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Cited by 684Virus-based gene therapy researchHemoglobinopathies and Related DisordersHematopoietic Stem Cell Transplantation

Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia

Open access
Thompson, Alexis A., Walters, Mark C., Kwiatkowski, Janet, Rasko, John E.J., Ribeil, Jean-Antoine, Hongeng, Suradej, Magrin, Elisa, Schiller, Gary J. +39 more·2018·New England Journal of Medicine
DOI 10.1056/nejmoa1705342
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Abstract

Background Donor availability and transplantation-related risks limit the broad use of allogeneic hematopoietic-cell transplantation in patients with transfusion-dependent β-thalassemia. After previously establishing that lentiviral transfer of a marked β-globin (β A-T87Q ) gene could substitute for long-term red-cell transfusions in a patient with β-thalassemia, we wanted to evaluate the safety and efficacy of such gene therapy in patients with transfusion-dependent β-thalassemia. Methods In two phase 1-2 studies, we obtained mobilized autologous CD34+ cells from 22 patients (12 to 35 years of age) with transfusion-dependent β-thalassemia and transduced the cells ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbA T87Q ). The cells were then reinfused after the patients had undergone myeloablative busulfan conditioning. We subsequently monitored adverse events, vector integration, and levels of replication-competent lentivirus. Efficacy assessments included levels of total hemoglobin and HbA T87Q , transfusion requirements, and average vector copy number. Results At a median of 26 months (range, 15 to 42) after infusion of the gene-modified cells, all but 1 of the 13 patients who had a non-β 0 /β 0 genotype had stopped receiving red-cell transfusions; the levels of HbA T87Q ranged from 3.4 to 10.0 g per deciliter, and the levels of total hemoglobin ranged from 8.2 to 13.7 g per deciliter. Correction of biologic…

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Crossref · 10.1056/nejmoa1705342

Cites

41 of 41 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

10 of 27 cited sources checked · 4 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Risks of serious complications from transfusion-related iron toxicity and viral infections persist despite improvements in care.

    “The risks of serious complications from transfusion-related iron toxicity and viral infections persist despite improvements in care.10,11”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [10] 10. Tubman VN, Fung EB, Vogiatzi M, et al. Guidelines for the standard monitoring of patients with thalassemia: report of the Thalassemia Longitudinal Cohort. J Pedi- atr Hematol Oncol 2015; 37(3): e162-e169. source
    • cites [11] 11. Bonifazi F, Conte R, Baiardi P, et al. Pattern of complications and burden of disease in patients affected by beta thal- assemia major. Curr Med Res Opin 2017; 33: 1525-33. source
  • Premisecitation

    The current standard of care for patients with β-thalassemia consists of lifelong, regular red-cell transfusions and iron chelation.

    “Thus, the current standard of care for patients with β-thalassemia consists of lifelong, regular red-cell transfusions and iron chelation.9”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [9] 9. Engert A, Balduini C, Brand A, et al. The European Hematology Association Roadmap for European Hematology Re- search: a consensus document. Haemato- logica 2016; 101: 115-208. source

      The Introduction mentions thalassemia as an inherited blood disease but does not describe its standard care. Searches for regular transfusions, iron chelation, and thalassemia treatment found relevant titles in the References, not a passage in the cited paper stating the claimed regimen. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
  • Findingcitation

    Limited changes in the LentiGlobin vector (HPV569 vs. BB305) did not significantly alter the expression of βA-T87Q-globin per integrated vector copy.

    “Limited changes in the LentiGlobin vector (HPV569 vs. BB305) did not significantly alter the expression of β A-T87Q -globin per integrated vector copy, but they contributed (along with changes in vector manufacturing) to an increase in vector titers by a factor of approximately 4. 14,24,37”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [14] 14. Negre O, Eggimann AV, Beuzard Y, et al. Gene therapy of the β-hemoglobin- opathies by lentiviral transfer of the β(A(T87Q))-globin gene. Hum Gene Ther 2016; 27: 148-65. source

      The BB305 lentiviral vector section says BB305 is identical to HPV569 after integration except for removal of the cHS4 insulator, whose effect on transgene expression was limited. It does not report a direct comparison of βA-T87Q-globin expression per integrated vector copy or establish that the difference was statistically nonsignificant. No page number is available in our copy. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [24] 24. Negre O, Bartholomae C, Beuzard Y, et al. Preclinical evaluation of efficacy and safety of an improved lentiviral vector for the treatment of β-thalassemia and sickle cell disease. Curr Gene Ther 2015; 15: 64-81. source
    • cites [37] 37. Walters MC, Thompson A, Hongeng S, et al. A phase 3 study to evaluate safety and efficacy of LentiGlobin gene therapy for transfusion-dependent beta-thalassemia in patients with non-beta0/beta0 geno- types: the Northstar-2 (HGB-207) trial. Haematologica 2017; 102: 335. abstract.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • Rests on an assumption: The BB305 vector is similar to the initial HPV569 vector.
  • Findingcitation

    Changes in the LentiGlobin vector (HPV569 vs. BB305) and vector manufacturing contributed to an increase in vector titers by a factor of approximately 4.

    “Limited changes in the LentiGlobin vector (HPV569 vs. BB305) did not significantly alter the expression of β A-T87Q -globin per integrated vector copy, but they contributed (along with changes in vector manufacturing) to an increase in vector titers by a factor of approximately 4. 14,24,37”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [14] 14. Negre O, Eggimann AV, Beuzard Y, et al. Gene therapy of the β-hemoglobin- opathies by lentiviral transfer of the β(A(T87Q))-globin gene. Hum Gene Ther 2016; 27: 148-65. source

      The BB305 lentiviral vector section (page unavailable) reports that changes from HPV569 to BB305 increased vector titers 3–4-fold, supporting the approximate fourfold figure. The Production of lentiviral vectors section describes manufacturing, but does not say manufacturing changes contributed to that increase. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [24] 24. Negre O, Bartholomae C, Beuzard Y, et al. Preclinical evaluation of efficacy and safety of an improved lentiviral vector for the treatment of β-thalassemia and sickle cell disease. Curr Gene Ther 2015; 15: 64-81. source
    • cites [37] 37. Walters MC, Thompson A, Hongeng S, et al. A phase 3 study to evaluate safety and efficacy of LentiGlobin gene therapy for transfusion-dependent beta-thalassemia in patients with non-beta0/beta0 geno- types: the Northstar-2 (HGB-207) trial. Haematologica 2017; 102: 335. abstract.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • Rests on an assumption: The BB305 vector is similar to the initial HPV569 vector.
  • Premisecitation

    The feasibility of adding a gene to autologous hematopoietic cells using a lentiviral vector was shown previously in a single patient with β-thalassemia who safely discontinued transfusions for more than 6 years with ongoing, sustained βA-T87Q-globin expression.

    “The feasibility of the addition of a gene to autologous hematopoietic cells using a lentiviral vector was shown previously in a single patient with β-thalassemia who safely discontinued transfusions for more than 6 years with ongoing, sustained β A-T87Q -globin expression.14,20”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [14] 14. Negre O, Eggimann AV, Beuzard Y, et al. Gene therapy of the β-hemoglobin- opathies by lentiviral transfer of the β(A(T87Q))-globin gene. Hum Gene Ther 2016; 27: 148-65. source
    • cites [20] 20. Cavazzana-Calvo M, Payen E, Negre O, et al. Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia. Nature 2010; 467: 318-22. source
  • Classified as probably not a substantial claim. 5
  • May combine two claims. 30

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    An earlier study at Memorial Sloan Kettering Cancer Center was suspended to allow for testing of a revised lentiviral vector.

    “whereas an earlier study at Memorial Sloan Kettering Cancer Center was suspended to allow for testing of a revised lentiviral vector.13”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [13] 13. Mansilla-Soto J, Riviere I, Boulad F, Sadelain M. Cell and gene therapy for the beta-thalassemias: advances and pros- pects. Hum Gene Ther 2016; 27: 295-304. source

      The Phase I Clinical Trials section describes the New York trial and says the authors planned to resume it with a modified lentiviral vector containing an added safety element. That supports a pause and a planned vector revision, but the paper does not say the trial was suspended to allow testing of the revised vector. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Another phase 1/2 study of lentiviral vector-mediated gene therapy in patients with β-thalassemia is ongoing in Italy and has shown reductions in transfusion requirements.

    “Another phase 1/2 study of lentiviral vectormediated gene therapy in patients with β-thalassemia is ongoing in Italy and has shown reductions in transfusion requirements, 14”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [14] 14. Negre O, Eggimann AV, Beuzard Y, et al. Gene therapy of the β-hemoglobin- opathies by lentiviral transfer of the β(A(T87Q))-globin gene. Hum Gene Ther 2016; 27: 148-65. source

      The Introduction’s Table 2 identifies an ongoing phase I/II lentiviral gene-therapy study for β-thalassemia in Italy. It reports only that the first patient was recently treated, not a reduction in transfusion requirements; the decrease it reports belongs to a separate US trial. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingnone given

    The preenrollment transfusion requirement, spleen status, and age were not observed to have an effect on the study outcome.

    “The preenrollment transfusion requirement, spleen status, and age were not observed to have an effect on the study outcome.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At the last study visit (12 to 36 months after infusion), the median HbA T87Q level was 6.0 g per deciliter (range, 3.4 to 10.0), and the median total hemoglobin level was 11.2 g per deciliter (range, 8.2 to 13.7).

    “At the last study visit (12 to 36 months after infusion), the median HbA T87Q level was 6.0 g per deciliter (range, 3.4 to 10.0), and the median total hemoglobin level was 11.2 g per deciliter (range, 8.2 to 13.7)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Neutrophil engraftment occurred within a median of 18.5 days (range, 14.0 to 30.0) in HGB-204 and 16.5 days (range, 14.0 to 29.0) in HGB-205.

    “neutrophil engraftment occurred within a median of 18.5 days (range, 14.0 to 30.0) in HGB-204 and 16.5 days (range, 14.0 to 29.0) in HGB-205.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At the most recent follow-up (12 to 30 months), the patients' HbA T87Q level ranged from 6.6 to 8.2 g per deciliter, and the total hemoglobin level ranged from 8.3 to 10.2 g per deciliter.

    “At the most recent follow-up (12 to 30 months), the patients' HbA T87Q level ranged from 6.6 to 8.2 g per deciliter, and the total hemoglobin level ranged from 8.3 to 10.2 g per deciliter.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Patient 1121, who had a vector copy number of 0.3 in the drug product, had a blood vector copy number of 0.10 at the last follow-up and continued to receive red-cell transfusions.

    “Patient 1121, who had a vector copy number of 0.3 in the drug product, had a blood vector copy number of 0.10 at the last follow-up and continued to receive red-cell transfusions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    After receiving the drug product, Patient 1003 had received no red-cell transfusions during year 2 through year 8 while maintaining a total hemoglobin level of approximately 8 g per deciliter.

    “After receiving the drug product, Patient 1003 had received no red-cell transfusions during year 2 through year 8 while maintaining a total hemoglobin level of approximately 8 g per deciliter.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    During year 9 through year 12, Patient 1003 resumed sporadic transfusions, although the HbA T87Q levels had remained stable above 2 g per deciliter since month 18.

    “During year 9 through year 12, the patient resumed sporadic transfusions, although the HbA T87Q levels had remained stable above 2 g per deciliter since month 18 20”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At the time of this report (year 12), the HMGA2 locus was no longer dominant in Patient 1003 and had not been associated with serious adverse events.

    “At the time of this report (year 12), the HMGA2 locus was no longer dominant in Patient 1003 and had not been associated with serious adverse events.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In HGB-205, in an exploratory analysis among patients who had stopped receiving red-cell transfusions after gene therapy, the degree of hemolysis at first stabilized relative to pretransplantation levels and was fully corrected in Patients 1201 and 1202 by 36 months after treatment.

    “In HGB-205, in an exploratory analysis that was performed among patients who had stopped receiving red-cell transfusions after gene therapy, the degree of hemolysis at first stabilized relative to pretransplantation levels and was fully corrected in Patients 1201 and 1202 by 36 months after treatment”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    BB305 and other lentiviral vectors have been used in more than 50 patients thus far without vector-related adverse events.

    “BB305 and other lentiviral vectors have been used in more than 50 patients thus far without vector-related adverse events.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The median vector copy number at 15 months was 0.3 copies per diploid genome (range, 0.1 to 0.9) in HGB-204 and 2.0 copies per diploid genome (range, 0.3 to 4.2) in HGB-205.

    “The median vector copy number at 15 months was 0.3 copies per diploid genome (range, 0.1 to 0.9) in HGB-204 and 2.0 copies per diploid genome (range, 0.3 to 4.2) in HGB-205.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At 12 months after infusion, the median number of unique integration sites was 1646 per patient (range, 202 to 5501) in HGB-204 and 5322 (range, 756 to 8685) in HGB-205.

    “At 12 months after infusion, the median number of unique integration sites was 1646 per patient (range, 202 to 5501) in HGB-204 and 5322 (range, 756 to 8685) in HGB-205.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    These 12 patients had steady-state hemoglobin levels of at least 9 g per deciliter, except Patient 1118 who had more than 8 g per deciliter.

    “with steady-state hemoglobin levels of at least 9 g per deciliter (>8 g per deciliter in Patient 1118)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Of the 22 treated patients, 7 expressed at least 8 g per deciliter of HbA T87Q, including 3 patients with a β0/β0 genotype or the severe IVS1-110 mutation.

    “Of the 22 treated patients, 7 expressed at least 8 g per deciliter of HbA T87Q , including 3 patients with a β 0 /β 0 genotype or the severe IVS1-110 mutation; all have been free from transfusion for more than 1 year.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Patient 1118 received a single transfusion 13 months after drug product infusion during an acute viral illness.

    “In addition, Patient 1118 received a single transfusion 13 months after drug product infusion during an acute viral illness.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Nine serious adverse events were reported, including two episodes of veno-occlusive liver disease attributed to busulfan conditioning.

    “Nine serious adverse events were reported, including two episodes of veno-occlusive liver disease attributed to busulfan conditioning.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Of the 22 treated patients, 13 had a non-β0/β0 genotype, and all but 1 of these 13 stopped receiving red-cell transfusions after gene therapy.

    “Of the 22 patients who were treated, 13 had a non-β 0 /β 0 genotype.Of these 13 patients, all but 1 stopped receiving red-cell transfusions after gene therapy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the 2 years before study enrollment, the median annual red-cell transfusion volume was 164 ml per kilogram per year (range, 124 to 261) in HGB-204, including 183 ml per kilogram per year in the 8 patients with a β0/β0 genotype and 147 ml per kilogram per year in the 10 patients with other genotypes.

    “In the 2 years before study enrollment, the median annual red-cell transfusion volume was 164 ml per kilogram per year (range, 124 to 261), which included 183 ml per kilogram per year in the 8 patients with a β 0 /β 0 genotype and 147 ml per kilogram per year in the 10 patients with other genotypes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Platelet engraftment occurred within a median of 39.5 days (range, 19.0 to 191.0) in HGB-204 and 23.0 days (range, 20.0 to 26.0) in HGB-205, with no bleeding complications resulting in serious adverse events.

    “Platelet engraftment occurred within a median of 39.5 days (range, 19.0 to 191.0) in HGB-204 and 23.0 days (range, 20.0 to 26.0) in HGB-205, during which time there were no bleeding complications resulting in serious adverse events.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Patient 1202 is no longer receiving iron chelation therapy and completed phlebotomy 36 months after gene therapy.

    “Such discontinuation of treatment was reported in Patient 1202, who is no longer receiving iron chelation therapy and who completed phlebotomy 36 months after gene therapy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    In the current studies, genomewide mapping of chromosomal sites of vector integration showed a highly polyclonal pattern with no dominance observed.

    “In the current studies, genomewide mapping of chromosomal sites of vector integration showed a highly polyclonal pattern with no dominance observed.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In several treated patients, hemoglobin levels reached or approached normal ranges, thereby correcting dyserythropoiesis.

    “In several treated patients, hemoglobin levels reached or approached normal ranges, thereby correcting dyserythropoiesis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    One patient had normalization of iron overload and was able to discontinue both iron chelation and therapeutic phlebotomy.

    “One patient also had normalization of iron overload and was able to discontinue both iron chelation and therapeutic phlebotomy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Broad use of allogeneic hematopoietic-cell transplantation in patients with transfusion-dependent β-thalassemia is limited by donor availability and transplantation-related risks, and transplantation is primarily reserved for young children with an HLA-identical sibling donor.

    “Donor availability and transplantation-related risks limit the broad use of allogeneic hematopoietic-cell transplantation in patients with transfusion-dependent β-thalassemia.”
    • Also stated in: § RESULTS · plain
      “The only potentially curative option for β-thalassemia is allogeneic hematopoietic-cell transplantation, but owing to risks of graft rejection, graft-versus-host disease, and other treatment-related toxic effects, transplantation is primarily reserved for young children with an HLA-identical sibling donor.[6][7][8]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6][7][8]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Vector-encoded βA-T87Q-globin was engineered with a single amino acid substitution (T87Q) that strongly inhibits polymerization of sickle hemoglobin and permits precise quantification of vector-derived therapeutic globin expression in vivo.

    “Vector-encoded β A-T87Q -globin was engineered with a single amino acid substitution (T87Q) that strongly inhibits the polymerization of sickle hemoglobin in patients with sickle cell disease and also permits precise quantification of vector-derived therapeutic globin expression in vivo.23”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] 23. Takekoshi KJ, Oh YH, Westerman KW, London IM, Leboulch P. Retroviral trans- fer of a human beta-globin/delta-globin hybrid gene linked to beta locus control region hypersensitive site 2 aimed at the gene therapy of sickle cell disease. Proc Natl Acad Sci U S A 1995; 92: 3014-8. source

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    The treatment population, which included all the patients who had received the LentiGlobin BB305 drug product, was the primary population for this interim analysis, and data were analyzed separately for each study.

    “The treatment population, which included all the patients who had received the LentiGlobin BB305 drug product, was the primary population for this interim analysis, and data were analyzed separately for each study.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Independent data and safety monitoring committees regularly reviewed safety data.

    “Independent data and safety monitoring committees regularly reviewed safety data.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Even the partial reduction in transfusion requirements observed in patients with a β0/β0 genotype may result in a reduction in iron loading and in increased life expectancy.

    “even the partial reduction in transfusion requirements that we observed in these patients may result in a reduction in iron loading (and thereby long-term damage to target organs) and in increased life expectancy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Two protocol-related features may have had an effect on efficacy: an enhanced series of red-cell transfusions before harvesting of CD34+ cells and monitoring of plasma busulfan concentrations with dose adjustments to optimize myeloablation.

    “In addition, two other protocol-related features may have had an effect on efficacy: an enhanced series of red-cell transfusions before harvesting of CD34+ cells to mitigate the dilution of hematopoietic-cell targets in the expanded erythroid CD34+ cell compartment in patients with β-thalassemia and monitoring of plasma busulfan con-centrations with dose adjustments to optimize myeloablation.30”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] 30. Bourget P, Falaschi L, Suarez F, et al. A medical-pharmaceutical partnership model as a contributor to the success in conditioning regimen for allogenic hema- topoietic stem cell transplantation in adults: a cross-reflection on our organizations. Bull Cancer 2012; 99: 643-53. (In French.)

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationown data

    Below 8.5 g per deciliter, ineffective erythropoiesis was maintained and hepcidin repressed.

    “Below 8.5 g per deciliter, ineffective erythropoiesis was maintained and hepcidin repressed”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    At values of more than 9.5 g per deciliter of hemoglobin, the erythroid mass was reduced and peripheral iron control was restored by hepcidin.

    “At values of more than 9.5 g per deciliter of hemoglobin, the erythroid mass was reduced and peripheral iron control was restored by hepcidin.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Extended follow-up is required to establish the durability of transduction of hematopoietic stem cells and progenitor cells after a single infusion.

    “The number of patients who were treated remains relatively small, so extended follow-up is required to establish the durability of transduction hematopoietic stem cells and progenitor cells after a single infusion.”
    Quote in the paperNot a substantial claim
34 of 34

  • The paper relies on this without support.

    A limited number of vector integration sites may suggest clonal outgrowth, a potential precursor to oncogenesis.

    “The observation of a limited number of integration sites may suggest clonal outgrowth, a potential precursor to oncogenesis.”

  • The paper relies on this without support.

    A histocompatible donor is lacking for allogeneic hematopoietic-cell transplantation.

    “which is a lack of a histocompatible donor.”

  • The paper relies on this without support.

    The theoretical possibility of genotoxicity by semirandom vector integration in the genome remains.

    “Although the theoretical possibility of genotoxicity by semirandom vector integration in the genome remains”

  • The paper relies on this without support.

    The clinical severity of the homozygous IVS1-110 mutation mirrors that of patients with a β0/β0 genotype.

    “the patient with two copies of the IVS1-110 mutation, in whom the clinical severity mirrored that of patients with a β 0 /β 0 genotype”

  • The paper relies on this without support.

    The threshold HbA T87Q level necessary for discontinuation of red-cell transfusion is higher in the absence of endogenous production of β-like globin chains.

    “for whom the threshold HbA T87Q level that was necessary for discontinuation of red-cell transfusion was higher in the absence of endogenous production of β-like globin chains”

  • The paper relies on this without support.

    The BB305 vector is similar to the initial HPV569 vector.

    “a lentiviral vector (BB305) that is similar to our initial HPV569 vector.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In a phase 1/2 study, a HbA T87Q-lentiviral construct introduced into autologous CD34+ stem and progenitor cells infused into myeloablated patients with severe β thalassemia reduced or eliminated the requirement for chronic transfusion in all patients.

    “In a phase 1/2 study, a similar HbA T87Q -lentiviral construct was introduced into autologous CD34 1 stem and progenitor cells that were infused into myeloablated patients with severe forms b thalassemia.The requirement for chronic transfusion was reduced or eliminated in all patients.116”

    From Fetal hemoglobin in sickle cell anemia (2020) · cites this paper as [116]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Betibeglogene autotemcel is approved in the EU for TDT with non-β0 mutations and no matched sibling donor, and is under study in β0/β0 TDT and SCD.

    “Betibeglogene autotemcel, a lentiviral vector-based gene-addition product, is approved in the European Union for the treatment of patients with TDT who have non-β 0 mutations and who do not have a matched sibling donor 14 and is being studied in patients with β 0 /β 0 TDT genotypes and in those with SCD.15,16”

    From CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia (2021) · cites this paper as [15]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • A patient counted as transfusion-free was still receiving transfusions

    Major

    The discussion says all seven patients with HbA T87Q of at least 8 g/dl had been free from transfusion for more than a year. Table 2 lists Patient 1103 at 8.7 g/dl but says the patient was still receiving transfusions.

  • Table 2 footnote gives a range incompatible with listed visit times

    Minor

    The footnote says the listed values were obtained 15 to 42 months after infusion, but Table 2 includes a last study visit at 12 months.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Walters MC, Thompson A, Hongeng S, et al. A phase 3 study to evaluate safety and efficacy of LentiGlobin gene therapy for transfusion-dependent beta-thalassemia in patients with non-beta0/beta0 genotypes: the Northstar-2 (HGB-207) trial. Haematologica 2017;102:335-335. abstract.

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Authors
Thompson, A. A., Walters, M. C., Kwiatkowski, J., Rasko, J. E. J., Ribeil, J.-A., Hongeng, S., Magrin, E., Schiller, G. J., Payen, E., Semeraro, M., Moshous, D., Lefrere, F., Puy, H., Bourget, P., Magnani, A., Caccavelli, L., Diana, J.-S., Suarez, F., Monpoux, F., Brousse, V., Poirot, C., Brouzes, C., Meritet, J.-F., Pondarré, C., Beuzard, Y., Chrétien, S., Lefebvre, T., Teachey, D. T., Anurathapan, U., Ho, P. J., von Kalle, C., Kletzel, M., Vichinsky, E., Soni, S., Veres, G., Negre, O., Ross, R. W., Davidson, D., Petrusich, A., Sandler, L., Asmal, M., Hermine, O., De Montalembert, M., Hacein-Bey-Abina, S., Blanche, S., Leboulch, P., & Cavazzana, M.
Affiliations
  • Brigham and Women's Hospital (US)
  • From the Ann and Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago (A.A.T., M.K.); University of California, San Francisco, Benioff Children’s Hospital, Oakland (M.C.W., E.V.), Lucile Salter Packard Children’s Hospital at Stanford, Palo Alto (S.S.), and David Geffen School of Medicine, University of California, Los Angeles, Los Angeles (G.J.S.) — all in California; Children’s Hospital of Philadelphia and University of Pennsylvania Perelman...
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2018-04-19
Volume
378
Issue
16
Pages
1479-1493
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa1705342
OpenAlex
W2802087233
Cited by
684
References
41
Citations by year
2026: 44 · 2025: 52 · 2024: 65 · 2023: 78 · 2022: 79 · 2021: 123 · 2020: 88 · 2019: 101 · 2018: 53
FWCI
55.95
Type
journal article
Language
en
Open access
Licence
www.nejmgroup.org/legal/terms-of-use.htm (vor)
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • bluebird bio
  • National Center for Advancing Translational Sciences (UL1TR000003 and UL1TR001878)
  • Assistance Publique - Hôpitaux de Paris
  • Institut National de la Santé et de la Recherche Médicale
  • Commissariat à l'Énergie Atomique et aux Énergies Alternatives
  • Agence Nationale de la Recherche
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
Keywords
beta-thalassemia, gene therapy, autologous stem cell transplantation, CD34+ cells, transfusion dependence, vector copy number, clonal dominance, beta-globin gene
MeSH terms
Adolescent, Adult, Child, Female, Genetic Vectors, Hemoglobins, Humans, Male, Mutation, Transplantation, Autologous, Genetic Therapy, Lentivirus, beta-Thalassemia, Erythrocyte Transfusion, Gene Transfer Techniques, Antigens, CD34, beta-Globins, Young Adult

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-11.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.

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