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Hagop M Kantarjian - One of the best experts on this subject based on the ideXlab platform.

  • frequency and impact of molecular response s with nilotinib tasigna in patients pts with newly diagnosed philadelphia chromosome ph positive chronic myelogenous leukemia in early chronic phase cml cp
    Blood, 2014
    Co-Authors: Naval Daver, Hagop M Kantarjian, Susan Obrien, Marina Konopleva, Elias J Jabbour, Sherry Pierce, Miranda Lim, Gautam Borthakur, Naveen Pemmaraju, Courtney D Dinardo
    Abstract:

    Background: Nilotinib is a Bcr-Abl tyrosine kinase Inhibitor with approximately 50-fold higher Inhibitory activity than imatinib in preclinical studies. Aim: We initiated a phase II study (in 2005) to evaluate the efficacy of frontline nilotinib in pts with newly diagnosed CML-CP. The primary objective of this report was to estimate major molecular response (MMR) and complete molecular response (CMR: minimum 100,000 ABL copies) rates with prolonged follow-up, and the impact of MMR and CMR on long-term outcome. Methods: Pts with Ph-positive or BCR-positive CML in early CML-CP [i.e., time from diagnosis 12 months] with Results: 140 pts have been treated as of August 1, 2014. Herein we focus on the initial 109 pts who have a minimum follow-up of 12 months. The median (med) follow-up for these 109 pts is 52.2 months (range, 0.9 to 108.0+). The med age was 50 years (range, 17 to 86). 73% of pts had Sokal low risk. 17 (16%) had received imatinib for Overall, 92% (100/109) pts achieved a complete cytogenetic response [CCyR] with a med time to CCyR of 2.9 months (range, 2.1 to 8.1+). The rates of CCyR at 3, 6, 12 and 18 months were 80% (eval:83%), 86% (eval:95%), 83% (eval:99%), and 77% (eval:100%), respectively. Overall, MMR and CMR were achieved in 90% (98/109) and 45% (49/109) of the pts. Med time to MMR and CMR was 3.3 months (range, 2.4 to 48.0+) and 23.1 months (range, 3.2 to 86.0+), respectively. Bcr-Abl/ABL at 3 months was Bcr-Abl/ABL at 6 months was 3 in 31%, MR 4 in 13%, MR 4.5 in 27%, and CMR in 19%. Estimated 3-year and 5-year overall survival (OS) is 98% and 91%, respectively. Estimated 3-year and 5-year failure-free survival (FFS) is 82% and 73%, respectively. On an intent-to-treat analysis the FFS among pts who achieved CMR was superior to those who did not achieve CMR ( P P =0.008) (Figure 1). Dose-reductions were performed in 41 (38%) pts: 30 pts required 1 dose-reduction and 11 pts required 2 or more dose-reductions. The most frequent reasons for dose-reductions included increased liver enzymes (n=8), rash (n=5), pain/arthralgia (n=4), cardiac and QTc (n=4), fatigue (n=5), and neutropenia (n=2). The actual med dose remains 800 mg daily. 29 (27%) pts are off study due to toxicity in 8 (cardiac=3, liver enzymes=4, fatigue=1), inadequate response in 5 (3 never achieved adequate and 2 lost adequate response), progression to blast-phase in 3, death in 5 (all 5 non-CML related causes), 8 due to pt choice (financial=1, non-compliance=3, pt choice=1) Conclusion: Nilotinib 400 mg twice daily is very effective. The cumulative rates of CCyR, MMR and CMR were 92%, 90%, and 45%, respectively. CMR rates continue to improve with long-term follow-up. Attainment of CMR is associated with improved long-term outcome. PCyr, partial cytogenetic response; Min, mimimal; Inev, inevaluable; IM, insufficient metaphase Disclosures Daver: Novartis: Research Funding. Jabbour: Novartis: Advisory board membership Other, Research Funding. Cortes: Novartis: Advisory Board membership Other, Research Funding.

  • long term follow up of a phase 1 study of ponatinib in patients with chronic phase chronic myeloid leukemia cp cml
    Blood, 2014
    Co-Authors: Moshe Talpaz, Neil P Shah, Victor M. Rivera, Thomas Ohare, Hagop M Kantarjian, Jorge E Cortes, Dale L Bixby, Ian W Flinn, Simin Hu, Tim Clackson
    Abstract:

    Background: Ponatinib is a potent oral pan–Bcr-Abl tyrosine kinase Inhibitor (TKI) active against native and mutated forms of Bcr-Abl, and is approved for patients with refractory CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia and those with the T315I mutant. Long-term follow-up of the anti-leukemic activity and safety of ponatinib in patients with CML or Ph+ ALL in this phase 1 clinical trial is reported. Methods: Patients (N=81) with resistant/refractory hematologic malignancies were enrolled in this ongoing, open-label, dose-escalation, phase 1 study ([NCT00660920][1]) . Ponatinib was dosed once daily (2 mg-60 mg). Intra-patient dose escalation was permitted. The 43 patients who had CP-CML are the focus of this analysis (data as of 6 Jan 2014). Median follow-up for CP-CML patients was 42.5 (1.7-59.1) months. Results: The median age of patients was 55 years; median time since diagnosis was 6.6 years. Patients were heavily pretreated (61% received ≥3 prior TKIs; 37% received 2 prior TKIs). At baseline, 63% of patients had Bcr-Abl mutations (28% with T315I). At the time of analysis, 56% of patients remained on study. Significant anti-leukemic activity was observed: major cytogenetic response (MCyR), complete cytogenetic response (CCyR), major molecular response (MMR) and molecular response 4 (MR4) rates were 72%, 65%, 51%, and 40% respectively; 76% of patients with MCyR and 54% with MMR are estimated (Kaplan-Meier [KM]) to maintain response for at least 4 years (3-year KM estimates: 76% MCyR, 70% CCyR, 54% MMR; [Figure 1][2] ). 15 patients started at a dose of 30 mg or below, and 10 of these patients (67%) achieved MCyR; all were receiving a dose of 30 mg or below at time of response ( Table 1 ). Of 28 patients with CCyR, 22 remained on study (16 with continuous CCyR); of 22 patients with MMR, 19 remained on study (11 with continuous MMR). Adverse events (AEs, 23%) and progression (9%) were the most common reasons for discontinuation. Of the 10 patients that discontinued due to AEs, 5 were in MCyR and, of those, 1 was in MMR. The most common treatment-emergent AEs were rash (63%), fatigue (61%), abdominal pain (58%), headache (56%), and arthralgia (54%). The most common treatment-emergent AEs occurring after 1 year of therapy were fatigue (35%), hypertension (31%), and abdominal pain (30%). Treatment-emergent arterial thrombotic events (AE [SAE]) were observed in 37% [28%] of patients (composite of cardiovascular 28% [19%], cerebrovascular 9% [7%], and peripheral vascular 12% [7%] events), and venous thromboembolic AEs were observed in 5% [no SAEs] of patients. Updated data will be presented. Conclusions: With a median follow-up of 42.5 months in CP-CML patients (maximum follow-up, 59.1 months), ponatinib continues to provide benefit to heavily pretreated patients with limited treatment options. Substantial and durable responses were observed with ponatinib, and responses were observed in patients treated with doses at or below 30 mg. The most common treatment-emergent AEs occurring after one year of therapy were similar to the overall AE profile, albeit with lower incidence rates. Risk and benefit considerations should be evaluated when utilizing ponatinib in this patient population. ![Figure 1:][3] Figure 1: Duration of Response in CP-CML Patients aLoss of response is defined as a single time point at which the criteria for response are not met. | Starting Dose | MCyR | MMR | | ------------- | ---------------------------------- | ----------------- | ---------------------------------- | | N (%) | Dose intensity*, Median (min, max) | N (%) | Dose intensity*, Median (min, max) | | 4 mg, N=3 | 2 (67) | 3.7 (3.5, 3.9) | 1 (33) | 14.3 (14.3, 14.3) | | 15 mg, N=7 | 5 (71) | 14.8 (14.7, 23.7) | 4 (57) | 15.0 (14.7, 36.6) | | 30 mg, N=5 | 3 (60) | 27.4 (10.6, 29.6) | 1 (20) | 29.9 (29.9, 29.9) | | ≤30 mg, N=15 | 10 (67) | 14.8 (3.5, 29.6) | 6 (40) | 15.0 (14.3, 36.6) | | 45 mg, N=14 | 13 (93) | 44.5 (23.4, 45.0) | 11 (79) | 43.5 (16.6, 45.0) | | 60 mg, N=14 | 8 (57) | 42.6 (14.2, 59.3) | 5 (36) | 56.5 (14.7, 59.5) | Table 1: Ponatinib Response Rate for CP-CML Patients by Dose *Dose intensity (mg/day) until time of response for responders only Disclosures Talpaz: ARIAD Pharmaceuticals, Inc., BMS, Sanofi, Incyte, Pfizer: Research Funding. Cortes: ARIAD Pharmaceuticals, Inc., BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding. Kantarjian: ARIAD, Pfizer, Amgen: Research Funding. Shah: ARIAD, BMS: Research Funding. Flinn: ARIAD Pharmaceuticals, Inc.: Research Funding. Hu: ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera: ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson: ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Turner: ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Haluska: ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Druker: BMS: Research Funding; ARIAD Pharmaceuticals, Inc.: PI and co-investigator on clinical trials, PI and co-investigator on clinical trials Other; MolecularMD: Consultancy, Equity Ownership. Deininger: BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding; BMS, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy. Mauro: ARIAD Pharmaceuticals, Inc.: Consultancy. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00660920&atom=%2Fbloodjournal%2F124%2F21%2F4558.atom [2]: #F1 [3]: pending:yes

  • long term evaluation of vascular toxicity in patients with ph leukemias treated with bosutinib
    Journal of Clinical Oncology, 2014
    Co-Authors: Jorge E Cortes, Jeffrey H Lipton, Hanna Jean Khoury, Hagop M Kantarjian, Tim H Brummendorf, Maureen G Conlan, Kongming Wang, Kolette D Fly, Mark Shapiro, Jeanbernard Durand
    Abstract:

    7060 Background: Vascular toxicities (eg, peripheral arterial occlusive disease [PAOD]) have been associated with Bcr-Abl tyrosine kinase Inhibitor (TKI) treatment (tx). Methods: We evaluated vascular (peripheral, cardiovascular, and cerebrovascular) toxicities based on tx-emergent adverse events (TEAEs) with bosutinib (BOS) in 2 ongoing studies: phase 1/2 study of BOS second/third/fourth-line tx (2L/3L/4L, up to 3 y) in Ph+ leukemia patients (pts) resistant/intolerant to prior TKIs; phase 3 study in chronic phase CML pts of BOS vs imatinib (IM) first-line tx (1L; up to 2 y). Results: 12.7% of BOS pts had vascular TEAEs (Table) with no significant differences for BOS vs IM (1L: P≥0.122). Individual cardiovascular TEAE incidences were low; only angina pectoris (1.2%) and coronary artery disease (CAD 1.2%) occurred in >1% of BOS pts. No individual cerebrovascular TEAE occurred in >3 BOS pts. Individual peripheral vascular TEAEs were rare; only hypertension (6.4%) occurred in >2 BOS pts (1L: 6.0% [BOS] vs 4....

  • safety and durability of ponatinib in patients with philadelphia chromosome positive ph leukemia long term follow up of an ongoing phase i study
    Journal of Clinical Oncology, 2013
    Co-Authors: Michael J Mauro, Neil P Shah, Victor M. Rivera, Thomas Ohare, Hagop M Kantarjian, Jorge E Cortes, Dale L Bixby, Ian W Flinn, Simin Hu, Tim Clackson
    Abstract:

    7063 Background: Ponatinib is a potent oral pan–Bcr-Abl tyrosine kinase Inhibitor (TKI) that is active against native and mutated forms of Bcr-Abl. The safety and anti-leukemic activity of ponatinib in patients (pts) with chronic myeloid leukemia (CML) or Ph+ acute lymphoblastic leukemia (ALL) were evaluated in a phase I clinical trial. Methods: Pts (N=81) with resistant/refractory hematologic malignancies were enrolled in this ongoing, open-label, dose escalation, phase I study. Ponatinib was dosed once daily (2–60 mg). 65 pts had Ph+ leukemia and are included in the present analysis (data as of 9 Nov 2012). Median follow-up was 25 (0.5–44) mos. Results: The median age of pts was 55 yrs; median time since diagnosis was 6.5 yrs. Pts were heavily pretreated (94% had received ≥2 prior TKIs, 62% ≥3). 65% had baseline Bcr-Abl mutations. 46% (67% chronic phase [CP] CML) of pts remained on study. Progression and adverse events (AEs) were the most common reasons for discontinuation (17% each). The most common tr...

  • tyrosine kinase Inhibitors in acute and chronic leukemias
    Expert Opinion on Pharmacotherapy, 2012
    Co-Authors: Maro Ohanian, Hagop M Kantarjian, Jorge E Cortes, Elias Jabbour
    Abstract:

    Introduction: Since the initial approval of imatinib much has been learned about its resistance mechanisms, and efforts have continued to improve upon Bcr-Abl tyrosine kinase Inhibitor therapy. Targeted therapy with TKIs has continued to be an area of active research and development in the care of acute and chronic leukemia patients. Areas covered: This article reviews current approved and investigational TKI treatments for chronic myelogenous leukemia (CML), Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph + ALL) and acute myelogenous leukemia (AML). Expert opinion: There are now more potent Bcr-Abl TKIs approved, which allow for additional options when determining front-line and second-line CML and Ph + ALL treatments. The T315I mutation is an ever-present challenge. Ponatinib, a pan Bcr-Abl TKI, while still under investigation, is very hopeful with its ability to overcome T315I mutations in resistant CML and Ph + ALL patients. Because nilotinib and dasatinib have not been directly comp...

Jingwu Kang - One of the best experts on this subject based on the ideXlab platform.

  • screening of break point cluster region abelson tyrosine kinase Inhibitors by capillary electrophoresis
    Journal of Chromatography A, 2018
    Co-Authors: Mengmeng Zheng, Guizhen Liu, Meng Zhang, Jingwu Kang
    Abstract:

    Abstract In the present study, a capillary electrophoresis (CE) method was developed for screening of Inhibitors against the break point cluster region Abelson tyrosine kinase (Bcr-Abl). The screening method was established by using 5-carboxyfluorescein labeled peptide substrate of Bcr-Abl (F-ABLS), a known Bcr-Abl tyrosine kinase Inhibitor dasatinib, as well as a small chemical library consisting of 37 natural products. Thus, the inhibition of BCL-ABL kinase by small Inhibitors was assayed by a CE system equipped with the laser induced fluorescence detector. The yield of phosphorylated product could be precisely measured through the separation by CE. The method is competent for enzymatic inhibition assay as well as the measurement of the inhibition kinetics. For screening Bcr-Abl tyrosine kinase Inhibitors, the hits were readily identified once the peak area of the phosphorylated products was reduced in comparison with the negative control. By taking the advantage of the screening method, luteolin and epicatechin gallate were discovered as the new Bcr-Abl Inhibitors.

  • screening of break point cluster region abelson tyrosine kinase Inhibitors by capillary electrophoresis
    Journal of Chromatography A, 2018
    Co-Authors: Mei Xu, Mengmeng Zheng, Meng Zhang, Jingwu Kang
    Abstract:

    Abstract In the present study, a capillary electrophoresis (CE) method was developed for screening of Inhibitors against the break point cluster region Abelson tyrosine kinase (Bcr-Abl). The screening method was established by using 5-carboxyfluorescein labeled peptide substrate of Bcr-Abl (F-ABLS), a known Bcr-Abl tyrosine kinase Inhibitor dasatinib, as well as a small chemical library consisting of 37 natural products. Thus, the inhibition of BCL-ABL kinase by small Inhibitors was assayed by a CE system equipped with the laser induced fluorescence detector. The yield of phosphorylated product could be precisely measured through the separation by CE. The method is competent for enzymatic inhibition assay as well as the measurement of the inhibition kinetics. For screening Bcr-Abl tyrosine kinase Inhibitors, the hits were readily identified once the peak area of the phosphorylated products was reduced in comparison with the negative control. By taking the advantage of the screening method, luteolin and epicatechin gallate were discovered as the new Bcr-Abl Inhibitors.

Jorge E Cortes - One of the best experts on this subject based on the ideXlab platform.

  • venetoclax and bcr abl tyrosine kinase Inhibitor combinations outcome in patients with philadelphia chromosome positive advanced myeloid leukemias
    Acta Haematologica, 2020
    Co-Authors: Abhishek Maiti, Jorge E Cortes, Elias Jabbour, Miguel Franquiz, Farhad Ravandi, Koji Sasaki, Kayleigh Marx, Naval Daver, Tapan M Kadia, Marina Konopleva
    Abstract:

    Background: Philadelphia chromosome-positive (Ph+) advanced leukemias, including acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) in myeloid blast phase (MBP), have poor outcomes. Venetoclax has shown synergism with Bcr-Abl1 tyrosine kinase Inhibitors (TKI) in preclinical studies. However, clinical activity of venetoclax and TKI-based regimens is unknown. Methods: We conducted a retrospective study on patients with Ph+ AML (n = 7) and CML-MBP (n = 9) who received venetoclax combined with TKI-based regimens at our institution. Results: Median patient age was 42 years, and the median number of prior therapy cycles was 5 (range 2–8). Nine patients received decitabine-based, and 7 received intensive chemotherapy-based regimens. Ten patients (63%) received ponatinib. The overall response rate (ORR) in 15 evaluable patients was 60% (1 complete remission [CR], 6 CR with incomplete hematologic recovery [CRi], 1 morphologic leukemia-free state, and 1 partial response). The ORR was 43% in Ph+ AML and 75% in CML-MBP. The median overall survival (OS) for all patients was 3.6 months, for AML OS was 2.0 months, and for CML-MBP OS was 10.9 months. The median relapse-free survival for AML and CML-MBP was 3.6 and 3.9 months, respectively. Compared to nonresponders, patients achieving CR/CRi had higher baseline Ph+ metaphases and Bcr-Abl1 PCR. Conclusions: Combination therapy of venetoclax with TKI-based regimens shows encouraging activity in very heavily pretreated, advanced Ph+ leukemias, particularly CML-MBP.

  • impact of dose intensity of ponatinib on selected adverse events multivariate analyses from a pooled population of clinical trial patients
    Blood, 2014
    Co-Authors: Ronald Knickerbocker, Michele Baccarani, Andreas Hochhaus, Jorge E Cortes, David J Dorer, Frank G Haluska, Moshe Talpaz
    Abstract:

    Background: Ponatinib is an approved potent pan–Bcr-Abl tyrosine kinase Inhibitor (TKI) with proven efficacy in refractory Ph+ leukemia, particularly CP-CML. Previous analyses suggest significant association between ponatinib dose intensity and adverse events (AEs). We explored this further using pooled data from phase 1, 2, and 3 ponatinib trials in refractory Ph+ leukemia or newly diagnosed CP-CML. Methods: Patients received ponatinib (range 2-60 mg/d) in all 3 trials; dose modification was allowed to manage AEs. Univariate and multivariate logistic regression analyses were conducted for each outcome (presence/absence of treatment-emergent AEs) and dose intensity measure (average daily dose through day of event) in 671 patients with all baseline covariates (Table 1) measured. AEs analyzed were vascular occlusive events; cardiac failure; myelosuppression; pancreatitis; increased lipase, ALT, AST; rash, arthralgia; hypertriglyceridemia; hypertension. Time to event modeling was performed for vascular occlusive AEs to find the optimal exposure window in proximity to events. Results: As of Jan 6, 2014, 683 patients received ponatinib. Median treatment duration: 224 days; median dose intensity: 37.2 mg/d. Notable differences were observed in distribution of covariates for vascular occlusive AEs by dose intensity quartile (Table 1): more frequent histories of diabetes and ischemic disease, older age, and longer time since diagnosis in lower 2 quartiles; lowest baseline platelet and neutrophil counts in highest quartile. This suggests the importance of adjusting for these covariates when evaluating impact of dose on AEs. After adjusting for covariates, there were significant associations in logistic regression analyses between dose intensity and most AEs (Table 2). Strongest associations (OR >2) were seen for pancreatitis, rash, and cardiac failure. Logistic regression analyses do not factor in event timing or follow up duration and use average dose intensity. Thus, time to event analyses using daily doses were performed for vascular occlusive AEs to find the exposure window with highest increase in risk in proximity to these AEs. These models show highly significant associations between dose intensity and event risk for all event types except venous thromboembolism. This also allows exploration of the relationship between timing of dose change and event occurrence. Generally, lags of ~≤30 days were most predictive, although in some models there was a higher risk increase with lags of ~6 months—suggesting that there may be up to a 6-month delay following dose reduction before a decrease in risk manifests for some arterial thrombotic events. Conclusions: These data in a pooled population with longer follow-up replicate previous findings that ponatinib dose intensity is highly associated with many AEs, and support investigating approaches to lower average dose intensity, such as starting at lower doses and/or reducing dose on response. A dose-ranging trial of ponatinib in refractory CML to evaluate benefit/risk of different dosing schemes is being planned. Disclosures Knickerbocker:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Dorer:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Haluska:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Baccarani:ARIAD, Novartis, BMS: Consultancy; ARIAD, Novartis, BMS, Pfizer, Teva: Honoraria; ARIAD, Novartis, BMS, Pfizer, Teva: Speakers Bureau. Cortes:ARIAD, BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Talpaz:ARIAD, BMS, Sanofi. Incyte, Pfizer: Research Funding.

  • long term follow up of a phase 1 study of ponatinib in patients with chronic phase chronic myeloid leukemia cp cml
    Blood, 2014
    Co-Authors: Moshe Talpaz, Neil P Shah, Victor M. Rivera, Thomas Ohare, Hagop M Kantarjian, Jorge E Cortes, Dale L Bixby, Ian W Flinn, Simin Hu, Tim Clackson
    Abstract:

    Background: Ponatinib is a potent oral pan–Bcr-Abl tyrosine kinase Inhibitor (TKI) active against native and mutated forms of Bcr-Abl, and is approved for patients with refractory CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia and those with the T315I mutant. Long-term follow-up of the anti-leukemic activity and safety of ponatinib in patients with CML or Ph+ ALL in this phase 1 clinical trial is reported. Methods: Patients (N=81) with resistant/refractory hematologic malignancies were enrolled in this ongoing, open-label, dose-escalation, phase 1 study ([NCT00660920][1]) . Ponatinib was dosed once daily (2 mg-60 mg). Intra-patient dose escalation was permitted. The 43 patients who had CP-CML are the focus of this analysis (data as of 6 Jan 2014). Median follow-up for CP-CML patients was 42.5 (1.7-59.1) months. Results: The median age of patients was 55 years; median time since diagnosis was 6.6 years. Patients were heavily pretreated (61% received ≥3 prior TKIs; 37% received 2 prior TKIs). At baseline, 63% of patients had Bcr-Abl mutations (28% with T315I). At the time of analysis, 56% of patients remained on study. Significant anti-leukemic activity was observed: major cytogenetic response (MCyR), complete cytogenetic response (CCyR), major molecular response (MMR) and molecular response 4 (MR4) rates were 72%, 65%, 51%, and 40% respectively; 76% of patients with MCyR and 54% with MMR are estimated (Kaplan-Meier [KM]) to maintain response for at least 4 years (3-year KM estimates: 76% MCyR, 70% CCyR, 54% MMR; [Figure 1][2] ). 15 patients started at a dose of 30 mg or below, and 10 of these patients (67%) achieved MCyR; all were receiving a dose of 30 mg or below at time of response ( Table 1 ). Of 28 patients with CCyR, 22 remained on study (16 with continuous CCyR); of 22 patients with MMR, 19 remained on study (11 with continuous MMR). Adverse events (AEs, 23%) and progression (9%) were the most common reasons for discontinuation. Of the 10 patients that discontinued due to AEs, 5 were in MCyR and, of those, 1 was in MMR. The most common treatment-emergent AEs were rash (63%), fatigue (61%), abdominal pain (58%), headache (56%), and arthralgia (54%). The most common treatment-emergent AEs occurring after 1 year of therapy were fatigue (35%), hypertension (31%), and abdominal pain (30%). Treatment-emergent arterial thrombotic events (AE [SAE]) were observed in 37% [28%] of patients (composite of cardiovascular 28% [19%], cerebrovascular 9% [7%], and peripheral vascular 12% [7%] events), and venous thromboembolic AEs were observed in 5% [no SAEs] of patients. Updated data will be presented. Conclusions: With a median follow-up of 42.5 months in CP-CML patients (maximum follow-up, 59.1 months), ponatinib continues to provide benefit to heavily pretreated patients with limited treatment options. Substantial and durable responses were observed with ponatinib, and responses were observed in patients treated with doses at or below 30 mg. The most common treatment-emergent AEs occurring after one year of therapy were similar to the overall AE profile, albeit with lower incidence rates. Risk and benefit considerations should be evaluated when utilizing ponatinib in this patient population. ![Figure 1:][3] Figure 1: Duration of Response in CP-CML Patients aLoss of response is defined as a single time point at which the criteria for response are not met. | Starting Dose | MCyR | MMR | | ------------- | ---------------------------------- | ----------------- | ---------------------------------- | | N (%) | Dose intensity*, Median (min, max) | N (%) | Dose intensity*, Median (min, max) | | 4 mg, N=3 | 2 (67) | 3.7 (3.5, 3.9) | 1 (33) | 14.3 (14.3, 14.3) | | 15 mg, N=7 | 5 (71) | 14.8 (14.7, 23.7) | 4 (57) | 15.0 (14.7, 36.6) | | 30 mg, N=5 | 3 (60) | 27.4 (10.6, 29.6) | 1 (20) | 29.9 (29.9, 29.9) | | ≤30 mg, N=15 | 10 (67) | 14.8 (3.5, 29.6) | 6 (40) | 15.0 (14.3, 36.6) | | 45 mg, N=14 | 13 (93) | 44.5 (23.4, 45.0) | 11 (79) | 43.5 (16.6, 45.0) | | 60 mg, N=14 | 8 (57) | 42.6 (14.2, 59.3) | 5 (36) | 56.5 (14.7, 59.5) | Table 1: Ponatinib Response Rate for CP-CML Patients by Dose *Dose intensity (mg/day) until time of response for responders only Disclosures Talpaz: ARIAD Pharmaceuticals, Inc., BMS, Sanofi, Incyte, Pfizer: Research Funding. Cortes: ARIAD Pharmaceuticals, Inc., BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding. Kantarjian: ARIAD, Pfizer, Amgen: Research Funding. Shah: ARIAD, BMS: Research Funding. Flinn: ARIAD Pharmaceuticals, Inc.: Research Funding. Hu: ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera: ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson: ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Turner: ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Haluska: ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Druker: BMS: Research Funding; ARIAD Pharmaceuticals, Inc.: PI and co-investigator on clinical trials, PI and co-investigator on clinical trials Other; MolecularMD: Consultancy, Equity Ownership. Deininger: BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding; BMS, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy. Mauro: ARIAD Pharmaceuticals, Inc.: Consultancy. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00660920&atom=%2Fbloodjournal%2F124%2F21%2F4558.atom [2]: #F1 [3]: pending:yes

  • long term evaluation of vascular toxicity in patients with ph leukemias treated with bosutinib
    Journal of Clinical Oncology, 2014
    Co-Authors: Jorge E Cortes, Jeffrey H Lipton, Hanna Jean Khoury, Hagop M Kantarjian, Tim H Brummendorf, Maureen G Conlan, Kongming Wang, Kolette D Fly, Mark Shapiro, Jeanbernard Durand
    Abstract:

    7060 Background: Vascular toxicities (eg, peripheral arterial occlusive disease [PAOD]) have been associated with Bcr-Abl tyrosine kinase Inhibitor (TKI) treatment (tx). Methods: We evaluated vascular (peripheral, cardiovascular, and cerebrovascular) toxicities based on tx-emergent adverse events (TEAEs) with bosutinib (BOS) in 2 ongoing studies: phase 1/2 study of BOS second/third/fourth-line tx (2L/3L/4L, up to 3 y) in Ph+ leukemia patients (pts) resistant/intolerant to prior TKIs; phase 3 study in chronic phase CML pts of BOS vs imatinib (IM) first-line tx (1L; up to 2 y). Results: 12.7% of BOS pts had vascular TEAEs (Table) with no significant differences for BOS vs IM (1L: P≥0.122). Individual cardiovascular TEAE incidences were low; only angina pectoris (1.2%) and coronary artery disease (CAD 1.2%) occurred in >1% of BOS pts. No individual cerebrovascular TEAE occurred in >3 BOS pts. Individual peripheral vascular TEAEs were rare; only hypertension (6.4%) occurred in >2 BOS pts (1L: 6.0% [BOS] vs 4....

  • safety and durability of ponatinib in patients with philadelphia chromosome positive ph leukemia long term follow up of an ongoing phase i study
    Journal of Clinical Oncology, 2013
    Co-Authors: Michael J Mauro, Neil P Shah, Victor M. Rivera, Thomas Ohare, Hagop M Kantarjian, Jorge E Cortes, Dale L Bixby, Ian W Flinn, Simin Hu, Tim Clackson
    Abstract:

    7063 Background: Ponatinib is a potent oral pan–Bcr-Abl tyrosine kinase Inhibitor (TKI) that is active against native and mutated forms of Bcr-Abl. The safety and anti-leukemic activity of ponatinib in patients (pts) with chronic myeloid leukemia (CML) or Ph+ acute lymphoblastic leukemia (ALL) were evaluated in a phase I clinical trial. Methods: Pts (N=81) with resistant/refractory hematologic malignancies were enrolled in this ongoing, open-label, dose escalation, phase I study. Ponatinib was dosed once daily (2–60 mg). 65 pts had Ph+ leukemia and are included in the present analysis (data as of 9 Nov 2012). Median follow-up was 25 (0.5–44) mos. Results: The median age of pts was 55 yrs; median time since diagnosis was 6.5 yrs. Pts were heavily pretreated (94% had received ≥2 prior TKIs, 62% ≥3). 65% had baseline Bcr-Abl mutations. 46% (67% chronic phase [CP] CML) of pts remained on study. Progression and adverse events (AEs) were the most common reasons for discontinuation (17% each). The most common tr...

Philipp Le Coutre - One of the best experts on this subject based on the ideXlab platform.

  • clinical impact of dose modification and dose intensity on response to ponatinib pon in patients pts with philadelphia chromosome positive ph leukemias
    Journal of Clinical Oncology, 2014
    Co-Authors: Andreas Hochhaus, Javier Pinillaibarz, Charles Chuah, Philipp Le Coutre, Franck E. Nicolini, Jane F Apperley, Ronald Paquette, Dongwook Kim, Hanna Jean Khoury, Michele Baccarani
    Abstract:

    7084 Background: PON is a potent oral pan–Bcr-Abl tyrosine kinase Inhibitor with clinical activity in pretreated pts with Ph+ leukemias. Dose modification of PON may be used to avoid or manage adve...

  • clinical impact of dose modification and dose intensity on response to ponatinib pon in patients pts with philadelphia chromosome positive ph leukemias
    Journal of Clinical Oncology, 2014
    Co-Authors: Andreas Hochhaus, Javier Pinillaibarz, Charles Chuah, Philipp Le Coutre, Michele Baccarani, Franck E. Nicolini, Jane F Apperley, Ronald Paquette, Hanna Jean Khoury, Stephanie Lustgarten
    Abstract:

    7084 Background: PON is a potent oral pan–Bcr-Abl tyrosine kinase Inhibitor with clinical activity in pretreated pts with Ph+ leukemias. Dose modification of PON may be used to avoid or manage adverse events (AEs). This post hoc analysis assessed the clinical impact of dose modification and dose intensity on outcomes of pts in the phase 2 PACE trial. Methods: PON starting dose was 45 mg QD. Dose reduction: any reduction below 45 mg/d; dose interruption: treatment held for ≥3 consecutive days. Efficacy analyses were performed on CP-CML pts (N=267). Analysis of arterial thrombotic events (ATEs) included all pts (CP/BP/AP-CML, Ph+ ALL; N=449). Data are as of 3 Sept 2013; median follow-up was 24 (0.1-35) mo for all pts. Results: 78% of CP-CML pts had dose modification within the first 12 mo (82% at any time). Responses in pts with/without modification were comparable (Table). Of 149 responders, 87 (58%) achieved MCyR at 45 mg/d, 46 (31%) at 30 mg/d, 16 (11%) at 15 mg/d. Most pts who had a dose reduction after...

  • ponatinib in heavily pretreated patients with chronic phase chronic myeloid leukemia cp cml management of adverse events aes
    Blood, 2013
    Co-Authors: Philipp Le Coutre, Javier Pinillaibarz, Jean H Khoury, Charles Chuah, Franck E. Nicolini, Moshe Talpaz, Jane F Apperley, Ronald Paquette, John F. Dipersio, Daniel J Deangelo
    Abstract:

    Background Ponatinib is a potent oral pan–Bcr-Abl tyrosine kinase Inhibitor (TKI) with activity against native and mutant Bcr-Abl. The efficacy and safety of ponatinib (45 mg once daily) in pts with CP-CML were evaluated in the phase 2 PACE trial. Objectives To review the management of treatment-related AEs (TRAEs) that emerged during therapy with ponatinib in the PACE trial. Methods A total of 270 CP-CML pts (267 in efficacy population) resistant or intolerant to dasatinib or nilotinib or with the T315I mutation were enrolled in this ongoing, phase 2, international, open-label clinical trial. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 mos. Safety monitoring included collection of AEs, and the following variables were evaluated: incidence, severity, time to onset, duration, and management. Select TRAEs are discussed. Data as of 01 Apr 2013 are reported, with a median follow-up of 20 (0.1–28) mos. Minimum follow-up for pts remaining on study was 18 mos. Results Median age was 60 (18-94) yrs; median time from diagnosis to first dose was 7 (0.5-27) yrs; 93% had ≥2 prior TKIs, 60% ≥3. Ponatinib demonstrated significant activity in CP-CML pts: 56% MCyR, 46% CCyR, and 36% MMR. At the time of analysis, 60% of pts remained on study. The most frequent reasons for discontinuation were AEs (14%) and progression (8%). The most common hematologic TRAE was thrombocytopenia (41% any grade, 32% grade 3/4). The incidence by time to initial onset is shown below ([Figure][1]). Pts experienced thrombocytopenia for a median total duration of 166 days (64% of whom had >1 event) and typically required dose modification: 13% drug withdrawn, 40% dose reduced, 29% dose interrupted only, 17% no dose modification. Among pts with thrombocytopenia, 27% required a platelet transfusion. Thirteen percent of CP-CML pts experienced treatment-related neutropenia and thrombocytopenia. ![Figure.][2] Figure. Incidencea of Select TRAEs by Time to Initial Onset in CP-CML The most common nonhematologic TRAE was rash (39% any grade, 4% grade 3/4), which includes erythematous, macular, and papular rash. Pts experienced rash for a median total duration of 65 days (46% of whom had >1 event) and most did not require dose modification: 0% drug withdrawn, 15% dose reduced, 11% dose interrupted only, 73% no dose modification. One additional pt discontinued due to grade 2 treatment-related exfoliative rash. Pancreatitis was observed (7% any grade, 6% grade 3/4). Median duration was 5 days. Pts were typically managed with dose modification: 5% drug withdrawn, 58% dose reduced, 32% dose interrupted only, 5% no dose modification. Treatment-emergent cardiovascular events were observed in 8% of pts and treatment-emergent cerebrovascular or peripheral vascular events in 11%. Cardiovascular events were considered treatment-related in 4%; cerebrovascular or peripheral vascular events were also considered treatment-related in 4%. The median time to initial onset was 9 mos for cardiovascular and 11 mos for cerebrovascular or peripheral vascular events. The median duration was 6 and 97 days, respectively. Management of pts with cardiovascular AEs: 20% drug withdrawn, 10% dose reduced, 40% dose interrupted only, 30% no dose modification. Management of pts with cerebrovascular or peripheral vascular AEs: 8% drug withdrawn; 8% dose reduced; 17% dose interrupted only; 67% no dose modification. Conclusions Ponatinib has robust antileukemic activity in heavily pretreated CP-CML pts (93% of whom received ≥2 prior TKIs). Treatment-related thrombocytopenia and pancreatitis generally occurred early in therapy and were manageable with dose modification. Treatment-related rash generally occurred early in therapy, was mild-to-moderate in severity, managed without the need for dose modification, and rarely led to discontinuation. Management of treatment-related arterial thrombotic events varied; pts with predisposing cardiovascular risk factors should be monitored closely and managed accordingly. [ClinicalTrials.gov][3] ID: [NCT01207440][4] aIncidence = (number of pts with initial onset during time interval) / (number of pts dosed during time interval [N] excluding those who previously experienced the event) X 100 Disclosures: Le Coutre: Novartis: Research Funding; Novartis, BMS, Pfizer: Honoraria. Kim: BMS, Novartis, IL-Yang: Consultancy; BMS, Novartis, Pfizer, ARIAD, IL-Yang: Research Funding; BMS, Novartis, Pfizer, IL-Yang: Honoraria; BMS, Novartis, Pfizer: Speakers Bureau; BMS, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Pinilla-Ibarz: Novartis, Ariad: Research Funding; Novartis, Ariad, BMS and Pfizer: Speakers Bureau. Paquette: Ariad, BMS, Novartis: Consultancy; Ariad, BMS, Novartis: Honoraria; Ariad, BMS, Novartis: Speakers Bureau. Chuah: Novartis, BMS: Honoraria. Nicolini: Novartis, ARIAD, Teva: Consultancy; Novartis, BMS: Research Funding; Novartis, BMS, Teva, Pfizer, ARIAD: Honoraria; Novartis, BMS, TEva: Speakers Bureau; Novartis, ARIAD, Teva, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Apperley: Novartis: Research Funding; Ariad, Bristol Myers Squibb, Novartis, Pfizer, Teva: Honoraria. Talpaz: Ariad, BMS, Sanofi, INCYTE: Research Funding; Ariad, Novartis: Speakers Bureau; Ariad, Sanofi, Novartis: Membership on an entity’s Board of Directors or advisory committees. DeAngelo: Ariad, Novartis, BMS: Consultancy. Abruzzese: BMS, Novartis: Consultancy. Rea: BMS, Novartis, Pfizer, Ariad, Teva: Honoraria. Baccarani: ARIAD, Novartis, BMS: Consultancy; ARIAD, Novartis, BMS, Pfizer, Teva: Honoraria; ARIAD, Novartis, BMS, Pfizer, Teva: Speakers Bureau. Muller: Novartis, BMS, ARIAD: Consultancy; Novartis, BMS: Research Funding; Novartis, BMS, ARIAD: Honoraria. Gambacorti-Passerini: Pfizer: Research Funding; Pfizer, BMS: Honoraria. Lustgarten: ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Yanase: ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc. Other, Employment. Turner: ARIAD: Employment. Haluska: ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Deininger: BMS, ARIAD, NOVARTIS: Consultancy; BMS, NOVARTIS, CELGENE, GILEAD: Research Funding; ARIAD, NOVARTIS: Advisory Boards, Advisory Boards Other. Hochhaus: Ariad, Novartis, BMS, MSD, Pfizer: Research Funding; Novartis, BMS, Pfizer: Honoraria. Hughes: Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman: ARIAD: Honoraria. Shah: Ariad, Bristol-Myers Squibb: Consultancy, Research Funding. Kantarjian: ARIAD, Novartis, BMS, Phizer: Research Funding. Cortes: Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding. [1]: #F1 [2]: pending:yes [3]: http://ClinicalTrials.gov [4]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01207440&atom=%2Fbloodjournal%2F122%2F21%2F1496.atom

  • clinical impact of dose modification on response to ponatinib in patients with chronic phase chronic myeloid leukemia cp cml
    Blood, 2013
    Co-Authors: Philipp Le Coutre, Jean H Khoury, Daniel J Deangelo, Charles Chuah, Franck E. Nicolini, Jane F Apperley, Ronald Paquette, John F. Dipersio, Elisabetta Abruzzese
    Abstract:

    Background Ponatinib is a potent oral pan–Bcr-Abl tyrosine kinase Inhibitor (TKI) that has demonstrated significant clinical activity in heavily pretreated CP-CML pts. A multivariate analysis of CP-CML pts in the PACE trial found significant associations between major cytogenetic response (MCyR) and higher dose intensity; however, dose reductions and/or interruptions (DR/I) of ponatinib occur often in pts who experience adverse events (AEs). The clinical significance of such DR/I are not well known. Objectives To assess the impact of DR/I and dose intensity of ponatinib on clinical outcomes in pts with CP-CML enrolled in the PACE trial. Methods A total of 270 CP-CML pts were enrolled in this ongoing, phase 2, international, open-label clinical trial. The efficacy population (N=267) was included in this post hoc analysis. Dose reductions were defined as any reduction below the standard 45 mg daily dose; interruptions were defined as a period in which ponatinib was held for ≥3 consecutive days between non-missing doses. Up to 2 reductions (to 30 or 15 mg/day) were permitted for managing AEs. To assess the impact of dose modification on response, pts were grouped according to tertiles of average dose intensity (mg/day), calculated as the cumulative dose divided by treatment exposure. All variables were calculated within 12 mos of the first dose to correspond to the primary outcome measure of MCyR by 12 mos. Secondary efficacy endpoints included complete cytogenetic response (CCyR) and major molecular response (MMR). Responses were assessed every 3 mos. The Cochran–Armitage trend test was used to assess whether response rates increased with higher average dose intensity tertiles; all P -values were 2-sided. Data are as of 01 Apr 2013, with a median follow-up of 20 (0.1–28) mos. Minimum follow-up for pts still on study was 18 mos. Results A total of 209 (78%) pts required DR/I at least once within 12 mos: 172 pts (64%) had at least 1 dose reduction (median time to first dose reduction was 64 days). In pts with >1 dose reduction (n=75, 28%), the median time between the first and second reduction was 91 days. Among pts with a dose reduction at any time, 35% re-escalated to 45 mg daily. Dose interruption was experienced by 199 (75%) pts (median total duration of 35 days). The most common reason for DR/I was thrombocytopenia (33%). For pts with average dose intensity ≤27 mg/day (N=89), >27 to ≤42 mg/day (N=88), and >42 mg/day (N=90), respectively, the median age was 62, 62, and 56 yrs; median time since initial diagnosis was 11, 7, and 6 yrs; each group had received a median of 3 prior TKIs. Among these tertiles, the best response to the most recent dasatinib- or nilotinib-containing regimen was MCyR or better in 21%, 22%, and 35%; CCyR or better in 11%, 14%, and 23%; MMR or better in 1%, 2%, and 6%, respectively. Within 12 mos of the first dose, median duration of treatment exposure was 356 (26–366), 366 (51–366) and 366 (3–366) days, respectively. Twenty-nine pts had 27 to ≤42 mg/day and >42 mg/day. Response rates were lower in pts with average dose intensity ≤27 mg/day; however, these pts still achieved MCyR, CCyR, and MMR rates that substantially exceeded those reported with the most recent dasatinib- or nilotinib-containing regimen. View this table: Conclusions Higher dose intensity of ponatinib was associated with higher response rates in this heavily pretreated CP-CML population, but lower dose intensity still led to positive clinical outcomes. It should be noted that higher responses to the most recent dasatinib- or nilotinib-containing regimen were also seen in pts with higher average dose intensity. In summary, these data indicate that although optimal responses were seen with average ponatinib dose intensity >42 mg/day, pts can be effectively managed with dose reduction or interruption if clinically indicated. Disclosures: Pinilla-Ibarz: Novartis, Ariad: Research Funding; Novartis, Ariad, BMS and Pfizer: Speakers Bureau. Cortes: Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding. Kim: BMS, Novartis, IL-Yang: Consultancy; BMS, Novartis, Pfizer, ARIAD, IL-Yang: Research Funding; BMS, Novartis, Pfizer, IL-Yang: Honoraria; BMS, Novartis, Pfizer: Speakers Bureau; BMS, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Le Coutre: Novartis: Research Funding; Novartis, BMS, Pfizer: Honoraria. Paquette: Ariad, BMS, Novartis: Consultancy; Ariad, BMS, Novartis: Honoraria; Ariad, BMS, Novartis: Speakers Bureau. Chuah: Novartis, BMS: Honoraria. Nicolini: Novartis, ARIAD, Teva: Consultancy; Novartis, BMS: Research Funding; Novartis, BMS, Teva, Pfizer, ARIAD: Honoraria; Novartis, BMS, TEva: Speakers Bureau; Novartis, ARIAD, Teva, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Apperley: Novartis: Research Funding; Ariad, Bristol Myers Squibb, Novartis, Pfizer, Teva: Honoraria. DeAngelo: Araid, Novartis, BMS: Consultancy. Abruzzese: BMS, Novartis: Consultancy. Rea: BMS, Novartis, Pfizer, Ariad, Teva: Honoraria. Baccarani: ARIAD, Novartis, BMS: Consultancy; ARIAD, Novartis, BMS, Pfizer, Teva: Honoraria; ARIAD, Novartis, BMS, Pfizer, Teva: Speakers Bureau. Muller: Novartis, BMS, ARIAD: Consultancy; Novartis, BMS: Research Funding; Novartis, BMS, ARIAD: Honoraria. Gambacorti-Passerini: Pfizer: Research Funding; Pfizer, BMS: Honoraria. Lustgarten: ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Rivera: ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc. Other, Employment. Clackson: ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Turner: ARIAD: Employment. Haluska: ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Deininger: BMS, ARIAD, NOVARTIS: Consultancy; BMS, NOVARTIS, CELGENE, GILEAD: Research Funding; ARIAD, NOVARTIS: Advisory Boards, Advisory Boards Other. Hochhaus: Ariad, Novartis, BMS, MSD, Pfizer: Research Funding; Novartis, BMS, Pfizer: Honoraria. Hughes: Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman: ARIAD: Honoraria. Shah: Ariad, Bristol-Myers Squibb: Consultancy, Research Funding. Kantarjian: ARIAD, Novartis, BMS, Phizer: Research Funding. Talpaz: Ariad, BMS, Sanofi, INCYTE: Research Funding; Ariad, Novartis: Speakers Bureau; Ariad, Sanofi, Novartis: Membership on an entity’s Board of Directors or advisory committees. [1]: #T1

  • nilotinib formerly amn107 a highly selective bcr abl tyrosine kinase Inhibitor is active in patients with imatinib resistant or intolerant accelerated phase chronic myelogenous leukemia
    Blood, 2008
    Co-Authors: Philipp Le Coutre, Norbert Gattermann, Elisabetta Abruzzese, Stephen G Obrien, Jane F Apperley, Oliver G. Ottmann, Richard A Larson, Kazimierz Kuliczkowski
    Abstract:

    Patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia (CML-AP) have very limited therapeutic options. Nilotinib is a highly selective Bcr-Abl tyrosine kinase Inhibitor. This phase 2 trial was designed to characterize the efficacy and safety of nilotinib (400 mg twice daily) in this patient population with hematologic response (HR) as primary efficacy endpoint. A total of 119 patients were enrolled and had a median duration of treatment of 202 days (range, 2–611 days). An HR was observed in 56 patients (47%; 95% confidence interval [CI], 38%-56%). Major cytogenetic response (MCyR) was observed in 35 patients (29%; 95% CI, 21%-39%). The median duration of HR has not been reached. Overall survival rate among the 119 patients after 12 months of follow-up was 79% (95% CI, 70%-87%). Nonhematologic adverse events were mostly mild to moderate. Severe peripheral edema and pleural effusions were not observed. The most common grade 3 or higher hematologic adverse events were thrombocytopenia (35%) and neutropenia (21%). Grade 3 or higher bilirubin and lipase elevations occurred in 9% and 18% of patients, respectively, resulting in treatment discontinuation in one patient. In conclusion, nilotinib is an effective and well-tolerated treatment in imatinib-resistant and -intolerant CML-AP. This trial is registered at [www.clinicaltrials.gov][1] as [NCT00384228][2]. [1]: http://www.clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00384228&atom=%2Fbloodjournal%2F111%2F4%2F1834.atom

Franck E. Nicolini - One of the best experts on this subject based on the ideXlab platform.

  • clinical impact of dose modification and dose intensity on response to ponatinib pon in patients pts with philadelphia chromosome positive ph leukemias
    Journal of Clinical Oncology, 2014
    Co-Authors: Andreas Hochhaus, Javier Pinillaibarz, Charles Chuah, Philipp Le Coutre, Franck E. Nicolini, Jane F Apperley, Ronald Paquette, Dongwook Kim, Hanna Jean Khoury, Michele Baccarani
    Abstract:

    7084 Background: PON is a potent oral pan–Bcr-Abl tyrosine kinase Inhibitor with clinical activity in pretreated pts with Ph+ leukemias. Dose modification of PON may be used to avoid or manage adve...

  • clinical impact of dose modification and dose intensity on response to ponatinib pon in patients pts with philadelphia chromosome positive ph leukemias
    Journal of Clinical Oncology, 2014
    Co-Authors: Andreas Hochhaus, Javier Pinillaibarz, Charles Chuah, Philipp Le Coutre, Michele Baccarani, Franck E. Nicolini, Jane F Apperley, Ronald Paquette, Hanna Jean Khoury, Stephanie Lustgarten
    Abstract:

    7084 Background: PON is a potent oral pan–Bcr-Abl tyrosine kinase Inhibitor with clinical activity in pretreated pts with Ph+ leukemias. Dose modification of PON may be used to avoid or manage adverse events (AEs). This post hoc analysis assessed the clinical impact of dose modification and dose intensity on outcomes of pts in the phase 2 PACE trial. Methods: PON starting dose was 45 mg QD. Dose reduction: any reduction below 45 mg/d; dose interruption: treatment held for ≥3 consecutive days. Efficacy analyses were performed on CP-CML pts (N=267). Analysis of arterial thrombotic events (ATEs) included all pts (CP/BP/AP-CML, Ph+ ALL; N=449). Data are as of 3 Sept 2013; median follow-up was 24 (0.1-35) mo for all pts. Results: 78% of CP-CML pts had dose modification within the first 12 mo (82% at any time). Responses in pts with/without modification were comparable (Table). Of 149 responders, 87 (58%) achieved MCyR at 45 mg/d, 46 (31%) at 30 mg/d, 16 (11%) at 15 mg/d. Most pts who had a dose reduction after...

  • ponatinib in heavily pretreated patients with chronic phase chronic myeloid leukemia cp cml management of adverse events aes
    Blood, 2013
    Co-Authors: Philipp Le Coutre, Javier Pinillaibarz, Jean H Khoury, Charles Chuah, Franck E. Nicolini, Moshe Talpaz, Jane F Apperley, Ronald Paquette, John F. Dipersio, Daniel J Deangelo
    Abstract:

    Background Ponatinib is a potent oral pan–Bcr-Abl tyrosine kinase Inhibitor (TKI) with activity against native and mutant Bcr-Abl. The efficacy and safety of ponatinib (45 mg once daily) in pts with CP-CML were evaluated in the phase 2 PACE trial. Objectives To review the management of treatment-related AEs (TRAEs) that emerged during therapy with ponatinib in the PACE trial. Methods A total of 270 CP-CML pts (267 in efficacy population) resistant or intolerant to dasatinib or nilotinib or with the T315I mutation were enrolled in this ongoing, phase 2, international, open-label clinical trial. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 mos. Safety monitoring included collection of AEs, and the following variables were evaluated: incidence, severity, time to onset, duration, and management. Select TRAEs are discussed. Data as of 01 Apr 2013 are reported, with a median follow-up of 20 (0.1–28) mos. Minimum follow-up for pts remaining on study was 18 mos. Results Median age was 60 (18-94) yrs; median time from diagnosis to first dose was 7 (0.5-27) yrs; 93% had ≥2 prior TKIs, 60% ≥3. Ponatinib demonstrated significant activity in CP-CML pts: 56% MCyR, 46% CCyR, and 36% MMR. At the time of analysis, 60% of pts remained on study. The most frequent reasons for discontinuation were AEs (14%) and progression (8%). The most common hematologic TRAE was thrombocytopenia (41% any grade, 32% grade 3/4). The incidence by time to initial onset is shown below ([Figure][1]). Pts experienced thrombocytopenia for a median total duration of 166 days (64% of whom had >1 event) and typically required dose modification: 13% drug withdrawn, 40% dose reduced, 29% dose interrupted only, 17% no dose modification. Among pts with thrombocytopenia, 27% required a platelet transfusion. Thirteen percent of CP-CML pts experienced treatment-related neutropenia and thrombocytopenia. ![Figure.][2] Figure. Incidencea of Select TRAEs by Time to Initial Onset in CP-CML The most common nonhematologic TRAE was rash (39% any grade, 4% grade 3/4), which includes erythematous, macular, and papular rash. Pts experienced rash for a median total duration of 65 days (46% of whom had >1 event) and most did not require dose modification: 0% drug withdrawn, 15% dose reduced, 11% dose interrupted only, 73% no dose modification. One additional pt discontinued due to grade 2 treatment-related exfoliative rash. Pancreatitis was observed (7% any grade, 6% grade 3/4). Median duration was 5 days. Pts were typically managed with dose modification: 5% drug withdrawn, 58% dose reduced, 32% dose interrupted only, 5% no dose modification. Treatment-emergent cardiovascular events were observed in 8% of pts and treatment-emergent cerebrovascular or peripheral vascular events in 11%. Cardiovascular events were considered treatment-related in 4%; cerebrovascular or peripheral vascular events were also considered treatment-related in 4%. The median time to initial onset was 9 mos for cardiovascular and 11 mos for cerebrovascular or peripheral vascular events. The median duration was 6 and 97 days, respectively. Management of pts with cardiovascular AEs: 20% drug withdrawn, 10% dose reduced, 40% dose interrupted only, 30% no dose modification. Management of pts with cerebrovascular or peripheral vascular AEs: 8% drug withdrawn; 8% dose reduced; 17% dose interrupted only; 67% no dose modification. Conclusions Ponatinib has robust antileukemic activity in heavily pretreated CP-CML pts (93% of whom received ≥2 prior TKIs). Treatment-related thrombocytopenia and pancreatitis generally occurred early in therapy and were manageable with dose modification. Treatment-related rash generally occurred early in therapy, was mild-to-moderate in severity, managed without the need for dose modification, and rarely led to discontinuation. Management of treatment-related arterial thrombotic events varied; pts with predisposing cardiovascular risk factors should be monitored closely and managed accordingly. [ClinicalTrials.gov][3] ID: [NCT01207440][4] aIncidence = (number of pts with initial onset during time interval) / (number of pts dosed during time interval [N] excluding those who previously experienced the event) X 100 Disclosures: Le Coutre: Novartis: Research Funding; Novartis, BMS, Pfizer: Honoraria. Kim: BMS, Novartis, IL-Yang: Consultancy; BMS, Novartis, Pfizer, ARIAD, IL-Yang: Research Funding; BMS, Novartis, Pfizer, IL-Yang: Honoraria; BMS, Novartis, Pfizer: Speakers Bureau; BMS, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Pinilla-Ibarz: Novartis, Ariad: Research Funding; Novartis, Ariad, BMS and Pfizer: Speakers Bureau. Paquette: Ariad, BMS, Novartis: Consultancy; Ariad, BMS, Novartis: Honoraria; Ariad, BMS, Novartis: Speakers Bureau. Chuah: Novartis, BMS: Honoraria. Nicolini: Novartis, ARIAD, Teva: Consultancy; Novartis, BMS: Research Funding; Novartis, BMS, Teva, Pfizer, ARIAD: Honoraria; Novartis, BMS, TEva: Speakers Bureau; Novartis, ARIAD, Teva, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Apperley: Novartis: Research Funding; Ariad, Bristol Myers Squibb, Novartis, Pfizer, Teva: Honoraria. Talpaz: Ariad, BMS, Sanofi, INCYTE: Research Funding; Ariad, Novartis: Speakers Bureau; Ariad, Sanofi, Novartis: Membership on an entity’s Board of Directors or advisory committees. DeAngelo: Ariad, Novartis, BMS: Consultancy. Abruzzese: BMS, Novartis: Consultancy. Rea: BMS, Novartis, Pfizer, Ariad, Teva: Honoraria. Baccarani: ARIAD, Novartis, BMS: Consultancy; ARIAD, Novartis, BMS, Pfizer, Teva: Honoraria; ARIAD, Novartis, BMS, Pfizer, Teva: Speakers Bureau. Muller: Novartis, BMS, ARIAD: Consultancy; Novartis, BMS: Research Funding; Novartis, BMS, ARIAD: Honoraria. Gambacorti-Passerini: Pfizer: Research Funding; Pfizer, BMS: Honoraria. Lustgarten: ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Yanase: ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc. Other, Employment. Turner: ARIAD: Employment. Haluska: ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Deininger: BMS, ARIAD, NOVARTIS: Consultancy; BMS, NOVARTIS, CELGENE, GILEAD: Research Funding; ARIAD, NOVARTIS: Advisory Boards, Advisory Boards Other. Hochhaus: Ariad, Novartis, BMS, MSD, Pfizer: Research Funding; Novartis, BMS, Pfizer: Honoraria. Hughes: Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman: ARIAD: Honoraria. Shah: Ariad, Bristol-Myers Squibb: Consultancy, Research Funding. Kantarjian: ARIAD, Novartis, BMS, Phizer: Research Funding. Cortes: Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding. [1]: #F1 [2]: pending:yes [3]: http://ClinicalTrials.gov [4]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01207440&atom=%2Fbloodjournal%2F122%2F21%2F1496.atom

  • clinical impact of dose modification on response to ponatinib in patients with chronic phase chronic myeloid leukemia cp cml
    Blood, 2013
    Co-Authors: Philipp Le Coutre, Jean H Khoury, Daniel J Deangelo, Charles Chuah, Franck E. Nicolini, Jane F Apperley, Ronald Paquette, John F. Dipersio, Elisabetta Abruzzese
    Abstract:

    Background Ponatinib is a potent oral pan–Bcr-Abl tyrosine kinase Inhibitor (TKI) that has demonstrated significant clinical activity in heavily pretreated CP-CML pts. A multivariate analysis of CP-CML pts in the PACE trial found significant associations between major cytogenetic response (MCyR) and higher dose intensity; however, dose reductions and/or interruptions (DR/I) of ponatinib occur often in pts who experience adverse events (AEs). The clinical significance of such DR/I are not well known. Objectives To assess the impact of DR/I and dose intensity of ponatinib on clinical outcomes in pts with CP-CML enrolled in the PACE trial. Methods A total of 270 CP-CML pts were enrolled in this ongoing, phase 2, international, open-label clinical trial. The efficacy population (N=267) was included in this post hoc analysis. Dose reductions were defined as any reduction below the standard 45 mg daily dose; interruptions were defined as a period in which ponatinib was held for ≥3 consecutive days between non-missing doses. Up to 2 reductions (to 30 or 15 mg/day) were permitted for managing AEs. To assess the impact of dose modification on response, pts were grouped according to tertiles of average dose intensity (mg/day), calculated as the cumulative dose divided by treatment exposure. All variables were calculated within 12 mos of the first dose to correspond to the primary outcome measure of MCyR by 12 mos. Secondary efficacy endpoints included complete cytogenetic response (CCyR) and major molecular response (MMR). Responses were assessed every 3 mos. The Cochran–Armitage trend test was used to assess whether response rates increased with higher average dose intensity tertiles; all P -values were 2-sided. Data are as of 01 Apr 2013, with a median follow-up of 20 (0.1–28) mos. Minimum follow-up for pts still on study was 18 mos. Results A total of 209 (78%) pts required DR/I at least once within 12 mos: 172 pts (64%) had at least 1 dose reduction (median time to first dose reduction was 64 days). In pts with >1 dose reduction (n=75, 28%), the median time between the first and second reduction was 91 days. Among pts with a dose reduction at any time, 35% re-escalated to 45 mg daily. Dose interruption was experienced by 199 (75%) pts (median total duration of 35 days). The most common reason for DR/I was thrombocytopenia (33%). For pts with average dose intensity ≤27 mg/day (N=89), >27 to ≤42 mg/day (N=88), and >42 mg/day (N=90), respectively, the median age was 62, 62, and 56 yrs; median time since initial diagnosis was 11, 7, and 6 yrs; each group had received a median of 3 prior TKIs. Among these tertiles, the best response to the most recent dasatinib- or nilotinib-containing regimen was MCyR or better in 21%, 22%, and 35%; CCyR or better in 11%, 14%, and 23%; MMR or better in 1%, 2%, and 6%, respectively. Within 12 mos of the first dose, median duration of treatment exposure was 356 (26–366), 366 (51–366) and 366 (3–366) days, respectively. Twenty-nine pts had 27 to ≤42 mg/day and >42 mg/day. Response rates were lower in pts with average dose intensity ≤27 mg/day; however, these pts still achieved MCyR, CCyR, and MMR rates that substantially exceeded those reported with the most recent dasatinib- or nilotinib-containing regimen. View this table: Conclusions Higher dose intensity of ponatinib was associated with higher response rates in this heavily pretreated CP-CML population, but lower dose intensity still led to positive clinical outcomes. It should be noted that higher responses to the most recent dasatinib- or nilotinib-containing regimen were also seen in pts with higher average dose intensity. In summary, these data indicate that although optimal responses were seen with average ponatinib dose intensity >42 mg/day, pts can be effectively managed with dose reduction or interruption if clinically indicated. Disclosures: Pinilla-Ibarz: Novartis, Ariad: Research Funding; Novartis, Ariad, BMS and Pfizer: Speakers Bureau. Cortes: Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding. Kim: BMS, Novartis, IL-Yang: Consultancy; BMS, Novartis, Pfizer, ARIAD, IL-Yang: Research Funding; BMS, Novartis, Pfizer, IL-Yang: Honoraria; BMS, Novartis, Pfizer: Speakers Bureau; BMS, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Le Coutre: Novartis: Research Funding; Novartis, BMS, Pfizer: Honoraria. Paquette: Ariad, BMS, Novartis: Consultancy; Ariad, BMS, Novartis: Honoraria; Ariad, BMS, Novartis: Speakers Bureau. Chuah: Novartis, BMS: Honoraria. Nicolini: Novartis, ARIAD, Teva: Consultancy; Novartis, BMS: Research Funding; Novartis, BMS, Teva, Pfizer, ARIAD: Honoraria; Novartis, BMS, TEva: Speakers Bureau; Novartis, ARIAD, Teva, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Apperley: Novartis: Research Funding; Ariad, Bristol Myers Squibb, Novartis, Pfizer, Teva: Honoraria. DeAngelo: Araid, Novartis, BMS: Consultancy. Abruzzese: BMS, Novartis: Consultancy. Rea: BMS, Novartis, Pfizer, Ariad, Teva: Honoraria. Baccarani: ARIAD, Novartis, BMS: Consultancy; ARIAD, Novartis, BMS, Pfizer, Teva: Honoraria; ARIAD, Novartis, BMS, Pfizer, Teva: Speakers Bureau. Muller: Novartis, BMS, ARIAD: Consultancy; Novartis, BMS: Research Funding; Novartis, BMS, ARIAD: Honoraria. Gambacorti-Passerini: Pfizer: Research Funding; Pfizer, BMS: Honoraria. Lustgarten: ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Rivera: ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc. Other, Employment. Clackson: ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Turner: ARIAD: Employment. Haluska: ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Deininger: BMS, ARIAD, NOVARTIS: Consultancy; BMS, NOVARTIS, CELGENE, GILEAD: Research Funding; ARIAD, NOVARTIS: Advisory Boards, Advisory Boards Other. Hochhaus: Ariad, Novartis, BMS, MSD, Pfizer: Research Funding; Novartis, BMS, Pfizer: Honoraria. Hughes: Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman: ARIAD: Honoraria. Shah: Ariad, Bristol-Myers Squibb: Consultancy, Research Funding. Kantarjian: ARIAD, Novartis, BMS, Phizer: Research Funding. Talpaz: Ariad, BMS, Sanofi, INCYTE: Research Funding; Ariad, Novartis: Speakers Bureau; Ariad, Sanofi, Novartis: Membership on an entity’s Board of Directors or advisory committees. [1]: #T1

  • nilotinib formerly amn107 a highly selective bcr abl tyrosine kinase Inhibitor is effective in patients with philadelphia chromosome positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance
    Blood, 2007
    Co-Authors: Norbert Gattermann, Stephen G Obrien, Francesca Palandri, Gert J Ossenkoppele, Franck E. Nicolini, Giuliana Alimena, Kapil Bhalla, Mark R. Litzow
    Abstract:

    Nilotinib, an orally bioavailable, selective Bcr-Abl tyrosine kinase Inhibitor, is 30-fold more potent than imatinib in pre-clinical models, and overcomes most imatinib resistant Bcr-Abl mutations. In this phase 2 open-label study, 400 mg nilotinib was administered orally twice daily to 280 patients with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) after imatinib failure or intolerance. Patients had at least 6 months of follow-up and were evaluated for hematologic and cytogenetic responses, as well as for safety and overall survival. At 6 months, the rate of major cytogenetic response (Ph ≤ 35%) was 48%: complete (Ph = 0%) in 31%, and partial (Ph = 1%-35%) in 16%. The estimated survival at 12 months was 95%. Nilotinib was effective in patients harboring Bcr-Abl mutations associated with imatinib resistance (except T315I), and also in patients with a resistance mechanism independent of Bcr-Abl mutations. Adverse events were mostly mild to moderate, and there was minimal cross-intolerance with imatinib. Grades 3 to 4 neutropenia and thrombocytopenia were observed in 29% of patients; pleural or pericardial effusions were observed in 1% (none were severe). In summary, nilotinib is highly active and safe in patients with CML-CP after imatinib failure or intolerance. This clinical trial is registered at as ID no. [NCT00109707][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00109707&atom=%2Fbloodjournal%2F110%2F10%2F3540.atom