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

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7 regimens on this page 13 variants on this page

Note: most published trials in this area are for "advanced systemic mastocytosis", which includes more than one WHO category. See individual regimens for details.

Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

NCCN

NCCN Guidelines - Systemic Mastocytosis

All lines of therapy

Avapritinib monotherapy

Regimen variant #1, 25 mg/day

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gotlib et al. 2023 (PIONEER)	2020-09 to 2022-01	Randomized Phase 2 (E-RT-esc)	Placebo	Superior mean change in total symptom score (primary endpoint)

Note: this is the dosing for indolent systemic mastocytosis (ISM).

Targeted therapy

Avapritinib (Ayvakit) 25 mg PO once per day

Continued indefinitely

Regimen variant #2, 200 mg/day

FDA-recommended dose

Study	Dates of enrollment	Evidence
DeAngelo et al. 2021 (EXPLORER)	2016-2020	Phase 1 (RT)
Gotlib et al. 2021 (PATHFINDER)	2018-2020	Phase 2 (RT)

Note: this is the dosing for advanced systemic mastocytosis (ASM).

Targeted therapy

Avapritinib (Ayvakit) 200 mg PO once per day

Continued indefinitely

References

EXPLORER: DeAngelo DJ, Radia DH, George TI, Robinson WA, Quiery AT, Drummond MW, Bose P, Hexner EO, Winton EF, Horny HP, Tugnait M, Schmidt-Kittler O, Evans EK, Lin HM, Mar BG, Verstovsek S, Deininger MW, Gotlib J. Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial. Nat Med. 2021 Dec;27(12):2183-2191. Epub 2021 Dec 6. link to original article link to PMC article contains dosing details in abstract PubMed NCT02561988
PATHFINDER: Gotlib J, Reiter A, Radia DH, Deininger MW, George TI, Panse J, Vannucchi AM, Platzbecker U, Alvarez-Twose I, Mital A, Hermine O, Dybedal I, Hexner EO, Hicks LK, Span L, Mesa R, Bose P, Pettit KM, Heaney ML, Oh ST, Sen J, Lin HM, Mar BG, DeAngelo DJ. Efficacy and safety of avapritinib in advanced systemic mastocytosis: interim analysis of the phase 2 PATHFINDER trial. Nat Med. 2021 Dec;27(12):2192-2199. Epub 2021 Dec 6. link to original article link to PMC article contains dosing details in manuscript PubMed NCT03580655
PIONEER: Gotlib J, Castells M, Elberink HO, Siebenhaar F, Hartmann K, Broesby-Olsen S, George TI, Panse J, Alvarez-Twose I, Radia DH, Tashi T, Bulai Livideanu C, Sabato V, Heaney M, Van Daele P, Cerquozzi S, Dybedal I, Reiter A, Pongdee T, Barete S, Ustun C, Schwartz L, Ward BR, Schafhausen P, Vadas P, Bose P, DeAngelo DJ, Rein L, Vachhani P, Triggiani M, Bonadonna P, Rafferty M, Butt NM, Oh ST, Wortmann F, Ungerstedt J, Guilarte M, Taparia M, Kuykendall AT, Arana Yi C, Ogbogu P, Gaudy-Marqueste C, Mattsson M, Shomali W, Giannetti MP, Bidollari I, Lin HM, Sulllivan E, Mar B, Scherber R, Roche M, Akin C, Maurer M. Avapritinib versus Placebo in Indolent Systemic Mastocytosis. NEJM Evidence. 2023 Jun;2(6):EVIDoa2200339. Epub 2023 May 23. link to original article PubMed NCT03731260

Cladribine monotherapy

Regimen variant #1, 0.13 mg/kg

Study	Evidence
Kluin-Nelemans et al. 2003	Pilot, fewer than 20 patients reported

Chemotherapy

Cladribine (Leustatin) 0.13 mg/kg IV over 2 hours once per day on days 1 to 5

Supportive therapy

Clemastine (Tavist) 1 to 2 mg IV once per day on days 1 to 5, prior to cladribine
Dexamethasone (Decadron) 5 mg IV once per day on days 1 to 5, prior to cladribine
Fluconazole (Diflucan) (dose not specified)
Co-trimaxazole (dose not specified)
Valacyclovir (Valtrex) (dose not specified) "in some patients"

4- to 6-week cycle for 6 cycles

Regimen variant #2, 0.14 mg/kg

Study	Evidence
Barete et al. 2015	Retrospective

Chemotherapy

Cladribine (Leustatin) 0.14 mg/kg SC or IV over 2 hours once per day on days 1 to 5

4- to 12-week cycle for 1 to 6 cycles

Regimen variant #3, 5 mg/m²

Study	Evidence
Lim et al. 2009	Retrospective

Note: This was a retrospective series; a range of weight-based dosing was also reported.

Chemotherapy

Cladribine (Leustatin) 5 mg/m² IV over 2 hours once per day on days 1 to 5

Median number of treatment cycles was 3 (range 1 to 9)

References

Kluin-Nelemans HC, Oldhoff JM, Van Doormaal JJ, Van 't Wout JW, Verhoef G, Gerrits WB, van Dobbenburgh OA, Pasmans SG, Fijnheer R. Cladribine therapy for systemic mastocytosis. Blood. 2003 Dec 15;102(13):4270-6. Epub 2003 Aug 21. link to original article contains dosing details in manuscript PubMed
Retrospective: Lim KH, Pardanani A, Butterfield JH, Li CY, Tefferi A. Cytoreductive therapy in 108 adults with systemic mastocytosis: Outcome analysis and response prediction during treatment with interferon-alpha, hydroxyurea, imatinib mesylate or 2-chlorodeoxyadenosine. Am J Hematol. 2009 Dec;84(12):790-4. link to original article PubMed
Retrospective: Barete S, Lortholary O, Damaj G, Hirsch I, Chandesris MO, Elie C, Hamidou M, Durieu I, Suarez F, Grosbois B, Limal N, Gyan E, Larroche C, Guillet G, Kahn JE, Casassus P, Amazzough K, Coignard-Biehler H, Georgin-Lavialle S, Lhermitte L, Fraitag S, Canioni D, Dubreuil P, Hermine O. Long-term efficacy and safety of cladribine (2-CdA) in adult patients with mastocytosis. Blood. 2015 Aug 20;126(8):1009-16. Epub 2015 May 22. link to original article PubMed

Dasatinib monotherapy

Regimen

Study	Evidence
Verstovsek et al. 2008	Phase 2

Note: Only 9 of 67 patients studied had ASM; 18 has ISM and 6 had SM-AHNMD.

Targeted therapy

Dasatinib (Sprycel) 70 mg PO twice per day on days 1 to 28
- Alternative dosing: 140 mg PO once per day

Supportive therapy

Hematopoietic growth factors at investigator discretion

28-day cycles

References

Verstovsek S, Tefferi A, Cortes J, O'Brien S, Garcia-Manero G, Pardanani A, Akin C, Faderl S, Manshouri T, Thomas D, Kantarjian H. Phase II study of dasatinib in Philadelphia chromosome-negative acute and chronic myeloid diseases, including systemic mastocytosis. Clin Cancer Res. 2008 Jun 15;14(12):3906-15. link to original article contains dosing details in manuscript link to PMC article PubMed

Imatinib monotherapy

Regimen variant #1, 100 mg/day

Study	Evidence
Pardanani et al. 2003	Phase 2, fewer than 20 pts reported

Targeted therapy

Imatinib (Gleevec) 100 mg PO once per day

Continued indefinitely

Regimen variant #2, 400 mg/day x 6 mo

Study	Evidence
Droogendijk et al. 2006	Phase 2, fewer than 20 pts reported

Targeted therapy

Imatinib (Gleevec) 400 mg PO once per day

Supportive therapy

Prednisone (Sterapred) 15 mg PO twice per day on days 1 to 14

6-month course

Regimen variant #3, 400 mg/day indefinitely

Study	Evidence
Pardanani et al. 2003	Phase 2, fewer than 20 pts reported

Targeted therapy

Imatinib (Gleevec) 400 mg PO once per day

Continued indefinitely

Regimen variant #4, 400 mg/day with dose escalation

Study	Evidence
Vega-Ruiz et al. 2009	Phase 2

Targeted therapy

Imatinib (Gleevec) as follows:
- Cycle 1: 400 mg PO once per day
- Cycle 2: 600 mg PO once per day
- Cycle 3 onwards: 800 mg PO once per day

Supportive therapy

Hematopoietic growth factors at investigator discretion

Monthly cycles

References

Pardanani A, Elliott M, Reeder T, Li CY, Baxter EJ, Cross NC, Tefferi A. Imatinib for systemic mast-cell disease. Lancet. 2003 Aug 16;362(9383):535-6. link to original article contains dosing details in abstract PubMed
Droogendijk HJ, Kluin-Nelemans HJ, van Doormaal JJ, Oranje AP, van de Loosdrecht AA, van Daele PL. Imatinib mesylate in the treatment of systemic mastocytosis: a phase II trial. Cancer. 2006 Jul 15;107(2):345-51. link to original article contains dosing details in manuscript PubMed
Retrospective: Pagano L, Valentini CG, Caira M, Rondoni M, Van Lint MT, Candoni A, Allione B, Cattaneo C, Marbello L, Caramatti C, Pogliani EM, Iannitto E, Giona F, Ferrara F, Invernizzi R, Fanci R, Lunghi M, Fianchi L, Sanpaolo G, Stefani PM, Pulsoni A, Martinelli G, Leone G, Musto P. Advanced mast cell disease: an Italian Hematological Multicenter experience. Int J Hematol. 2008 Dec;88(5):483-8. Epub 2008 Nov 26. link to original article PubMed
Vega-Ruiz A, Cortes JE, Sever M, Manshouri T, Quintás-Cardama A, Luthra R, Kantarjian HM, Verstovsek S. Phase II study of imatinib mesylate as therapy for patients with systemic mastocytosis. Leuk Res. 2009 Nov;33(11):1481-4. Epub 2009 Feb 3. link to original article contains dosing details in manuscript link to PMC article PubMed
Retrospective: Lim KH, Pardanani A, Butterfield JH, Li CY, Tefferi A. Cytoreductive therapy in 108 adults with systemic mastocytosis: Outcome analysis and response prediction during treatment with interferon-alpha, hydroxyurea, imatinib mesylate or 2-chlorodeoxyadenosine. Am J Hematol. 2009 Dec;84(12):790-4. link to original article PubMed

Interferon alfa-2b monotherapy

Regimen

Study	Evidence
Casassus et al. 2002	Phase 2

Note: Doses were escalated based on tolerance.

Immunotherapy

Interferon alfa-2b (Intron-A) as follows:
- Week 1: 1,000,000 units SC once per day
- Week 2: 3,000,000 units SC once per day
- Weeks 3 & 4: 3,000,000 units/m² SC once per day
- Week 5 onwards: 5,000,000 units/m² SC once per day

6-month course, continued at physician's and patient's discretion

References

Casassus P, Caillat-Vigneron N, Martin A, Simon J, Gallais V, Beaudry P, Eclache V, Laroche L, Lortholary P, Raphaël M, Guillevin L, Lortholary O. Treatment of adult systemic mastocytosis with interferon-alpha: results of a multicentre phase II trial on 20 patients. Br J Haematol. 2002 Dec;119(4):1090-7. link to original article contains dosing details in manuscript PubMed
Retrospective: Lim KH, Pardanani A, Butterfield JH, Li CY, Tefferi A. Cytoreductive therapy in 108 adults with systemic mastocytosis: Outcome analysis and response prediction during treatment with interferon-alpha, hydroxyurea, imatinib mesylate or 2-chlorodeoxyadenosine. Am J Hematol. 2009 Dec;84(12):790-4. link to original article PubMed

Midostaurin monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Efficacy
Gotlib et al. 2016 (CPKC412D2201)	2009-2012	Phase 2 (RT)	ORR: 60% (95% CI 49 to 70)
Chandesris et al. 2016 (CEREMAST)	2012-2015	Phase 2 (RT)

Note: CPKC412D2201 included untreated and previously untreated patients.

Targeted therapy

Midostaurin (Rydapt) 100 mg PO twice per day on days 1 to 28

28-day cycles

References

CPKC412D2201: Gotlib J, Kluin-Nelemans HC, George TI, Akin C, Sotlar K, Hermine O, Awan FT, Hexner E, Mauro MJ, Sternberg DW, Villeneuve M, Huntsman Labed A, Stanek EJ, Hartmann K, Horny HP, Valent P, Reiter A. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med. 2016 Jun 30;374(26):2530-41. link to original article contains dosing details in manuscript link to supplementary appendix PubMed NCT00233454
CEREMAST: Chandesris MO, Damaj G, Canioni D, Brouzes C, Lhermitte L, Hanssens K, Frenzel L, Cherquaoui Z, Durieu I, Durupt S, Gyan E, Beyne-Rauzy O, Launay D, Faure C, Hamidou M, Besnard S, Diouf M, Schiffmann A, Niault M, Jeandel PY, Ranta D, Gressin R, Chantepie S, Barete S, Dubreuil P, Bourget P, Lortholary O, Hermine O; CEREMAST Study Group. Midostaurin in advanced systemic mastocytosis. N Engl J Med. 2016 Jun 30;374(26):2605-7. link to original article PubMed

Nilotinib monotherapy

Regimen

Study	Dates of enrollment	Evidence
Kantarjian et al. 2006 (A2101)	2004-2005	Phase 1/2

Targeted therapy

Nilotinib (Tasigna) 400 mg PO twice per day on days 1 to 28

28-day cycles

References

A2101: Kantarjian H, Giles F, Wunderle L, Bhalla K, O'Brien S, Wassmann B, Tanaka C, Manley P, Rae P, Mietlowski W, Bochinski K, Hochhaus A, Griffin JD, Hoelzer D, Albitar M, Dugan M, Cortes J, Alland L, Ottmann OG. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006 Jun 15;354(24):2542-51. link to original article PubMed NCT00109707
1. Subgroup analysis: Hochhaus A, Baccarani M, Giles FJ, le Coutre PD, Müller MC, Reiter A, Santanastasio H, Leung M, Novick S, Kantarjian HM. Nilotinib in patients with systemic mastocytosis: analysis of the phase 2, open-label, single-arm nilotinib registration study. J Cancer Res Clin Oncol. 2015 Nov;141(11):2047-60. Epub 2015 May 23. link to original article contains dosing details in manuscript link to PMC article PubMed

Response criteria

IWG-MRT & ECNM consensus response criteria (2013)

Gotlib J, Pardanani A, Akin C, Reiter A, George T, Hermine O, Kluin-Nelemans H, Hartmann K, Sperr WR, Brockow K, Schwartz LB, Orfao A, Deangelo DJ, Arock M, Sotlar K, Horny HP, Metcalfe DD, Escribano L, Verstovsek S, Tefferi A, Valent P. International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) & European Competence Network on Mastocytosis (ECNM) consensus response criteria in advanced systemic mastocytosis. Blood. 2013 Mar 28;121(13):2393-401. Epub 2013 Jan 16. link to original article link to PMC article PubMed

Systemic mastocytosis

Guidelines

NCCN

All lines of therapy

Avapritinib monotherapy

Regimen variant #1, 25 mg/day

Targeted therapy

Regimen variant #2, 200 mg/day

Targeted therapy

References

Cladribine monotherapy

Regimen variant #1, 0.13 mg/kg

Chemotherapy

Supportive therapy

Regimen variant #2, 0.14 mg/kg

Chemotherapy

Regimen variant #3, 5 mg/m2

Chemotherapy

References

Dasatinib monotherapy

Regimen

Targeted therapy

Supportive therapy

References

Imatinib monotherapy

Regimen variant #1, 100 mg/day

Targeted therapy

Regimen variant #2, 400 mg/day x 6 mo

Targeted therapy

Supportive therapy

Regimen variant #3, 400 mg/day indefinitely

Targeted therapy

Regimen variant #4, 400 mg/day with dose escalation

Targeted therapy

Supportive therapy

References

Interferon alfa-2b monotherapy

Regimen

Immunotherapy

References

Midostaurin monotherapy

Regimen

Targeted therapy

References

Nilotinib monotherapy

Regimen

Targeted therapy

References

Response criteria

IWG-MRT & ECNM consensus response criteria (2013)

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Regimen variant #3, 5 mg/m²