New insights into the pathophysiology and novel therapies for sickle cell disease
Main Article Content
Abstract
Sickle cell disease (SCD) is one of the world’s most common severe monogenic disorders affecting millions of people worldwide and represents a significant public health problem. The last two decades have seen a major increase in knowledge about the cascade of events that follow the polymerization of hemoglobin, the main pathophysiological event in SCD, including impaired biorheology and increased adhesion-mediated vaso-occlusion, hemolysis-mediated endothelial dysfunction, and inflammation. As a result, several distinctive therapeutic targets have been discovered, and a few drugs with innovative mechanisms of action are already on the Market. In contrast, several others are the focus of ongoing trials. This narrative review aims to describe some of the more recent data in the SCD literature regarding pathophysiology and novel treatments.
Keywords:
Sickle cell disease, pathophysiology, perspective, treatment
Article Details
How to Cite
CANCADO, Rodolfo Delfini.
New insights into the pathophysiology and novel therapies for sickle cell disease.
Medical Research Archives, [S.l.], v. 12, n. 7, july 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5495>. Date accessed: 21 dec. 2024.
doi: https://doi.org/10.18103/mra.v12i7.5495.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010; 376:2018–31.
2. Ware RE, de Montalembert M, Tshilolo L, Abboud MR. Sickle cell disease. Lancet. 2017; 390:311–23.
3. Piel FB, Steinberg MH, Rees DC. Sickle cell disease. Nat Rev Dis Primers. 2018;4:18010.
4. Kato GJ, Piel FB, Reid CD, Gaston MH, Ohene-Frempong K, Krishnamurti L, et al. Sickle cell disease. Nat Rev Dis Primers. 2018;4:18010.
5. 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. 2013;381:142–51.
6. GBD 2021 Sickle Cell Disease Collaborators: Global, regional, and national prevalence and mortality burden of sickle cell disease, 2000-2021: a systematic analysis from the global burden of disease study 2021. Lancet Haematol. 2023, 10.1016/s2352-3026(23)00118-7
7. Sundd P, Gladwin MT, Novelli EM. Pathophysiology of Sickle Cell Disease. Annu Rev Pathol. 2019; 14: 263–292.
8. Araújo ADS, Silva Pinto AC, Lobo CLC, Figueiredo MS, Menosi Gualandro SF, Olalla Saad ST, Cancado RD. Novel Insights into the Pathophysiology and Treatment of Sickle Cell Disease. Hemoglobin. 2023 Nov;47(2):71-79.
9. Moerdler S, Manwani D. New insights into the pathophysiology and development of novel therapies for sickle cell disease. Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):493-506.
10. Brittenham GM, Schechter AN, Noguchi CT. Hemoglobin S polymerization: primary determinant of the hemolytic and clinical severity of the sickling syndromes. Blood. 1985; 65:183–89.
11. Manwani D, Frenette PS.Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies. Blood.2013; 122:3892–98.
12. Zhang D, Xu C, Manwani D, Frenette PS. Neutrophils, platelets, and inflammatory pathways at the nexus of sickle cell disease pathophysiology. Blood. 2016; 127:801–9.
13. Steinberg MH, Sebastiani P. Genetic modifiers of sickle cell disease. Am J Hematol 2012; 87: 795-803.
14. Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev 2007; 21: 37-47.
15. Tewari S, Brousse V, Piel FB, Menzel S, Rees DC. Environmental determinants of severity in sickle cell disease. Haematologica. 2015;100: 1108–16.
16. Salinas Cisneros G, Thein SL. Research in sickle cell disease: From bedside to bench to bedside. Hemasphere. 2021;5:e584.
17. da Silva Araújo A, Silva Pinto AC, de Castro Lobo CL, Figueiredo MS, Menosi Gualandro SF, Olalla Saad ST, Cançado RD. Sickle Cell Disease in Brazil: Current Management. Hemoglobin. 2024 Apr 25:1-13.
18. Telen MJ. Beyond hydroxyurea: new and old drugs in the pipeline for sickle cell disease. Blood 2016; 127: 810-9.
19. Guarino S & Lanzkron S. How to utilize new therapies for sickle cell disease. Hematology Am Soc Hematol Educ Program. 2022 Dec 9;2022(1):283-285.
20. Lugthart S, Ginete C, Kuona P, Brito M, Inusa BPD. An updated review of new therapies in sickle cell disease: the prospects for drug combinations. Expert Opin Pharmacother. 2024; 25(2):157-170.
21. Voskaridou E, Christoulas D, Bilalis A, Plata E, Varvagiannis K, Stamatopoulos G, et al. The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS) Blood. 2010;115:2354–63.
22. John CC, Opoka RO, Latham TS, Hume HA, Nabaggala C, Kasirye P, et al. Hydroxyurea dose escalation for sickle cell anemia in Sub-Saharan Africa. N Engl J Med. 2020;382:2524–33.
23. Power-Hays A, Ware RE. Effective use of hydroxyurea for sickle cell anemia in low-resource countries. Curr Opin Hematol. 2020;27:172–80.
24. Wong TE, Brandow AM, Lim W, Lottenberg R. Update on the use of hydroxyurea therapy in sickle cell disease. Blood 2014; 124: 3850-3857, quiz 4004.
25. Joseph L, Jean C, Manceau S, Chalas C, Arnaud C, Kamdem A, et al. Effect of hydroxyurea exposure before puberty on sperm parameters in males with sickle cell disease. Blood. 2021;137: 826–9.
26. Niihara Y, Miller ST, Kanter J, et al; Investigators of the Phase 3 Trial of l-Glutamine in Sickle Cell Disease. A phase 3 trial of L-glutamine in sickle cell disease. N Engl J Med. 2018;379(3) :226-235.
27. Ogu UO, Thomas M, Chan F, et al. L-glutamine use in adults with sickle cell disease: clinical trials where success meets reality. Am J Hematol. 2021;96(1):E38-E40.
28. Vichinsky E, Hoppe CC, Ataga KI, et al. HOPE Trial Investigators. A phase 3 randomized trial of voxelotor in sickle cell disease. N Engl J Med. 2019;381(6):509-519.
29. Zaidi AU, Lipato T, Alvarez OA, et al. Real-world effectiveness of voxelotor for treating sickle cell disease in the US. Blood. 2020;136(suppl 1):25.
30. Saraf SL, Abdullahi SU, Akinsete AM, et al. Preliminary results from a multicenter phase 2/3 study of next-generation HbS polymerization inhibitor GBT021601 for the treatment of patients with sickle cell disease. Blood. 2023;142 (Supplement 1):274.
31. Ataga KI, Kutlar A, Kanter J, Liles D, Cancado R, Friedrisch J, Guthrie TH, Knight-Madden J, Alvarez OA, Gordeuk VR, Gualandro S, Colella MP, Smith WR, Rollins SA, Stocker JW, Rother RP. Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease. N Engl J Med. 2017 Feb 2;376(5):429-439.
32. Kutlar A, Kanter J, Liles DK, et al. Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: a SUSTAIN study analysis. Am J Hematol. 2019;94(1):55-61.
33. Andemariam B, Inati A, Colombatti R, Minniti C, Brown C, Hottmann M et al. Trial in progress: the thrive studies evaluating the efficacy, safety, and long-term treatment with inclacumab, a p-selectin inhibitor, in patientes with sickle cell disease. HemaSphere, 2023; 7(S1):23-24.
34. Xu JZ, Conrey A, Frey I, et al. A phase 1 dose escalation study of the pyruvate kinase activator mitapivat (AG-348) in sickle cell disease. Blood. 2022;140(19):2053–2062
35. van Dijk MJ, Rab MAE, van Oirschot BA, et al. Safety and efficacy of mitapivat, an oral pyruvate kinase activator, in sickle cell disease: a phase 2, open-label study. Am J Hematol. 2022;97(7):E226–E229.
36. Study details | a study evaluating the efficacy and safety of mitapivat (AG-348) in participants with sickle cell disease (RISE UP) | ClinicalTrials.Gov [Internet]. [cited 2023 Dec 10]. Available from: https://clinicaltrials.gov/study/NCT05031780
37. Forsyth S, Schroeder P, Geib J, et al. Safety, pharmacokinetics, and pharmacodynamics of etavopivat (FT-4202), an allosteric activator of pyruvate kinase-R, in healthy adults: a randomized, placebo-controlled, double-blind, first-in-human phase 1 trial. Clin Pharmacol Drug Dev. 2022;11(5) :654–665.
38. Study details | a study of Etavopivat in adults and adolescents with sickle cell disease (HIBISCUS) | ClinicalTrials.Gov [Internet]. [cited 2023 Dec 10]. Available from: https://www.clinicaltrials.gov/study/NCT04624659
39. Bernaudin F, Dalle JH, Bories D, 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. Haematologica. 2020;105(1):91–101. doi: 10.3324/haematol.2018.21320786
40. Guilcher GMT, Truong TH, Saraf SL, Joseph JJ, Rondelli D, Hsieh MM. Curative therapies: Allogeneic hematopoietic cell transplantation from matched related donors using myeloablative, reduced intensity, and nonmyeloablative conditioning in sickle cell disease. Seminars in Hematology 55 (2018) 87–93.
41. Inam Z, Tisdale JF, Leonard A. Outcomes and long-term effects of hematopoietic stem cell transplant in sickle cell disease. Expert Rev Hematol. 2023;16(11):879–903.
42. Lidonnici MR, Scaramuzza S, Ferrari G. Gene therapy for hemoglobinopathies. Hum Gene Ther. 2023;34(17–18):793–807.
43. Frangoul H, Locatelli F, Bhatia M, et al. Efficacy and safety of a single dose of exagamglogene autotemcel for severe sickle cell disease. Blood. 2022;140(Supplement 1):29–31.
44. Kanter J, Thompson AA, Pierciey FJJ, et al. Lovo-cel gene therapy for sickle cell disease: treatment process evolution and outcomes in the initial groups of the HGB-206 study. Am J Hematol. 2023;98 (1):11–22.
45. Kanter J, Walters MC, Krishnamurti L, et al. Biologic and clinical efficacy of LentiGlobin for sickle cell disease. N Engl J Med. 2022;386(7):617–628.
46. Spencer Chapman M, Cull AH, Ciuculescu MF, et al. Clonal selection of hematopoietic stem cells after gene therapy for sickle cell disease. Nat Med. 2023;29(12):3175–3183.
47. Goyal S, Tisdale J, Schmidt M, et al. Acute myeloid leukemia case after gene therapy for sickle cell disease. N Engl J Med. 2022;386 (2):138–147.
2. Ware RE, de Montalembert M, Tshilolo L, Abboud MR. Sickle cell disease. Lancet. 2017; 390:311–23.
3. Piel FB, Steinberg MH, Rees DC. Sickle cell disease. Nat Rev Dis Primers. 2018;4:18010.
4. Kato GJ, Piel FB, Reid CD, Gaston MH, Ohene-Frempong K, Krishnamurti L, et al. Sickle cell disease. Nat Rev Dis Primers. 2018;4:18010.
5. 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. 2013;381:142–51.
6. GBD 2021 Sickle Cell Disease Collaborators: Global, regional, and national prevalence and mortality burden of sickle cell disease, 2000-2021: a systematic analysis from the global burden of disease study 2021. Lancet Haematol. 2023, 10.1016/s2352-3026(23)00118-7
7. Sundd P, Gladwin MT, Novelli EM. Pathophysiology of Sickle Cell Disease. Annu Rev Pathol. 2019; 14: 263–292.
8. Araújo ADS, Silva Pinto AC, Lobo CLC, Figueiredo MS, Menosi Gualandro SF, Olalla Saad ST, Cancado RD. Novel Insights into the Pathophysiology and Treatment of Sickle Cell Disease. Hemoglobin. 2023 Nov;47(2):71-79.
9. Moerdler S, Manwani D. New insights into the pathophysiology and development of novel therapies for sickle cell disease. Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):493-506.
10. Brittenham GM, Schechter AN, Noguchi CT. Hemoglobin S polymerization: primary determinant of the hemolytic and clinical severity of the sickling syndromes. Blood. 1985; 65:183–89.
11. Manwani D, Frenette PS.Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies. Blood.2013; 122:3892–98.
12. Zhang D, Xu C, Manwani D, Frenette PS. Neutrophils, platelets, and inflammatory pathways at the nexus of sickle cell disease pathophysiology. Blood. 2016; 127:801–9.
13. Steinberg MH, Sebastiani P. Genetic modifiers of sickle cell disease. Am J Hematol 2012; 87: 795-803.
14. Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev 2007; 21: 37-47.
15. Tewari S, Brousse V, Piel FB, Menzel S, Rees DC. Environmental determinants of severity in sickle cell disease. Haematologica. 2015;100: 1108–16.
16. Salinas Cisneros G, Thein SL. Research in sickle cell disease: From bedside to bench to bedside. Hemasphere. 2021;5:e584.
17. da Silva Araújo A, Silva Pinto AC, de Castro Lobo CL, Figueiredo MS, Menosi Gualandro SF, Olalla Saad ST, Cançado RD. Sickle Cell Disease in Brazil: Current Management. Hemoglobin. 2024 Apr 25:1-13.
18. Telen MJ. Beyond hydroxyurea: new and old drugs in the pipeline for sickle cell disease. Blood 2016; 127: 810-9.
19. Guarino S & Lanzkron S. How to utilize new therapies for sickle cell disease. Hematology Am Soc Hematol Educ Program. 2022 Dec 9;2022(1):283-285.
20. Lugthart S, Ginete C, Kuona P, Brito M, Inusa BPD. An updated review of new therapies in sickle cell disease: the prospects for drug combinations. Expert Opin Pharmacother. 2024; 25(2):157-170.
21. Voskaridou E, Christoulas D, Bilalis A, Plata E, Varvagiannis K, Stamatopoulos G, et al. The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS) Blood. 2010;115:2354–63.
22. John CC, Opoka RO, Latham TS, Hume HA, Nabaggala C, Kasirye P, et al. Hydroxyurea dose escalation for sickle cell anemia in Sub-Saharan Africa. N Engl J Med. 2020;382:2524–33.
23. Power-Hays A, Ware RE. Effective use of hydroxyurea for sickle cell anemia in low-resource countries. Curr Opin Hematol. 2020;27:172–80.
24. Wong TE, Brandow AM, Lim W, Lottenberg R. Update on the use of hydroxyurea therapy in sickle cell disease. Blood 2014; 124: 3850-3857, quiz 4004.
25. Joseph L, Jean C, Manceau S, Chalas C, Arnaud C, Kamdem A, et al. Effect of hydroxyurea exposure before puberty on sperm parameters in males with sickle cell disease. Blood. 2021;137: 826–9.
26. Niihara Y, Miller ST, Kanter J, et al; Investigators of the Phase 3 Trial of l-Glutamine in Sickle Cell Disease. A phase 3 trial of L-glutamine in sickle cell disease. N Engl J Med. 2018;379(3) :226-235.
27. Ogu UO, Thomas M, Chan F, et al. L-glutamine use in adults with sickle cell disease: clinical trials where success meets reality. Am J Hematol. 2021;96(1):E38-E40.
28. Vichinsky E, Hoppe CC, Ataga KI, et al. HOPE Trial Investigators. A phase 3 randomized trial of voxelotor in sickle cell disease. N Engl J Med. 2019;381(6):509-519.
29. Zaidi AU, Lipato T, Alvarez OA, et al. Real-world effectiveness of voxelotor for treating sickle cell disease in the US. Blood. 2020;136(suppl 1):25.
30. Saraf SL, Abdullahi SU, Akinsete AM, et al. Preliminary results from a multicenter phase 2/3 study of next-generation HbS polymerization inhibitor GBT021601 for the treatment of patients with sickle cell disease. Blood. 2023;142 (Supplement 1):274.
31. Ataga KI, Kutlar A, Kanter J, Liles D, Cancado R, Friedrisch J, Guthrie TH, Knight-Madden J, Alvarez OA, Gordeuk VR, Gualandro S, Colella MP, Smith WR, Rollins SA, Stocker JW, Rother RP. Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease. N Engl J Med. 2017 Feb 2;376(5):429-439.
32. Kutlar A, Kanter J, Liles DK, et al. Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: a SUSTAIN study analysis. Am J Hematol. 2019;94(1):55-61.
33. Andemariam B, Inati A, Colombatti R, Minniti C, Brown C, Hottmann M et al. Trial in progress: the thrive studies evaluating the efficacy, safety, and long-term treatment with inclacumab, a p-selectin inhibitor, in patientes with sickle cell disease. HemaSphere, 2023; 7(S1):23-24.
34. Xu JZ, Conrey A, Frey I, et al. A phase 1 dose escalation study of the pyruvate kinase activator mitapivat (AG-348) in sickle cell disease. Blood. 2022;140(19):2053–2062
35. van Dijk MJ, Rab MAE, van Oirschot BA, et al. Safety and efficacy of mitapivat, an oral pyruvate kinase activator, in sickle cell disease: a phase 2, open-label study. Am J Hematol. 2022;97(7):E226–E229.
36. Study details | a study evaluating the efficacy and safety of mitapivat (AG-348) in participants with sickle cell disease (RISE UP) | ClinicalTrials.Gov [Internet]. [cited 2023 Dec 10]. Available from: https://clinicaltrials.gov/study/NCT05031780
37. Forsyth S, Schroeder P, Geib J, et al. Safety, pharmacokinetics, and pharmacodynamics of etavopivat (FT-4202), an allosteric activator of pyruvate kinase-R, in healthy adults: a randomized, placebo-controlled, double-blind, first-in-human phase 1 trial. Clin Pharmacol Drug Dev. 2022;11(5) :654–665.
38. Study details | a study of Etavopivat in adults and adolescents with sickle cell disease (HIBISCUS) | ClinicalTrials.Gov [Internet]. [cited 2023 Dec 10]. Available from: https://www.clinicaltrials.gov/study/NCT04624659
39. Bernaudin F, Dalle JH, Bories D, 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. Haematologica. 2020;105(1):91–101. doi: 10.3324/haematol.2018.21320786
40. Guilcher GMT, Truong TH, Saraf SL, Joseph JJ, Rondelli D, Hsieh MM. Curative therapies: Allogeneic hematopoietic cell transplantation from matched related donors using myeloablative, reduced intensity, and nonmyeloablative conditioning in sickle cell disease. Seminars in Hematology 55 (2018) 87–93.
41. Inam Z, Tisdale JF, Leonard A. Outcomes and long-term effects of hematopoietic stem cell transplant in sickle cell disease. Expert Rev Hematol. 2023;16(11):879–903.
42. Lidonnici MR, Scaramuzza S, Ferrari G. Gene therapy for hemoglobinopathies. Hum Gene Ther. 2023;34(17–18):793–807.
43. Frangoul H, Locatelli F, Bhatia M, et al. Efficacy and safety of a single dose of exagamglogene autotemcel for severe sickle cell disease. Blood. 2022;140(Supplement 1):29–31.
44. Kanter J, Thompson AA, Pierciey FJJ, et al. Lovo-cel gene therapy for sickle cell disease: treatment process evolution and outcomes in the initial groups of the HGB-206 study. Am J Hematol. 2023;98 (1):11–22.
45. Kanter J, Walters MC, Krishnamurti L, et al. Biologic and clinical efficacy of LentiGlobin for sickle cell disease. N Engl J Med. 2022;386(7):617–628.
46. Spencer Chapman M, Cull AH, Ciuculescu MF, et al. Clonal selection of hematopoietic stem cells after gene therapy for sickle cell disease. Nat Med. 2023;29(12):3175–3183.
47. Goyal S, Tisdale J, Schmidt M, et al. Acute myeloid leukemia case after gene therapy for sickle cell disease. N Engl J Med. 2022;386 (2):138–147.