Living with Recurrent Vaso-Occlusive Crises: A Narrative Review of Gene Therapy for Sickle Cell Disease and What Curative Intent Changes for Patients and Families
DOI:
https://doi.org/10.5281/zenodo.22236439Keywords:
Sickle Cell Disease, Gene Therapy, Vaso-Occlusive Crisis, CRISPR-Cas9, Curative IntentAbstract
For most of the history of sickle cell disease, treatment meant reducing the frequency of crises rather than ending them. Gene
therapy offers something the field has not previously had to describe to patients: the prospect of a life without vaso-occlusive
crises at all.
Objectives: To review the published evidence on gene therapy for severe sickle cell disease: what the trials achieved, on how
many patients and over what period, what the treatment requires of the person receiving it, and what remains unknown at the
point of licensing.
Material and Methods: Narrative review of phase 1 to 3 trials, natural history studies, guideline documents and health-economic
analyses indexed in PubMed and the major haematology journals. No new patient data were generated; every estimate quoted is
one published by the original investigators.
Results: In the pivotal phase 3 study, 44 patients aged 12 to 35 with at least two severe vaso-occlusive crises in each of the two
preceding years received exagamglogene autotemcel. Of the 30 with sufficient follow-up, 29 (97 per cent, 95% CI 83 to 100) were
free of severe vaso-occlusive crises for at least 12 consecutive months, and all 30 (100 per cent, 95% CI 88 to 100) were free of
hospitalisation for one. Median follow-up was 19.3 months (range 0.8 to 48.1). The safety profile was consistent with
myeloablative busulfan conditioning, and no cancers occurred.
Conclusion: The effect size is as large as any in haematology, and the evidence base is thirty patients followed for a median of
nineteen months. Both statements are true and both belong in the conversation, alongside the cost of the treatment itself:
myeloablative conditioning, probable infertility, weeks in hospital, and a price that places it out of reach of most of the world's
patients.
Abbreviations: exa-cel – Exagamglogene Autotemcel, HbF – Fetal Haemoglobin, HSCT – Haematopoietic Stem Cell
Transplantation, HSPC – Haematopoietic Stem and Progenitor Cell, SCD – Sickle Cell Disease, VOC – Vaso-Occlusive Crisis,
CI – Confidence Interval.
References
Piel FB, Steinberg MH, Rees DC. "Sickle cell disease". N Engl J Med 376(2017):1561-1573.
Kato GJ, Piel FB, Reid CD, Gaston MH, Ohene-Frempong K, Krishnamurti L, et al. "Sickle cell disease". Nat Rev Dis Primers 4(2018):18010.
Piel FB, Patil AP, Howes RE, Nyangiri OA, Gething PW, Dewi M, et al. "Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates". Lancet 381(2013):142-151.
Ware RE, de Montalembert M, Tshilolo L, Abboud MR. "Sickle cell disease". Lancet 390(2017):311-323.
Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, et al. "Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia". N Engl J Med 332(1995):1317-1322.
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)". Lancet 377(2011):1663-1672.
Vichinsky E, Hoppe CC, Ataga KI, Ware RE, Nduba V, El-Beshlawy A, et al. "A phase 3 randomized trial of voxelotor in sickle cell disease". N Engl J Med 381(2019):509-519.
Ataga KI, Kutlar A, Kanter J, Liles D, Cancado R, Friedrisch J, et al. "Crizanlizumab for the prevention of pain crises in sickle cell disease". N Engl J Med 376(2017):429-439.
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". Blood 129(2017):1548-1556.
Walters MC, Patience M, Leisenring W, Eckman JR, Scott JP, Mentzer WC, et al. "Bone marrow transplantation for sickle cell disease". N Engl J Med 335(1996):369-376.
Frangoul H, Locatelli F, Sharma A, Bhatia M, Mapara M, Molinari L, et al. "Exagamglogene autotemcel for severe sickle cell disease". N Engl J Med 390(2024):1649-1662.
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". N Engl J Med 384(2021):252-260.
Kanter J, Walters MC, Krishnamurti L, Mapara MY, Kwiatkowski JL, Rifkin-Zenenberg S, et al. "Biologic and clinical efficacy of LentiGlobin for sickle cell disease". N Engl J Med 386(2022):617-628.
Ribeil JA, Hacein-Bey-Abina S, Payen E, Magnani A, Semeraro M, Magrin E, et al. "Gene therapy in a patient with sickle cell disease". N Engl J Med 376(2017):848-855.
Kanter J, Liem RI, Bernaudin F, Bolanos-Meade J, Fitzhugh CD, Hankins JS, et al. "American Society of Hematology 2021 guidelines for sickle cell disease: stem cell transplantation". Blood Adv 5(2021):3668-3689.
Brandow AM, Carroll CP, Creary S, Edwards-Elliott R, Glassberg J, Hurley RW, et al. "American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain". Blood Adv 4(2020):2656-2701.
Sharma A, Boelens JJ, Cancio M, Hankins JS, Bhad P, Azizy M, et al. "CRISPR-Cas9 editing of the HBG1 and HBG2 promoters to treat sickle cell disease". N Engl J Med 389(2023):820-832.
Leonard A, Tisdale JF, Bonner M. "Gene therapy for hemoglobinopathies: beta-thalassemia, sickle cell disease". Hematol Oncol Clin North Am 36(2022):769-795.
Nickel RS, Maher JY, Hsieh MH, Davis MF, Hsieh MM, Pecker LH. "Fertility after curative therapy for sickle cell disease: a comprehensive review to guide care". J Clin Med 11(2022):2318.
Beaudoin FL, Richardson M, Synnott PG, Chapman R, Herron-Smith S, Rind D, et al. "Gene therapies for sickle cell disease: effectiveness and value". Institute for Clinical and Economic Review (2023).
Salcedo J, Bulovic J, Young CM. "Cost-effectiveness of a hypothetical cell or gene therapy cure for sickle cell disease". Sci Rep 11(2021):10838.
Tshilolo L, Tomlinson G, Williams TN, Santos B, Olupot-Olupot P, Lane A, et al. "Hydroxyurea for children with sickle cell anemia in sub-Saharan Africa". N Engl J Med 380(2019):121-131.
DeBaun MR, Jordan LC, King AA, Schatz J, Vichinsky E, Fox CK, et al. "American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of cerebrovascular disease in children and adults". Blood Adv 4(2020):1554-1588.
Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, et al. "Mortality in sickle cell disease: life expectancy and risk factors for early death". N Engl J Med 330(1994):1639-1644.
Platt OS, Thorington BD, Brambilla DJ, Milner PF, Rosse WF, Vichinsky E, et al. "Pain in sickle cell disease: rates and risk factors". N Engl J Med 325(1991):11-16.
Gardner K, Douiri A, Drasar E, Allman M, Mwirigi A, Awogbade M, et al. "Survival in adults with sickle cell disease in a high-income setting". Blood 128(2016):1436-1438.
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". N Engl J Med 384(2021):205-215.
Bauer DE, Kamran SC, Lessard S, Xu J, Fujiwara Y, Lin C, et al. "An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level". Science 342(2013):253-257.
Canver MC, Smith EC, Sher F, Pinello L, Sanjana NE, Shalem O, et al. "BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis". Nature 527(2015):192-197.
Sankaran VG, Menne TF, Xu J, Akie TE, Lettre G, Van Handel B, et al. "Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A". Science 322(2008):1839-1842.
Hoban MD, Orkin SH, Bauer DE. "Genetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease". Blood 127(2016):839-848.
Walters MC, Hardee I, Sabatino D, et al. "Toward gene therapy for sickle cell disease: clinical development and regulatory considerations". Blood Adv 8(2024):1-12.
Thompson AA, Walters MC, Kwiatkowski J, Rasko JEJ, Ribeil JA, Hongeng S, et al. "Gene therapy in patients with transfusion-dependent beta-thalassemia". N Engl J Med 378(2018):1479-1493.
Locatelli F, Lang P, Wall D, Meisel R, Corbacioglu S, Li AM, et al. "Exagamglogene autotemcel for transfusion-dependent beta-thalassemia". N Engl J Med 390(2024):1663-1676.
Osunkwo I, Andemariam B, Minniti CP, Inusa BPD, El Rassi F, Francis-Gibson B, et al. "Impact of sickle cell disease on patients daily lives, symptoms reported, and disease management strategies: results from the international Sickle Cell World Assessment Survey (SWAY)". Am J Hematol 96(2021):404-417.
