Page 39 - 2019_09-HaematologicaMondo-web

Disease-modifying therapies for SCD
patients with SCD. Therefore, optimizing non-curative approaches, i.e. those that do not involve stem cell or gene therapy, but which prevent or abort the complications of SCD, remains an important step in improving health and diminishing symptom burden in most people with SCD, in the USA and worldwide. Collaboration among the gov- ernment (National Institutes of Health), industry, and aca- demia has led to the development of a range of novel ther- apies that target many pathways which have been impli- cated in SCD-related pathophysiology. Through success- ful enrollment in numerous studies investigating novel therapies, it is also clear that many patients with SCD are eager to explore the potential clinical benefits of these agents. Less clear, unfortunately, are the optimal endpoints that investigators should choose when determining the beneficial role these agents may have in the clinical course and complications of SCD. Risk-benefit analyses by patients, their families, and their healthcare providers are also important. We suggest that treatments ‘closer’ to the proximate pathophysiological causes of SCD, such as polymer formation, may warrant greater risk exposure than do strategies that solely address downstream conse- quences (Figure 3), although this assessment will be fur-
ther complicated when multi-modality therapies are applied. In addition, pain is such a prominent symptom and burden in SCD that its relief may warrant riskier approaches than would otherwise be considered for a sin- gle symptom or organ.
It is a time of great optimism, and in the future it may be feasible to take a multimodal approach with a combi- nation of therapies, as seen in cancer treatment regimens, to adequately address both cause and effect in SCD. For example, agents that improve red cell health, such as L- glutamine and hydroxyurea, could be successfully com- bined with non-overlapping agents, such as anti-selectin therapies, which block inflammatory adhesion during painful crises. As members of the broader sickle cell com- munity (while optimistic and enthusiastic), we must remain vigilant but reasonable, using long-term, prospec- tive data as available to guide assessments about benefits and long-term safety of emerging treatments. We must do better in the coming years to identify complications of all novel therapies rapidly so that we can ensure that (unavoidable) risks and complications are detected, miti- gated, and managed in the context of their impact on dis- ease in order to optimize care in SCD.
References
1. Pauling L, Itano HA, et al. Sickle cell anemia a molecular disease. Science. 1949;110 (2865):543-548.
2. Piel FB, Steinberg MH, Rees DC. Sickle cell disease. N Engl J Med. 2017;377(3):305.
3. Kato GJ, Piel FB, Reid CD, et al. Sickle cell disease. Nat Rev Dis Primers. 2018;4:18010.
4. Eaton WA, Hofrichter J. Hemoglobin S gela- tion and sickle cell disease. Blood.
1987;70(5):1245-1266.
5. Kaul DK, Fabry ME, Windisch P, Baez S,
Nagel RL. Erythrocytes in sickle cell anemia are heterogeneous in their rheological and hemodynamic characteristics. J Clin Invest. 1983;72(1):22-31.
6. Hebbel RP. Beyond hemoglobin polymeriza- tion: the red blood cell membrane and sickle disease pathophysiology. Blood. 1991;77(2): 214-237.
7. Kuross SA, Rank BH, Hebbel RP. Excess heme in sickle erythrocyte inside-out mem- branes: possible role in thiol oxidation. Blood. 1988;71(4):876-882.
8. Barabino GA, Platt MO, Kaul DK. Sickle cell biomechanics. Annu Rev Biomed Eng. 2010;12:345-367.
9. Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med. 1997;337(11):762-769.
10. Zhang D, Xu C, Manwani D, Frenette PS. Neutrophils, platelets, and inflammatory pathways at the nexus of sickle cell disease pathophysiology. Blood. 2016;127(7):801- 809.
11. Sparkenbaugh E, Pawlinski R. Interplay between coagulation and vascular inflam- mation in sickle cell disease. Br J Haematol. 2013;162(1):3-14.
12. Sparkenbaugh E, Pawlinski R. Prothrombotic aspects of sickle cell disease. J Thromb Haemost. 2017;15(7):1307-1316.
13. Noubouossie D, Key NS, Ataga KI. Coagulation abnormalities of sickle cell dis- ease: relationship with clinical outcomes
and the effect of disease modifying thera-
pies. Blood Rev. 2016;30(4):245-256.
14. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death.
N Engl J Med. 1994;330(23):1639-1644.
15. Telen MJ. Beyond hydroxyurea: new and old drugs in the pipeline for sickle cell dis-
ease. Blood. 2016;127(7):810-819.
16. 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;2018(1):493-506.
17. Kapoor S, Little JA, Pecker LH. Advances in
the treatment of sickle cell disease. Mayo
Clin Proc. 2018;93(12):1810-1824.
18. Hoban MD, Orkin SH, Bauer DE. Genetic treatment of a molecular disorder: gene ther- apy approaches to sickle cell disease. Blood.
2016;127(7):839-848.
19. Walters MC. Update of hematopoietic cell
transplantation for sickle cell disease. Curr
Opin Hematol. 2015;22(3):227-233.
20. Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA.
2014;312(10):1033-1048.
21. Telen MJ, Malik P, Vercellotti GM.
Therapeutic strategies for sickle cell disease: towards a multi-agent approach. Nat Rev Drug Discov. 2019;18(2):139-158.
22. Fitzhugh CD, Abraham AA, Tisdale JF, Hsieh MM. Hematopoietic stem cell trans- plantation for patients with sickle cell dis- ease: progress and future directions. Hematol Oncol Clin North Am. 2014;28(6):1171-1185.
23. Orkin SH, Bauer DE. Emerging genetic ther- apy for sickle cell disease. Annu Rev Med. 2019;70:257-271.
24. Morrone K, Mitchell WB, Manwani D. Novel sickle cell disease therapies: targeting pathways downstream of sickling. Semin Hematol. 2018;55(2):68-75.
25. Field JJ, Nathan DG. Advances in sickle cell therapies in the hydroxyurea era. Mol Med. 2014;20 Suppl 1:S37-42.
26. Strouse J. Sickle cell disease. Handb Clin Neurol. 2016;138:311-324.
27. Sundd P, Gladwin MT, Novelli EM. Pathophysiology of sickle cell disease. Annu Rev Pathol. 2019;14:263-292.
28. Ataga KI, Desai PC. Advances in new drug therapies for the management of sickle cell disease. Expert Opin Orphan Drugs. 2018;6(5):329-343.
29. Eaton WA, Bunn HF. Treating sickle cell dis- ease by targeting HbS polymerization. Blood. 2017;129(20):2719:2726.
30. Platt OS. Hydroxyurea for the treatment of sickle cell anemia. N Engl J Med. 2008;358(13):1362-1369.
31. McGann PT, Ware RE. Hydroxyurea thera- py for sickle cell anemia. Expert Opin Drug Saf. 2015;14(11):1749-1758.
32. Paikari A, Sheehan VA. Fetal haemoglobin induction in sickle cell disease. Br J Haematol. 2018;180(2):189-200.
33. Ginder GD. Epigenetic regulation of fetal globin gene expression in adult erythroid cells. Transl Res. 2015;165(1):115-125.
34. Molokie R, Lavelle D, Gowhari M, et al. Oral tetrahydrouridine and decitabine for non-cytotoxic epigenetic gene regulation in sickle cell disease: a randomized phase 1 study. PLoS Med. 2017;14(9):e1002382.
35. Reid ME, El Beshlawy A, Inati A, et al. A double-blind, placebo-controlled phase II study of the efficacy and safety of 2,2- dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease. Am J Hematol. 2014;89(7):709-713.
36. Bradner JE, Mak R, Tanguturi SK, et al. Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as ther- apeutic targets in sickle cell disease. Proc Natl Acad Sci U S A. 2010;107(28):12617- 12622.
37. Dulmovits BM, Appiah-Kubi AO, Papoin J, et al. Pomalidomide reverses gamma-globin
haematologica | 2019; 104(9)
1717