Sickle cell anemia

Section editor
	Benjamin Tillman, MD Vanderbilt University Nashville, TN

6 regimens on this page 6 variants on this page

Guidelines

ASH

• 2020: Brandow et al American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain
• 2019: Liem et al. American Society of Hematology 2019 guidelines for sickle cell disease: cardiopulmonary and kidney disease

"How I Treat"

• 2019: Stenger et al. How I treat sickle cell disease with hematopoietic cell transplantation

NHLBI

• 2014: Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, 2014

All lines of therapy

Crizanlizumab monotherapy

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ataga et al. 2016 (SUSTAIN)	2013-2015	Randomized Phase II (E-RT-esc)	Placebo	Superior annual rate of crises
			Crizanlizumab; 2.5 mg/kg	Not reported

Targeted therapy

• Crizanlizumab (Adakveo) 5 mg/kg IV once on day 1

14-day cycle for 26 cycles (1 year)

References

1. SUSTAIN: 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. Epub 2016 Dec 3. link to original article link to PMC article contains protocol PubMed

Hydroxyurea monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Charache et al. 1995 (MSH)	1992-1994	Phase III (E-esc)	Placebo	Superior annual rate of crises

Chemotherapy

• Hydroxyurea (Hydrea) 15 mg/kg/day PO

Doses were subsequently adjusted, see article for details.

References

1. Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, McMahon RP, Bonds DR; Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med. 1995 May 18;332(20):1317-22. link to original article contains protocol PubMed
   1. Update: Steinberg MH, Barton F, Castro O, Pegelow CH, Ballas SK, Kutlar A, Orringer E, Bellevue R, Olivieri N, Eckman J, Varma M, Ramirez G, Adler B, Smith W, Carlos T, Ataga K, DeCastro L, Bigelow C, Saunthararajah Y, Telfer M, Vichinsky E, Claster S, Shurin S, Bridges K, Waclawiw M, Bonds D, Terrin M. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. JAMA. 2003 Apr 2;289(13):1645-51. Erratum in: JAMA. 2003 Aug 13;290(6):756. link to original article PubMed
2. QoL analysis: Ballas SK, Barton FB, Waclawiw MA, Swerdlow P, Eckman JR, Pegelow CH, Koshy M, Barton BA, Bonds DR. Hydroxyurea and sickle cell anemia: effect on quality of life. Health Qual Life Outcomes. 2006 Aug 31;4:59. link to original article link to PMC article PubMed
3. NOHARM MTD: John CC, Opoka RO, Latham TS, Hume HA, Nabaggala C, Kasirye P, Ndugwa CM, Lane A, Ware RE. Hydroxyurea Dose Escalation for Sickle Cell Anemia in Sub-Saharan Africa. N Engl J Med. 2020 Jun 25;382(26):2524-2533. link to original article PubMed

Hydroxyurea & Voxelotor

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Vichinsky et al. 2019 (HOPE)	2017-2018	Phase III (E-esc)	1. Placebo	Superior hemoglobin response
			2. Voxelotor; 900 mg/day	Not reported

Note: no specific dose of hydroxyurea is specified, just that the dose had to be stable for at least 3 months prior to trial enrollment. Approximately two-thirds of the patients were noted to be on hydroxyurea at baseline.

Supportive therapy

• Hydroxyurea (Hydrea)
• Voxelotor (Oxbryta) 1500 mg PO once per day

References

1. HOPE: Vichinsky E, Hoppe CC, Ataga KI, Ware RE, Nduba V, El-Beshlawy A, Hassab H, Achebe MM, Alkindi S, Brown RC, Diuguid DL, Telfer P, Tsitsikas DA, Elghandour A, Gordeuk VR, Kanter J, Abboud MR, Lehrer-Graiwer J, Tonda M, Intondi A, Tong B, Howard J; HOPE Trial Investigators. A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease. N Engl J Med. 2019 Aug 8;381(6):509-519. Epub 2019 Jun 14. link to original article contains protocol PubMed NCT03036813
   1. Update: Howard J, Ataga KI, Brown RC, Achebe M, Nduba V, El-Beshlawy A, Hassab H, Agodoa I, Tonda M, Gray S, Lehrer-Graiwer J, Vichinsky E. Voxelotor in adolescents and adults with sickle cell disease (HOPE): long-term follow-up results of an international, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Haematol. 2021 Apr 7:S2352-3026(21)00059-4. Epub ahead of print. link to original article PubMed

L-glutamine monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Niihara et al. 2018 (GLUSCC09-01)	2010-2013	Phase III (E-switch-ooc)	Placebo +/- Hydroxyurea	Superior reduction in the number of sickle cell crises through week 48

Supportive therapy

• L-glutamine (Endari) 300 mg/kg PO twice per day

48-week course

References

1. GLUSCC09-01: Niihara Y, Miller ST, Kanter J, Lanzkron S, Smith WR, Hsu LL, Gordeuk VR, Viswanathan K, Sarnaik S, Osunkwo I, Guillaume E, Sadanandan S, Sieger L, Lasky JL, Panosyan EH, Blake OA, New TN, Bellevue R, Tran LT, Razon RL, Stark CW, Neumayr LD, Vichinsky EP; 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 Jul 19;379(3):226-235. link to original article contains protocol PubMed

RBC transfusions

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
DeBaun et al. 2014 (SIT)	2004-2010	Phase III (E-esc)	Observation	Seems to have fewer cerebral infarcts

To be completed

Supportive therapy

• RBC transfusions

References

1. SIT: DeBaun MR, Gordon M, McKinstry RC, Noetzel MJ, White DA, Sarnaik SA, Meier ER, Howard TH, Majumdar S, Inusa BP, Telfer PT, Kirby-Allen M, McCavit TL, Kamdem A, Airewele G, Woods GM, Berman B, Panepinto JA, Fuh BR, Kwiatkowski JL, King AA, Fixler JM, Rhodes MM, Thompson AA, Heiny ME, Redding-Lallinger RC, Kirkham FJ, Dixon N, Gonzalez CE, Kalinyak KA, Quinn CT, Strouse JJ, Miller JP, Lehmann H, Kraut MA, Ball WS Jr, Hirtz D, Casella JF. Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia. N Engl J Med. 2014 Aug 21;371(8):699-710. link to original article link to PMC article PubMed NCT00072761

Voxelotor monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Vichinsky et al. 2019 (HOPE)	2017-2018	Phase III (E-esc)	1. Placebo	Superior hemoglobin response
			2. Voxelotor; 900 mg/day	Not reported

Supportive therapy

• Voxelotor (Oxbryta) 1500 mg PO once per day

References

1. HOPE: Vichinsky E, Hoppe CC, Ataga KI, Ware RE, Nduba V, El-Beshlawy A, Hassab H, Achebe MM, Alkindi S, Brown RC, Diuguid DL, Telfer P, Tsitsikas DA, Elghandour A, Gordeuk VR, Kanter J, Abboud MR, Lehrer-Graiwer J, Tonda M, Intondi A, Tong B, Howard J; HOPE Trial Investigators. A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease. N Engl J Med. 2019 Aug 8;381(6):509-519. Epub 2019 Jun 14. link to original article contains protocol PubMed NCT03036813
   1. Update: Howard J, Ataga KI, Brown RC, Achebe M, Nduba V, El-Beshlawy A, Hassab H, Agodoa I, Tonda M, Gray S, Lehrer-Graiwer J, Vichinsky E. Voxelotor in adolescents and adults with sickle cell disease (HOPE): long-term follow-up results of an international, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Haematol. 2021 Apr 7:S2352-3026(21)00059-4. Epub ahead of print. link to original article PubMed