Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: A single-centre, phase 2 study

Elias Jabbour, Hagop Kantarjian, Farhad Ravandi, Deborah Thomas, Xuelin Huang, Stefan Faderl, Naveen Pemmaraju, Naval Daver, Guillermo Garcia-Manero, Koji Sasaki, Jorge Cortes, Rebecca Garris, C. Cameron Yin, Joseph D. Khoury, Jeffrey Jorgensen, Zeev Estrov, Zachary Bohannan, Marina Konopleva, Tapan Kadia, Nitin JainCourtney DiNardo, William Wierda, Vicky Jeanis, Susan O'Brien

Research output: Contribution to journalArticle

Abstract

Background: Combination of chemotherapy with a tyrosine-kinase inhibitor is effective in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia. Ponatinib is a more potent BCR-ABL1 inhibitor than all other tyrosine-kinase inhibitors and selectively suppresses the resistant T315I clones. We examined the activity and safety of combining chemotherapy with ponatinib for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia in this continuing phase 2 trial. Methods: In this single-centre, phase 2, single-arm trial, adult patients with previously untreated Philadelphia chromosome-positive acute lymphoblastic leukaemia were sequentially enrolled. Patients who had received fewer than two courses of previous chemotherapy with or without tyrosine-kinase inhibitors were also eligible. Patients had to be aged 18 years or older, have an Eastern Cooperative Oncology Group performance status of 2 or less, have normal cardiac function (defined by ejection fraction above 50%), and have adequate organ function (serum bilirubin ≤3·0 mg/dL and serum creatinine ≤3·0 mg/dL, unless higher concentrations were believed to be due to a tumour). Patients received eight cycles of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) alternating with high-dose methotrexate and cytarabine every 21 days. Ponatinib 45 mg was given daily for the first 14 days of cycle 1 then continuously for the subsequent cycles. Patients in complete remission received maintenance with ponatinib 45 mg daily with vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. The primary endpoint for this study was event-free survival. The trial is registered at ClinicalTrials.gov, number NCT01424982. Findings: 37 patients were enrolled and treated from Nov 1, 2011, to Sept 1, 2013. 2-year event-free survival rate was 81% (95% CI 64-90). Grade 3 or more toxic effects included infections during induction (20 [54%] patients), increased aspartate aminotransferase and alanine aminotransferase concentration (14 [38%] patients), thrombotic events (three [8%]), myocardial infarction (three [8%]), hypertension (six [16%]), skin rash (eight [22%]), and pancreatitis (six [16%] patients). Two patients died from from myocardial infarction potentially related to treatment; another patient also died from myocardial infarction related to sepsis. Two further patients died, one from bleeding and another from infection, both deemed unrelated to treatment. Interpretation: The first results of this ongoing trial indicate that the combination of chemotherapy with ponatinib is effective in achieving early sustained remissions in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia. New strategies, including dosing titration of ponatinib and optimised control of vascular risk factors, might further improve outcomes. Funding: ARIAD Pharmaceuticals Inc.

Original languageEnglish (US)
Pages (from-to)1547-1555
Number of pages9
JournalThe Lancet Oncology
Volume16
Issue number15
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

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Philadelphia Chromosome
Vincristine
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Doxorubicin
Cyclophosphamide
Dexamethasone
Therapeutics
Protein-Tyrosine Kinases
Myocardial Infarction
ponatinib
Combination Drug Therapy
Disease-Free Survival
Drug Therapy
Poisons
Cytarabine
Aspartate Aminotransferases
Prednisone
Infection
Exanthema
Serum

ASJC Scopus subject areas

  • Oncology

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Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia : A single-centre, phase 2 study. / Jabbour, Elias; Kantarjian, Hagop; Ravandi, Farhad; Thomas, Deborah; Huang, Xuelin; Faderl, Stefan; Pemmaraju, Naveen; Daver, Naval; Garcia-Manero, Guillermo; Sasaki, Koji; Cortes, Jorge; Garris, Rebecca; Yin, C. Cameron; Khoury, Joseph D.; Jorgensen, Jeffrey; Estrov, Zeev; Bohannan, Zachary; Konopleva, Marina; Kadia, Tapan; Jain, Nitin; DiNardo, Courtney; Wierda, William; Jeanis, Vicky; O'Brien, Susan.

In: The Lancet Oncology, Vol. 16, No. 15, 01.01.2015, p. 1547-1555.

Research output: Contribution to journalArticle

Jabbour, E, Kantarjian, H, Ravandi, F, Thomas, D, Huang, X, Faderl, S, Pemmaraju, N, Daver, N, Garcia-Manero, G, Sasaki, K, Cortes, J, Garris, R, Yin, CC, Khoury, JD, Jorgensen, J, Estrov, Z, Bohannan, Z, Konopleva, M, Kadia, T, Jain, N, DiNardo, C, Wierda, W, Jeanis, V & O'Brien, S 2015, 'Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: A single-centre, phase 2 study', The Lancet Oncology, vol. 16, no. 15, pp. 1547-1555. https://doi.org/10.1016/S1470-2045(15)00207-7
Jabbour, Elias ; Kantarjian, Hagop ; Ravandi, Farhad ; Thomas, Deborah ; Huang, Xuelin ; Faderl, Stefan ; Pemmaraju, Naveen ; Daver, Naval ; Garcia-Manero, Guillermo ; Sasaki, Koji ; Cortes, Jorge ; Garris, Rebecca ; Yin, C. Cameron ; Khoury, Joseph D. ; Jorgensen, Jeffrey ; Estrov, Zeev ; Bohannan, Zachary ; Konopleva, Marina ; Kadia, Tapan ; Jain, Nitin ; DiNardo, Courtney ; Wierda, William ; Jeanis, Vicky ; O'Brien, Susan. / Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia : A single-centre, phase 2 study. In: The Lancet Oncology. 2015 ; Vol. 16, No. 15. pp. 1547-1555.
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abstract = "Background: Combination of chemotherapy with a tyrosine-kinase inhibitor is effective in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia. Ponatinib is a more potent BCR-ABL1 inhibitor than all other tyrosine-kinase inhibitors and selectively suppresses the resistant T315I clones. We examined the activity and safety of combining chemotherapy with ponatinib for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia in this continuing phase 2 trial. Methods: In this single-centre, phase 2, single-arm trial, adult patients with previously untreated Philadelphia chromosome-positive acute lymphoblastic leukaemia were sequentially enrolled. Patients who had received fewer than two courses of previous chemotherapy with or without tyrosine-kinase inhibitors were also eligible. Patients had to be aged 18 years or older, have an Eastern Cooperative Oncology Group performance status of 2 or less, have normal cardiac function (defined by ejection fraction above 50{\%}), and have adequate organ function (serum bilirubin ≤3·0 mg/dL and serum creatinine ≤3·0 mg/dL, unless higher concentrations were believed to be due to a tumour). Patients received eight cycles of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) alternating with high-dose methotrexate and cytarabine every 21 days. Ponatinib 45 mg was given daily for the first 14 days of cycle 1 then continuously for the subsequent cycles. Patients in complete remission received maintenance with ponatinib 45 mg daily with vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. The primary endpoint for this study was event-free survival. The trial is registered at ClinicalTrials.gov, number NCT01424982. Findings: 37 patients were enrolled and treated from Nov 1, 2011, to Sept 1, 2013. 2-year event-free survival rate was 81{\%} (95{\%} CI 64-90). Grade 3 or more toxic effects included infections during induction (20 [54{\%}] patients), increased aspartate aminotransferase and alanine aminotransferase concentration (14 [38{\%}] patients), thrombotic events (three [8{\%}]), myocardial infarction (three [8{\%}]), hypertension (six [16{\%}]), skin rash (eight [22{\%}]), and pancreatitis (six [16{\%}] patients). Two patients died from from myocardial infarction potentially related to treatment; another patient also died from myocardial infarction related to sepsis. Two further patients died, one from bleeding and another from infection, both deemed unrelated to treatment. Interpretation: The first results of this ongoing trial indicate that the combination of chemotherapy with ponatinib is effective in achieving early sustained remissions in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia. New strategies, including dosing titration of ponatinib and optimised control of vascular risk factors, might further improve outcomes. Funding: ARIAD Pharmaceuticals Inc.",
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TY - JOUR

T1 - Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia

T2 - A single-centre, phase 2 study

AU - Jabbour, Elias

AU - Kantarjian, Hagop

AU - Ravandi, Farhad

AU - Thomas, Deborah

AU - Huang, Xuelin

AU - Faderl, Stefan

AU - Pemmaraju, Naveen

AU - Daver, Naval

AU - Garcia-Manero, Guillermo

AU - Sasaki, Koji

AU - Cortes, Jorge

AU - Garris, Rebecca

AU - Yin, C. Cameron

AU - Khoury, Joseph D.

AU - Jorgensen, Jeffrey

AU - Estrov, Zeev

AU - Bohannan, Zachary

AU - Konopleva, Marina

AU - Kadia, Tapan

AU - Jain, Nitin

AU - DiNardo, Courtney

AU - Wierda, William

AU - Jeanis, Vicky

AU - O'Brien, Susan

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Background: Combination of chemotherapy with a tyrosine-kinase inhibitor is effective in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia. Ponatinib is a more potent BCR-ABL1 inhibitor than all other tyrosine-kinase inhibitors and selectively suppresses the resistant T315I clones. We examined the activity and safety of combining chemotherapy with ponatinib for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia in this continuing phase 2 trial. Methods: In this single-centre, phase 2, single-arm trial, adult patients with previously untreated Philadelphia chromosome-positive acute lymphoblastic leukaemia were sequentially enrolled. Patients who had received fewer than two courses of previous chemotherapy with or without tyrosine-kinase inhibitors were also eligible. Patients had to be aged 18 years or older, have an Eastern Cooperative Oncology Group performance status of 2 or less, have normal cardiac function (defined by ejection fraction above 50%), and have adequate organ function (serum bilirubin ≤3·0 mg/dL and serum creatinine ≤3·0 mg/dL, unless higher concentrations were believed to be due to a tumour). Patients received eight cycles of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) alternating with high-dose methotrexate and cytarabine every 21 days. Ponatinib 45 mg was given daily for the first 14 days of cycle 1 then continuously for the subsequent cycles. Patients in complete remission received maintenance with ponatinib 45 mg daily with vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. The primary endpoint for this study was event-free survival. The trial is registered at ClinicalTrials.gov, number NCT01424982. Findings: 37 patients were enrolled and treated from Nov 1, 2011, to Sept 1, 2013. 2-year event-free survival rate was 81% (95% CI 64-90). Grade 3 or more toxic effects included infections during induction (20 [54%] patients), increased aspartate aminotransferase and alanine aminotransferase concentration (14 [38%] patients), thrombotic events (three [8%]), myocardial infarction (three [8%]), hypertension (six [16%]), skin rash (eight [22%]), and pancreatitis (six [16%] patients). Two patients died from from myocardial infarction potentially related to treatment; another patient also died from myocardial infarction related to sepsis. Two further patients died, one from bleeding and another from infection, both deemed unrelated to treatment. Interpretation: The first results of this ongoing trial indicate that the combination of chemotherapy with ponatinib is effective in achieving early sustained remissions in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia. New strategies, including dosing titration of ponatinib and optimised control of vascular risk factors, might further improve outcomes. Funding: ARIAD Pharmaceuticals Inc.

AB - Background: Combination of chemotherapy with a tyrosine-kinase inhibitor is effective in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia. Ponatinib is a more potent BCR-ABL1 inhibitor than all other tyrosine-kinase inhibitors and selectively suppresses the resistant T315I clones. We examined the activity and safety of combining chemotherapy with ponatinib for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia in this continuing phase 2 trial. Methods: In this single-centre, phase 2, single-arm trial, adult patients with previously untreated Philadelphia chromosome-positive acute lymphoblastic leukaemia were sequentially enrolled. Patients who had received fewer than two courses of previous chemotherapy with or without tyrosine-kinase inhibitors were also eligible. Patients had to be aged 18 years or older, have an Eastern Cooperative Oncology Group performance status of 2 or less, have normal cardiac function (defined by ejection fraction above 50%), and have adequate organ function (serum bilirubin ≤3·0 mg/dL and serum creatinine ≤3·0 mg/dL, unless higher concentrations were believed to be due to a tumour). Patients received eight cycles of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) alternating with high-dose methotrexate and cytarabine every 21 days. Ponatinib 45 mg was given daily for the first 14 days of cycle 1 then continuously for the subsequent cycles. Patients in complete remission received maintenance with ponatinib 45 mg daily with vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. The primary endpoint for this study was event-free survival. The trial is registered at ClinicalTrials.gov, number NCT01424982. Findings: 37 patients were enrolled and treated from Nov 1, 2011, to Sept 1, 2013. 2-year event-free survival rate was 81% (95% CI 64-90). Grade 3 or more toxic effects included infections during induction (20 [54%] patients), increased aspartate aminotransferase and alanine aminotransferase concentration (14 [38%] patients), thrombotic events (three [8%]), myocardial infarction (three [8%]), hypertension (six [16%]), skin rash (eight [22%]), and pancreatitis (six [16%] patients). Two patients died from from myocardial infarction potentially related to treatment; another patient also died from myocardial infarction related to sepsis. Two further patients died, one from bleeding and another from infection, both deemed unrelated to treatment. Interpretation: The first results of this ongoing trial indicate that the combination of chemotherapy with ponatinib is effective in achieving early sustained remissions in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia. New strategies, including dosing titration of ponatinib and optimised control of vascular risk factors, might further improve outcomes. Funding: ARIAD Pharmaceuticals Inc.

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