AN EVALUATION OF THE TYROSINE KINASE INHIBITOR PACRITINIB IN PATIENTS WITH RELAPSED FLT3-MUTATED ACUTE MYELOID LEUKAEMIA (THE UK NCRI AML17 STUDY)
(Abstract release date: 05/19/16)
EHA Library. S. 06/10/16; 133172; P184
Dr. Steven
Contributions
Contributions
Abstract
Abstract: P184
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
Pacritinib (formerly SB1518) is a third generation tyrosine kinase inhibitor with activity against a number of targets of relevance to acute myeloid leukaemia (AML). Kinases with IC50 <50nM to pacritinib include JAK2 (6nM), JAK2V617F (9nM), FLT3 (15nM), interleukin-1 receptor-associated kinase (IRAK1) (14nM) and c-FMS / colony-stimulating factor-1 (CSF1R) (40nM). FLT3 remains of intense interest as a therapeutic target in AML; activating mutations of FLT3 are associated with early relapse after chemotherapy and poor survival. Efficacy against JAK2 has motivated study of pacritinib in myelofibrosis. Although JAK2 mutations are rare in AML, the JAK-STAT pathway is frequently activated and may represent a mechanism of resistance to FLT3 inhibitors. There is also pre-clinical evidence that activity against IRAK1 and CSF1R may overcome microenvironmental resistance mechanisms. For these reasons we undertook a preliminary assessment of pacritinib as part of the UK NCRI AML17 Trial (ISRCTN55675535).
Aims
To assess the safety and efficacy of pacritinib monotherapy in FLT3-mutated AML patients who had relapsed following chemotherapy.
Methods
Patients commenced pacritinib at an oral dose of 200mg bid with the option, if well-tolerated, of increasing to 300mg bid after 14 days of treatment. Clinical assessments included optional bone marrow at day 14 and formal response assessment including blood and bone marrow examination at day 28. Toxicity was assessed using NCI-CTC Version 3.0. Treatment beyond day 28 was at the investigator’s discretion. Patients were permitted to continue on pacritinib for up to 12 months and/or proceed to salvage chemotherapy with or without allogeneic SCT.
Results
A total of 30 patients received pacritinib therapy. Median age was 54 years (16-68), median presenting WBC was 35.6x109/l (1.2-182) and all had cytogenetically intermediate risk disease. 26 patients (87%) had FLT3-ITD mutations (median FLT3-ITD allelic burden 30% [7-94]) and 4(13%) had FLT3-TKD point mutations; 16 patients (53%) had concomitant mutated NPM1. Four patients had received previous TKI therapy, all with lestaurtinib (CEP701) alongside first-line chemotherapy. Eight patients had received prior allogeneic SCT. 28 of the patients had relapsed disease; median duration of first CR was 6.5 months (1-65). 23 patients were in first relapse (including 1 molecular relapse) and 5 in second relapse. Two patients had primary refractory disease.Patients received a median of 64 days pacritinib (3-200); all were dosed at 200mg bid with 1 patient escalating to 300mg bid. Most toxicities were minor (grade1/2). The most common toxicities were nausea/vomiting (53%), diarrhoea (33%) and raised ALT (30%). One patient stopped pacritinib after 3 days due to nausea (grade 2). 6 further patients were considered non-evaluable either due to early death (2 patients; infections), inadequate response evaluation sampling (2 patients) or the addition of salvage chemotherapy within the 28-day evaluation period (2 patients). In evaluable patients, the overall rate of response to pacritinib monotherapy at the day 28 assessment was 17% (4/23) including 3 CRi (2 CRp) and 1 PR; 3 of these patients were successfully bridged to allogeneic SCT with the fourth patient relapsing at day 60. 3 additional patients (13%) achieved >50% reduction in bone marrow blasts without evidence of peripheral count recovery, 2 going on to receive salvage chemotherapy with FLAG-Ida . 16 patients (70%) were considered non-responders. The 7 clinical responders included 6 patients treated in first relapse and 1 with primary refractory disease; all had FLT3-ITD mutations.
Conclusion
This is the first clinical experience of pacritinib in AML. Tolerability was encouraging and, in the challenging setting of relapsed / primary refractory FLT3-mutated AML where FLT3-directed monotherapy has seldom achieved complete remission, clinical responses were seen in one-third of evaluable patients. Importantly, several patients were successfully bridged to potentially-curative allogeneic SCT. Further clinical evaluation of pacritinib in this setting is warranted.
Session topic: Acute myeloid leukemia - Clinical 1
Keyword(s): Acute myeloid leukemia, FLT3, Flt3 inhibitor, Janus Kinase inhibitor
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
Pacritinib (formerly SB1518) is a third generation tyrosine kinase inhibitor with activity against a number of targets of relevance to acute myeloid leukaemia (AML). Kinases with IC50 <50nM to pacritinib include JAK2 (6nM), JAK2V617F (9nM), FLT3 (15nM), interleukin-1 receptor-associated kinase (IRAK1) (14nM) and c-FMS / colony-stimulating factor-1 (CSF1R) (40nM). FLT3 remains of intense interest as a therapeutic target in AML; activating mutations of FLT3 are associated with early relapse after chemotherapy and poor survival. Efficacy against JAK2 has motivated study of pacritinib in myelofibrosis. Although JAK2 mutations are rare in AML, the JAK-STAT pathway is frequently activated and may represent a mechanism of resistance to FLT3 inhibitors. There is also pre-clinical evidence that activity against IRAK1 and CSF1R may overcome microenvironmental resistance mechanisms. For these reasons we undertook a preliminary assessment of pacritinib as part of the UK NCRI AML17 Trial (ISRCTN55675535).
Aims
To assess the safety and efficacy of pacritinib monotherapy in FLT3-mutated AML patients who had relapsed following chemotherapy.
Methods
Patients commenced pacritinib at an oral dose of 200mg bid with the option, if well-tolerated, of increasing to 300mg bid after 14 days of treatment. Clinical assessments included optional bone marrow at day 14 and formal response assessment including blood and bone marrow examination at day 28. Toxicity was assessed using NCI-CTC Version 3.0. Treatment beyond day 28 was at the investigator’s discretion. Patients were permitted to continue on pacritinib for up to 12 months and/or proceed to salvage chemotherapy with or without allogeneic SCT.
Results
A total of 30 patients received pacritinib therapy. Median age was 54 years (16-68), median presenting WBC was 35.6x109/l (1.2-182) and all had cytogenetically intermediate risk disease. 26 patients (87%) had FLT3-ITD mutations (median FLT3-ITD allelic burden 30% [7-94]) and 4(13%) had FLT3-TKD point mutations; 16 patients (53%) had concomitant mutated NPM1. Four patients had received previous TKI therapy, all with lestaurtinib (CEP701) alongside first-line chemotherapy. Eight patients had received prior allogeneic SCT. 28 of the patients had relapsed disease; median duration of first CR was 6.5 months (1-65). 23 patients were in first relapse (including 1 molecular relapse) and 5 in second relapse. Two patients had primary refractory disease.Patients received a median of 64 days pacritinib (3-200); all were dosed at 200mg bid with 1 patient escalating to 300mg bid. Most toxicities were minor (grade1/2). The most common toxicities were nausea/vomiting (53%), diarrhoea (33%) and raised ALT (30%). One patient stopped pacritinib after 3 days due to nausea (grade 2). 6 further patients were considered non-evaluable either due to early death (2 patients; infections), inadequate response evaluation sampling (2 patients) or the addition of salvage chemotherapy within the 28-day evaluation period (2 patients). In evaluable patients, the overall rate of response to pacritinib monotherapy at the day 28 assessment was 17% (4/23) including 3 CRi (2 CRp) and 1 PR; 3 of these patients were successfully bridged to allogeneic SCT with the fourth patient relapsing at day 60. 3 additional patients (13%) achieved >50% reduction in bone marrow blasts without evidence of peripheral count recovery, 2 going on to receive salvage chemotherapy with FLAG-Ida . 16 patients (70%) were considered non-responders. The 7 clinical responders included 6 patients treated in first relapse and 1 with primary refractory disease; all had FLT3-ITD mutations.
Conclusion
This is the first clinical experience of pacritinib in AML. Tolerability was encouraging and, in the challenging setting of relapsed / primary refractory FLT3-mutated AML where FLT3-directed monotherapy has seldom achieved complete remission, clinical responses were seen in one-third of evaluable patients. Importantly, several patients were successfully bridged to potentially-curative allogeneic SCT. Further clinical evaluation of pacritinib in this setting is warranted.
Session topic: Acute myeloid leukemia - Clinical 1
Keyword(s): Acute myeloid leukemia, FLT3, Flt3 inhibitor, Janus Kinase inhibitor
Abstract: P184
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
Pacritinib (formerly SB1518) is a third generation tyrosine kinase inhibitor with activity against a number of targets of relevance to acute myeloid leukaemia (AML). Kinases with IC50 <50nM to pacritinib include JAK2 (6nM), JAK2V617F (9nM), FLT3 (15nM), interleukin-1 receptor-associated kinase (IRAK1) (14nM) and c-FMS / colony-stimulating factor-1 (CSF1R) (40nM). FLT3 remains of intense interest as a therapeutic target in AML; activating mutations of FLT3 are associated with early relapse after chemotherapy and poor survival. Efficacy against JAK2 has motivated study of pacritinib in myelofibrosis. Although JAK2 mutations are rare in AML, the JAK-STAT pathway is frequently activated and may represent a mechanism of resistance to FLT3 inhibitors. There is also pre-clinical evidence that activity against IRAK1 and CSF1R may overcome microenvironmental resistance mechanisms. For these reasons we undertook a preliminary assessment of pacritinib as part of the UK NCRI AML17 Trial (ISRCTN55675535).
Aims
To assess the safety and efficacy of pacritinib monotherapy in FLT3-mutated AML patients who had relapsed following chemotherapy.
Methods
Patients commenced pacritinib at an oral dose of 200mg bid with the option, if well-tolerated, of increasing to 300mg bid after 14 days of treatment. Clinical assessments included optional bone marrow at day 14 and formal response assessment including blood and bone marrow examination at day 28. Toxicity was assessed using NCI-CTC Version 3.0. Treatment beyond day 28 was at the investigator’s discretion. Patients were permitted to continue on pacritinib for up to 12 months and/or proceed to salvage chemotherapy with or without allogeneic SCT.
Results
A total of 30 patients received pacritinib therapy. Median age was 54 years (16-68), median presenting WBC was 35.6x109/l (1.2-182) and all had cytogenetically intermediate risk disease. 26 patients (87%) had FLT3-ITD mutations (median FLT3-ITD allelic burden 30% [7-94]) and 4(13%) had FLT3-TKD point mutations; 16 patients (53%) had concomitant mutated NPM1. Four patients had received previous TKI therapy, all with lestaurtinib (CEP701) alongside first-line chemotherapy. Eight patients had received prior allogeneic SCT. 28 of the patients had relapsed disease; median duration of first CR was 6.5 months (1-65). 23 patients were in first relapse (including 1 molecular relapse) and 5 in second relapse. Two patients had primary refractory disease.Patients received a median of 64 days pacritinib (3-200); all were dosed at 200mg bid with 1 patient escalating to 300mg bid. Most toxicities were minor (grade1/2). The most common toxicities were nausea/vomiting (53%), diarrhoea (33%) and raised ALT (30%). One patient stopped pacritinib after 3 days due to nausea (grade 2). 6 further patients were considered non-evaluable either due to early death (2 patients; infections), inadequate response evaluation sampling (2 patients) or the addition of salvage chemotherapy within the 28-day evaluation period (2 patients). In evaluable patients, the overall rate of response to pacritinib monotherapy at the day 28 assessment was 17% (4/23) including 3 CRi (2 CRp) and 1 PR; 3 of these patients were successfully bridged to allogeneic SCT with the fourth patient relapsing at day 60. 3 additional patients (13%) achieved >50% reduction in bone marrow blasts without evidence of peripheral count recovery, 2 going on to receive salvage chemotherapy with FLAG-Ida . 16 patients (70%) were considered non-responders. The 7 clinical responders included 6 patients treated in first relapse and 1 with primary refractory disease; all had FLT3-ITD mutations.
Conclusion
This is the first clinical experience of pacritinib in AML. Tolerability was encouraging and, in the challenging setting of relapsed / primary refractory FLT3-mutated AML where FLT3-directed monotherapy has seldom achieved complete remission, clinical responses were seen in one-third of evaluable patients. Importantly, several patients were successfully bridged to potentially-curative allogeneic SCT. Further clinical evaluation of pacritinib in this setting is warranted.
Session topic: Acute myeloid leukemia - Clinical 1
Keyword(s): Acute myeloid leukemia, FLT3, Flt3 inhibitor, Janus Kinase inhibitor
Type: Poster Presentation
Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45
Location: Poster area (Hall H)
Background
Pacritinib (formerly SB1518) is a third generation tyrosine kinase inhibitor with activity against a number of targets of relevance to acute myeloid leukaemia (AML). Kinases with IC50 <50nM to pacritinib include JAK2 (6nM), JAK2V617F (9nM), FLT3 (15nM), interleukin-1 receptor-associated kinase (IRAK1) (14nM) and c-FMS / colony-stimulating factor-1 (CSF1R) (40nM). FLT3 remains of intense interest as a therapeutic target in AML; activating mutations of FLT3 are associated with early relapse after chemotherapy and poor survival. Efficacy against JAK2 has motivated study of pacritinib in myelofibrosis. Although JAK2 mutations are rare in AML, the JAK-STAT pathway is frequently activated and may represent a mechanism of resistance to FLT3 inhibitors. There is also pre-clinical evidence that activity against IRAK1 and CSF1R may overcome microenvironmental resistance mechanisms. For these reasons we undertook a preliminary assessment of pacritinib as part of the UK NCRI AML17 Trial (ISRCTN55675535).
Aims
To assess the safety and efficacy of pacritinib monotherapy in FLT3-mutated AML patients who had relapsed following chemotherapy.
Methods
Patients commenced pacritinib at an oral dose of 200mg bid with the option, if well-tolerated, of increasing to 300mg bid after 14 days of treatment. Clinical assessments included optional bone marrow at day 14 and formal response assessment including blood and bone marrow examination at day 28. Toxicity was assessed using NCI-CTC Version 3.0. Treatment beyond day 28 was at the investigator’s discretion. Patients were permitted to continue on pacritinib for up to 12 months and/or proceed to salvage chemotherapy with or without allogeneic SCT.
Results
A total of 30 patients received pacritinib therapy. Median age was 54 years (16-68), median presenting WBC was 35.6x109/l (1.2-182) and all had cytogenetically intermediate risk disease. 26 patients (87%) had FLT3-ITD mutations (median FLT3-ITD allelic burden 30% [7-94]) and 4(13%) had FLT3-TKD point mutations; 16 patients (53%) had concomitant mutated NPM1. Four patients had received previous TKI therapy, all with lestaurtinib (CEP701) alongside first-line chemotherapy. Eight patients had received prior allogeneic SCT. 28 of the patients had relapsed disease; median duration of first CR was 6.5 months (1-65). 23 patients were in first relapse (including 1 molecular relapse) and 5 in second relapse. Two patients had primary refractory disease.Patients received a median of 64 days pacritinib (3-200); all were dosed at 200mg bid with 1 patient escalating to 300mg bid. Most toxicities were minor (grade1/2). The most common toxicities were nausea/vomiting (53%), diarrhoea (33%) and raised ALT (30%). One patient stopped pacritinib after 3 days due to nausea (grade 2). 6 further patients were considered non-evaluable either due to early death (2 patients; infections), inadequate response evaluation sampling (2 patients) or the addition of salvage chemotherapy within the 28-day evaluation period (2 patients). In evaluable patients, the overall rate of response to pacritinib monotherapy at the day 28 assessment was 17% (4/23) including 3 CRi (2 CRp) and 1 PR; 3 of these patients were successfully bridged to allogeneic SCT with the fourth patient relapsing at day 60. 3 additional patients (13%) achieved >50% reduction in bone marrow blasts without evidence of peripheral count recovery, 2 going on to receive salvage chemotherapy with FLAG-Ida . 16 patients (70%) were considered non-responders. The 7 clinical responders included 6 patients treated in first relapse and 1 with primary refractory disease; all had FLT3-ITD mutations.
Conclusion
This is the first clinical experience of pacritinib in AML. Tolerability was encouraging and, in the challenging setting of relapsed / primary refractory FLT3-mutated AML where FLT3-directed monotherapy has seldom achieved complete remission, clinical responses were seen in one-third of evaluable patients. Importantly, several patients were successfully bridged to potentially-curative allogeneic SCT. Further clinical evaluation of pacritinib in this setting is warranted.
Session topic: Acute myeloid leukemia - Clinical 1
Keyword(s): Acute myeloid leukemia, FLT3, Flt3 inhibitor, Janus Kinase inhibitor
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