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

  • impact of dose intensity of Ponatinib on selected adverse events multivariate analyses from a pooled population of clinical trial patients
    Leukemia Research, 2016
    Co-Authors: David J. Dorer, Jorge E Cortes, Michele Baccarani, Andreas Hochhaus, Moshe Talpaz, Ronald Knickerbocker, Frank G. Haluska
    Abstract:

    Abstract Ponatinib is approved for adults with refractory chronic myeloid leukemia or Philadelphia chromosome–positive acute lymphoblastic leukemia, including those with the T315I BCR-ABL1 mutation. We pooled data from 3 clinical trials (N = 671) to determine the impact of Ponatinib dose intensity on the following adverse events: arterial occlusive events (cardiovascular, cerebrovascular, and peripheral vascular events), venous thromboembolic events, cardiac failure, thrombocytopenia, neutropenia, hypertension, pancreatitis, increased lipase, increased alanine aminotransferase, increased aspartate aminotransferase, rash, arthralgia, and hypertriglyceridemia. Multivariate analyses allowed adjustment for covariates potentially related to changes in dosing or an event. Logistic regression analysis identified significant associations between dose intensity and most events after adjusting for covariates. Pancreatitis, rash, and cardiac failure had the strongest associations with dose intensity (odds ratios >2). Time-to-event analyses showed significant associations between dose intensity and risk of arterial occlusive events and each subcategory. Further, these analyses suggested that a lag exists between a change in dose and the resulting change in event risk. No significant association between dose intensity and risk of venous thromboembolic events was evident. Collectively, these findings suggest a potential causal relationship between Ponatinib dose and certain adverse events and support prospective investigations of approaches to lower average Ponatinib dose intensity.

  • compound mutations in bcr abl1 are not major drivers of primary or secondary resistance to Ponatinib in cp cml patients
    Blood, 2016
    Co-Authors: Michael W. Deininger, Jorge E Cortes, Michele Baccarani, Franck E Nicolini, Neil P Shah, Moshe Talpaz, Graeme J Hodgson, Martin C Muller, Jin Li, Wendy T Parker
    Abstract:

    BCR-ABL1 kinase domain mutations can confer resistance to first- and second-generation tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). In preclinical studies, clinically achievable concentrations of the third-generation BCR-ABL1 TKI Ponatinib inhibit T315I and all other single BCR-ABL1 mutants except T315M, which generates a single amino acid exchange, but requires 2 sequential nucleotide exchanges. In addition, certain compound mutants (containing ≥2 mutations in cis) confer resistance. Initial analyses based largely on conventional Sanger sequencing (SS) have suggested that the preclinical relationship between BCR-ABL1 mutation status and Ponatinib efficacy is generally recapitulated in patients receiving therapy. Thus far, however, such analyses have been limited by the inability of SS to definitively identify compound mutations or mutations representing less than ∼20% of total alleles (referred to as “low-level mutations”), as well as limited patient follow-up. Here we used next-generation sequencing (NGS) to define the baseline BCR-ABL1 mutation status of 267 heavily pretreated chronic phase (CP)-CML patients from the PACE trial, and used SS to identify clonally dominant mutants that may have developed on Ponatinib therapy (30.1 months median follow-up). Durable cytogenetic and molecular responses were observed irrespective of baseline mutation status and included patients with compound mutations. No single or compound mutation was identified that consistently conferred primary and/or secondary resistance to Ponatinib in CP-CML patients. Ponatinib is effective in CP-CML irrespective of baseline mutation status.

  • phase ii trial of Ponatinib in patients with chronic myeloid leukemia resistant to one previous tyrosine kinase inhibitor
    Haematologica, 2015
    Co-Authors: David Sanford, Hagop M Kantarjian, Elias Jabbour, Jeffrey Skinner, Jorge E Cortes
    Abstract:

    Ponatinib is a tyrosine kinase inhibitor (TKI) designed to overcome resistance-inducing mutations, including the T315I mutation, in the ABL kinase domain. Initial clinical trials of Ponatinib reported major cytogenetic response (MCyR) rates over 60% in heavily treated patients with chronic myeloid

  • phase ii study of combination of hyper cvad with Ponatinib in frontline therapy of patients with philadelphia chromosome positive acute lymphoblastic leukemia ph positive all
    Clinical Lymphoma Myeloma & Leukemia, 2015
    Co-Authors: Koji Sasaki, Naveen Pemmaraju, Tapan M Kadia, Farhad Ravandi, Susan Obrien, Deborah A Thomas, Haim G Moore, Jorge E Cortes, Musa Yilmaz, Rebecca Garris
    Abstract:

    Background: PonatinibisamorepotentBCR-ABLinhibitor,and covers the T315I clones. The combinations of chemotherapy and Ponatinib may be associated with better response rates and higher likelihood of eradication of minimal residual disease (MRD) in patients with Ph-positive ALL. Methods: Patients with newly diagnosed Ph-positive ALL received 8 cycles of hyper-CVAD alternating with high-dose methotrexate/cytarabine. Ponatinib was given at 45 mg po daily for the first 14 days of cycle 1 then continuously for the subsequent 7 cycles. Patients in CR received maintenance with Ponatinib 45 mg daily and vincristine/prednisone monthly for 2 years followed by Ponatinib indefinitely. Results: To date, 37 patients with untreated Ph-positive ALL and 3 patients previously treated (1 previous course) have received a median of 6 cycles (2-8); 13 patients are receiving maintenance in CR. The overall CCyR, MMR, and CMR rates were 100%, 95%, and 78%, respectively. By multiparameter flow cytometry, 95% had undetectable MRD after a median of 3 weeks of therapy. Grade 3 toxicity included infections during induction (54%), increased liver functional tests (38%), thrombotic events (8%), myocardial infarction (14%), hypertension (16%), skin rash (22%), and pancreatitis (22%). Two potentially related deaths from myocardial infarction were observed after 2 (Ponatinib 45 mg) and 5 (Ponatinib 30 mg) cycles of therapy. After the emergence of vascular toxicities on Ponatinib trials in 2013, patients were offered for the option to switch TKIs or to reduce the dose of Ponatinib to 30 mg and further decreased to 15 mg in patients in CMR. No further vascular events were observed in patients receiving lower doses of Ponatinib. Nine patients underwent allogeneic stem cell transplantation after a median of 4 cycles (3-10). The 3-year event-free and overall survival rates are 81% and 80%, respectively. Conclusion: The combination of hyper-CVAD with Ponatinib is highly effective in patients with Phpositive ALL. Dose titration of Ponatinib with optimized control of vascular risk factors may minimize the risk of cardiovascular event.

  • the role of Ponatinib in philadelphia chromosome positive acute lymphoblastic leukemia
    Expert Review of Anticancer Therapy, 2015
    Co-Authors: David Sanford, Hagop M Kantarjian, Elias Jabbour, Susan Obrien, Jorge E Cortes, Farhad Ravandi
    Abstract:

    The introduction of tyrosine kinase inhibitors has improved outcomes in Philadelphia chromosome-positive acute lymphoblastic leukemia, yet relapse due to the development of resistance mutations remains a major obstacle. Ponatinib is a novel tyrosine kinase inhibitor designed to overcome single-resistance mutations in the ABL kinase. Three clinical trials confirmed the efficacy of Ponatinib in the relapsed and front-line setting in Philadelphia positive acute lymphoblastic leukemia, even in the presence of the T315I mutation, which confers resistance to other tyrosine kinase inhibitors. The rate of relapse appears to be very low when used in combination with chemotherapy, suggesting a role for Ponatinib in newly diagnosed patients. A major concern with the use of Ponatinib is the associated high risk of life-threatening vascular thrombotic events. Potential strategies to reduce this risk include minimizing the use of Ponatinib in patients with significant baseline cardiovascular risk, careful surveillance ...

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

  • efficacy of Ponatinib versus earlier generation tyrosine kinase inhibitors for front line treatment of newly diagnosed philadelphia positive acute lymphoblastic leukemia
    Clinical Lymphoma Myeloma & Leukemia, 2018
    Co-Authors: Elias Jabbour, Farhad Ravandi, Susan Obrien, Maral Dersarkissian, Nora Mccormick, Wendy Y Cheng, Lisa Mcgarry, Ariadne Souroutzidis, Hui Huang, Hagop M Kantarjian
    Abstract:

    Abstract Introduction Complete molecular response (CMR) and 2- and 3-year overall survival (OS) were compared for patients with newly diagnosed Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) who had undergone front-line combination chemotherapy plus Ponatinib versus combination therapy plus earlier generation tyrosine kinase inhibitors (TKIs; imatinib, dasatinib, and nilotinib). Patients and Methods We identified 26 Ph + ALL studies: 25 of earlier generation TKIs and 1 of Ponatinib. The outcomes from studies of combination chemotherapy plus earlier generation TKIs were summarized using pooled estimates with 95% confidence intervals (CIs) from a random-effects meta-analysis. A binomial distribution was assumed to calculate the 95% CIs for the results from the single-arm combination chemotherapy plus Ponatinib trial. Adjusted logistic meta-regression analyses were used to compare the outcomes between the TKI groups. Results The percentage of patients achieving a CMR was greater with combination chemotherapy plus Ponatinib (79%) than the pooled percentage of patients achieving a CMR with combination chemotherapy plus earlier generation TKIs (34%). Greater OS was observed with Ponatinib compared with the pooled OS for earlier generation TKIs (2-year, 83% vs. 58%; 3-year, 79% vs. 50%). Odds ratios for Ponatinib versus earlier generation TKIs were 6.09 (95% CI, 1.16-31.90; P  = .034) for CMR, 3.70 (95% CI, 0.93-14.73; P  = .062) for 2-year OS, and 4.49 (95% CI, 1.00-20.13; P  = .050) for 3-year OS. Conclusion Ponatinib plus chemotherapy might be associated with better outcomes than chemotherapy with earlier generation TKIs in patients with newly diagnosed Ph + ALL.

  • frontline hyper cvad plus Ponatinib for patients with philadelphia chromosome positive acute lymphoblastic leukemia updated results of a phase ii study
    Journal of Clinical Oncology, 2017
    Co-Authors: Nicholas J Short, Hagop M Kantarjian, Naveen Pemmaraju, Tapan M Kadia, Naval Daver, Farhad Ravandi, Koji Sasaki, Deborah A Thomas, Musa Yilmaz, Rebecca Garris
    Abstract:

    7013Background: The combination of chemotherapy plus a TKI is highly effective in Ph+ ALL. In this phase II study, we evaluated the safety and efficacy of HCVAD in combination with the third-generation pan-BCR-ABL inhibitor, Ponatinib. Methods: Patients (pts) with newly diagnosed Ph+ ALL received 8 cycles of HCVAD alternating with high dose MTX/Ara-C every 21 days. Ponatinib was given at 45 mg daily for the first 14 days of cycle 1. Initially Ponatinib 45 mg daily was given indefinitely beginning at cycle 2. Due to concern for vascular events, a protocol amendment was made in which, beginning in cycle 2, pts in CR received 30mg daily and pts in CMR received 15mg daily. Rituximab and IT chemotherapy were given with the first 4 courses. After 8 cycles of HCVAD, pts in CR received maintenance with Ponatinib, vincristine and prednisone for 2 years followed by indefinite Ponatinib. Results: 64 pts have been treated, 10 of whom had received prior treatment with another regimen (8 in CR, 2 not in CR). Median age...

  • life after Ponatinib failure outcomes of chronic and accelerated phase cml patients who discontinued Ponatinib in the salvage setting
    Blood, 2016
    Co-Authors: Prajwal Boddu, Hagop M Kantarjian, Gautam Borthakur, Tapan M Kadia, Naval Daver, Farhad Ravandi, Srdan Verstovsek, Guillermo Garciamanero, Abdul Rashid Shah, Nitin Jain
    Abstract:

    INTRODUCTION: Ponatinib is a pan-tyrosine kinase inhibitor (TKI) with proven efficacy in multi-refractory CML patients (pts) who have failed other TKIs and approved in all CML stages after failure to other TKIs and for pts with T315I mutation. Despite excellent response rates, resistance or intolerance may develop in some cases. Treatment options in these pts are limited and the outcomes have not been described. METHODS: We conducted a retrospective review of the outcomes of pts with refractory chronic (CP) and accelerated (AP) phase CML who discontinued Ponatinib in the salvage setting. Pts were assessed for the cause of Ponatinib discontinuation, therapies (Rxs) received after discontinuation, response to such Rx, and survival post-Ponatinib discontinuation. RESULTS: Among 55 pts treated (32 treated in CP, 23 in AP), 36 (65 %) have discontinued Ponatinib at the time of this analysis. Nineteen pts were either lost to follow up (F/U) or died on Rx and excluded from this analysis. Of the 36 pts analyzed, 19 were in CP and 17 in AP at initiation of Ponatinib. Pts had received a median of 4 Rxs (2-6) prior to Ponatinib. Median age at discontinuation was 67 yrs (22-94). Median duration on Ponatinib Rx was 17 mo (1-61). Of 19 CP pts, 5 discontinued due to toxicity (pancreatitis = 2, stroke = 1, headache = 1, thrombocytopenia = 1), 13 for lack of response, 1 per pt choice. At discontinuation, 14 were still in CP [complete cytogenetic response (CCyR) = 3, no/minor CyR (NR/mCyR) = 10, major molecular response (MMR) = 1]; 3 had progressed to AP, and 2 to blast phase (BP). Subsequent therapy for those still in CP included stem cell transplant (SCT) = 4, supportive care only (NT) = 3, dasatinib = 2, omacetaxine = 2, and bosutinib + decitabine (DAC), nilotinib, and imatinib (1 each); the 3 pts that progressed to AP received dasatinib + DAC, low-dose Ara-C (LDAC), and NT = 1 each, respectively; and BP pts received Hyper - CVAD + dasatinib followed by SCT = 1, Ponatinib + LDAC = 1. Of the 3 CP pts in CCyR, 1 died from sepsis 1 mo after discontinuing Ponatinib due to thrombocytopenia; 1 pt received SCT and died in MMR 11 mo post SCT; 1 developed 7q- /Ph- on Ponatinib and received SCT (MMR at 47 mo F/U). The CP pt in MMR discontinued Ponatinib after a stroke and lost MMR 38 mo later (still in CCyR off Rx). Two CP pts improved to CCyR after SCT (1 died in 8 mos; 1 in MMR at 25 mo). Thirteen pts (CP 9, AP 3, BP 2; all non-SCT Rx) did not improve their responses post Ponatinib (remained in NR/mCyR). The Median survival (OS) post Ponatinib discontinuation of the 19 CP pts was 26 mo [Fig 1]. Twelve pts have died: 5 disease related (CP 2, BP 2, AP 1), 4 cause unknown (CP 3, AP 1), 3 from sepsis (CP 2, AP 1). Of 17 AP pts who discontinued, 15 stopped due to poor response and 2 for toxicity (stroke = 1, nausea = 1). At discontinuation, 14 were still in AP [NR/mCyR = 13, partial CyR (PCyR) = 1], 3 had progressed to BP. Subsequent therapy included NT = 5, dasatinib = 4, dasatinib + DAC = 2, SCT = 2, hydroxyurea = 1 for those still in AP, and SCT = 1, BIDFA = 1, mitoxantrone + etoposide + Ponatinib = 1 for those in BP. The pt with PCyR at discontinuation died 3 mos after discontinuation of heart failure. Three pts (AP = 2, BP = 1) received SCT: 1 BP pt achieved MMR but died 12 mos post SCT of unknown cause; 1 AP pt maintains MMR 63 mos after SCT; the other AP pt did not respond and relapsed in AP, then received Rx with dasatinib + DAC and died of progressive disease 5 mos later. The remaining 14 pts (AP 12, BP 2; all non-SCT Rx) did not improve their responses post Ponatinib (remained in NR/mCyR). The OS post Ponatinib discontinuation (17 AP) was 9 mo [Fig 1]. Twelve pts have died: sepsis 3 (AP 3); progression 4 (AP 3, BP1), unidentified 5 (BP 1, AP 4); other 1 (BP 1). The OS for all 36 pts was 16 mos [Fig 2]; OS by stage at discontinuation was 31mo in CP, 9 mo in AP, 13 mo in BP [Fig 3]. The 12-mo survival probabilities for individual post-discontinuation Rx cohorts were: TKI 74%, SCT 56%, supportive 30%, other 50%. The OS for pts who stopped Ponatinib because of toxicity vs resistance was 60 mo and 11 mo respectively. CONCLUSIONS: Long term outcomes of pts with Ponatinib failure are poor with estimated 1-year OS and EFS rates of 54% and 40% respectively. Lack of response to Ponatinib, after failing other TKIs, predicts a considerable risk for subsequent Rx failure. New Rx options are required for this small subset of patients. Disclosures Kantarjian: Amgen: Research Funding; ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Daver: Otsuka: Consultancy, Honoraria; Sunesis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Karyopharm: Honoraria, Research Funding; Kiromic: Research Funding; BMS: Research Funding; Ariad: Research Funding. Kadia: BMS: Research Funding; Novartis: Honoraria. Ravandi: BMS: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Jain: Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Infinity: Research Funding; BMS: Research Funding; Servier: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Novartis: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Novimmune: Consultancy, Honoraria; Seattle Genetics: Research Funding; Celgene: Research Funding. Burger: Gilead: Research Funding; Portola: Consultancy; Roche: Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Research Funding. Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Cortes: ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

  • a meta analysis and meta regression of the efficacy of front line treatment combinations with Ponatinib versus 1st and 2nd generation tyrosine kinase inhibitors for ph acute lymphoblastic leukemia
    Blood, 2016
    Co-Authors: Elias Jabbour, Maral Dersarkissian, Nora Mccormick, Wendy Y Cheng, Ariadne Souroutzidis, Hui Huang, Lisa J. Mcgarry, Hagop M Kantarjian
    Abstract:

    Background: The current standard induction therapy for de novo Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is a tyrosine kinase inhibitor (TKI) in combination with chemotherapy or corticosteroids. Three generations of TKIs are currently available for the treatment of Ph+ ALL. Ponatinib, a third generation multi-targeted TKI, is a more potent inhibitor of BCR/ABL than previous generations. It also is effective in cases where there is a threonine-to-isoleucine substitution at position 315 (T315I mutation), which confers resistance to all first- and second-generation TKIs (i.e., imatinib, dasatinib, and nilotinib). However, evidence on the comparative effectiveness of front-line combination therapy with Ponatinib relative to other TKIs in de novo Ph+ ALL has not been well-established. Aims: The purpose of this study is to evaluate the effectiveness, as measured by complete molecular response (CMR) and 2- and 3-year overall survival (OS), of front-line treatment combinations with Ponatinib versus first- and second-generation TKIs in de novo Ph+ ALL. Methods: Twenty-six studies of front-line Ph+ ALL treatment with TKI in combination with chemotherapy or corticosteroids (18 studies of imatinib, 5 of dasatinib, 2 of nilotinib, and 1 of Ponatinib) were identified from published targeted literature reviews and recently published trials. These consisted of 25 phase 2 through 4 trials and 1 retrospective analysis. Study arms in which patients received chemotherapy or corticosteroids only, a single TKI agent, or in which they received autologous stem cell transplant exclusively were excluded. Data on aggregated patient characteristics were extracted and summarized using the median (range). The proportions of patients achieving CMR (following induction or consolidation therapy) and 2- and 3-year OS were also extracted from all study arms and summarized by TKI group (Ponatinib versus all other first and second generation TKIs) using pooled estimates with 95% confidence intervals (CIs) from a random-effects meta-analysis. A binomial distribution was assumed to calculate the 95% CIs for the Ponatinib trial. Multivariate logistic meta-regressions were conducted to examine the association between each TKI treatment group and CMR rates, 2-year OS, and 3-year OS, separately, adjusting for age and gender. Results: A total of 32 TKI treatment arms were included in the analysis. The median (range) of age across trial arms was 46 years (36-69 years) and proportion of male patients was 53% (42-67%). The pooled proportion of patients achieving CMR with Ponatinib was higher than that with first and second generation TKIs (79% versus 34%). The pooled 2- and 3-year OS with Ponatinib were also higher than those with other TKIs (2-year: 83% versus 58%; 3-year: 79% versus 50%). Relative to other TKIs, Ponatinib was associated with a statistically significant 6.09-fold increase in the odds of achieving CMR (N=25) [odds ratio=6.09 (95% CI: 1.16-31.90), p=0.034]. While Ponatinib was not significantly associated with an increase in the odds of 2-year OS (N=27) [odds ratio=3.70 (95% CI: 0.93-14.73), p=0.062], it was associated with a statistically significant 4.49-fold increase in the odds of 3-year OS (N=19) [odds ratio=4.49 (95% CI: 1.00-20.13), p=0.050] compared to earlier generation TKIs. Conclusion: Frontline treatment with Ponatinib in combination with chemotherapy or corticosteroids was associated with significantly better odds of CMR and 3-year OS in patients newly diagnosed with Ph+ ALL than combination therapy with earlier generations of TKIs. In particular, Ponatinib was associated with a 6-fold increase in CMR, the most important factor in predicting long-term survival outcomes. The improved efficacy of Ponatinib in Ph+ ALL may be particularly important for patients who are ineligible to undergo stem cell transplantation due to lack of suitably matched donors, advanced age, or significant comorbidities. In such cases, combination therapy with TKI may be a suitable alternative. Though the number of studies included was small and few covariates could be used to adjust for heterogeneity across trials, the results suggest that Ponatinib in combination with chemotherapy may represent an effective front-line treatment option for patients with Ph+ ALL. Prospective head-to-head clinical trials are needed to confirm these results. Sponsor: ARIAD Pharmaceuticals, Inc. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. DerSarkissian: ARIAD: Research Funding. Duh: Allergan: Consultancy; Abbvie: Consultancy; Novartis: Research Funding; GSK: Research Funding; Bayer: Research Funding; Janssen: Research Funding; Eisai: Research Funding; Pfizer: Research Funding; Medtronic: Research Funding; Takeda: Research Funding; Novo Nordisk: Research Funding; Sanofi: Research Funding; Ariad: Research Funding. McCormick: ARIAD: Research Funding. Cheng: ARIAD: Research Funding. McGarry: ARIAD: Employment, Equity Ownership. Souroutzidis: ARIAD: Research Funding. Huang: ARIAD: Employment, Equity Ownership. Kantarjian: Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding.

  • outcomes of patients with chronic phase cml who discontinued Ponatinib in the frontline setting
    Blood, 2015
    Co-Authors: Preetesh Jain, Hagop M Kantarjian, Elias Jabbour, Zeev Estrov, Gautam Borthakur, Naveen Pemmaraju, Tapan M Kadia, Naval Daver, Farhad Ravandi, Srdan Verstovsek
    Abstract:

    Background: Ponatinib is a novel TKI efficacious in relapsed refractory patients (pts) with CML and in those with T315I mutation. Despite the achievement of deep early responses in most pts observed in the frontline setting, the concern for arterio-thrombotic events led to the discontinuation (DC) of Ponatinib frontline clinical trial. In this study, we have assessed the outcomes after DC of Ponatinib of pts in a clinical trial of frontline Ponatinib in CML-CP. Methods: Fifty one pts with CML-CP were treated with frontline Ponatinib in a single-arm, clinical trial between May 2012 and September 2013. Initial dose of Ponatinib was 45 mg orally daily in 43 pts and, after amendment, 30 mg in 8 pts. All pts DC Ponatinib therapy after June 2014 and were switched to another TKI. Patients were assessed for cause of DC, treatment received after Ponatinib DC, response achieved/maintained on subsequent TKI, adverse events (AE) and survival after Ponatinib DC. Survival was calculated from the time of Ponatinib DC to the time of last follow up. Results: All 51 patients DC Ponatinib: 38 per FDA recommendation and 13 due to AE. Median duration of Ponatinib therapy was 13.2 months (range-2.1-25.4). At the time of DC, 47/51 (92%) pts were in complete cytogenetic response (CCyR) and 4 (8%) in partial cytogenetic response (PCyR); 1 pt DC before 3-mo evaluation. Forty (78%) pts were in MMR and 26 (51%) in molecular response 4.5-log (MR4.5). Thirty-six (70%) pts were switched to dasatinib, 7 (14%) to imatinib, and 4 (8%) each to nilotinib and bosutinib. After switching to another TKI, with a median of 13 months (range, 0.2 to 26.3) of follow-up, 2 pts have lost their cytogenetic response (both PCyR on Ponatinib), 1 pt improved from PCyR to CCyR and one maintained PCyR; all 47 (92%) pts with CCyR on Ponatinib maintained this response. Molecular responses improved in some pts: 6 improved from no MMR to MMR; 1 to MR4.5 (median time on Ponatinib 4 months; median time on subsequent TKI 17 months); 11 from MMR to MR4.5 (median time on Ponatinib 13 months; median time on subsequent TKI 17 months). One pt (treated with imatinib 400) lost MR4.5 to no MMR after 2 months. At last follow-up 37 pts (72%) had MR4.5 and 45 (90%) MMR. Two pts died after Ponatinib DC. One pt was treated with imatinib 400 and developed grade-3 edema and recurrent lung cancer; the second was switched to dasatinib and had recurrent progressive peripheral arterial disease (PAD). Four pts had events (2 deaths, 1 secondary MDS with -7 and 1 pt lost major CyR). Median post Ponatinib survival (Figure-1) and median post Ponatinib event free survival (not shown) was not reached (1-year OS 98% and EFS 95%). Forty five pts continued on their first post-Ponatinib TKIs, 5 required 2 post-Ponatinib TKI and 1 pt received 3 different TKIs after DC. The most common cause for post-Ponatinib TKI switch was toxicity (n=6). Of the 36 pts switched to dasatinib, 5 discontinued: 4 due to pleural effusion and 1 with acute renal failure. 29/36 pts (81%) were in MMR before switch and all maintained MMR; 4 pts achieved MMR after switch to dasatinib. Four pts developed grade 3-4 non hematological vascular AEs (3 among pts with such events while on Ponatinib and 1 new vascular event within 3 months of Ponatinib DC). Of the 4 pts switched to nilotinib, 1 DC within 3 months due to grade-3 pancreatitis and also developed grade-1 pulmonary hypertension with 1 month of discontinuing Ponatinib. This pt was then switched to bosutinib. The other 3 pts maintained MMR and had no vascular events. Of the 4 pts switched to bosutinib, one developed MDS, one was switched back to Ponatinib off protocol (patient's choice), 1 lost cytogenetic response and one DC therapy after 1 month and maintains MR4.5 (this pt had TIA while on Ponatinib, developed cerebral infarct within 1 month post Ponatinib). Seven pts switched to imatinib. One developed a new PAD within 3 months of Ponatinib DC (history of MI while on Ponatinib). The other 6 pts maintained MMR on imatinib. Overall, 15 pts who had aggravated hypertension on Ponatinib were under control after DC of Ponatinib. Conclusion: Treatment with 2nd generation TKIs and imatinib was effective and safe in pts who DC Ponatinib, and most pts were able to maintain/improve the responses achieved on Ponatinib. Ponatinib-associated hypertension was usually reversible after DC and most vascular events with subsequent TKIs occurred in patients with prior such events while on Ponatinib. ![Figure 1.][1] Figure 1. Post Ponatinib survival in patients Disclosures Jabbour: pfizer: Research Funding; ariad: Research Funding; teva: Consultancy; teva: Research Funding; pfizer: Consultancy; bms: Consultancy; ariad: Consultancy. Estrov: incyte: Consultancy, Research Funding. Pemmaraju: Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes: Pfizer: Consultancy, Research Funding; BerGenBio AS: Research Funding; Novartis: Consultancy, Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. [1]: pending:yes

Farhad Ravandi - One of the best experts on this subject based on the ideXlab platform.

  • efficacy of Ponatinib versus earlier generation tyrosine kinase inhibitors for front line treatment of newly diagnosed philadelphia positive acute lymphoblastic leukemia
    Clinical Lymphoma Myeloma & Leukemia, 2018
    Co-Authors: Elias Jabbour, Farhad Ravandi, Susan Obrien, Maral Dersarkissian, Nora Mccormick, Wendy Y Cheng, Lisa Mcgarry, Ariadne Souroutzidis, Hui Huang, Hagop M Kantarjian
    Abstract:

    Abstract Introduction Complete molecular response (CMR) and 2- and 3-year overall survival (OS) were compared for patients with newly diagnosed Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) who had undergone front-line combination chemotherapy plus Ponatinib versus combination therapy plus earlier generation tyrosine kinase inhibitors (TKIs; imatinib, dasatinib, and nilotinib). Patients and Methods We identified 26 Ph + ALL studies: 25 of earlier generation TKIs and 1 of Ponatinib. The outcomes from studies of combination chemotherapy plus earlier generation TKIs were summarized using pooled estimates with 95% confidence intervals (CIs) from a random-effects meta-analysis. A binomial distribution was assumed to calculate the 95% CIs for the results from the single-arm combination chemotherapy plus Ponatinib trial. Adjusted logistic meta-regression analyses were used to compare the outcomes between the TKI groups. Results The percentage of patients achieving a CMR was greater with combination chemotherapy plus Ponatinib (79%) than the pooled percentage of patients achieving a CMR with combination chemotherapy plus earlier generation TKIs (34%). Greater OS was observed with Ponatinib compared with the pooled OS for earlier generation TKIs (2-year, 83% vs. 58%; 3-year, 79% vs. 50%). Odds ratios for Ponatinib versus earlier generation TKIs were 6.09 (95% CI, 1.16-31.90; P  = .034) for CMR, 3.70 (95% CI, 0.93-14.73; P  = .062) for 2-year OS, and 4.49 (95% CI, 1.00-20.13; P  = .050) for 3-year OS. Conclusion Ponatinib plus chemotherapy might be associated with better outcomes than chemotherapy with earlier generation TKIs in patients with newly diagnosed Ph + ALL.

  • frontline hyper cvad plus Ponatinib for patients with philadelphia chromosome positive acute lymphoblastic leukemia updated results of a phase ii study
    Journal of Clinical Oncology, 2017
    Co-Authors: Nicholas J Short, Hagop M Kantarjian, Naveen Pemmaraju, Tapan M Kadia, Naval Daver, Farhad Ravandi, Koji Sasaki, Deborah A Thomas, Musa Yilmaz, Rebecca Garris
    Abstract:

    7013Background: The combination of chemotherapy plus a TKI is highly effective in Ph+ ALL. In this phase II study, we evaluated the safety and efficacy of HCVAD in combination with the third-generation pan-BCR-ABL inhibitor, Ponatinib. Methods: Patients (pts) with newly diagnosed Ph+ ALL received 8 cycles of HCVAD alternating with high dose MTX/Ara-C every 21 days. Ponatinib was given at 45 mg daily for the first 14 days of cycle 1. Initially Ponatinib 45 mg daily was given indefinitely beginning at cycle 2. Due to concern for vascular events, a protocol amendment was made in which, beginning in cycle 2, pts in CR received 30mg daily and pts in CMR received 15mg daily. Rituximab and IT chemotherapy were given with the first 4 courses. After 8 cycles of HCVAD, pts in CR received maintenance with Ponatinib, vincristine and prednisone for 2 years followed by indefinite Ponatinib. Results: 64 pts have been treated, 10 of whom had received prior treatment with another regimen (8 in CR, 2 not in CR). Median age...

  • life after Ponatinib failure outcomes of chronic and accelerated phase cml patients who discontinued Ponatinib in the salvage setting
    Blood, 2016
    Co-Authors: Prajwal Boddu, Hagop M Kantarjian, Gautam Borthakur, Tapan M Kadia, Naval Daver, Farhad Ravandi, Srdan Verstovsek, Guillermo Garciamanero, Abdul Rashid Shah, Nitin Jain
    Abstract:

    INTRODUCTION: Ponatinib is a pan-tyrosine kinase inhibitor (TKI) with proven efficacy in multi-refractory CML patients (pts) who have failed other TKIs and approved in all CML stages after failure to other TKIs and for pts with T315I mutation. Despite excellent response rates, resistance or intolerance may develop in some cases. Treatment options in these pts are limited and the outcomes have not been described. METHODS: We conducted a retrospective review of the outcomes of pts with refractory chronic (CP) and accelerated (AP) phase CML who discontinued Ponatinib in the salvage setting. Pts were assessed for the cause of Ponatinib discontinuation, therapies (Rxs) received after discontinuation, response to such Rx, and survival post-Ponatinib discontinuation. RESULTS: Among 55 pts treated (32 treated in CP, 23 in AP), 36 (65 %) have discontinued Ponatinib at the time of this analysis. Nineteen pts were either lost to follow up (F/U) or died on Rx and excluded from this analysis. Of the 36 pts analyzed, 19 were in CP and 17 in AP at initiation of Ponatinib. Pts had received a median of 4 Rxs (2-6) prior to Ponatinib. Median age at discontinuation was 67 yrs (22-94). Median duration on Ponatinib Rx was 17 mo (1-61). Of 19 CP pts, 5 discontinued due to toxicity (pancreatitis = 2, stroke = 1, headache = 1, thrombocytopenia = 1), 13 for lack of response, 1 per pt choice. At discontinuation, 14 were still in CP [complete cytogenetic response (CCyR) = 3, no/minor CyR (NR/mCyR) = 10, major molecular response (MMR) = 1]; 3 had progressed to AP, and 2 to blast phase (BP). Subsequent therapy for those still in CP included stem cell transplant (SCT) = 4, supportive care only (NT) = 3, dasatinib = 2, omacetaxine = 2, and bosutinib + decitabine (DAC), nilotinib, and imatinib (1 each); the 3 pts that progressed to AP received dasatinib + DAC, low-dose Ara-C (LDAC), and NT = 1 each, respectively; and BP pts received Hyper - CVAD + dasatinib followed by SCT = 1, Ponatinib + LDAC = 1. Of the 3 CP pts in CCyR, 1 died from sepsis 1 mo after discontinuing Ponatinib due to thrombocytopenia; 1 pt received SCT and died in MMR 11 mo post SCT; 1 developed 7q- /Ph- on Ponatinib and received SCT (MMR at 47 mo F/U). The CP pt in MMR discontinued Ponatinib after a stroke and lost MMR 38 mo later (still in CCyR off Rx). Two CP pts improved to CCyR after SCT (1 died in 8 mos; 1 in MMR at 25 mo). Thirteen pts (CP 9, AP 3, BP 2; all non-SCT Rx) did not improve their responses post Ponatinib (remained in NR/mCyR). The Median survival (OS) post Ponatinib discontinuation of the 19 CP pts was 26 mo [Fig 1]. Twelve pts have died: 5 disease related (CP 2, BP 2, AP 1), 4 cause unknown (CP 3, AP 1), 3 from sepsis (CP 2, AP 1). Of 17 AP pts who discontinued, 15 stopped due to poor response and 2 for toxicity (stroke = 1, nausea = 1). At discontinuation, 14 were still in AP [NR/mCyR = 13, partial CyR (PCyR) = 1], 3 had progressed to BP. Subsequent therapy included NT = 5, dasatinib = 4, dasatinib + DAC = 2, SCT = 2, hydroxyurea = 1 for those still in AP, and SCT = 1, BIDFA = 1, mitoxantrone + etoposide + Ponatinib = 1 for those in BP. The pt with PCyR at discontinuation died 3 mos after discontinuation of heart failure. Three pts (AP = 2, BP = 1) received SCT: 1 BP pt achieved MMR but died 12 mos post SCT of unknown cause; 1 AP pt maintains MMR 63 mos after SCT; the other AP pt did not respond and relapsed in AP, then received Rx with dasatinib + DAC and died of progressive disease 5 mos later. The remaining 14 pts (AP 12, BP 2; all non-SCT Rx) did not improve their responses post Ponatinib (remained in NR/mCyR). The OS post Ponatinib discontinuation (17 AP) was 9 mo [Fig 1]. Twelve pts have died: sepsis 3 (AP 3); progression 4 (AP 3, BP1), unidentified 5 (BP 1, AP 4); other 1 (BP 1). The OS for all 36 pts was 16 mos [Fig 2]; OS by stage at discontinuation was 31mo in CP, 9 mo in AP, 13 mo in BP [Fig 3]. The 12-mo survival probabilities for individual post-discontinuation Rx cohorts were: TKI 74%, SCT 56%, supportive 30%, other 50%. The OS for pts who stopped Ponatinib because of toxicity vs resistance was 60 mo and 11 mo respectively. CONCLUSIONS: Long term outcomes of pts with Ponatinib failure are poor with estimated 1-year OS and EFS rates of 54% and 40% respectively. Lack of response to Ponatinib, after failing other TKIs, predicts a considerable risk for subsequent Rx failure. New Rx options are required for this small subset of patients. Disclosures Kantarjian: Amgen: Research Funding; ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Daver: Otsuka: Consultancy, Honoraria; Sunesis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Karyopharm: Honoraria, Research Funding; Kiromic: Research Funding; BMS: Research Funding; Ariad: Research Funding. Kadia: BMS: Research Funding; Novartis: Honoraria. Ravandi: BMS: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Jain: Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Infinity: Research Funding; BMS: Research Funding; Servier: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Novartis: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Novimmune: Consultancy, Honoraria; Seattle Genetics: Research Funding; Celgene: Research Funding. Burger: Gilead: Research Funding; Portola: Consultancy; Roche: Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Research Funding. Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Cortes: ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

  • hyper cvad plus Ponatinib versus hyper cvad plus dasatinib as frontline therapy for patients with philadelphia chromosome positive acute lymphoblastic leukemia a propensity score analysis
    Cancer, 2016
    Co-Authors: Koji Sasaki, Elias Jabbour, Tapan M Kadia, Naval Daver, Farhad Ravandi, Deborah A Thomas, Nicholas J Short, Guillermo Garciamanero, Marina Konopleva, Nitin Jain
    Abstract:

    BACKGROUND The clinical efficacy of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HCVAD) plus Ponatinib has not been compared with that of HCVAD plus dasatinib in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in a randomized clinical trial. METHODS The authors analyzed 110 patients with newly diagnosed Ph+ ALL who were enrolled in 2 consecutive, prospective, phase 2 clinical trials of frontline HCVAD with either dasatinib (63 patients) or Ponatinib (47 patients). Propensity score analysis with 1:1 matching with the nearest neighbor matching method and inverse probability of treatment weighting (IPTW) analysis based on the propensity scores were performed to assess response rates, event-free survival (EFS), and overall survival (OS) between the cohorts. RESULTS Propensity score matching identified 41 patients in each cohort. With propensity score matching, the 3-year EFS rates for patients treated with HCVAD plus Ponatinib and HCVAD plus dasatinib were 69% and 46%, respectively (P =.04), and the 3-year OS rates were 83% and 56%, respectively (P =.03). IPTW analysis using prematching cohorts demonstrated that patients treated with HCVAD plus Ponatinib had significantly higher rates of minimal residual disease negativity by flow cytometry on day 21, complete cytogenetic response at complete response, major molecular response at complete response and at 3 months, and complete molecular response at 3 months. IPTW confirmed that treatment with HCVAD plus Ponatinib was associated with longer EFS (P =.003) and OS (P =.001) compared with treatment with HCVAD plus dasatinib. CONCLUSIONS The clinical outcome of patients treated with HCVAD plus Ponatinib appears to be superior to that of patients treated with HCVAD plus dasatinib among individuals with Ph+ ALL. Cancer 2016;122:3650-6. © 2016 American Cancer Society.

  • outcomes of patients with chronic phase cml who discontinued Ponatinib in the frontline setting
    Blood, 2015
    Co-Authors: Preetesh Jain, Hagop M Kantarjian, Elias Jabbour, Zeev Estrov, Gautam Borthakur, Naveen Pemmaraju, Tapan M Kadia, Naval Daver, Farhad Ravandi, Srdan Verstovsek
    Abstract:

    Background: Ponatinib is a novel TKI efficacious in relapsed refractory patients (pts) with CML and in those with T315I mutation. Despite the achievement of deep early responses in most pts observed in the frontline setting, the concern for arterio-thrombotic events led to the discontinuation (DC) of Ponatinib frontline clinical trial. In this study, we have assessed the outcomes after DC of Ponatinib of pts in a clinical trial of frontline Ponatinib in CML-CP. Methods: Fifty one pts with CML-CP were treated with frontline Ponatinib in a single-arm, clinical trial between May 2012 and September 2013. Initial dose of Ponatinib was 45 mg orally daily in 43 pts and, after amendment, 30 mg in 8 pts. All pts DC Ponatinib therapy after June 2014 and were switched to another TKI. Patients were assessed for cause of DC, treatment received after Ponatinib DC, response achieved/maintained on subsequent TKI, adverse events (AE) and survival after Ponatinib DC. Survival was calculated from the time of Ponatinib DC to the time of last follow up. Results: All 51 patients DC Ponatinib: 38 per FDA recommendation and 13 due to AE. Median duration of Ponatinib therapy was 13.2 months (range-2.1-25.4). At the time of DC, 47/51 (92%) pts were in complete cytogenetic response (CCyR) and 4 (8%) in partial cytogenetic response (PCyR); 1 pt DC before 3-mo evaluation. Forty (78%) pts were in MMR and 26 (51%) in molecular response 4.5-log (MR4.5). Thirty-six (70%) pts were switched to dasatinib, 7 (14%) to imatinib, and 4 (8%) each to nilotinib and bosutinib. After switching to another TKI, with a median of 13 months (range, 0.2 to 26.3) of follow-up, 2 pts have lost their cytogenetic response (both PCyR on Ponatinib), 1 pt improved from PCyR to CCyR and one maintained PCyR; all 47 (92%) pts with CCyR on Ponatinib maintained this response. Molecular responses improved in some pts: 6 improved from no MMR to MMR; 1 to MR4.5 (median time on Ponatinib 4 months; median time on subsequent TKI 17 months); 11 from MMR to MR4.5 (median time on Ponatinib 13 months; median time on subsequent TKI 17 months). One pt (treated with imatinib 400) lost MR4.5 to no MMR after 2 months. At last follow-up 37 pts (72%) had MR4.5 and 45 (90%) MMR. Two pts died after Ponatinib DC. One pt was treated with imatinib 400 and developed grade-3 edema and recurrent lung cancer; the second was switched to dasatinib and had recurrent progressive peripheral arterial disease (PAD). Four pts had events (2 deaths, 1 secondary MDS with -7 and 1 pt lost major CyR). Median post Ponatinib survival (Figure-1) and median post Ponatinib event free survival (not shown) was not reached (1-year OS 98% and EFS 95%). Forty five pts continued on their first post-Ponatinib TKIs, 5 required 2 post-Ponatinib TKI and 1 pt received 3 different TKIs after DC. The most common cause for post-Ponatinib TKI switch was toxicity (n=6). Of the 36 pts switched to dasatinib, 5 discontinued: 4 due to pleural effusion and 1 with acute renal failure. 29/36 pts (81%) were in MMR before switch and all maintained MMR; 4 pts achieved MMR after switch to dasatinib. Four pts developed grade 3-4 non hematological vascular AEs (3 among pts with such events while on Ponatinib and 1 new vascular event within 3 months of Ponatinib DC). Of the 4 pts switched to nilotinib, 1 DC within 3 months due to grade-3 pancreatitis and also developed grade-1 pulmonary hypertension with 1 month of discontinuing Ponatinib. This pt was then switched to bosutinib. The other 3 pts maintained MMR and had no vascular events. Of the 4 pts switched to bosutinib, one developed MDS, one was switched back to Ponatinib off protocol (patient's choice), 1 lost cytogenetic response and one DC therapy after 1 month and maintains MR4.5 (this pt had TIA while on Ponatinib, developed cerebral infarct within 1 month post Ponatinib). Seven pts switched to imatinib. One developed a new PAD within 3 months of Ponatinib DC (history of MI while on Ponatinib). The other 6 pts maintained MMR on imatinib. Overall, 15 pts who had aggravated hypertension on Ponatinib were under control after DC of Ponatinib. Conclusion: Treatment with 2nd generation TKIs and imatinib was effective and safe in pts who DC Ponatinib, and most pts were able to maintain/improve the responses achieved on Ponatinib. Ponatinib-associated hypertension was usually reversible after DC and most vascular events with subsequent TKIs occurred in patients with prior such events while on Ponatinib. ![Figure 1.][1] Figure 1. Post Ponatinib survival in patients Disclosures Jabbour: pfizer: Research Funding; ariad: Research Funding; teva: Consultancy; teva: Research Funding; pfizer: Consultancy; bms: Consultancy; ariad: Consultancy. Estrov: incyte: Consultancy, Research Funding. Pemmaraju: Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes: Pfizer: Consultancy, Research Funding; BerGenBio AS: Research Funding; Novartis: Consultancy, Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. [1]: pending:yes

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  • efficacy of Ponatinib versus earlier generation tyrosine kinase inhibitors for front line treatment of newly diagnosed philadelphia positive acute lymphoblastic leukemia
    Clinical Lymphoma Myeloma & Leukemia, 2018
    Co-Authors: Elias Jabbour, Farhad Ravandi, Susan Obrien, Maral Dersarkissian, Nora Mccormick, Wendy Y Cheng, Lisa Mcgarry, Ariadne Souroutzidis, Hui Huang, Hagop M Kantarjian
    Abstract:

    Abstract Introduction Complete molecular response (CMR) and 2- and 3-year overall survival (OS) were compared for patients with newly diagnosed Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) who had undergone front-line combination chemotherapy plus Ponatinib versus combination therapy plus earlier generation tyrosine kinase inhibitors (TKIs; imatinib, dasatinib, and nilotinib). Patients and Methods We identified 26 Ph + ALL studies: 25 of earlier generation TKIs and 1 of Ponatinib. The outcomes from studies of combination chemotherapy plus earlier generation TKIs were summarized using pooled estimates with 95% confidence intervals (CIs) from a random-effects meta-analysis. A binomial distribution was assumed to calculate the 95% CIs for the results from the single-arm combination chemotherapy plus Ponatinib trial. Adjusted logistic meta-regression analyses were used to compare the outcomes between the TKI groups. Results The percentage of patients achieving a CMR was greater with combination chemotherapy plus Ponatinib (79%) than the pooled percentage of patients achieving a CMR with combination chemotherapy plus earlier generation TKIs (34%). Greater OS was observed with Ponatinib compared with the pooled OS for earlier generation TKIs (2-year, 83% vs. 58%; 3-year, 79% vs. 50%). Odds ratios for Ponatinib versus earlier generation TKIs were 6.09 (95% CI, 1.16-31.90; P  = .034) for CMR, 3.70 (95% CI, 0.93-14.73; P  = .062) for 2-year OS, and 4.49 (95% CI, 1.00-20.13; P  = .050) for 3-year OS. Conclusion Ponatinib plus chemotherapy might be associated with better outcomes than chemotherapy with earlier generation TKIs in patients with newly diagnosed Ph + ALL.

  • a meta analysis and meta regression of the efficacy of front line treatment combinations with Ponatinib versus 1st and 2nd generation tyrosine kinase inhibitors for ph acute lymphoblastic leukemia
    Blood, 2016
    Co-Authors: Elias Jabbour, Maral Dersarkissian, Nora Mccormick, Wendy Y Cheng, Ariadne Souroutzidis, Hui Huang, Lisa J. Mcgarry, Hagop M Kantarjian
    Abstract:

    Background: The current standard induction therapy for de novo Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is a tyrosine kinase inhibitor (TKI) in combination with chemotherapy or corticosteroids. Three generations of TKIs are currently available for the treatment of Ph+ ALL. Ponatinib, a third generation multi-targeted TKI, is a more potent inhibitor of BCR/ABL than previous generations. It also is effective in cases where there is a threonine-to-isoleucine substitution at position 315 (T315I mutation), which confers resistance to all first- and second-generation TKIs (i.e., imatinib, dasatinib, and nilotinib). However, evidence on the comparative effectiveness of front-line combination therapy with Ponatinib relative to other TKIs in de novo Ph+ ALL has not been well-established. Aims: The purpose of this study is to evaluate the effectiveness, as measured by complete molecular response (CMR) and 2- and 3-year overall survival (OS), of front-line treatment combinations with Ponatinib versus first- and second-generation TKIs in de novo Ph+ ALL. Methods: Twenty-six studies of front-line Ph+ ALL treatment with TKI in combination with chemotherapy or corticosteroids (18 studies of imatinib, 5 of dasatinib, 2 of nilotinib, and 1 of Ponatinib) were identified from published targeted literature reviews and recently published trials. These consisted of 25 phase 2 through 4 trials and 1 retrospective analysis. Study arms in which patients received chemotherapy or corticosteroids only, a single TKI agent, or in which they received autologous stem cell transplant exclusively were excluded. Data on aggregated patient characteristics were extracted and summarized using the median (range). The proportions of patients achieving CMR (following induction or consolidation therapy) and 2- and 3-year OS were also extracted from all study arms and summarized by TKI group (Ponatinib versus all other first and second generation TKIs) using pooled estimates with 95% confidence intervals (CIs) from a random-effects meta-analysis. A binomial distribution was assumed to calculate the 95% CIs for the Ponatinib trial. Multivariate logistic meta-regressions were conducted to examine the association between each TKI treatment group and CMR rates, 2-year OS, and 3-year OS, separately, adjusting for age and gender. Results: A total of 32 TKI treatment arms were included in the analysis. The median (range) of age across trial arms was 46 years (36-69 years) and proportion of male patients was 53% (42-67%). The pooled proportion of patients achieving CMR with Ponatinib was higher than that with first and second generation TKIs (79% versus 34%). The pooled 2- and 3-year OS with Ponatinib were also higher than those with other TKIs (2-year: 83% versus 58%; 3-year: 79% versus 50%). Relative to other TKIs, Ponatinib was associated with a statistically significant 6.09-fold increase in the odds of achieving CMR (N=25) [odds ratio=6.09 (95% CI: 1.16-31.90), p=0.034]. While Ponatinib was not significantly associated with an increase in the odds of 2-year OS (N=27) [odds ratio=3.70 (95% CI: 0.93-14.73), p=0.062], it was associated with a statistically significant 4.49-fold increase in the odds of 3-year OS (N=19) [odds ratio=4.49 (95% CI: 1.00-20.13), p=0.050] compared to earlier generation TKIs. Conclusion: Frontline treatment with Ponatinib in combination with chemotherapy or corticosteroids was associated with significantly better odds of CMR and 3-year OS in patients newly diagnosed with Ph+ ALL than combination therapy with earlier generations of TKIs. In particular, Ponatinib was associated with a 6-fold increase in CMR, the most important factor in predicting long-term survival outcomes. The improved efficacy of Ponatinib in Ph+ ALL may be particularly important for patients who are ineligible to undergo stem cell transplantation due to lack of suitably matched donors, advanced age, or significant comorbidities. In such cases, combination therapy with TKI may be a suitable alternative. Though the number of studies included was small and few covariates could be used to adjust for heterogeneity across trials, the results suggest that Ponatinib in combination with chemotherapy may represent an effective front-line treatment option for patients with Ph+ ALL. Prospective head-to-head clinical trials are needed to confirm these results. Sponsor: ARIAD Pharmaceuticals, Inc. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. DerSarkissian: ARIAD: Research Funding. Duh: Allergan: Consultancy; Abbvie: Consultancy; Novartis: Research Funding; GSK: Research Funding; Bayer: Research Funding; Janssen: Research Funding; Eisai: Research Funding; Pfizer: Research Funding; Medtronic: Research Funding; Takeda: Research Funding; Novo Nordisk: Research Funding; Sanofi: Research Funding; Ariad: Research Funding. McCormick: ARIAD: Research Funding. Cheng: ARIAD: Research Funding. McGarry: ARIAD: Employment, Equity Ownership. Souroutzidis: ARIAD: Research Funding. Huang: ARIAD: Employment, Equity Ownership. Kantarjian: Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding.

  • hyper cvad plus Ponatinib versus hyper cvad plus dasatinib as frontline therapy for patients with philadelphia chromosome positive acute lymphoblastic leukemia a propensity score analysis
    Cancer, 2016
    Co-Authors: Koji Sasaki, Elias Jabbour, Tapan M Kadia, Naval Daver, Farhad Ravandi, Deborah A Thomas, Nicholas J Short, Guillermo Garciamanero, Marina Konopleva, Nitin Jain
    Abstract:

    BACKGROUND The clinical efficacy of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HCVAD) plus Ponatinib has not been compared with that of HCVAD plus dasatinib in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in a randomized clinical trial. METHODS The authors analyzed 110 patients with newly diagnosed Ph+ ALL who were enrolled in 2 consecutive, prospective, phase 2 clinical trials of frontline HCVAD with either dasatinib (63 patients) or Ponatinib (47 patients). Propensity score analysis with 1:1 matching with the nearest neighbor matching method and inverse probability of treatment weighting (IPTW) analysis based on the propensity scores were performed to assess response rates, event-free survival (EFS), and overall survival (OS) between the cohorts. RESULTS Propensity score matching identified 41 patients in each cohort. With propensity score matching, the 3-year EFS rates for patients treated with HCVAD plus Ponatinib and HCVAD plus dasatinib were 69% and 46%, respectively (P =.04), and the 3-year OS rates were 83% and 56%, respectively (P =.03). IPTW analysis using prematching cohorts demonstrated that patients treated with HCVAD plus Ponatinib had significantly higher rates of minimal residual disease negativity by flow cytometry on day 21, complete cytogenetic response at complete response, major molecular response at complete response and at 3 months, and complete molecular response at 3 months. IPTW confirmed that treatment with HCVAD plus Ponatinib was associated with longer EFS (P =.003) and OS (P =.001) compared with treatment with HCVAD plus dasatinib. CONCLUSIONS The clinical outcome of patients treated with HCVAD plus Ponatinib appears to be superior to that of patients treated with HCVAD plus dasatinib among individuals with Ph+ ALL. Cancer 2016;122:3650-6. © 2016 American Cancer Society.

  • outcomes of patients with chronic phase cml who discontinued Ponatinib in the frontline setting
    Blood, 2015
    Co-Authors: Preetesh Jain, Hagop M Kantarjian, Elias Jabbour, Zeev Estrov, Gautam Borthakur, Naveen Pemmaraju, Tapan M Kadia, Naval Daver, Farhad Ravandi, Srdan Verstovsek
    Abstract:

    Background: Ponatinib is a novel TKI efficacious in relapsed refractory patients (pts) with CML and in those with T315I mutation. Despite the achievement of deep early responses in most pts observed in the frontline setting, the concern for arterio-thrombotic events led to the discontinuation (DC) of Ponatinib frontline clinical trial. In this study, we have assessed the outcomes after DC of Ponatinib of pts in a clinical trial of frontline Ponatinib in CML-CP. Methods: Fifty one pts with CML-CP were treated with frontline Ponatinib in a single-arm, clinical trial between May 2012 and September 2013. Initial dose of Ponatinib was 45 mg orally daily in 43 pts and, after amendment, 30 mg in 8 pts. All pts DC Ponatinib therapy after June 2014 and were switched to another TKI. Patients were assessed for cause of DC, treatment received after Ponatinib DC, response achieved/maintained on subsequent TKI, adverse events (AE) and survival after Ponatinib DC. Survival was calculated from the time of Ponatinib DC to the time of last follow up. Results: All 51 patients DC Ponatinib: 38 per FDA recommendation and 13 due to AE. Median duration of Ponatinib therapy was 13.2 months (range-2.1-25.4). At the time of DC, 47/51 (92%) pts were in complete cytogenetic response (CCyR) and 4 (8%) in partial cytogenetic response (PCyR); 1 pt DC before 3-mo evaluation. Forty (78%) pts were in MMR and 26 (51%) in molecular response 4.5-log (MR4.5). Thirty-six (70%) pts were switched to dasatinib, 7 (14%) to imatinib, and 4 (8%) each to nilotinib and bosutinib. After switching to another TKI, with a median of 13 months (range, 0.2 to 26.3) of follow-up, 2 pts have lost their cytogenetic response (both PCyR on Ponatinib), 1 pt improved from PCyR to CCyR and one maintained PCyR; all 47 (92%) pts with CCyR on Ponatinib maintained this response. Molecular responses improved in some pts: 6 improved from no MMR to MMR; 1 to MR4.5 (median time on Ponatinib 4 months; median time on subsequent TKI 17 months); 11 from MMR to MR4.5 (median time on Ponatinib 13 months; median time on subsequent TKI 17 months). One pt (treated with imatinib 400) lost MR4.5 to no MMR after 2 months. At last follow-up 37 pts (72%) had MR4.5 and 45 (90%) MMR. Two pts died after Ponatinib DC. One pt was treated with imatinib 400 and developed grade-3 edema and recurrent lung cancer; the second was switched to dasatinib and had recurrent progressive peripheral arterial disease (PAD). Four pts had events (2 deaths, 1 secondary MDS with -7 and 1 pt lost major CyR). Median post Ponatinib survival (Figure-1) and median post Ponatinib event free survival (not shown) was not reached (1-year OS 98% and EFS 95%). Forty five pts continued on their first post-Ponatinib TKIs, 5 required 2 post-Ponatinib TKI and 1 pt received 3 different TKIs after DC. The most common cause for post-Ponatinib TKI switch was toxicity (n=6). Of the 36 pts switched to dasatinib, 5 discontinued: 4 due to pleural effusion and 1 with acute renal failure. 29/36 pts (81%) were in MMR before switch and all maintained MMR; 4 pts achieved MMR after switch to dasatinib. Four pts developed grade 3-4 non hematological vascular AEs (3 among pts with such events while on Ponatinib and 1 new vascular event within 3 months of Ponatinib DC). Of the 4 pts switched to nilotinib, 1 DC within 3 months due to grade-3 pancreatitis and also developed grade-1 pulmonary hypertension with 1 month of discontinuing Ponatinib. This pt was then switched to bosutinib. The other 3 pts maintained MMR and had no vascular events. Of the 4 pts switched to bosutinib, one developed MDS, one was switched back to Ponatinib off protocol (patient's choice), 1 lost cytogenetic response and one DC therapy after 1 month and maintains MR4.5 (this pt had TIA while on Ponatinib, developed cerebral infarct within 1 month post Ponatinib). Seven pts switched to imatinib. One developed a new PAD within 3 months of Ponatinib DC (history of MI while on Ponatinib). The other 6 pts maintained MMR on imatinib. Overall, 15 pts who had aggravated hypertension on Ponatinib were under control after DC of Ponatinib. Conclusion: Treatment with 2nd generation TKIs and imatinib was effective and safe in pts who DC Ponatinib, and most pts were able to maintain/improve the responses achieved on Ponatinib. Ponatinib-associated hypertension was usually reversible after DC and most vascular events with subsequent TKIs occurred in patients with prior such events while on Ponatinib. ![Figure 1.][1] Figure 1. Post Ponatinib survival in patients Disclosures Jabbour: pfizer: Research Funding; ariad: Research Funding; teva: Consultancy; teva: Research Funding; pfizer: Consultancy; bms: Consultancy; ariad: Consultancy. Estrov: incyte: Consultancy, Research Funding. Pemmaraju: Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes: Pfizer: Consultancy, Research Funding; BerGenBio AS: Research Funding; Novartis: Consultancy, Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. [1]: pending:yes

  • phase ii trial of Ponatinib in patients with chronic myeloid leukemia resistant to one previous tyrosine kinase inhibitor
    Haematologica, 2015
    Co-Authors: David Sanford, Hagop M Kantarjian, Elias Jabbour, Jeffrey Skinner, Jorge E Cortes
    Abstract:

    Ponatinib is a tyrosine kinase inhibitor (TKI) designed to overcome resistance-inducing mutations, including the T315I mutation, in the ABL kinase domain. Initial clinical trials of Ponatinib reported major cytogenetic response (MCyR) rates over 60% in heavily treated patients with chronic myeloid

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  • overall survival with Ponatinib versus allogeneic stem cell transplantation in philadelphia chromosome positive leukemias with the t315i mutation
    Cancer, 2017
    Co-Authors: Franck E Nicolini, Charles Chuah, Timothy P Hughes, Michael J Mauro, Javier Pinillaibarz, Jane F Apperley, Grzegorz W Basak, Eduardo Olavarria, Dietger Niederwieser, Andreas Hochhaus
    Abstract:

    BACKGROUND Effective treatment options for patients with chronic myeloid leukemia (CML) or Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) who have the threonine to isoleucine mutation at codon 315 (T315I) are few. The objective of this study was to compare overall survival (OS) between patients with CML and those with Ph+ ALL who received treatment with Ponatinib versus allogeneic stem cell transplantation (allo-SCT). METHODS A post hoc, retrospective, indirect comparison of OS among patients who received single-agent Ponatinib in the Ponatinib Ph+ ALL and CML Evaluation (PACE) trial with those who underwent allo-SCT as reported to the European Bone Marrow Transplant registry, stratified by CML disease phase and Ph+ ALL, was conducted. Kaplan-Meier survival curves and multivariate Cox proportional-hazards models were used to compare OS between intervention groups, adjusting for time from diagnosis to intervention, age, sex, and geographic region; 24-month and 48-month OS rates and median OS were reported. RESULTS After adjustment for potential confounders, 24-month and 48-month OS rates were significantly higher in patients with chronic-phase CML (CP-CML) who received Ponatinib compared with those who underwent allo-SCT (24 months: 84% vs 60.5%, respectively; P = .004; 48 months: 72.7% vs 55.8%, respectively; P = .013), with a hazard ratio (HR) of 0.37 (95% confidence interval [CI], 0.16-0.84; P = .017). In patients who had accelerated-phase CML, OS rates were not significantly different between the groups (HR, 0.90; 95% CI, 0.20-4.10; P = .889). In patients who had blast-crisis CML and those with Ph+ ALL, Ponatinib was associated with shorter OS compared with allo-SCT (blast-crisis CML: HR, 2.29 [95% CI, 1.08-4.82; P = .030]; Ph+ ALL: HR, 2.77 [95% CI, 0.73-10.56; P = .146]). CONCLUSIONS Although allo-SCT remains an important treatment option for patients with T315I-positive advanced CML and Ph+ ALL, Ponatinib represents a valuable alternative for patients with T315I-positive CP-CML. Cancer 2017;123:2875–80. © 2017 American Cancer Society.

  • impact of dose intensity of Ponatinib on selected adverse events multivariate analyses from a pooled population of clinical trial patients
    Leukemia Research, 2016
    Co-Authors: David J. Dorer, Jorge E Cortes, Michele Baccarani, Andreas Hochhaus, Moshe Talpaz, Ronald Knickerbocker, Frank G. Haluska
    Abstract:

    Abstract Ponatinib is approved for adults with refractory chronic myeloid leukemia or Philadelphia chromosome–positive acute lymphoblastic leukemia, including those with the T315I BCR-ABL1 mutation. We pooled data from 3 clinical trials (N = 671) to determine the impact of Ponatinib dose intensity on the following adverse events: arterial occlusive events (cardiovascular, cerebrovascular, and peripheral vascular events), venous thromboembolic events, cardiac failure, thrombocytopenia, neutropenia, hypertension, pancreatitis, increased lipase, increased alanine aminotransferase, increased aspartate aminotransferase, rash, arthralgia, and hypertriglyceridemia. Multivariate analyses allowed adjustment for covariates potentially related to changes in dosing or an event. Logistic regression analysis identified significant associations between dose intensity and most events after adjusting for covariates. Pancreatitis, rash, and cardiac failure had the strongest associations with dose intensity (odds ratios >2). Time-to-event analyses showed significant associations between dose intensity and risk of arterial occlusive events and each subcategory. Further, these analyses suggested that a lag exists between a change in dose and the resulting change in event risk. No significant association between dose intensity and risk of venous thromboembolic events was evident. Collectively, these findings suggest a potential causal relationship between Ponatinib dose and certain adverse events and support prospective investigations of approaches to lower average Ponatinib dose intensity.

  • the impact of Ponatinib versus allogeneic stem cell transplant sct on outcomes in patients with chronic myeloid leukemia cml or philadelphia chromosome positive acute lymphoblastic leukemia ph all with the t315i mutation
    Blood, 2015
    Co-Authors: Franck E Nicolini, Charles Chuah, Timothy P Hughes, Michael J Mauro, Javier Pinillaibarz, Jane F Apperley, Grzegorz W Basak, Eduardo Olavarria, Dietger Niederwieser, Andreas Hochhaus
    Abstract:

    Background: Allogeneic SCT is considered standard treatment for patients with advanced phase CML (accelerated phase, blast crisis), de novo Ph+ ALL, or patients in chronic phase (CP) resistant or intolerant to at least 2 tyrosine kinase inhibitors (TKI). Ponatinib is FDA and EMA approved for the treatment of CML or Ph+ ALL in patients with the BCR-ABL1 T315I mutation or for whom no other TKI therapy is indicated. In patients harboring the T315I mutation, Ponatinib currently represents a suitable alternative treatment option to allogeneic SCT. However, differences in outcomes between patients treated with Ponatinib and allogeneic SCT have not been analyzed. Objective: To compare overall survival (OS) among CML and Ph+ ALL patients with the BCR-ABL1 T315I mutation treated with Ponatinib (in PACE) versus allogeneic SCT (in the EBMT database). Methods: Data from a Phase II trial of Ponatinib (PACE trial; Cortes et al., New Engl J Med 2013; NCT01207440) and European Bone Marrow Transplant (EBMT) registry were pooled to conduct an indirect comparison of Ponatinib with allogeneic SCT. Both Ponatinib and allogeneic SCT cohorts comprised patients with the T315I mutation age 18 years or older in any phase of CML or with Ph+ ALL. All patients harbored the T315I mutation detected by Sanger sequencing, DHPLC, PCR-RFLP, or other equivalent tests. Allogeneic SCT patients in their second CP phase were excluded, and no patients in the EBMT database were treated with Ponatinib prior to receiving allogeneic SCT. The date of intervention (Ponatinib or SCT) served as the index date. Baseline demographic and clinical characteristics were compared between the two intervention groups. OS was compared between the two groups using adjusted Kaplan-Meier (KM) survival curves and multivariate Cox proportional hazards models; all comparisons were adjusted for age (as a continuous variable), gender, geographic region (Europe, Asia, and Australia vs. North America), time from CML diagnosis to intervention, and CML phase or Ph+ ALL at intervention to control confounding by these variables. Results were presented overall and stratified by phase of CML or Ph+ ALL. Results: A total of 184 (128 Ponatinib, 56 allogeneic SCT) patients were included in the analysis: 90 were in CP-CML, 26 were in accelerated phase (AP-CML), 41 were in blast phase (BP-CML), and 27 had Ph+ ALL. On average, Ponatinib patients were older than allogeneic SCT patients on the date of intervention (median age 53 vs. 45 years, p=0.006). In addition, a larger proportion of patients in the Ponatinib group were from North America than in the allogeneic SCT group (43.8% vs. 26.8%, p=0.030). Median time from diagnosis to intervention was longer for patients treated with Ponatinib compared with those treated with allogeneic SCT in CP-CML (58 vs. 32 months, p=0.029), but not significantly different in AP-CML (80 vs. 49 months, p=0.075) nor Ph+ ALL (17 vs. 10 months, p=0.212). This period was nominally shorter for the Ponatinib cohort in BP-CML (26 vs. 43 months, p=0.340). Over 93% of patients in both treatment cohorts in all disease phases reported previous use of imatinib. Adjusted median OS was significantly longer in CP-CML patients treated with Ponatinib as opposed to allogeneic SCT patients (KM median: not reached [NR] vs. 103.3 months, p=0.013), with a hazard ratio (HR) of 0.37 (95% CI: 0.16, 0.84, p=0.017). Median OS was not significantly different between the two treatment groups in patients with AP-CML (NR vs. 55.6 months, p=0.889; HR=0.90 [95% CI: 0.20, 4.10, p=0.889]). However, among patients with BP-CML, Ponatinib was associated with significantly shorter OS compared with allogeneic SCT: median 7.0 vs. 10.5 months (p=0.026), HR=2.29 (95% CI: 1.08, 4.82, p=0.030). Ph+ ALL patients treated with Ponatinib had nominally shorter median OS than allogeneic SCT (6.7 vs. 32.4 months, p=0.119; HR=2.77 [95% CI: 0.73, 10.56, p=0.136]). See Figures 1a-1d for adjusted KM survival curves. Conclusion: AllogeneicSCT remains a potential curative therapy for patients with BP-CML. However, Ponatinib was associated with significantly longer OS than allogeneic SCT in patients with CP-CML that harbor the T315I mutation and could represent a promising therapeutic alternative in this setting, although follow-up remains short to date. OS was similar between intervention groups in AP-CML and longer for allogeneic SCT patients in BP-CML and Ph+ ALL. Disclosures Nicolini:Ariad Pharmaceuticals: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Basak:MSD: Consultancy, Honoraria; Astellas: Honoraria; Sanofi: Honoraria; Pierre-Fabre: Honoraria. Kim:Pfizer: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Il-Yang: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pinilla-Ibarz:BMS: Consultancy, Speakers Bureau; Novartis: Consultancy; ARIAD: Consultancy; Pfizer: Consultancy, Speakers Bureau. Apperley:ARIAD: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Hughes:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Niederwieser:Novartis: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Mauro:Ariad: Consultancy; Pfizer: Consultancy; Novartis Pharmaceutical Corporation: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Chuah:Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Chiltern International: Honoraria. Hochhaus:Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Martinelli:Novartis: Consultancy, Speakers Bureau; MSD: Consultancy; Pfizer: Consultancy; Ariad: Consultancy; ROCHE: Consultancy; BMS: Consultancy, Speakers Bureau; AMGEN: Consultancy. DerSarkissian:ARIAD: Research Funding. Kageleiry:ARIAD: Research Funding. Yang:ARIAD: Employment. Huang:ARIAD: Employment, Equity Ownership. McGarry:ARIAD: Employment, Equity Ownership. Cortes:Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; BerGenBio AS: Research Funding; Teva: Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

  • high resolution analysis of the relationship between dose and molecular response in cp cml patients treated with Ponatinib or imatinib
    Blood, 2014
    Co-Authors: Justin R. Pritchard, Michael W. Deininger, Graeme Hodgson, Jorge E Cortes, Stephanie Lustgarten, Michele Baccarani, Francois Guilhot, Andreas Hochhaus, Timothy P Hughes, Neil P Shah
    Abstract:

    Background: Ponatinib is a potent pan-BCR-ABL tyrosine kinase inhibitor (TKI). The phase 2 PACE study demonstrated that Ponatinib is highly active in heavily pretreated CP-CML patients, 58% of whom received ≥3 prior TKIs. The phase 3 EPIC study, in which Ponatinib was compared with imatinib, was terminated early due to concerns about arterial thrombotic events observed in the Ponatinib development program, though analysis of existing data suggests that Ponatinib has improved efficacy over imatinib in newly diagnosed CP-CML patients. Fixed starting doses of Ponatinib and imatinib were used in these studies (45 mg and 400 mg once daily, respectively), but the allowance for treatment interruptions and dose reductions, coupled with multiple assessments of molecular response per patient, enables exploration of dose-response relationships. Here we describe a novel approach called BARD (BCR-ABL Response-Dose association) that allows associations between dose, based on patient daily dosing records, and efficacy, based on frequent measurement of BCR-ABL transcript levels, to be examined with high resolution. Methods: BCR-ABL levels were measured every 1-3 months in peripheral blood samples from CP-CML patients in the PACE (N=267) and EPIC studies (N=154 [Ponatinib] and 152 [imatinib]), which had median follow-ups of 27.9 and 5.1 months, respectively. The change in BCR-ABL levels (expressed as 1/doubling time [1/DT]) and average daily dose were calculated for every measurement interval (window). Local regression was utilized to smooth scatter plots of 1/DT values across all patients versus dose. Smoothing-adjusted 1/DT values were replotted relative to the average daily dose for each window. Scatter plots of 1/DT values for ranges of dose levels were analyzed for differences by t-test. Average 1/DT values were transformed using an exponential growth/decay model to estimate the number of days required to achieve a 10-fold decrease in BCR-ABL levels. Results: In newly diagnosed patients (EPIC), across all dose levels, BARD analysis showed that the average number of days required to decrease BCR-ABL levels 10-fold was 47.5 (± 3.2) for Ponatinib and 89.9 (± 4.6) for imatinib, consistent with the more rapid molecular responses observed in the Ponatinib arm. Though increased doses of both Ponatinib and imatinib were associated with trends towards more rapid decreases in BCR-ABL levels, the rate of decrease induced by Ponatinib was greater overall (Table). Within windows that included only continuous dosing at starting dose levels, 10-fold decreases in BCR-ABL levels were achieved significantly more rapidly (p 0.05), 15 to In heavily pretreated patients (PACE), increased doses of Ponatinib were also associated with a trend towards more rapid decreases in BCR-ABL levels, although the rate of decrease induced by 45 mg Ponatinib (129.9 [± 18.5] days to reduce BCR-ABL levels 10-fold in the first 6 months) was reduced compared with that observed in newly diagnosed patients. Importantly, across the entire PACE study, average daily doses of Ponatinib as low as 10 mg were associated with net decreases in BCR-ABL levels. Conclusions: BARD enables a detailed exploration of dose-response relationships in CP-CML. In newly diagnosed patients, Ponatinib doses as low as 15 mg induced more rapid decreases in BCR-ABL levels than 400 mg imatinib. Consistent with the possibility that sequential treatment with TKIs increases the degree of BCR-ABL independence, the magnitude of BCR-ABL decreases induced by Ponatinib in heavily pretreated patients was reduced compared with newly diagnosed patients. Nonetheless, Ponatinib doses as low as 10 mg were still associated with disease control overall. These analyses will help inform the design of future studies aimed at optimizing the benefit/risk of Ponatinib treatment for patients with CML. *Number of BCR-ABL measurement intervals when average dose was within the indicated range Disclosures Pritchard:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Hodgson:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Baccarani:ARIAD, Novartis, BMS: Consultancy; ARIAD, BMS, Novartis, Pfizer, Teva: Honoraria, Speakers Bureau. Cortes:ARIAD, BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding. Deininger:BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding; BMS, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy. Guilhot:ARIAD Pharmaceuticals, Inc.: Honoraria. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Hughes:Novartis, BMS, ARIAD Pharmaceuticals, Inc.: Honoraria, Research Funding. Shah:ARIAD Pharmaceuticals, Inc., BMS: Research Funding. Talpaz:ARIAD Pharmaceuticals, Inc., BMS, Sanofi, Incyte, Pfizer: Research Funding. Clackson:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Haluska:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Knickerbocker:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership.

  • epic a phase iii randomized open label study of Ponatinib versus imatinib in adult patients with newly diagnosed chronic myeloid leukemia in chronic phase
    Journal of Clinical Oncology, 2013
    Co-Authors: Jeffrey H Lipton, Christopher D. Turner, Michael W. Deininger, Victor M. Rivera, Jorge E Cortes, Stephanie Lustgarten, Tim Clackson, Michele Baccarani, Francois Guilhot, Andreas Hochhaus
    Abstract:

    TPS7129 Background: The hallmark genetic abnormality of chronic myeloid leukemia (CML), known as the Philadelphia chromosome, generates the BCR-ABL fusion gene; expression of BCR-ABL in hematopoietic stem cells gives rise to CML. Ponatinib is a potent oral pan–BCR-ABL tyrosine kinase inhibitor (TKI) that is active against native and mutated forms of BCR-ABL, including the T315I gatekeeper mutant. Results from the phase 1 and phase 2 studies of Ponatinib demonstrated that Ponatinib is generally well tolerated and has substantial anti-leukemic activity in patients with CML who are resistant or intolerant to prior TKI therapy, regardless of baseline mutation status. In addition, multivariate analyses suggest that Ponatinib has greater activity in younger patients who are less heavily pretreated and have a shorter time since diagnosis. The phase 3 EPIC (Evaluation of Ponatinib vs Imatinib in CML) study is testing the hypothesis that Ponatinib is an effective treatment for newly diagnosed chronic phase (CP) CM...