bonner M
      • Pierciey FJ
      • Uchida N
      • Rottman J
      • Demopoulos L
      • et al.
      Myelodysplastic syndrome unrelated to lentiviral vector in a patient treated with gene therapy for sickle cell disease.
      ], and there was one death in Group C (unlikely related to LentiGlobin) >18 months post-treatment in a patient with significant baseline SCD-related cardiopulmonary disease. Investigations are ongoing to determine the etiology of the recent SUSAR events, though an updated report suggests that LV-derived mutagenesis was unlikely [
      • Leonard A
      • Tisdale JF.
      A pause in gene therapy: Reflecting on the unique challenges of sickle cell disease.
      ,
      bluebird bio Provides Updated Findings from Reported Case of Acute Myeloid Leukemia (AML) in LentiGlobin for Sickle Cell Disease (SCD) Gene Therapy Program [press release].
      ].
      The investigators of NCT03282656 recently published data from six participants (age, 7–25 years) who had follow-up for at least 6 months (range, 7–29) after receiving BCH-BB694 gene therapy (LV vector transfer of a short hairpin RNA targeting BCL11a for increased γ-globin expression) [
      • Esrick EB
      • Lehmann LE
      • Biffi A
      • Achebe M
      • Brendel C
      • Ciuculescu MF
      • et al.
      Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease.
      ]. HbF induction at most recent follow-up was 20.4–41.3%, with broad distribution of HbF among red cells. All patients had engraftment, and adverse events were consistent with the effects of preparative chemotherapy. Clinical manifestations of SCD were reduced or absent during the follow-up period. This study has also been paused pending an investigation by the data safety and monitoring board regarding the SUSAR occurrence in the aforementioned, unrelated gene therapy study involving SCD patients.
      NCT02186418 is a phase 1/2 study investigating the efficacy and safety of γ-globin gene transfer, and as of July 28, 2020, data from three patients are available [
      • Grimley M
      • Asnani M
      • Shrestha A
      • Felker S
      • Lutzko C
      • Arumugam PI
      • et al.
      Early Results from a Phase 1/2 Study of Aru-1801 Gene Therapy for Sickle Cell Disease (SCD): Manufacturing Process Enhancements Improve Efficacy of a Modified Gamma Globin Lentivirus Vector and Reduced Intensity Conditioning Transplant.
      ]. Participants range in age from 19 years to 34 years, with 6–30 months of follow-up. Anti-sickling globin expression ranged from 22% to 38% at last follow-up, there have been no treatment-related adverse events to date and all participants have maintained improvements in vaso-occlusive events.

      Gene editing outcomes in TDT

      Clinical trials investigating gene editing for TDT are listed in Table 3. Given the several hundred mutations in the β-globin locus that result in TDT, increasing HbF levels rather than directly targeting the β-globin mutation is a strategy for stabilizing the α:non-α globin ratio sufficiently to prevent intra-marrow apoptosis in developing RBCs.
      Table 3Clinical Trials in Gene Editing for TDT and SCD
      Gene Editing Clinical Trials
      ClinicalTrials.gov IdentifierStart DateTitleDiseaseStatusPhaseAgeNStudy ObjectiveLocation
      NCT03655678, NCT037452872018A Safety and Efficacy Study Evaluating CTX001 in Subjects With Transfusion-Dependent β-Thalassemia (NCT03655678) or Severe SCD (NCT03745287)TDT, SCDRecruiting1/212-3545To evaluate the safety and efficacy of autologous CRISPR-Cas9 Modified CD34+ Human HPCs using CTX001 (autologous CD34+ HPCs modified with CRISPR-Cas9 at the erythroid lineage-specific enhancer of the BCL11A gene)USA, multicenter; Canada, multicenter; Rome, Italy; UK, multicenter; Brussels, Belgium
      NCT034323642018A Study to Assess the Safety, Tolerability, and Efficacy of ST-400 for Treatment of Transfusion-Dependent Beta-thalassemia (TDT)TDTActive, not recruiting1/218-406To understand safety and tolerability of ST-400 (zinc finger nuclease technology to disrupt a the BCL11A enhancer), and secondary objectives are to assess the effects on fetal hemoglobin levels and transfusion requirementsUSA, multicenter
      NCT042114802019Safety and Efficacy Evaluation of γ-globin Reactivated Autologous Hematopoietic Stem CellsTDTRecruitingNR5-1512To evaluate the safety and efficacy of the treatment with γ-globin reactivated autologous hematopoietic stem cells in subjects with β-thalassemia major using Crispr/Cas9 gene editing systemShanghai, China
      NCT036532472019A Study to Assess the Safety, Tolerability, and Efficacy of BIVV003 for Autologous HCT in Patients With Severe SCD (PRECIZN-1)SCDRecruiting1/218-408To evaluate the safety, tolerability, and efficacy of autologous HCT using BIVV003 (zinc finger nuclease messenger ribonucleic acid (mRNAs) targeting the BCL11A locusUSA, multicenter
      NCT044439072020Study of Safety and Efficacy of Genome-edited Hematopoietic Stem and Progenitor Cells in SCDSCDRecruiting1/22-4030To evaluate two genome-edited, autologous, hematopoietic stem and progenitor cell (HSPC) products - OTQ923 and HIX763 - each reducing the biologic activity of BCL11A, increasing fetal hemoglobin (HbF) and reducing complications of SCDUSA, multicenter
      HCT: hematopoietic stem cell transplantation, HPC: hematopoietic progenitor cells, SCD: sickle cell disease, TDT: transfusion dependent thalassemia
      Results from the first TDT patient treated in NCT03655678, a study investigating CRISPR-Cas9 targeting of the BCL11A erythroid-specific enhancer for increased HbF expression, were recently reported [
      • Frangoul H
      • Altshuler D
      • Cappellini MD
      • Chen YS
      • Domm J
      • Eustace BK
      • et al.
      CRISPR-Cas9 Gene Editing for Sickle Cell Disease and beta-Thalassemia.
      ]. Approximately 80% of the alleles at this locus were modified, with no evidence of off-target editing. More than a year later, there remains high levels of allelic editing in BM and blood and increases in HbF that were distributed pancellularly and had achieved transfusion independence. Levels of HbF increased rapidly, from 0.3 g/dL at baseline to 13.1 g/dL at month 18, with an increase in F-cell expression, from 10.1% at baseline to 99.7% at month 6, maintained through month 18. The patient's Hb level normalized to 12.1 g/dL at month 4 and remained normal through month 18.

      Gene editing outcomes in SCD

      Clinical trials for gene editing in SCD are focused first on editing HbF expression rather than directly correcting the sickle mutation, as the former does not require homology-directed repair. Clinical trials investigating gene editing for SCD are listed in Table 3.
      Preliminary data in the first two participants in NCT03745287, a study investigating CRISPR-Cas9 editing of the BCL11A erythroid-specific enhancer, were recently published [
      • Frangoul H
      • Altshuler D
      • Cappellini MD
      • Chen YS
      • Domm J
      • Eustace BK
      • et al.
      CRISPR-Cas9 Gene Editing for Sickle Cell Disease and beta-Thalassemia.
      ,
      • Frangoul H
      • Bobruff Y
      • Cappellini MD
      • Corbacioglu S
      • Fernandez CM
      • de la Fuente J
      • et al.
      Safety and Efficacy of CTX001 in Patients with Transfusion-Dependent β-Thalassemia and Sickle Cell Disease: Early Results from the Climb THAL-111 and Climb SCD-121 Studies of Autologous CRISPR-CAS9-Modified CD34+ Hematopoietic Stem and Progenitor Cells.
      ]. Total Hb and HbF% were 10.3 g/dL and 42.4% (12-month follow-up) and 10.0 g/dL and 46.8% (3-month follow-up), respectively. Participants had 7.0 and 7.5 VOCs per year, respectively, prior to enrollment and reported no VOCs after infusion. No other CTX001-related serious adverse events were reported. For one patient with longer follow-up, HbF increased from a baseline of 9.1% to 43.2% at month 15, and F-cell expression was maintained at nearly 100% through month 15 [
      • Frangoul H
      • Altshuler D
      • Cappellini MD
      • Chen YS
      • Domm J
      • Eustace BK
      • et al.
      CRISPR-Cas9 Gene Editing for Sickle Cell Disease and beta-Thalassemia.
      ]. This participant had no VOC episodes during the 16.6 months after the infusion of gene-modified cells, and the last transfusion of packed red cells was 19 days after infusion.
      One additional study, NCT03653247, is evaluating the safety, tolerability and efficacy of autologous HSCT using BIVV003, a gene editing therapy that uses zinc finger nuclease technology. Information regarding recruitment and/or preliminary results has not yet been published.

      Evidence-Based Assessment of Allogeneic HSCT Versus Gene Therapy in TDT and SCD

      Thousands of patients with TDT and SCD have undergone allogeneic HSCT worldwide with high OS [
      • Baronciani D
      • Angelucci E
      • Potschger U
      • Gaziev J
      • Yesilipek A
      • Zecca M
      • et al.
      Hemopoietic stem cell transplantation in thalassemia: a report from the European Society for Blood and Bone Marrow Transplantation Hemoglobinopathy Registry, 2000-2010.
      ]. Allogeneic HSCT with either BM or umbilical CB is an established therapeutic option for patients with symptomatic SCD and an HLA-matched sibling donor with an OS and EFS of >90%. Evidence-based assessments for allogeneic HSCT in TDT and SCD are listed in Table 4.
      Table 4Evidence Based Assessment for Allogeneic HCT and autologous gene therapy in TDT and SCD
      Allogeneic HCT in Thalassemia
      HLA-Matched Sibling
      • HLA matched sibling allogeneic HSC represents standard of care for patients with TDT, preferably before the development of iron overload and iron-related tissue damage
      Alternative Donors
      • If a well-matched unrelated donor is available, allogeneic HSC is a suitable option for a child with life-long control of iron overload and absence of iron-related tissue complications.
      • The MUD must be selected using high-resolution molecular typing for both HLA class I and II loci, and according to stringent criteria of compatibility with the recipient.
      • HSC from all other alternative donors should be considered an experimental approach and should be conducted in the context of well-designed clinical trials.
      Allogeneic HCT in SCD
      HLA-Matched Sibling
      • Matched sibling HSC is a well-established therapeutic option for patients with symptomatic SCD and an HLA-matched sibling donor
      • There is support for early referral for patients with an HLA-matched sibling
      Alternative Donors
      • When there is not an HLA-identical sibling, alternative donor sources should primarily be pursued for symptomatic patients with SCD and done on a clinical trial
      Gene Therapy in Thalassemia
      Gene Transfer
      • Early gene transfer data shows continued requirement of blood transfusions for patients with β0/β0, therefore allogeneic matched sibling HSC is preferred.
      • When a matched sibling is not available for patients with β0/β0, alternative donor curative HCT vs gene transfer strategies require weighing the individual risks of GVHD and graft failure in alternative donor HCT vs the reduction in transfusion requirement and iron overload with gene transfer-based gene therapy
      • Gene transfer for non- β0/β0 can be considered as possibly curative, particularly if there is no matched sibling
      Gene Editing
      • There is insufficient data (patient numbers and length of follow-up) regarding gene editing
      Gene Therapy in SCD
      Gene Transfer
      • More information regarding the risks of vector derived malignant transformation are required before widespread use of gene addition strategies
      • If malignant transformation is not related to DP, gene transfer may be considered over alternative donor HSC after weighing risks of GVHD and DFS and potentially malignancy with either option
      • More data is needed to establish therapeutic benefit of gene transfer vs disease amelioration if production of modified globin is insufficient or wanes over time
      Gene Editing
      • There is insufficient data (patient numbers and length of follow-up) regarding gene editing
      Early gene transfer data demonstrate a possible cure for patients with non-β0/β0 TDT and SCD, and may be considered for patients without a matched sibling donor. The decision to pursue an alternative donor source when there is not an HLA-matched sibling versus autologous gene therapy must take into account multiple factors with regard to outcomes, including transplant efficacy, short- and long-term transplant-associated morbidity and mortality, conditioning regimens, patient disease status, donor/patient match, safety, patient preference, donor availability and cost.
      The risks associated with genetic manipulation are significant. LV addition strategies require integration into the host genome; therefore, thousands of insertional mutations occur in a population of treated cells. Likewise, off-target CRISPR-induced DNA modifications present potentially deleterious off-target effects. Though CRISPR is non-integrating, the requirement for double-stranded DNA breaks may reduce engraftment and proliferative capacity such that a population with proliferative advantages becomes selected for. Though the reports of AML and myelodysplastic syndrome are highly concerning, investigations appear to exonerate vector-mediated dyserythropoiesis [
      • Leonard A
      • Tisdale JF.
      A pause in gene therapy: Reflecting on the unique challenges of sickle cell disease.
      ,
      bluebird bio Provides Updated Findings from Reported Case of Acute Myeloid Leukemia (AML) in LentiGlobin for Sickle Cell Disease (SCD) Gene Therapy Program [press release].
      ], and multiple factors contribute to the increased risk of post-HSCT malignancy, particularly in patients with SCD [
      • Leonard A
      • Tisdale JF.
      A pause in gene therapy: Reflecting on the unique challenges of sickle cell disease.
      ]. At this time, there are a limited number of patients being treated, and long-term data with regard to gene editing in both TDT and SCD are insufficient to pursue this option without first considering allogeneic HSCT.

      Accessibility: Allogeneic HSCT Versus Gene Therapy for Hemoglobinopathies

      The evidence-based assessment regarding accessibility of allogeneic HSCT versus gene therapy in hemoglobinopathies takes into consideration location, follow-up needs and patient eligibility and is summarized in Table 5.
      Table 5Evidence Based Assessment of Accessibility of allogeneic HCT and autologous gene therapy
      • Location
      • Both allogeneic HCT and autologous HCT after genetic modification require specialized centers for stem cell collection and processing, therefore HCT is more feasible and practical in developed countries
      • Follow-up
      • Patients require optimized long-term healthcare monitoring of nearly every organ system to ensure post-transplant well-being and early recognition of late complications.
      • Gene therapy follow-up is likely to be less onerous given lack of allogeneic specific complications, therefore gene therapy follow-up may ultimately be more feasible for developing countries provided the follow-up care is minimal.
      • Though the complexity of gene therapy requires a specialized center, the reduced monitoring required post-HCT may allow patients to be treated in a centralized center but return to their local center for monitoring.
      • Both allogeneic HCT and gene therapy require continued monitoring for the development of malignancy post-HCT
      • Eligibility
      • In the current format of using chemotherapy, allogeneic HCT is more feasible for patients with pre-existing co- morbidity as reduced toxicity conditioning regimens are available
      • Myeloablative therapy, and by extension gene therapy in its current form, is limited by the short and long-term toxicities of conditioning
      • Gene therapy eligibility is dependent on the ability to collect a sufficient number of CD34+ cells to generate a gene therapy product

      Location

      Both allogeneic HSCT and gene therapy methods require specialized centers for patient care. Both modalities share a common pre-transplant period in which the ability to perform HLA screening and collect stem cells is required. During the peritransplant period, both modalities require prolonged hospitalization and adequate resources to support the patient through conditioning, cell infusion and engraftment. Resources necessary during this period include transfusion support, general laboratory services, pharmacy services, ability to screen for blood-borne infections, ability to escalate care in the event of known potential complications and medical expertise, particularly skilled nursing.
      Stem cell collection requires a skilled apheresis team and a stem cell processing laboratory. Gene therapy has the added complexity of cell manufacturing, requiring sophisticated labs that are Good Manufacturing Practice-certified. Additionally, all gene therapy applications are conducted in the setting of a clinical trial and therefore have extensive requirements for screening and monitoring that often include multiple specialties and a large investigative team.
      The significant infrastructure and health care provider training required to provide curative options for patients with TDT and SCD have prohibited wide adoption where the burden of disease is greatest. The highest prevalence of disease is found in low- and middle-income countries, where easy access to medical care may be limited. Models for HSCT program development exist and include establishing a global partnership, developing infrastructure and building human resource capacity [
      • Yeh AC
      • Khan MA
      • Harlow J
      • Biswas AR
      • Akter M
      • Ferdous J
      • et al.
      Hematopoietic Stem-Cell Transplantation in the Resource-Limited Setting: Establishing the First Bone Marrow Transplantation Unit in Bangladesh.
      ]; however, the long-term sustainability of such programs often depends on government resources, which are often limited. Positive patient outcomes and an economic justification for maintenance of HSCT programs are therefore imperative. At the present time, given the breadth of experience and data in the allogeneic setting, exportability may be more suited to allogeneic HSCT than gene therapy.

      Follow-up needs

      HSCT conditioning requires myelosuppression to prevent outcompetition by host HSCs and immunosuppression to prevent graft rejection and GVHD. As a result, patients continue to be immunocompromised and require close monitoring and follow-up over a period of months to years. Many variables impact the timing of immune reconstitution, including the conditioning regimen used, source of stem cells and any required manipulation to the graft, degree of HLA match, immunosuppressive therapy, presence of GVHD and use of steroids.
      Gene therapy methods have the advantage of not requiring post-HSCT immunosuppression for the prevention of GVHD. Gene therapy follow-up is therefore likely less onerous, focusing only on disease resolution and monitoring for malignancy and long-term complications.
      Patients require optimized long-term health care monitoring of nearly every organ system to ensure post-transplant well-being and early recognition of late complications. A consensus summary reviewing late effects after HSCT in children with SCD and thalassemia [
      • Shenoy S
      • Angelucci E
      • Arnold SD
      • Baker KS
      • Bhatia M
      • Bresters D
      • et al.
      Current Results and Future Research Priorities in Late Effects after Hematopoietic Stem Cell Transplantation for Children with Sickle Cell Disease and Thalassemia: A Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric Hematopoietic Stem Cell Transplantation.
      ] has now been followed up with comprehensive late effects screening guidelines [
      • Shenoy S
      • Gaziev J
      • Angelucci E
      • King A
      • Bhatia M
      • Smith A
      • et al.
      Late Effects Screening Guidelines after Hematopoietic Cell Transplantation (HCT) for Hemoglobinopathy: Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric HCT.
      ]. Specifically with regard to patients with TDT, the guidelines focus on organ toxicities associated with iron overload and the susceptibility to hepatic veno-occlusive disease. For patients with SCD, monitoring of the central nervous system as well as cardiac, pulmonary and renal systems, in addition to continued management of chronic pain, is critical.
      For both TDT and SCD, hypogonadism and risk of infertility are high both pre- and post-HSCT as a result of iron overload, HU use and recurrent priapism in SCD as well as HSCT conditioning regimens. Risks are impacted by the stage of pubertal development at HSCT [
      • Walters MC
      • Hardy K
      • Edwards S
      • Adamkiewicz T
      • Barkovich J
      • Bernaudin F
      • et al.
      Pulmonary, gonadal, and central nervous system status after bone marrow transplantation for sickle cell disease.
      ,
      • Borgmann-Staudt A
      • Rendtorff R
      • Reinmuth S
      • Hohmann C
      • Keil T
      • Schuster FR
      • et al.
      Fertility after allogeneic haematopoietic stem cell transplantation in childhood and adolescence.
      ,
      • Smith-Whitley K.
      Reproductive issues in sickle cell disease.
      ] and the preparative regimen utilized [
      • King AA
      • Kamani N
      • Bunin N
      • Sahdev I
      • Brochstein J
      • Hayashi RJ
      • et al.
      Successful matched sibling donor marrow transplantation following reduced intensity conditioning in children with hemoglobinopathies.
      ,
      • Madden LM
      • Hayashi RJ
      • Chan KW
      • Pulsipher MA
      • Douglas D
      • Hale GA
      • et al.
      Long-Term Follow-Up after Reduced-Intensity Conditioning and Stem Cell Transplantation for Childhood Nonmalignant Disorders.
      ]. Presumably, gonadal dormancy and shorter exposure to iron overload contribute to better preservation of fertility when HSCT is performed early in life [
      • De Sanctis V
      • Galimberti M
      • Lucarelli G
      • Polchi P
      • Ruggiero L
      • Vullo C.
      Gonadal function after allogenic bone marrow transplantation for thalassaemia.
      ]; however, when not possible, hormonal therapy may be of benefit [
      • Madden LM
      • Hayashi RJ
      • Chan KW
      • Pulsipher MA
      • Douglas D
      • Hale GA
      • et al.
      Long-Term Follow-Up after Reduced-Intensity Conditioning and Stem Cell Transplantation for Childhood Nonmalignant Disorders.
      ,
      • Gharwan H
      • Neary NM
      • Link M
      • Hsieh MM
      • Fitzhugh CD
      • Sherins RJ
      • et al.
      Successful fertility restoration after allogeneic hematopoietic stem cell transplantation.
      ,
      • Rahal I
      • Galambrun C
      • Bertrand Y
      • Garnier N
      • Paillard C
      • Frange P
      • et al.
      Late effects after hematopoietic stem cell transplantation for beta-thalassemia major: the French national experience.
      ,
      • Santarone S
      • Natale A
      • Olioso P
      • Onofrillo D
      • D'Incecco C
      • Parruti G
      • et al.
      Pregnancy outcome following hematopoietic cell transplantation for thalassemia major.
      ,
      • Bernaudin F
      • Dalle JH
      • Bories D
      • de Latour RP
      • Robin M
      • Bertrand Y
      • et al.
      Long-term event-free survival, chimerism and fertility outcomes in 234 patients with sickle-cell anemia younger than 30 years after myeloablative conditioning and matched-sibling transplantation in France.
      ].

      Patient eligibility

      HSCT morbidity is significantly influenced by the preparative conditioning regimen regardless of whether allogeneic or autologous HSCT methodology is used. Therefore, the broad applicability of either curative therapy is limited by the patient's disease status and ability to undergo conditioning.
      Unlike current allogeneic HSCT protocols, almost all gene therapy studies utilize myeloablative conditioning to maximize marrow repopulation with genetically modified cells (exception, NCT02186418). In the allogeneic setting, 20–25% donor myeloid chimerism is sufficient to reverse the sickle phenotype in SCD [
      • Abraham A
      • Cluster A
      • Jacobsohn D
      • Delgado D
      • Hulbert ML
      • Kukadiya D
      • et al.
      Unrelated Umbilical Cord Blood Transplantation for Sickle Cell Disease Following Reduced-Intensity Conditioning: Results of a Phase I Trial.
      ,
      • Fitzhugh CD
      • Cordes S
      • Taylor T
      • Coles W
      • Roskom K
      • Link M
      • et al.
      At least 20% donor myeloid chimerism is necessary to reverse the sickle phenotype after allogeneic HSCT.
      ], and chimerism as low as 10% has been reported in TDT [
      • Alfred A
      • Vora AJ
      What is the minimum level of donor chimerism necessary to sustain transfusion independence in thalassaemia?.
      ]; therefore, RIC is possible and may be preferred, though early and late graft failure remains a challenge. RIC allows access to curative therapies for a greater number of patients who may have substantial comorbidities and be otherwise unable to tolerate myeloablation.
      There are also additional patient factors that may limit either therapy. A history of antibodies directed against either donor HLA or red cell antigens may preclude a patient from undergoing haploidentical HSCT because of the increased risk of graft rejection and pure red cell aplasia post-HSCT. Desensitization approaches such as plasmapheresis combined with anti-B-cell antibodies (rituximab) and immune modulators (bortezomib) have been used to overcome these concerns in some cases [
      • Ciurea SO
      • Cao K
      • Fernandez-Vina M
      • Kongtim P
      • Malki MA
      • Fuchs E
      • et al.
      Correction: The European Society for Blood and Marrow Transplantation (EBMT) Consensus Guidelines for the Detection and Treatment of Donor-specific Anti-HLA Antibodies (DSA) in Haploidentical Hematopoietic Cell Transplantation.
      ,
      • Ciurea SO
      • Cao K
      • Fernandez-Vina M
      • Kongtim P
      • Malki MA
      • Fuchs E
      • et al.
      The European Society for Blood and Marrow Transplantation (EBMT) Consensus Guidelines for the Detection and Treatment of Donor-specific Anti-HLA Antibodies (DSA) in Haploidentical Hematopoietic Cell Transplantation.
      ]. With regard to gene therapy, success is dependent on safely obtaining a sufficient quantity of autologous SCD patient HSCs to enable lifelong engraftment. In patients with SCD, steady-state BM harvesting is associated with suboptimal HSC quality and yield [
      • Leonard A
      • Bonifacino A
      • Dominical VM
      • Luo M
      • Haro-Mora JJ
      • Demirci S
      • et al.
      Bone marrow characterization in sickle cell disease: inflammation and stress erythropoiesis lead to suboptimal CD34 recovery.
      ], and PBSC mobilization with granulocyte colony-stimulating factor is contraindicated [
      • Abboud M
      • Laver J
      • Blau CA.
      Granulocytosis causing sickle-cell crisis.
      ,
      • Adler BK
      • Salzman DE
      • Carabasi MH
      • Vaughan WP
      • Reddy VV
      • Prchal JT.
      Fatal sickle cell crisis after granulocyte colony-stimulating factor administration.
      ,
      • Fitzhugh CD
      • Hsieh MM
      • Bolan CD
      • Saenz C
      • Tisdale JF.
      Granulocyte colony-stimulating factor (G-CSF) administration in individuals with sickle cell disease: time for a moratorium?.
      ], though single-agent plerixafor mobilization appears to be safe and effective [
      • Boulad F
      • Shore T
      • van Besien K
      • Minniti C
      • Barbu-Stevanovic M
      • Fedus SW
      • et al.
      Safety and efficacy of plerixafor dose escalation for the mobilization of CD34(+) hematopoietic progenitor cells in patients with sickle cell disease: interim results.
      ,
      • Esrick EB
      • Manis JP
      • Daley H
      • Baricordi C
      • Trebeden-Negre H
      • Pierciey FJ
      • et al.
      Successful hematopoietic stem cell mobilization and apheresis collection using plerixafor alone in sickle cell patients.
      ,
      • Lagresle-Peyrou C
      • Lefrere F
      • Magrin E
      • Ribeil JA
      • Romano O
      • Weber L
      • et al.
      Plerixafor enables safe, rapid, efficient mobilization of hematopoietic stem cells in sickle cell disease patients after exchange transfusion.
      ,
      • Uchida N
      • Leonard A
      • Stroncek D
      • Panch SR
      • West K
      • Molloy E
      • et al.
      Safe and efficient peripheral blood stem cell collection in patients with sickle cell disease using plerixafor.
      ]. Some patients may be unable to mobilize a sufficient number of CD34+ cells following plerixafor administration to generate a gene therapy product. It is likely that these patient factors will be less of a concern in pediatric patients, who have better overall organ function and less exposure to RBC antigens from a lifetime of RBC transfusions, and this is a compelling reason to offer these therapies earlier in the disease course.

      Cost

      The evidence-based assessment regarding the cost of allogeneic HSCT versus gene therapy in hemoglobinopathies takes into consideration the cost of standard of care versus allogeneic HSCT versus gene therapy and is summarized in Table 6.
      Table 6Evidence Based Assessment of Cost of allogeneic HCT and autologous gene therapy
      • Cost of allogeneic HCT
      • The cost of allogeneic HSC is dependent on donor source, preparative regimen (myeloablative vs. non-myeloablative) and the risk for post-transplant complications
      • Cost of gene therapy vs. allogeneic HCT
      • In the U.S. and Europe gene therapy is more expensive than allogeneic HSC due to increased manufacturing demands
      • Gene therapy may ultimately be the more feasible for developing countries provided the follow-up care is minimal. This may allow patients to be treated in a centralized center but return to local center for monitoring
      • While upfront costs of either approach may be high, quality-adjusted life-years gained and potential to reduce overall lifetime healthcare costs may render curative therapy cost-effective
      • To make curative therapies financially feasible, there is a need to shift from fee-for-service to a value-based payment system

      Cost of standard care for Hb disorders

      Both TDT and SCD are chronic diseases with high health care utilization; therefore, management becomes more costly over time. Costs for patients with TDT are associated with regular transfusions, iron chelation therapy and monitoring and management of complications, including iron overload and infections [
      • Borgna-Pignatti C
      • Cappellini MD
      • De Stefano P
      • Del Vecchio GC
      • Forni GL
      • Gamberini MR
      • et al.
      Survival and complications in thalassemia.
      ]. SCD is a chronic, debilitating condition that causes increased organ damage over time. In the US, SCD accounts for an estimated $1.6 billion per year in health care costs [
      • Kauf TL
      • Coates TD
      • Huazhi L
      • Mody-Patel N
      • Hartzema AG.
      The cost of health care for children and adults with sickle cell disease.
      ]. For a patient with TDT who survives to age 50, total health care costs are estimated to be $720,201 (£483,454) [
      • Weidlich D
      • Kefalas P
      • Guest JF.
      Healthcare costs and outcomes of managing beta-thalassemia major over 50 years in the United Kingdom.
      ], and total health care costs are estimated to exceed $8 million in a patient with SCD [
      • Ballas SK.
      The cost of health care for patients with sickle cell disease.
      ]. When addressing health care costs, however, hidden costs are often not factored into health care estimates, including loss of wages due to frequent health care visits, unemployment among patients and parents and reduced quality of life. Although advances in iron chelation in TDT, maximizing HU therapy in SCD and the discovery of new therapeutics improve disease management, a greater focus on curative approaches for these diseases might also represent a suitable strategy for reducing personal lifetime health care costs and improving quality of life.

      Cost of allogeneic HSCT in Hb disorders

      In the US, the majority of HSCT costs (>75%) for both autologous and allogeneic patients occur during the initial transplant hospitalization and are estimated to be $100,000 for autologous HSCT and $200,000 for allogeneic HSCT during the first 100 days post-HSCT [
      • Majhail NS
      • Mau LW
      • Denzen EM
      • Arneson TJ.
      Costs of autologous and allogeneic hematopoietic cell transplantation in the United States: a study using a large national private claims database.
      ]. Average HSCT cost per patient with TDT is $251,723 (€215,571) [
      • Coquerelle S
      • Ghardallou M
      • Rais S
      • Taupin P
      • Touzot F
      • Boquet L
      • et al.
      Innovative Curative Treatment of Beta Thalassemia: Cost-Efficacy Analysis of Gene Therapy Versus Allogenic Hematopoietic Stem-Cell Transplantation.
      ], though significantly lower costs have been approximated in resource-limited countries [
      • Swaminathan VV
      • Uppuluri R
      • Patel S
      • Ravichandran N
      • Ramanan KM
      • Vaidhyanathan L
      • et al.
      Matched Family versus Alternative Donor Hematopoietic Stem Cell Transplantation for Patients with Thalassemia Major: Experience from a Tertiary Referral Center in South India.
      ]. Median HSCT cost per patient with SCD is estimated at $467,747 (range, $344,029–799,219) [
      • Arnold SD
      • Brazauskas R
      • He N
      • Li Y
      • Aplenc R
      • Jin Z
      • et al.
      Clinical risks and healthcare utilization of hematopoietic cell transplantation for sickle cell disease in the USA using merged databases.
      ], though this may be nearly 50% lower in patients who receive a non-myeloablative regimen [
      • Saenz C
      • Tisdale JF.
      Assessing Costs, Benefits, and Risks in Chronic Disease: Taking the Long View.
      ]. Such costs therefore limit these therapies to developed countries and countries with higher gross national incomes, governmental health care expenditures and team densities [
      • Gratwohl A
      • Baldomero H
      • Aljurf M
      • Pasquini MC
      • Bouzas LF
      • Yoshimi A
      • et al.
      Hematopoietic stem cell transplantation: a global perspective.
      ]. Nevertheless, resource-limited settings have an increased interest in developing HSCT programs given the potential ability to cure chronic, debilitating and expensive diseases such as TDT and SCD. Although the upfront costs of HSCT are high, chronic diseases exert their deleterious effects over the long term, and interventions that seek to change the course of the disease may be economically justified [
      • Saenz C
      • Tisdale JF.
      Assessing Costs, Benefits, and Risks in Chronic Disease: Taking the Long View.
      ]. Ultimately, the quality-adjusted life-years gained for the patient and the potential to reduce overall lifetime health care costs may render curative therapy cost-effective [
      • Leonard A
      • Tisdale JF.
      Stem cell transplantation in sickle cell disease: therapeutic potential and challenges faced.
      ].

      Comparison of projected gene therapy costs in the US and Europe versus allogeneic HSCT

      Costs for gene therapy are less certain and suggested to be as high as $900,000–2.1 million [

      Jensen K. Bluebird proposes installment plan for LentiGlobin gene therapy2019. Available from: https://www.biopharmadive.com/news/jpm19-bluebird-proposes-installment-plan-for-lentiglobin-gene-therapy/545646/. Accessed 1 June 2021.

      ], severely limiting real-world applicability. In the current market, the majority of expenses for gene therapy occur in the pre-transplant period given the complexity of DP collection, manufacture and compliance with safety and regulatory standards in addition to the more intensive preparatory patient management leading up to HSCT. During HSCT, total average medical costs excluding vector costs have been shown to be relatively homogeneous among patients with TDT treated with either allogeneic HSCT (£173,497) or gene therapy (£188,334) [
      • Coquerelle S
      • Ghardallou M
      • Rais S
      • Taupin P
      • Touzot F
      • Boquet L
      • et al.
      Innovative Curative Treatment of Beta Thalassemia: Cost-Efficacy Analysis of Gene Therapy Versus Allogenic Hematopoietic Stem-Cell Transplantation.
      ]. Patients treated with gene therapy have lower costs in the follow-up period owing to fewer infectious complications, treatments, imaging, outpatient care and inpatient admissions. Gene therapy patients have fewer productivity losses, experience fewer complications and hospital admissions and have a shorter length of hospital stay, but gene therapy costs on average an additional £300,000–400,000 per patient. Nearly half of this total cost is due to expenses associated with the vector, whereas nearly half of the cost of allogeneic HSCT is due to outpatient care and inpatient admissions. An increase in manufacturer competition and evolution of practices should decrease these manufacturing costs. Increasing the number of patients treated and factoring in age and weight at the time of collection/manufacture could further impact manufacturing costs. Finally, gene editing techniques that utilize more readily available and inexpensive editing tools and eliminate the costly vector component may reduce the overall expenditure and increase the potential broader feasibility of gene therapy.
      To justify the additional costs associated with gene therapy, comparing clinical effectiveness with established curative options, assessing value and determining affordability are necessary [
      • Hampson G
      • Towse A
      • Pearson SD
      • Dreitlein WB
      • Henshall C.
      Gene therapy: evidence, value and affordability in the US health care system.
      ]. Gene therapy trials are non-randomized, single-arm trials using historical cohorts for comparison; therefore, there may be an overestimation of benefit [
      • Hettle R
      • Corbett M
      • Hinde S
      • Hodgson R
      • Jones-Diette J
      • Woolacott N
      • et al.
      The assessment and appraisal of regenerative medicines and cell therapy products: an exploration of methods for review, economic evaluation and appraisal.
      ]. The assessment of value is similar for allogeneic HSCT versus gene therapy, as curative therapies may be valued more highly by society than treatments that reduce but do not eliminate ongoing costs of patient support and management of chronic comorbidities. Payers typically focus on health gains for the patient and net direct costs to the health system when evaluating payment for therapy, though this does not take into account hidden patient costs. For patients with TDT and SCD, this equates to easily measurable outcomes such as a reduced need for transfusions, hospitalizations, emergency room visits, prescription medications such as treatment for iron overload or acute and chronic pain and health care utilization overall. This does not, however, account for improved quality of life, steady employment, increased wages or other productivity gains. To assess the full financial impact, long-term savings, hidden costs, quality-adjusted life-year adjustments and productivity gains and losses should be included in affordability considerations. Based on the initial pricing experience with gene therapy in Europe, with an estimated upfront treatment price of over US$1 million per patient, the cumulative budget impact is not sustainable. According to health policy experts, “The cumulative budget impact at that price could rise to US$3 trillion, as much as is currently spent in a year on all health care in the USA” [
      • Hampson G
      • Towse A
      • Pearson SD
      • Dreitlein WB
      • Henshall C.
      Gene therapy: evidence, value and affordability in the US health care system.
      ]. Although there may be a cost benefit to gene editing strategies over vector-based therapies, there are too little data to suggest a clear benefit of one gene therapy methodology over another at this time. Having multiple gene therapy strategies investigated is of utmost benefit to patients who are in search of curative therapies and whose options are limited by donor selection. Data from multiple methodologies maturing simultaneously will help to identify whether there is a superior method, as identified by measurable outcomes, sustainability of therapy (Hb production) over time and safety, all while simultaneously bringing competition into the manufacturing market.
      Ultimately, the gene therapy cost model may need to shift from fee-for-service to value-based payment systems [

      Gregory Daniel NL, Jeff Marrazzo, Mark B. McClellan. Advancing Gene Therapies And Curative Health Care Through Value-Based Payment Reform2017. Available from: https://www.healthaffairs.org/do/10.1377/hblog20171027.83602/full/. Accessed 1 June 2021.

      ]. One proposal suggests that 80% of the cost of gene therapy is put at risk to prove the value of its treatment; after an initial upfront charge, DP manufacturers would get paid only if the one-time infusion continued to benefit patients. Recently, the US Centers for Medicare & Medicaid Services presented a proposal to ease value-based payment models for gene therapies, increasing payer price negotiating power and the ability to arrange payment based on outcome over quantity [

      Services CfMM. Medicaid Program; Establishing Minimum Standards in Medicaid State Drug Utilization Review (DUR) and Supporting Value-Based Purchasing (VBP) for Drugs Covered in Medicaid, Revising Medicaid Drug Rebate and Third Party Liability (TPL) Requirements. 2020. p. 37286-322. Accessed 1 June 2021.

      ]. Other proposed mechanisms for handling affordability include reinsurance, consumer loans, third-party financing, manufacturer-managed financing and government financing, though many of these remain untested and impractical [
      • Hampson G
      • Towse A
      • Pearson SD
      • Dreitlein WB
      • Henshall C.
      Gene therapy: evidence, value and affordability in the US health care system.
      ]. In the current form, the financial burdens of gene therapy preclude the inclusion of this treatment as a realistic option for a cure available to all.

      Discussion

      TDT and SCD are growing global health disorders with limited disease-modifying therapies. Both TDT and SCD can be cured by HSCT, with recent evidence suggesting that gene modification of autologous HSCs could become a universal cure. Allogeneic transplantation is limited by donor selection, morbidity and mortality related to transplant conditioning, GVHD and graft rejection, whereas significant concerns regarding long-term safety, efficacy and cost limit the broad applicability of gene therapy. Patient-specific factors and location further limit the widespread applicability of curative therapies. Therefore, strategies that aim to improve patient outcomes, reduce disease morbidity and dramatically reduce costs are needed to improve the lives of millions of patients with hereditary hemoglobinopathies.

      Declaration of Competing Interest

      JJB is a member of the International Society for Cell & Gene Therapy Stem Cell Engineering Committee and consults for Avrobio, BlueRock Therapeutics, Race Oncology, Advanced Clinical, Omeros, Sanofi and Medexus Pharmaceuticals. AAA served on the safety monitoring committee for Sangamo Therapeutics. CB consults for Zodiac Pharmaceuticals, Amgen and Novartis. SP receives support for the conduct of clinical trials through Memorial Sloan Kettering from AlloVir, Atara Biotherapeutics and Jasper Therapeutics and is the inventor of intellectual property related to the development of a third-party, virus-specific T-cell program, with all rights assigned to Memorial Sloan Kettering.

      Funding

      No funding was received.

      Author Contributions

      All authors have approved the final article. All authors contributed to conception/design, acquisition of data, analysis/interpretation, drafting/revising.

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