Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial

Ruben Mesa, Alessandro M. Vannucchi, Adam Mead, Miklos Egyed, Anita Szoke, Aleksandr Suvorov, Janos Jakucs, Andrew Perkins, Ritam Prasad, Jiri Mayer, Judit Demeter, Peter Ganly, Jack W. Singer, Huafeng Zhou, James P. Dean, Peter A. te Boekhorst, Jyoti Nangalia, Jean Jacques Kiladjian, Claire N. Harrison

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Abstract

Background Available therapies for myelofibrosis can exacerbate cytopenias and are not indicated for patients with severe thrombocytopenia. Pacritinib, which inhibits both JAK2 and FLT3, induced spleen responses with limited myelosuppression in phase 1/2 trials. We aimed to assess the efficacy and safety of pacritinib versus best available therapy in patients with myelofibrosis irrespective of baseline cytopenias. Methods This international, multicentre, randomised, phase 3 trial (PERSIST-1) was done at 67 sites in 12 countries. Patients with higher-risk myelofibrosis (with no exclusions for baseline anaemia or thrombocytopenia) were randomly assigned (2:1) to receive oral pacritinib 400 mg once daily or best available therapy (BAT) excluding JAK2 inhibitors until disease progression or unacceptable toxicity. Randomisation was stratified by risk category, platelet count, and region. Treatment assignments were known to investigators, site personnel, patients, clinical monitors, and pharmacovigilance personnel. The primary endpoint was spleen volume reduction (SVR) of 35% or more from baseline to week 24 in the intention-to-treat population as assessed by blinded, centrally reviewed MRI or CT. We did safety analyses in all randomised patients who received either treatment. Here we present the final data. This trial is registered with ClinicalTrials.gov, number NCT01773187. Findings Between Jan 8, 2013, and Aug 1, 2014, 327 patients were randomly assigned to pacritinib (n=220) or BAT (n=107). Median follow-up was 23·2 months (IQR 14·8–28·7). At week 24, the primary endpoint of SVR of 35% or more was achieved by 42 (19%) patients in the pacritinib group versus five (5%) patients in the BAT group (p=0·0003). 90 patients in the BAT group crossed over to receive pacritinib at a median of 6·3 months (IQR 5·8–6·7). The most common grade 3–4 adverse events through week 24 were anaemia (n=37 [17%]), thrombocytopenia (n=26 [12%]), and diarrhoea (n=11 [5%]) in the pacritinib group, and anaemia (n=16 [15%]), thrombocytopenia (n=12 [11%]), dyspnoea (n=3 [3%]), and hypotension (n=3 [3%]) in the BAT group. The most common serious adverse events that occurred through week 24 were anaemia (10 [5%]), cardiac failure (5 [2%]), pyrexia (4 [2%]), and pneumonia (4 [2%]) with pacritinib, and anaemia (5 [5%]), sepsis (2 [2%]), and dyspnoea (2 [2%]) with BAT. Deaths due to adverse events were observed in 27 (12%) patients in the pacritinib group and 14 (13%) patients in the BAT group throughout the duration of the study. Interpretation Pacritinib therapy was well tolerated and induced significant and sustained SVR and symptom reduction, even in patients with severe baseline cytopenias. Pacritinib could be a treatment option for patients with myelofibrosis, including those with baseline cytopenias for whom options are particularly limited. Funding CTI BioPharma Corp.

Original languageEnglish (US)
Pages (from-to)e225-e236
JournalThe Lancet Haematology
Volume4
Issue number5
DOIs
StatePublished - May 1 2017
Externally publishedYes

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Primary Myelofibrosis
Anemia
Group Psychotherapy
Thrombocytopenia
Therapeutics
Spleen
11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene
Dyspnea
Pharmacovigilance
Safety
Random Allocation
Platelet Count
Hypotension
Disease Progression
Diarrhea
Sepsis
Pneumonia

ASJC Scopus subject areas

  • Hematology

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Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1) : an international, randomised, phase 3 trial. / Mesa, Ruben; Vannucchi, Alessandro M.; Mead, Adam; Egyed, Miklos; Szoke, Anita; Suvorov, Aleksandr; Jakucs, Janos; Perkins, Andrew; Prasad, Ritam; Mayer, Jiri; Demeter, Judit; Ganly, Peter; Singer, Jack W.; Zhou, Huafeng; Dean, James P.; te Boekhorst, Peter A.; Nangalia, Jyoti; Kiladjian, Jean Jacques; Harrison, Claire N.

In: The Lancet Haematology, Vol. 4, No. 5, 01.05.2017, p. e225-e236.

Research output: Contribution to journalArticle

Mesa, R, Vannucchi, AM, Mead, A, Egyed, M, Szoke, A, Suvorov, A, Jakucs, J, Perkins, A, Prasad, R, Mayer, J, Demeter, J, Ganly, P, Singer, JW, Zhou, H, Dean, JP, te Boekhorst, PA, Nangalia, J, Kiladjian, JJ & Harrison, CN 2017, 'Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial', The Lancet Haematology, vol. 4, no. 5, pp. e225-e236. https://doi.org/10.1016/S2352-3026(17)30027-3
Mesa, Ruben ; Vannucchi, Alessandro M. ; Mead, Adam ; Egyed, Miklos ; Szoke, Anita ; Suvorov, Aleksandr ; Jakucs, Janos ; Perkins, Andrew ; Prasad, Ritam ; Mayer, Jiri ; Demeter, Judit ; Ganly, Peter ; Singer, Jack W. ; Zhou, Huafeng ; Dean, James P. ; te Boekhorst, Peter A. ; Nangalia, Jyoti ; Kiladjian, Jean Jacques ; Harrison, Claire N. / Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1) : an international, randomised, phase 3 trial. In: The Lancet Haematology. 2017 ; Vol. 4, No. 5. pp. e225-e236.
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abstract = "Background Available therapies for myelofibrosis can exacerbate cytopenias and are not indicated for patients with severe thrombocytopenia. Pacritinib, which inhibits both JAK2 and FLT3, induced spleen responses with limited myelosuppression in phase 1/2 trials. We aimed to assess the efficacy and safety of pacritinib versus best available therapy in patients with myelofibrosis irrespective of baseline cytopenias. Methods This international, multicentre, randomised, phase 3 trial (PERSIST-1) was done at 67 sites in 12 countries. Patients with higher-risk myelofibrosis (with no exclusions for baseline anaemia or thrombocytopenia) were randomly assigned (2:1) to receive oral pacritinib 400 mg once daily or best available therapy (BAT) excluding JAK2 inhibitors until disease progression or unacceptable toxicity. Randomisation was stratified by risk category, platelet count, and region. Treatment assignments were known to investigators, site personnel, patients, clinical monitors, and pharmacovigilance personnel. The primary endpoint was spleen volume reduction (SVR) of 35{\%} or more from baseline to week 24 in the intention-to-treat population as assessed by blinded, centrally reviewed MRI or CT. We did safety analyses in all randomised patients who received either treatment. Here we present the final data. This trial is registered with ClinicalTrials.gov, number NCT01773187. Findings Between Jan 8, 2013, and Aug 1, 2014, 327 patients were randomly assigned to pacritinib (n=220) or BAT (n=107). Median follow-up was 23·2 months (IQR 14·8–28·7). At week 24, the primary endpoint of SVR of 35{\%} or more was achieved by 42 (19{\%}) patients in the pacritinib group versus five (5{\%}) patients in the BAT group (p=0·0003). 90 patients in the BAT group crossed over to receive pacritinib at a median of 6·3 months (IQR 5·8–6·7). The most common grade 3–4 adverse events through week 24 were anaemia (n=37 [17{\%}]), thrombocytopenia (n=26 [12{\%}]), and diarrhoea (n=11 [5{\%}]) in the pacritinib group, and anaemia (n=16 [15{\%}]), thrombocytopenia (n=12 [11{\%}]), dyspnoea (n=3 [3{\%}]), and hypotension (n=3 [3{\%}]) in the BAT group. The most common serious adverse events that occurred through week 24 were anaemia (10 [5{\%}]), cardiac failure (5 [2{\%}]), pyrexia (4 [2{\%}]), and pneumonia (4 [2{\%}]) with pacritinib, and anaemia (5 [5{\%}]), sepsis (2 [2{\%}]), and dyspnoea (2 [2{\%}]) with BAT. Deaths due to adverse events were observed in 27 (12{\%}) patients in the pacritinib group and 14 (13{\%}) patients in the BAT group throughout the duration of the study. Interpretation Pacritinib therapy was well tolerated and induced significant and sustained SVR and symptom reduction, even in patients with severe baseline cytopenias. Pacritinib could be a treatment option for patients with myelofibrosis, including those with baseline cytopenias for whom options are particularly limited. Funding CTI BioPharma Corp.",
author = "Ruben Mesa and Vannucchi, {Alessandro M.} and Adam Mead and Miklos Egyed and Anita Szoke and Aleksandr Suvorov and Janos Jakucs and Andrew Perkins and Ritam Prasad and Jiri Mayer and Judit Demeter and Peter Ganly and Singer, {Jack W.} and Huafeng Zhou and Dean, {James P.} and {te Boekhorst}, {Peter A.} and Jyoti Nangalia and Kiladjian, {Jean Jacques} and Harrison, {Claire N.}",
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TY - JOUR

T1 - Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1)

T2 - an international, randomised, phase 3 trial

AU - Mesa, Ruben

AU - Vannucchi, Alessandro M.

AU - Mead, Adam

AU - Egyed, Miklos

AU - Szoke, Anita

AU - Suvorov, Aleksandr

AU - Jakucs, Janos

AU - Perkins, Andrew

AU - Prasad, Ritam

AU - Mayer, Jiri

AU - Demeter, Judit

AU - Ganly, Peter

AU - Singer, Jack W.

AU - Zhou, Huafeng

AU - Dean, James P.

AU - te Boekhorst, Peter A.

AU - Nangalia, Jyoti

AU - Kiladjian, Jean Jacques

AU - Harrison, Claire N.

PY - 2017/5/1

Y1 - 2017/5/1

N2 - Background Available therapies for myelofibrosis can exacerbate cytopenias and are not indicated for patients with severe thrombocytopenia. Pacritinib, which inhibits both JAK2 and FLT3, induced spleen responses with limited myelosuppression in phase 1/2 trials. We aimed to assess the efficacy and safety of pacritinib versus best available therapy in patients with myelofibrosis irrespective of baseline cytopenias. Methods This international, multicentre, randomised, phase 3 trial (PERSIST-1) was done at 67 sites in 12 countries. Patients with higher-risk myelofibrosis (with no exclusions for baseline anaemia or thrombocytopenia) were randomly assigned (2:1) to receive oral pacritinib 400 mg once daily or best available therapy (BAT) excluding JAK2 inhibitors until disease progression or unacceptable toxicity. Randomisation was stratified by risk category, platelet count, and region. Treatment assignments were known to investigators, site personnel, patients, clinical monitors, and pharmacovigilance personnel. The primary endpoint was spleen volume reduction (SVR) of 35% or more from baseline to week 24 in the intention-to-treat population as assessed by blinded, centrally reviewed MRI or CT. We did safety analyses in all randomised patients who received either treatment. Here we present the final data. This trial is registered with ClinicalTrials.gov, number NCT01773187. Findings Between Jan 8, 2013, and Aug 1, 2014, 327 patients were randomly assigned to pacritinib (n=220) or BAT (n=107). Median follow-up was 23·2 months (IQR 14·8–28·7). At week 24, the primary endpoint of SVR of 35% or more was achieved by 42 (19%) patients in the pacritinib group versus five (5%) patients in the BAT group (p=0·0003). 90 patients in the BAT group crossed over to receive pacritinib at a median of 6·3 months (IQR 5·8–6·7). The most common grade 3–4 adverse events through week 24 were anaemia (n=37 [17%]), thrombocytopenia (n=26 [12%]), and diarrhoea (n=11 [5%]) in the pacritinib group, and anaemia (n=16 [15%]), thrombocytopenia (n=12 [11%]), dyspnoea (n=3 [3%]), and hypotension (n=3 [3%]) in the BAT group. The most common serious adverse events that occurred through week 24 were anaemia (10 [5%]), cardiac failure (5 [2%]), pyrexia (4 [2%]), and pneumonia (4 [2%]) with pacritinib, and anaemia (5 [5%]), sepsis (2 [2%]), and dyspnoea (2 [2%]) with BAT. Deaths due to adverse events were observed in 27 (12%) patients in the pacritinib group and 14 (13%) patients in the BAT group throughout the duration of the study. Interpretation Pacritinib therapy was well tolerated and induced significant and sustained SVR and symptom reduction, even in patients with severe baseline cytopenias. Pacritinib could be a treatment option for patients with myelofibrosis, including those with baseline cytopenias for whom options are particularly limited. Funding CTI BioPharma Corp.

AB - Background Available therapies for myelofibrosis can exacerbate cytopenias and are not indicated for patients with severe thrombocytopenia. Pacritinib, which inhibits both JAK2 and FLT3, induced spleen responses with limited myelosuppression in phase 1/2 trials. We aimed to assess the efficacy and safety of pacritinib versus best available therapy in patients with myelofibrosis irrespective of baseline cytopenias. Methods This international, multicentre, randomised, phase 3 trial (PERSIST-1) was done at 67 sites in 12 countries. Patients with higher-risk myelofibrosis (with no exclusions for baseline anaemia or thrombocytopenia) were randomly assigned (2:1) to receive oral pacritinib 400 mg once daily or best available therapy (BAT) excluding JAK2 inhibitors until disease progression or unacceptable toxicity. Randomisation was stratified by risk category, platelet count, and region. Treatment assignments were known to investigators, site personnel, patients, clinical monitors, and pharmacovigilance personnel. The primary endpoint was spleen volume reduction (SVR) of 35% or more from baseline to week 24 in the intention-to-treat population as assessed by blinded, centrally reviewed MRI or CT. We did safety analyses in all randomised patients who received either treatment. Here we present the final data. This trial is registered with ClinicalTrials.gov, number NCT01773187. Findings Between Jan 8, 2013, and Aug 1, 2014, 327 patients were randomly assigned to pacritinib (n=220) or BAT (n=107). Median follow-up was 23·2 months (IQR 14·8–28·7). At week 24, the primary endpoint of SVR of 35% or more was achieved by 42 (19%) patients in the pacritinib group versus five (5%) patients in the BAT group (p=0·0003). 90 patients in the BAT group crossed over to receive pacritinib at a median of 6·3 months (IQR 5·8–6·7). The most common grade 3–4 adverse events through week 24 were anaemia (n=37 [17%]), thrombocytopenia (n=26 [12%]), and diarrhoea (n=11 [5%]) in the pacritinib group, and anaemia (n=16 [15%]), thrombocytopenia (n=12 [11%]), dyspnoea (n=3 [3%]), and hypotension (n=3 [3%]) in the BAT group. The most common serious adverse events that occurred through week 24 were anaemia (10 [5%]), cardiac failure (5 [2%]), pyrexia (4 [2%]), and pneumonia (4 [2%]) with pacritinib, and anaemia (5 [5%]), sepsis (2 [2%]), and dyspnoea (2 [2%]) with BAT. Deaths due to adverse events were observed in 27 (12%) patients in the pacritinib group and 14 (13%) patients in the BAT group throughout the duration of the study. Interpretation Pacritinib therapy was well tolerated and induced significant and sustained SVR and symptom reduction, even in patients with severe baseline cytopenias. Pacritinib could be a treatment option for patients with myelofibrosis, including those with baseline cytopenias for whom options are particularly limited. Funding CTI BioPharma Corp.

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