Essential thrombocythemia

Section editor
	Sanjay R. Mohan, MD, MSCI Vanderbilt University Nashville, TN

8 regimens on this page 9 variants on this page

Guidelines

• Tefferi A, Vannucchi AM, Barbui T. Essential thrombocythemia treatment algorithm 2018. Blood Cancer J. 2018 Jan 10;8(1):2. link to original article PubMed

ELN

• 2011: Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet

ESMO

• 2015: Vannucchi et al. Philadelphia chromosome-negative chronic myeloproliferative neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

NCCN

• NCCN Guidelines - Myeloproliferative Neoplasms

First-line therapy

Anagrelide monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Gisslinger et al. 2013 (ANAHYDRET)	Phase III (E)	Hydroxyurea +/- Aspirin	Non-inferior composite endpoint
Gisslinger et al. 2019 (TEAM-ET 2.0)	Phase III (C)	A-PR	Non-inferior mean platelet count

Anticoagulation

• Anagrelide (Agrylin) 0.5 mg PO twice per day
  • ANAHYDRET: Increased until maintenance of the platelet count at normal (less than or equal to 450 x 10⁹/L) or close to normal levels (450 to 600 x 10⁹/L)
  • TEAM-ET 2.0: Titrated to goal platelet count of 150 to 400 x 10⁹/L

Supportive medications

• ANAHYDRET: Neither aspirin nor Clopidogrel (Plavix) were required in the study, but patients who were already taking either drug for at least two weeks were allowed to continue taking it during the study per investigator discretion

Continued indefinitely

References

1. ANAHYDRET: Gisslinger H, Gotic M, Holowiecki J, Penka M, Thiele J, Kvasnicka HM, Kralovics R, Petrides PE; for all members of the ANAHYDRET Study Group. Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial. Blood. 2013 Mar 7;121(10):1720-8. Epub 2013 Jan 11. link to original article contains verified protocol link to PMC article PubMed
2. TEAM-ET 2.0: Gisslinger H, Buxhofer-Ausch V, Hodisch J, Radinoff A, Karyagina E, Kyrcz-Krzemień S, Abdulkadyrov K, Gerbutavicius R, Melikyan A, Burgstaller S, Hus M, Kłoczko J, Yablokova V, Tzvetkov N, Całbecka M, Shneyder T, Warzocha K, Jurgutis M, Kaplanov K, Jilma B, Schoergenhofer C, Klade C. A phase III randomized, multicentre, double blind, active controlled trial to compare the efficacy and safety of two different anagrelide formulations in patients with essential thrombocythaemia - the TEAM-ET 2·0 trial. Br J Haematol. 2019 May;185(4):691-700. Epub 2019 Mar 28. link to original article contains verified protocol PubMed

Aspirin & Anagrelide

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Harrison et al. 2005 (UK MRC PT-1)	Phase III (E)	Aspirin & Hydroxyurea	Seems to have inferior composite primary end point

Anticoagulation

• Aspirin 75 mg (100 mg in Australia) PO once per day
• Anagrelide (Agrylin) 0.5 mg PO twice per day
  • Doses were subsequently adjusted to maintain the platelet count at less than 400 x 10⁹/L

Continued indefinitely

References

1. UK MRC PT-1: Harrison CN, Campbell PJ, Buck G, Wheatley K, East CL, Bareford D, Wilkins BS, van der Walt JD, Reilly JT, Grigg AP, Revell P, Woodcock BE, Green AR; United Kingdom Medical Research Council Primary Thrombocythemia 1 Study. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med. 2005 Jul 7;353(1):33-45. link to original article contains verified protocol PubMed content property of HemOnc.org

Aspirin & Hydroxyurea

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Variant #1

Study	Evidence	Comparator	Comparative Efficacy
Harrison et al. 2005 (UK MRC PT-1)	Phase III (C)	Aspirin & Anagrelide	Seems to have superior composite primary end point

Chemotherapy

• Hydroxyurea (Hydrea) 500 to 1000 mg PO once per day
  • Doses were subsequently adjusted to maintain the platelet count at less than 400 x 10⁹/L

Supportive medications

• Aspirin 75 mg (100 mg in Australia) PO once per day

Continued indefinitely

Variant #2

Study	Evidence	Comparator	Comparative Efficacy
Gisslinger et al. 2013 (ANAHYDRET)	Phase III (E)	Anagrelide +/- Aspirin	Non-inferior

Chemotherapy

• Hydroxyurea (Hydrea) 1500 mg PO once per day
  • Increased until maintenance of the platelet count at normal (less than or equal to 450 x 10⁹/L) or close to normal levels (450 to 600 x 10⁹/L)

Supportive medications

• Neither aspirin nor Clopidogrel (Plavix) were required in the study, but patients who were already taking either drug for at least two weeks were allowed to continue taking it during the study per investigator discretion

Continued indefinitely

References

1. UK MRC PT-1: Harrison CN, Campbell PJ, Buck G, Wheatley K, East CL, Bareford D, Wilkins BS, van der Walt JD, Reilly JT, Grigg AP, Revell P, Woodcock BE, Green AR; United Kingdom Medical Research Council Primary Thrombocythemia 1 Study. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med. 2005 Jul 7;353(1):33-45. link to original article contains verified protocol PubMed
2. ANAHYDRET: Gisslinger H, Gotic M, Holowiecki J, Penka M, Thiele J, Kvasnicka HM, Kralovics R, Petrides PE; for all members of the ANAHYDRET Study Group. Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial. Blood. 2013 Mar 7;121(10):1720-8. Epub 2013 Jan 11. link to original article contains verified protocol link to PMC article PubMed

Hydroxyurea monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Cortelazzo et al. 1995	Phase III (E)	Observation	Superior thrombotic episode rate

Chemotherapy

• Hydroxyurea (Hydrea) 15 mg/kg/day PO
  • Doses were subsequently adjusted to maintain the platelet count at less than 600 x 10⁹/L without lowering the WBC count below 4 x 10⁹/L

References

1. Cortelazzo S, Finazzi G, Ruggeri M, Vestri O, Galli M, Rodeghiero F, Barbui T. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med. 1995 Apr 27;332(17):1132-6. link to original article contains verified protocol PubMed

Observation

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Cortelazzo et al. 1995	Phase III (C)	Hydroxyurea	Inferior thrombotic episode rate

No active antineoplastic treatment; used as a comparator arm.

References

1. Cortelazzo S, Finazzi G, Ruggeri M, Vestri O, Galli M, Rodeghiero F, Barbui T. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med. 1995 Apr 27;332(17):1132-6. link to original article contains verified protocol PubMed

Peginterferon alfa-2a monotherapy

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Regimen

Study	Evidence
Quintás-Cardama et al. 2009	Phase II

This trial had several dose de-escalations due to toxicity and the dose here is the reported final starting dose.

Immunotherapy

• Peginterferon alfa-2a (Pegasys) 90 mcg SC once per week

Continued for as long as the patient experiences clinical benefit

References

1. Quintás-Cardama A, Kantarjian H, Manshouri T, Luthra R, Estrov Z, Pierce S, Richie MA, Borthakur G, Konopleva M, Cortes J, Verstovsek S. Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol. 2009 Nov 10;27(32):5418-24. Epub 2009 Oct 13. link to original article contains protocol link to PMC article PubMed
   1. Update: Quintás-Cardama A, Abdel-Wahab O, Manshouri T, Kilpivaara O, Cortes J, Roupie AL, Zhang SJ, Harris D, Estrov Z, Kantarjian H, Levine RL, Verstovsek S. Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon α-2a. Blood. 2013 Aug 8;122(6):893-901. Epub 2013 Jun 19. link to original article link to PMC article PubMed
   2. Update: Masarova L, Patel KP, Newberry KJ, Cortes J, Borthakur G, Konopleva M, Estrov Z, Kantarjian H, Verstovsek S. Pegylated interferon alfa-2a in patients with essential thrombocythaemia or polycythaemia vera: a post-hoc, median 83 month follow-up of an open-label, phase 2 trial. Lancet Haematol. 2017 Apr;4(4):e165-e175. Epub 2017 Mar 10. link to original article link to PMC article PubMed

Relapsed, refractory, or intolerant to initial therapy

Peginterferon alfa-2a monotherapy

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Regimen

Study	Evidence
Verger et al. 2015	Observational

Verger et al. 2015 do not specify a protocol but rather point to the European LeukemiaNet guidelines from 2011. All patients in this study had CALR mutations.

Immunotherapy

• Peginterferon alfa-2a (Pegasys)

References

1. Verger E, Cassinat B, Chauveau A, Dosquet C, Giraudier S, Schlageter MH, Ianotto JC, Yassin MA, Al-Dewik N, Carillo S, Legouffe E, Ugo V, Chomienne C, Kiladjian JJ. Clinical and molecular response to interferon-α therapy in essential thrombocythemia patients with CALR mutations. Blood. 2015 Dec 10;126(24):2585-91. Epub 2015 Oct 20. link to original article does not contain protocol PubMed

Ruxolitinib monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Harrison et al. 2017 (MAJIC-ET)	Randomized Phase II (E)	"Best available therapy"	Seems not superior
Verstovsek et al. 2017	Phase II

Note: Harrison et al. 2017 does not specify a starting dose.

Chemotherapy

• Ruxolitinib (Jakafi) as follows:
  • Starting dose: 25 mg PO twice per day
  • Titrate to keep platelets less than 400 x 10⁹/L

Continued indefinitely

References

1. MAJIC-ET: Harrison CN, Mead AJ, Panchal A, Fox S, Yap C, Gbandi E, Houlton A, Alimam S, Ewing J, Wood M, Chen F, Coppell J, Panoskaltsis N, Knapper S, Ali S, Hamblin A, Scherber R, Dueck AC, Cross NCP, Mesa R, McMullin MF. Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide. Blood. 2017 Oct 26;130(17):1889-1897. Epub 2017 Aug 9. link to original article PubMed
2. Verstovsek S, Passamonti F, Rambaldi A, Barosi G, Rumi E, Gattoni E, Pieri L, Zhen H, Granier M, Assad A, Cazzola M, Kantarjian HM, Barbui T, Vannucchi AM. Ruxolitinib for essential thrombocythemia refractory to or intolerant of hydroxyurea: long-term phase 2 study results. Blood. 2017 Oct 12;130(15):1768-1771. Epub 2017 Aug 21. link to original article contains verified protocol PubMed

Response criteria

ELN

• 2009: Response criteria for essential thrombocythemia and polycythemia vera: result of a European LeukemiaNet consensus conference