49 results on '"Cortes, Jorge E."'
Search Results
2. Bosutinib versus imatinib for newly diagnosed chronic phase chronic myeloid leukemia : final results from the BFORE trial
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Brümmendorf, Tim H., Cortes, Jorge E., Milojkovic, Dragana, Gambacorti-Passerini, Carlo, Clark, Richard E., le Coutre, Philipp, Garcia-Gutierrez, Valentin, Chuah, Charles, Kota, Vamsi, Lipton, Jeffrey H., Rousselot, Philippe, Mauro, Michael J., Hochhaus, Andreas, Hurtado Monroy, Rafael, Leip, Eric, Purcell, Simon, Yver, Anne, Viqueira, Andrea, Deininger, Michael W., Brümmendorf, T, Cortes, J, Milojkovic, D, Gambacorti-Passerini, C, Clark, R, le Coutre, P, Garcia-Gutierrez, V, Chuah, C, Kota, V, Lipton, J, Rousselot, P, Mauro, M, Hochhaus, A, Hurtado Monroy, R, Leip, E, Purcell, S, Yver, A, Viqueira, A, and Deininger, M
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Cancer Research ,Aniline Compounds ,Antineoplastic Agents ,Hematology ,randomized controlled trials, haematological cancer, bosutinib, imatinib, chronic myeloid leukemia ,Treatment Outcome ,Oncology ,Leukemia, Myeloid, Chronic-Phase ,Nitriles ,Imatinib Mesylate ,Quinolines ,Humans ,ddc:610 ,Protein Kinase Inhibitors - Abstract
Leukemia : normal and malignant hemopoiesis 36(7), 1825-1833 (2022). doi:10.1038/s41375-022-01589-y, Published by Springer Nature, London
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- 2022
3. Clinical benefit of glasdegib plus low-dose cytarabine in patients with de novo and secondary acute myeloid leukemia: long-term analysis of a phase II randomized trial (vol 100, pg 1181, 2021)
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Heuser, Michael, Smith, B. Douglas, Fiedler, Walter, Sekeres, Mikkael A., Montesinos, Pau, Leber, Brian, Merchant, Akil, Papayannidis, Cristina, Perez-Simon, Jose A., Hoang, Caroline J., O'Brien, Thomas, Ma, Weidong Wendy, Zeremski, Mirjana, O'Connell, Ashleigh, Chan, Geoffrey, and Cortes, Jorge E.
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- 2021
4. Additional file 1 of Impact of frontline treatment approach on outcomes of myeloid blast phase CML
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Saxena, Kapil, Jabbour, Elias, Issa, Ghayas, Sasaki, Koji, Ravandi, Farhad, Maiti, Abhishek, Daver, Naval, Kadia, Tapan, DiNardo, Courtney D., Konopleva, Marina, Cortes, Jorge E., Yilmaz, Musa, Chien, Kelly, Pierce, Sherry, Kantarjian, Hagop, and Short, Nicholas J.
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Additional file 1. Supplementary Tables 1-5 and Supplementary Figure 1.
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- 2021
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5. Additional file 1 of Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of CPX-351 versus 7 + 3 in older adults with newly diagnosed high-risk/secondary AML
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Cortes, Jorge E., Lin, Tara L., Uy, Geoffrey L., Ryan, Robert J., Faderl, Stefan, and Lancet, Jeffrey E.
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Additional file 1: Mean and relative Q-TWiST gains across sensitivity analysis variations.
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- 2021
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6. Clinical benefit of glasdegib plus low-dose cytarabine in patients with de novo and secondary acute myeloid leukemia: long-term analysis of a phase II randomized trial
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Heuser, Michael, Smith, B. Douglas, Fiedler, Walter, Sekeres, Mikkael A., Montesinos, Pau, Leber, Brian, Pérez Simón, José Antonio, Cortes, Jorge E., and Universidad de Sevilla. Departamento de Medicina
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Clinical trial ,Secondary acute myeloid leukemia ,Acute myeloid leukemia ,Glasdegib - Abstract
This analysis from the phase II BRIGHT AML 1003 trial reports the long-term efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized (2:1) patients to receive glasdegib + LDAC (de novo, n = 38; secondary acute myeloid leukemia, n = 40) or LDAC alone (de novo, n = 18; secondary acute myeloid leukemia, n = 20). At the time of analysis, 90% of patients had died, with the longest follow-up since randomization 36 months. The combination of glasdegib and LDAC conferred superior overall survival (OS) versus LDAC alone; hazard ratio (HR) 0.495; (95% confidence interval [CI] 0.325–0.752); p = 0.0004; median OS was 8.3 versus 4.3 months. Improvement in OS was consistent across cytogenetic risk groups. In a post-hoc subgroup analysis, a survival trend with glasdegib + LDAC was observed in patients with de novo acute myeloid leukemia (HR 0.720; 95% CI 0.395– 1.312; p = 0.14; median OS 6.6 vs 4.3 months) and secondary acute myeloid leukemia (HR 0.287; 95% CI 0.151–0.548; p < 0.0001; median OS 9.1 vs 4.1 months). The incidence of adverse events in the glasdegib + LDAC arm decreased after 90 days’ therapy: 83.7% versus 98.7% during the first 90 days. Glasdegib + LDAC versus LDAC alone continued to demonstrate superior OS in patients with acute myeloid leukemia; the clinical benefit with glasdegib + LDAC was particularly prominent in patients with secondary acute myeloid leukemia. ClinicalTrials.gov identifier: NCT01546038.
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- 2021
7. Additional file 1 of Outcomes with sequential FLT3-inhibitor-based therapies in patients with AML
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Yilmaz, Musa, Alfayez, Mansour, DiNardo, Courtney D., Borthakur, Gautam, Kadia, Tapan M., Konopleva, Marina Y., Loghavi, Sanam, Kanagal-Shamanna, Rashmi, Keyur P. Patel, Jabbour, Elias J., Garcia-Manero, Guillermo, Pemmaraju, Naveen, Pierce, Sherry A., Ghayas, Issa, Short, Nicholas J., Montalban-Bravo, Guillermo, Takahashi, Koichi, Assi, Rita, Alotaibi, Ahmad S., Ohanian, Maro, Andreeff, Michael, Cortes, Jorge E., Hagop M. Kantarjian, Ravandi, Farhad, and Naval G. Daver
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Additional file 1. Manuscript Supplementary Information.
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- 2020
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8. Additional file 4 of Survival outcomes and clinical benefit in patients with acute myeloid leukemia treated with glasdegib and low-dose cytarabine according to response to therapy
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Cortes, Jorge E., Heidel, Florian H., Fiedler, Walter, B. Douglas Smith, Robak, Tadeusz, Montesinos, Pau, Candoni, Anna, Leber, Brian, Mikkael A. Sekeres, Pollyea, Daniel A., Ferdinand, Roxanne, Weidong Wendy Ma, O’Brien, Thomas, O’Connell, Ashleigh, Chan, Geoffrey, and Heuser, Michael
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Additional file 4: Fig S4. Blood count recovery in patients who did not achieve CR. Percentage of patients with a. ANC b. hemoglobin c. platelets recovery during cycles one to ten. One threshold measurement was required; all patients were included regardless of their BL levels but each cycle only included remaining patients at risk in that cycle. Analysis set, N = number of patients with ANC results in the cycle; patients, n = number of patients meeting recovery criteria in the cycle. Abbreviations: ANC, absolute neutrophil count; BL, baseline; CR, complete remission; LDAC, low-dose cytarabine.
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- 2020
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9. Additional file 5 of Survival outcomes and clinical benefit in patients with acute myeloid leukemia treated with glasdegib and low-dose cytarabine according to response to therapy
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Cortes, Jorge E., Heidel, Florian H., Fiedler, Walter, B. Douglas Smith, Robak, Tadeusz, Montesinos, Pau, Candoni, Anna, Leber, Brian, Mikkael A. Sekeres, Pollyea, Daniel A., Ferdinand, Roxanne, Weidong Wendy Ma, O’Brien, Thomas, O’Connell, Ashleigh, Chan, Geoffrey, and Heuser, Michael
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Additional file 5: Table S1. Patient disposition
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- 2020
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10. Additional file 1 of Survival outcomes and clinical benefit in patients with acute myeloid leukemia treated with glasdegib and low-dose cytarabine according to response to therapy
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Cortes, Jorge E., Heidel, Florian H., Fiedler, Walter, B. Douglas Smith, Robak, Tadeusz, Montesinos, Pau, Candoni, Anna, Leber, Brian, Mikkael A. Sekeres, Pollyea, Daniel A., Ferdinand, Roxanne, Weidong Wendy Ma, O’Brien, Thomas, O’Connell, Ashleigh, Chan, Geoffrey, and Heuser, Michael
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Additional file 1: Fig. S1. Duration of treatment with best overall response. a For patients receiving glasdegib + LDAC. b For patients receiving LDAC alone. Abbreviations: CR, complete remission; CRi, CR with incomplete hematologic response; EOT, end of treatment; LDAC, low-dose cytarabine; MR, minor response; PR, partial response; SD, stable disease
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- 2020
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11. Additional file 6 of Survival outcomes and clinical benefit in patients with acute myeloid leukemia treated with glasdegib and low-dose cytarabine according to response to therapy
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Cortes, Jorge E., Heidel, Florian H., Fiedler, Walter, B. Douglas Smith, Robak, Tadeusz, Montesinos, Pau, Candoni, Anna, Leber, Brian, Mikkael A. Sekeres, Pollyea, Daniel A., Ferdinand, Roxanne, Weidong Wendy Ma, O’Brien, Thomas, O’Connell, Ashleigh, Chan, Geoffrey, and Heuser, Michael
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Additional file 6: Table S2. Treatment-emergent all-causality adverse events* occurring during first 90 days and after 90 days of therapy
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- 2020
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12. Additional file 3 of Survival outcomes and clinical benefit in patients with acute myeloid leukemia treated with glasdegib and low-dose cytarabine according to response to therapy
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Cortes, Jorge E., Heidel, Florian H., Fiedler, Walter, B. Douglas Smith, Robak, Tadeusz, Montesinos, Pau, Candoni, Anna, Leber, Brian, Mikkael A. Sekeres, Pollyea, Daniel A., Ferdinand, Roxanne, Weidong Wendy Ma, O’Brien, Thomas, O’Connell, Ashleigh, Chan, Geoffrey, and Heuser, Michael
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Additional file 3: Fig. S3. Kaplan–Meier plots of OS with censoring for systemic follow-up therapies. a In patients who achieved CR. b In patients who did not achieve CR. Abbreviations: CI, confidence interval; CR, complete remission; LDAC, low-dose cytarabine; N/E, not evaluable; OS, overall survival
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- 2020
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13. Additional file 2 of Survival outcomes and clinical benefit in patients with acute myeloid leukemia treated with glasdegib and low-dose cytarabine according to response to therapy
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Cortes, Jorge E., Heidel, Florian H., Fiedler, Walter, B. Douglas Smith, Robak, Tadeusz, Montesinos, Pau, Candoni, Anna, Leber, Brian, Mikkael A. Sekeres, Pollyea, Daniel A., Ferdinand, Roxanne, Weidong Wendy Ma, O’Brien, Thomas, O’Connell, Ashleigh, Chan, Geoffrey, and Heuser, Michael
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endocrine system - Abstract
Additional file 2: Fig. S2. Kaplan–Meier plots of OS. a In patients who achieved CR or CRi. b In patients who did not achieve CR or CRi. Abbreviations: CI, confidence interval; CR, complete remission; CRi, CR with incomplete hematologic response; LDAC, low-dose cytarabine; OS, overall survival
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- 2020
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14. Additional file 1 of Prevention, recognition, and management of adverse events associated with gemtuzumab ozogamicin use in acute myeloid leukemia
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Cortes, Jorge E., Lima, Marcos De, Dombret, Hervé, Estey, Elihu H., Giralt, Sergio A., Montesinos, Pau, Röllig, Christoph, Venditti, Adriano, and Wang, Eunice S.
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hemic and lymphatic diseases - Abstract
Additional file 1. Prevention, recognition, and management of adverse events associated with gemtuzumab ozogamicin use in acute myeloid leukemia.
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- 2020
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15. Outcomes of Venetoclax and BCR-ABL Tyrosine Kinase Inhibitor Combinations in Patients with Philadelphia Chromosome-Positive Advanced Myeloid Leukemias
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Maiti, Abhishek, Franquiz, Miguel, Ravandi, Farhad, Cortes, Jorge E., Jabbour, Elias J., Sasaki, Koji, Marx, Kayleigh, Daver, Naval G., Kadia, Tapan M., Konopleva, Marina Y., Masarova, Lucia, Borthakur, Gautam, DiNardo, Courtney D., Naqvi, Kiran, Pierce, Sherry, Kantarjian, Hagop M., and Short, Nicholas J.
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Adult ,Male ,Sulfonamides ,Fusion Proteins, bcr-abl ,Imidazoles ,Middle Aged ,Bridged Bicyclo Compounds, Heterocyclic ,Article ,Disease-Free Survival ,Pyridazines ,Survival Rate ,Leukemia, Myeloid, Acute ,hemic and lymphatic diseases ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Female ,Blast Crisis ,Protein Kinase Inhibitors ,Aged ,Retrospective Studies - Abstract
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.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.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.Combination therapy of venetoclax with TKI-based regimens shows encouraging activity in very heavily pretreated, advanced Ph+ leukemias, particularly CML-MBP.
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- 2020
16. Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A Non-randomized, Open-label, Phase 2 Study
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Daver, Naval, Garcia-Manero, Guillermo, Basu, Sreyashi, Boddu, Prajwal C., Alfayez, Mansour, Cortes, Jorge E., Konopleva, Marina, Ravandi-Kashani, Farhad, Jabbour, Elias, Kadia, Tapan, Nogueras-Gonzalez, Graciela M., Ning, Jing, Pemmaraju, Naveen, DiNardo, Courtney D., Andreeff, Michael, Pierce, Sherry A., Gordon, Tauna, Kornblau, Steven M., Flores, Wilmer, Alhamal, Zainab, Bueso-Ramos, Carlos, Jorgensen, Jeffrey L., Patel, Keyur P., Blando, Jorge, Allison, James P., Sharma, Padmanee, and Kantarjian, Hagop
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Adult ,Aged, 80 and over ,Male ,Salvage Therapy ,Middle Aged ,Article ,Leukemia, Myeloid, Acute ,Young Adult ,Nivolumab ,Treatment Outcome ,Drug Resistance, Neoplasm ,Antineoplastic Combined Chemotherapy Protocols ,Azacitidine ,Biomarkers, Tumor ,Humans ,CTLA-4 Antigen ,Female ,Neoplasm Recurrence, Local ,Aged - Abstract
BACKGROUND: Preclinical models showed that blocking PD-1/PD-L1 pathways enhanced anti-leukemic responses. Azacitidine up-regulates PD-1 and interferon-gamma signaling. METHODS: In this single arm trial, patients with relapsed/refractory (R/R) AML were treated with azacitidine 75mg/m(2) Days 1–7 intravenously or subcutaneously with nivolumab 3mg/kg intravenously on Day 1 and 14, every 4–6 weeks. FINDINGS: Seventy patients were treated. The median age was 70 years (range, 22–90). The median number of prior therapies received was 2 (range, 1–7). The overall response rate (ORR) was 33% including 15 (22%) complete remission (CR)/complete remission with insufficient recovery of counts (CRi), 1 partial response, and 7 patients with hematologic improvement (HI) maintained >6 months. Six patients (9%) had stable disease >6 months. The ORR was 58% and 22%, in HMA-naïve (n=25) and HMA pre-treated (n=45) patients, respectively. Grade 3–4 immune related adverse events occurred in 8 (11%) patients. Pretherapy bone marrow and peripheral blood CD3 and CD8 were significantly predictive for response on flow-cytometry. CTLA-4 was significantly up-regulated on CD4(+)Teff in non-responders after 2 and 4 doses of nivolumab. INTERPRETATION: Azacitidine and nivolumab therapy produced an encouraging response rate and overall survival in patients with R/R AML, particularly in HMA-naïve and Salvage 1 patients. Pretherapy bone marrow aspirate and peripheral blood CD3 percentage may be biomarkers for patient selection. TRIAL REGISTRATION ID: Clinicaltrials.gov identifier: NCT02397720
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- 2018
17. Dasatinib in imatinib‐resistant or ‐intolerant chronic‐phase, chronic myeloid leukemia patients: 7‐year follow‐up of study CA180‐034
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Shah, Neil P, Rousselot, Philippe, Schiffer, Charles, Rea, Delphine, Cortes, Jorge E, Milone, Jorge, Mohamed, Hesham, Healey, Diane, Kantarjian, Hagop, Hochhaus, Andreas, and Saglio, Giuseppe
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Myeloid ,Pancytopenia ,Immunology ,Drug Resistance ,Dasatinib ,Antineoplastic Agents ,Cardiorespiratory Medicine and Haematology ,Disease-Free Survival ,chronic myeloid leukemia ,clinical trial ,dasatinib ,tyrosine kinase inhibitors ,hemic and lymphatic diseases ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Humans ,Chronic ,Protein Kinase Inhibitors ,Research Articles ,Leukemia ,Pleural Effusion ,Treatment Outcome ,Drug Resistance, Neoplasm ,Leukemia, Myeloid, Chronic-Phase ,Imatinib Mesylate ,Neoplasm ,Chronic-Phase ,BCR-ABL Positive ,Patient Safety ,Myelogenous ,Research Article ,Follow-Up Studies - Abstract
Dasatinib was approved at 100 mg once daily for imatinib-resistant or -intolerant patients with chronic myeloid leukemia (CML) in chronic phase, based on results of the phase 3 CA180-034 (NCT00123474) study. Here we present the final 7-year analysis of this pivotal study, the longest follow-up to date of any second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI). Patients (n = 670) with imatinib-resistant or -intolerant CML in chronic phase received dasatinib. Nineteen percent of patients continued on study treatment, with a greater proportion in the 100 mg once daily arm remaining on therapy. Seven-year rates for major molecular response (MMR), progression-free survival (PFS), and overall survival (OS) were similar across doses; MMR, PFS, and OS results were 46, 42, and 65% at 100 mg once daily, respectively. Improved PFS and OS rates were reported in patients who achieved BCR-ABL1 ≤10% at 3 and 6 months. No new safety signals were identified. The incidence of drug-related pleural effusion was 28% at 100 mg once daily and 35% at the other three dose groups. Incidence of drug-related pulmonary hypertension and pulmonary arterial hypertension remained low (≤3% across all doses). Arterial ischemic events occurred in ≤4% of patients across all doses. These data support the long-term efficacy and well-established safety profile of dasatinib for patients with imatinib-resistant or -intolerant CML in chronic phase. Am. J. Hematol. 91:869-874, 2016. © 2016 Wiley Periodicals, Inc.
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- 2016
18. 05 / Asciminib (ABL001) in Combination With Imatinib in Patients With Chronic Myeloid Leukemia in Chronic Phase Who Have Not Achieved a Deep Molecular Response With Long-Term Frontline Imatinib: A Randomized, Open-Label, Multicenter, Phase 2 Study
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Cortes Jorge E.
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- 2018
19. 16 / The OPTIC Study: a Multicenter, Randomized, Phase 2 Trial to Evaluate Three Starting Doses of Ponatinib With Response-Based Dose Reduction in Patients with Chronic Phase Chronic Myeloid Leukemia Resistant to Prior Tyrosine Kinase Therapy
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Cortes Jorge E.
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- 2018
20. Final Results of a Phase 2, Open-Label Study of Indisulam, Idarubicin and Cytarabine in Patients with Relapsed or Refractory Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome
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Assi, Rita, Kantarjian, Hagop, Kadia, Tapan M., Pemmaraju, Naveen, Jabbour, Elias, Jain, Nitin, Daver, Naval, Estrov, Zeev, Uehara, Taisuke, Owa, Takashi, Cortes, Jorge E., and Borthakur, Gautam
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Adult ,Male ,Sulfonamides ,Remission Induction ,Cytarabine ,Drug Synergism ,Kaplan-Meier Estimate ,Middle Aged ,Water-Electrolyte Balance ,Article ,Leukemia, Myeloid, Acute ,Treatment Outcome ,Drug Resistance, Neoplasm ,Myelodysplastic Syndromes ,Antineoplastic Combined Chemotherapy Protocols ,Mutation ,Humans ,Female ,RNA Splicing Factors ,Neoplasm Recurrence, Local ,Idarubicin ,Aged ,Febrile Neutropenia - Abstract
BACKGROUND: Indisulam possesses anticancer properties through down-regulation of various cell cycle checkpoint molecules, thereby blocking the phosphorylation of retinoblastoma protein and inducing p53 and p21. Indisulam exhibits synergy with nucleoside analogs and topoisomerase inhibitors. METHODS: We designed a phase 2, study of indisulam in combination with idarubicin and cytarabine in relapsed/refractory AML and high-risk myelodysplastic syndrome. In stage 1, patients were treated with indisulam at 400 mg/m2 intravenously on days 1 and 8 in a 28-day cycle. If no response, patients received same dose-schedule of indisulam followed by idarubicin 8 mg/m2 IV daily x3 and cytarabine 1.0 g/m2 over 24 hours daily on days 9–12 (age 60 years) in a 28-day cycle. Primary endpoints included overall response rate and secondary objectives included overall survival. RESULTS: Forty patients were enrolled. Of the 37 evaluable patients, 31 received indisulam with chemotherapy. Of them, 11 (35%) responded for a median duration of 5.3 months. The estimated 1-year overall survival was 51% for responders compared to 8 % for non-responders (p
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- 2018
21. Long-term patient-reported outcomes from an open-label safety and efficacy study of bosutinib in Philadelphia chromosome–positive chronic myeloid leukemia patients resistant or intolerant to prior therapy
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Kantarjian, Hagop M., Mamolo, Carla M., Gambacorti‐Passerini, Carlo, Cortes, Jorge E., Brümmendorf, Tim H., Su, Yun, Reisman, Arlene L., Shapiro, Mark, Lipton, Jeff H., Kantarjian, H, Mamolo, C, Gambacorti Passerini, C, Cortes, J, Brümmendorf, T, Su, Y, Reisman, A, Shapiro, M, and Lipton, J
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Adult ,Diarrhea ,Male ,Cancer Research ,bosutinib ,patient-reported outcome ,Discipline ,tyrosine kinase inhibitor ,chronic myeloid leukemia ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,tyrosine kinase inhibitors ,Nitriles ,Humans ,Philadelphia Chromosome ,Patient Reported Outcome Measures ,Aged ,Aniline Compounds ,Original Articles ,Middle Aged ,quality of life ,Oncology ,Chronic Disease ,Quinolines ,Original Article ,Female ,patient‐reported outcomes - Abstract
BACKGROUND Health‐related quality of life (HRQOL) in patients with chronic‐phase chronic myeloid leukemia (CML) is important because of the requirement for long‐term treatment. This study assessed HRQOL in bosutinib‐treated patients with Philadelphia chromosome–positive CML and resistance or intolerance to 1 (chronic‐phase second‐line [CP2L]) or more (chronic‐phase third‐line [CP3L]) tyrosine kinase inhibitors who had 264 weeks or more of follow‐up (ClinicalTrials.gov identifier NCT00261846). METHODS Patient‐reported HRQOL was assessed with the EuroQol 5‐Dimensions Questionnaire (EQ‐5D) and the Functional Assessment of Cancer Therapy–Leukemia (FACT‐Leu). RESULTS In total, 284 and 119 patients composed the CP2L and CP3L cohorts, respectively. At treatment completion, more than 50% of the patients in the CP2L and CP3L cohorts completed the EQ‐5D and FACT‐Leu assessments. The EQ‐5D and EQ‐5D visual analog scale scores were stable in both cohorts throughout treatment. The mean FACT‐Leu scores were generally stable over time but were lower in magnitude in the CP3L cohort versus the CP2L cohort. The FACT‐Leu scale scores of a subset of patients with chronic diarrhea (CP2L, n = 101; CP3L, n = 30) were similar to the scores of the larger cohorts. Minimally important differences (MIDs) from baseline for the FACT‐Leu scale scores were observed for the following: emotional well‐being (EWB), Functional Assessment of Cancer Therapy–General (FACT‐G) Total, FACT‐Leu Total, and Functional Assessment of Cancer Therapy Trial Outcome Index (FACT‐TOI) in the CP2L cohort and FACT‐Leu Total in the CP3L cohort. Among patients with chronic diarrhea, MIDs were observed for EWB, FACT‐G Total, FACT‐Leu Total, and FACT‐TOI in the CP2L cohort and for EWB, FACT‐G Total, and FACT‐Leu Total in the CP3L cohort. CONCLUSIONS HRQOL was maintained with long‐term bosutinib treatment for patients with CP2L and CP3L CML. Cancer 2018;124:587‐95. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes., Health‐related quality of life (assessed with the Functional Assessment of Cancer Therapy–Leukemia) and the general health status (assessed with the EuroQol 5‐Dimensions Questionnaire) were largely maintained in chronic‐phase chronic myeloid leukemia patients receiving bosutinib for 264 weeks or longer. Health‐related quality of life was maintained by patients who receive bosutinib as a second‐ or third‐line treatment for chronic‐phase chronic myeloid leukemia.
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- 2018
22. Prediction for Sustained Deep Molecular Response of BCR-ABL1 Levels in Patients with Chronic Myeloid Leukemia in Chronic Phase
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Sasaki, Koji, Kantarjian, Hagop, O'Brien, Susan, Ravandi, Farhad, Konopleva, Marina, Borthakur, Gautam, Garcia-Manero, Guillermo, Wierda, William, Daver, Naval, Ferrajoli, Alessandra, Takahashi, Koichi, Jain, Preetesh, Rios, Mary Beth, Pierce, Sherry, Jabbour, Elias, and Cortes, Jorge E.
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Adult ,Aged, 80 and over ,Male ,Adolescent ,Fusion Proteins, bcr-abl ,Antineoplastic Agents ,Middle Aged ,Prognosis ,Models, Biological ,Article ,Young Adult ,Treatment Outcome ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Humans ,Female ,Prospective Studies ,Protein Kinase Inhibitors ,Aged ,Follow-Up Studies ,Randomized Controlled Trials as Topic - Abstract
BACKGROUND: Achievement of sustained deep molecular response is a goal of increasing relevance as it opens the possibility of treatment discontinuation. The objective of this analysis is to develop a prediction model for sustained molecular response 4.5 (MR(4.5)) for at least 2 years according to BCR-ABL1 levels achieved within the first 12 months of therapy. METHODS: Data for 603 patients with newly diagnosed chronic myeloid leukemia in chronic phase in consecutive prospective clinical trials were analyzed. The “best fit average” molecular response was defined by robust linear regression models, with which the average molecular levels were defined. The “minimum acceptable” molecular response was defined by quantile regression for the 95th percentile, with which the worst 5% BCR-ABL1 levels were identified. RESULTS: In 603 patients with a median follow-up of 104 months, 2002 BCR-ABL1 level data points within 1 year of TKI were identified. The regression equations for best fit average levels for sustained MR(4.5) was Log(10)(PCR) = -0.1424 × (Months) – 0.8668; for minimum acceptable levels, Log(10)(PCR) = -0.1403 × (Months) + 0.6142. To achieve sustained MR(4.5), the best fit average level was 0.051%, 0.019%, 0.007%, and 0.003% at 3, 6, 9, and 12 months, respectively; the minimum acceptable level was 1.561%, 0.592%, 0.225%, and 0.085% at 3, 6, 9, and 12 months, respectively. CONCLUSIONS: Our model proposes optimal values that predict the highest probability of reaching such goal. These values can be used to guide therapy when sustained MR(4.5) is the objective.
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- 2017
23. A Randomized Phase 2 Study of Idarubicin and Cytarabine With Clofarabine or Fludarabine in Patients With Newly Diagnosed Acute Myeloid Leukemia
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Jabbour, Elias, Short, Nicholas J., Ravandi, Farhad, Huang, Xuelin, Xiao, Lianchun, Garcia-Manero, Guillermo, Plunkett, William, Gandhi, Varsha, Sasaki, Koji, Pemmaraju, Naveen, Daver, Naval G., Borthakur, Gautam, Jain, Nitin, Konopleva, Marina, Estrov, Zeev, Kadia, Tapan M., Wierda, William G., DiNardo, Courtney D., Brandt, Mark, O’Brien, Susan M., Cortes, Jorge E., and Kantarjian, Hagop
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Article - Published
- 2017
24. Prognostic impact of pretreatment cytogenetics in adult Philadelphia chromosome-negative ALL in the era of MRD
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Issa, Ghayas C., Kantarjian, Hagop, Yin, C. Cameron, Qiao, Wei, Ravandi, Farhad, Thomas, Deborah, Short, Nicholas J., Sasaki, Koji, Garcia-Manero, Guillermo, Kadia, Tapan M., Cortes, Jorge E., Daver, Naval, Borthakur, Gautam, Jain, Nitin, Konopleva, Marina, Khouri, Issa, Kebriaei, Partow, Champlin, Richard E., Pierce, Sherry, O'Brien, Susan M., and Jabbour, Elias
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Adult ,Aged, 80 and over ,Male ,Neoplasm, Residual ,Adolescent ,Cytodiagnosis ,Remission Induction ,Cytarabine ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,Article ,Disease-Free Survival ,Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative ,Treatment Outcome ,Doxorubicin ,Vincristine ,Humans ,Female ,Aged - Abstract
The introduction of novel prognostic factors such as minimal residual disease (MRD) and genomic profiling has led to the reevaluation of the role of cytogenetics and other conventional factors in risk stratification for acute lymphoblastic leukemia (ALL).This study assessed the impact of baseline cytogenetics on the outcomes of 428 adult patients with Philadelphia chromosome-negative ALL who were receiving frontline chemotherapy. Three hundred thirty patients (77%) were treated with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone-based regimens, and 98 (23%) were treated with the augmented Berlin-Frankfurt-Munster regimen.The median age was 40 years (range, 13-86 years). One hundred eighty-six patients (43%) had diploid cytogenetics, 32 (7%) had complex cytogenetics (defined as ≥ 5 chromosomal abnormalities), 27 (6%) had low hypodiploidy/near-triploidy (Ho-Tr), 24 (6%) had high hyperdiploidy, and 24 (6%) had a mixed-lineage leukemia (MLL) rearrangement. Patients with an MLL rearrangement, Ho-Tr, or a complex karyotype had significantly worse relapse-free survival (RFS) and overall survival (OS) than the diploid group. According to a multivariate analysis including all the baseline characteristics and MRD status, Ho-Tr and a complex karyotype were independent predictive factors for worse RFS and OS. Furthermore, survival among all cytogenetic groups was similar, regardless of the treatment received.A complex karyotype and Ho-Tr are adverse prognostic factors for adults with ALL independently of the MRD status. These findings suggest that pretreatment cytogenetics remain a valuable prognostic tool in this population. Cancer 2017;123:459-467. © 2016 American Cancer Society.
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- 2016
25. A Propensity Score Matching Analysis of Dasatinib and Nilotonib as a Frontline Therapy for Patients with Chronic Myeloid Leukemia in Chronic Phase
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Takahashi, Koichi, Kantarjian, Hagop, Yang, Yulong, Sasaki, Koji, Jain, Preetesh, DellaSala, Sara, Ravandi, Farhad, Kadia, Tapan, Pemmaraju, Naveen, Daver, Naval, Borthakur, Gautam, Garcia-Manero, Guillermo, Jabbour, Elias, and Cortes, Jorge E.
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Adult ,Aged, 80 and over ,Male ,Adolescent ,Dasatinib ,Middle Aged ,Prognosis ,Article ,Survival Rate ,Young Adult ,Pyrimidines ,Antineoplastic Combined Chemotherapy Protocols ,Leukemia, Myeloid, Chronic-Phase ,Humans ,Female ,Propensity Score ,Aged ,Follow-Up Studies ,Neoplasm Staging - Abstract
Both dasatinib and nilotinib are approved frontline therapy for chronic myeloid leukemia in chronic phase (CML-CP) based on randomized trials compared with imatinib. However, no head-to-head comparison of dasatinib and nilotinib has been conducted in patients with newly diagnosed CML-CP.The authors conducted a propensity score (PS) matched comparison of patients with CML-CP who received frontline therapy with either dasatinib (N = 102) or nilotinib (N = 104) under the respective phase 2 trials conducted in parallel.PS matching resulted in 87 patients from each trial being matched for pretreatment characteristics. The 3-month BCR-ABL1/ABL1 ratio10% rate was 93% with dasatinib and 94% with nilotinib (P = .25); the rates of major molecular response at 12 months were 77% and 85%, respectively (P = .13); and the rates of molecular response with 4.5-log reduction in the ratio at 36 months were 66% and 64%, respectively (P = .96). All other clinically relevant responses were similar between the 2 treatment cohorts. The 3-year probability of event-free survival was 89% among the patients who received dasatinib and 87% among those who received nilotinib (P = .99), and the corresponding 3-year overall survival probabilities were 99% and 93%, respectively (P = .95). No statistical difference was observed between the dasatinib and nilotinib groups in any of the other survival endpoints. The treatment discontinuation rate also was similar between the 2 cohorts (dasatinib group, 18%; nilotinib group, 19%; P = .82).In a PS-matched cohort of patients with newly diagnosed CML-CP, dasatinib and nilotinib offer similar response and survival outcomes. Both drugs can be considered reasonable standard-of-care options as first-line therapy for patients with CML-CP. Cancer 2016;122:3336-3343. © 2016 American Cancer Society.
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- 2016
26. Hyper-CVAD + ponatinib vs. hyper-CVAD + dasatinib as frontline therapy for Ph-positive ALL: a propensity score analysis
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Sasaki, Koji, Jabbour, Elias, Ravandi, Farhad, Short, Nicholas J., Thomas, Deborah, Garcia-Manero, Guillermo, Daver, Naval, Kadia, Tapan, Konopleva, Marina, Jain, Nitin, Issa, Ghayas C., Jeanis, Vicki, Moore, Gal, Garris, Rebecca, Pemmaraju, Naveen, Cortes, Jorge E., O'Brien, Susan, and Kantarjian, Hagop
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Adult ,Aged, 80 and over ,Male ,Dasatinib ,Imidazoles ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Article ,Dexamethasone ,Disease-Free Survival ,Pyridazines ,Survival Rate ,Young Adult ,Doxorubicin ,Vincristine ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Female ,Philadelphia Chromosome ,Prospective Studies ,Propensity Score ,Cyclophosphamide ,Aged - Abstract
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.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.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.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.
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- 2016
27. A Phase I Study of Evofosfamide, an Investigational Hypoxia-Activated Prodrug, in Patients with Advanced Leukemia
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Badar, Talha, Handisides, Damian R., Benito, Juliana M., Richie, Mary Ann, Borthakur, Gautam, Jabbour, Elias, Harutyunyan, Karine, Konoplev, Sergej, Faderl, Stefan, Kroll, Stew, Andreeff, Michael, Pearce, Tillman, Kantarjian, Hagop M., Cortes, Jorge E., Thomas, Deborah A., and Konopleva, Marina
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Adult ,Male ,Salvage Therapy ,Stomatitis ,Leukemia ,Maximum Tolerated Dose ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Article ,Leukemia, Myeloid, Acute ,Young Adult ,Bone Marrow ,Nitroimidazoles ,Esophagitis ,Humans ,Female ,Phosphoramide Mustards ,Prodrugs ,Hypoxia ,Aged ,Hyperbilirubinemia - Abstract
Tumor hypoxia causes resistance to radiation and chemotherapy. Evofosfamide (TH-302) has exhibited specific hypoxia-dependent cytotoxicity against primary acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) samples in vitro. Based on these findings, a Phase I study of evofosfamide was designed for patients with relapsed/refractory leukemia (NCT01149915). In this open-label study, patients were treated with evofosfamide as a 30-60 min/day infusion on Days 1-5 of a 21-day cycle (Arm A, n = 38) or as a continuous infusion over 120 hr over Days 1-5 of a 21-day cycle (Arm B, n = 11). Forty-nine patients were treated including 39 (80%) with AML and 9 (18%) with ALL. Patients had received a median of five prior therapies. In Arm A, the dose-limiting toxicities (DLTs) were grade 3 esophagitis, observed at a dose of 550 mg/m(2) . The maximum tolerated dose (MTD) was a daily dose of 460 mg/m(2) . In Arm B, the DLTs were grade 3 stomatitis and hyperbilirubinemia, observed at a daily dose of 460 mg/m(2) . The continuous infusion MTD was a daily dose of 330 mg/m(2) . Hypoxia markers HIF-1α and CAIX were highly expressed in leukemic bone marrow and were significantly reduced after evofosfamide therapy. The combined overall response rate in Arms A and B was 6% (2 CR/CRi and 1 PR), with all responses seen in Arm A. Evofosfamide has shown limited activity in heavily pretreated leukemia patients. Further evaluation investigating evofosfamide in combination with cytotoxic or demethylating agents is warranted. Am. J. Hematol. 91:800-805, 2016. © 2016 Wiley Periodicals, Inc.
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- 2016
28. Prognostic impact of persistent cytogenetic abnormalities at complete remission in adult patients with acute lymphoblastic leukemia
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Short, Nicholas J., Kantarjian, Hagop M., Jabbour, Elias J., O’Brien, Susan M., Faderl, Stefan, Burger, Jan A., Garris, Rebecca, Qiao, Wei, Huang, Xuelin, Jain, Nitin, Konopleva, Marina, Kadia, Tapan M., Daver, Naval, Borthakur, Gautam, Cortes, Jorge E., and Ravandi, Farhad
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Adult ,Aged, 80 and over ,Chromosome Aberrations ,Male ,Neoplasm, Residual ,Adolescent ,Remission Induction ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Flow Cytometry ,Prognosis ,Combined Modality Therapy ,Survival Analysis ,Article ,Immunophenotyping ,Young Adult ,Treatment Outcome ,Humans ,Female ,Aged ,Follow-Up Studies - Abstract
In acute myelogenous leukemia, the persistent detection of abnormal cytogenetics at complete remission (ACCR) is associated with inferior outcomes. However, the prognostic significance of ACCR in adult patients with acute lymphoblastic leukemia (ALL) is unknown. We evaluated 272 adult patients with ALL and abnormal cytogenetics at baseline who were treated with frontline induction chemotherapy, achieved complete remission (CR) and had cytogenetic analysis performed at the time of CR. ACCR was observed in 26 patients (9.6%). Median relapse-free survival was 22 months (95% CI, 12 months to not reached) for patients with ACCR vs. 48 months (range, 30-125 months) in patients with normal cytogenetics at CR (NCCR; P = 0.31). Median overall survival also did not differ significantly between the ACCR (99 months [range, 17 months to not reached]) and NCCR groups (67 months [range, 47 months to not reached], P = 0.86). The specificity of ACCR for minimal residual disease (MRD) positivity by multi-parameter flow cytometry (MFC) was 43%, and there was overall poor correlation between these two methods for the detection of residual disease. When patients were stratified by MRD status, the presence or absence of persistent cytogenetic abnormalities at CR did not add additional prognostic information. This study suggests that there is poor association between MRD assessment by MFC and the presence or absence of cytogenetic abnormalities at CR in adult patients with ALL. ACCR was not associated with adverse outcomes in ALL and did not add additional prognostic information when MRD status by MFC was known.
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- 2016
29. Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia
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Ravandi, Farhad, O'Brien, Susan M, Cortes, Jorge E, Thomas, Deborah M, Garris, Rebecca, Faderl, Stefan, Burger, Jan A, Rytting, Michael E, Ferrajoli, Alessandra, Wierda, William G, Verstovsek, Srdan, Champlin, Richard, Kebriaei, Partow, McCue, Deborah A, Huang, Xuelin, Jabbour, Elias, Garcia-Manero, Guillermo, Estrov, Zeev, and Kantarjian, Hagop M
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Adult ,Male ,Pediatric Research Initiative ,Childhood Leukemia ,Pediatric Cancer ,Oncology and Carcinogenesis ,Dasatinib ,Antineoplastic Agents ,acute lymphoblastic leukemia ,Philadelphia chromosome ,chemotherapy ,Dexamethasone ,Young Adult ,Rare Diseases ,Clinical Research ,Antineoplastic Combined Chemotherapy Protocols ,80 and over ,Genetics ,Humans ,Oncology & Carcinogenesis ,Cyclophosphamide ,Aged ,Cancer ,combination ,Pediatric ,Cytarabine ,Evaluation of treatments and therapeutic interventions ,Hematology ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Stem Cell Research ,Survival Analysis ,Methotrexate ,Treatment Outcome ,Vincristine ,Doxorubicin ,Residual ,6.1 Pharmaceuticals ,Public Health and Health Services ,Neoplasm ,Female ,Follow-Up Studies - Abstract
BackgroundThe long-term efficacy of a combination of chemotherapy and dasatinib in patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is not well established.MethodsPatients received dasatinib with 8 cycles of alternating hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone and high-dose cytarabine and methotrexate. Patients in complete remission (CR) continued maintenance dasatinib, vincristine, and prednisone for 2 years, which was followed by dasatinib indefinitely. Patients eligible for allogeneic stem cell transplantation (SCT) received it during their first CR.ResultsSeventy-two patients with a median age of 55 years (range, 21-80 years) were treated; 69 (96%) achieved CR. Among them, 57 (83%) achieved cytogenetic CR after 1 cycle, and 64 (93%) achieved a major molecular response at a median of 4 weeks (range, 2-38 weeks). Sixty-five patients (94%) were negative for minimal residual disease assessed by flow cytometry at a median of 3 weeks (range, 2-37 weeks). Dasatinib-related grade 3 and 4 adverse events included bleeding, pleural/pericardial effusions, and elevated transaminases. With a median follow-up of 67 months (range, 33-97 months), 33 patients (46%) were alive, and 30 (43%) were in CR; 12 underwent allogeneic SCT. Thirty-nine patients died (3 at induction, 19 after relapse, 7 after SCT performed during first CR, and 10 during CR). The median disease-free survival and overall survival were 31 (range, 0.3-97 months) and 47 months (range, 0.2-97 months), respectively. Seven relapsed patients had BCR-ABL kinase domain mutations, including 4 with T315I.ConclusionsA combination of chemotherapy with dasatinib is effective in achieving long-term remission for patients with newly diagnosed Ph + ALL.
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- 2015
30. Estimated glomerular filtration rate changes in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors
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Yilmaz, Musa, Lahoti, Amit, O'Brien, Susan, Nogueras-González, Graciela M, Burger, Jan, Ferrajoli, Alessandra, Borthakur, Gautam, Ravandi, Farhad, Pierce, Sherry, Jabbour, Elias, Kantarjian, Hagop, and Cortes, Jorge E
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Adult ,Male ,Kidney Disease ,Adolescent ,Oncology and Carcinogenesis ,Dasatinib ,Renal and urogenital ,Kidney ,Dose-Response Relationship ,Young Adult ,tyrosine kinase inhibitor ,Rare Diseases ,chronic myeloid leukemia ,Clinical Research ,80 and over ,Humans ,Renal Insufficiency ,Oncology & Carcinogenesis ,Chronic ,Protein Kinase Inhibitors ,nilotinib ,Retrospective Studies ,Aged ,Cancer ,Leukemia ,Incidence ,Evaluation of treatments and therapeutic interventions ,glomerular filtration rate changes ,Hematology ,Middle Aged ,Protein-Tyrosine Kinases ,Acute Kidney Injury ,Pyrimidines ,Treatment Outcome ,imatinib ,Creatinine ,6.1 Pharmaceuticals ,Imatinib Mesylate ,kidney injury ,outcome ,Public Health and Health Services ,Female ,BCR-ABL Positive ,Drug ,Glomerular Filtration Rate ,Follow-Up Studies ,Myelogenous - Abstract
BackgroundChronic use of tyrosine kinase inhibitors (TKIs) may lead to previously unrecognized adverse events. This study evaluated the incidence of acute kidney injury (AKI) and chronic kidney disease (CKD) in chronic-phase (CP) chronic myeloid leukemia (CML) patients treated with imatinib, dasatinib, and nilotinib.MethodsFour hundred sixty-eight newly diagnosed CP CML patients treated with TKIs were analyzed. The molecular and cytogenetic response data, creatinine, and glomerular filtration rate (GFR) were followed from the start of therapy to the last follow-up (median, 52 months). GFR was estimated with the Modification of Diet in Renal Disease equation.ResultsNineteen patients (4%) had TKI-associated AKI. Imatinib was associated with a higher incidence of AKI in comparison with dasatinib and nilotinib (P = .014). Fifty-eight patients (14%) developed CKD while they were receiving a TKI; 49 of these patients (84%) did so while they were being treated with imatinib (P
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- 2015
31. Conditional Survival in Patients with Chronic Myeloid Leukemia in Chronic Phase in the Era of Tyrosine Kinase Inhibitors
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Sasaki, Koji, Kantarjian, Hagop M, Jain, Preetesh, Jabbour, Elias J, Ravandi, Farhad, Konopleva, Marina, Borthakur, Gautam, Takahashi, Koichi, Pemmaraju, Naveen, Daver, Naval, Pierce, Sherry A, O'Brien, Susan M, and Cortes, Jorge E
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Myeloid ,Male ,Dasatinib ,Severity of Illness Index ,tyrosine kinase inhibitors ,80 and over ,Prospective Studies ,Chronic ,Cancer ,Randomized Controlled Trials as Topic ,Aged, 80 and over ,Leukemia ,conditional survival ,response ,Age Factors ,Hematology ,Middle Aged ,Treatment Outcome ,6.1 Pharmaceuticals ,Leukemia, Myeloid, Chronic-Phase ,Public Health and Health Services ,Imatinib Mesylate ,Female ,Drug ,Adult ,Adolescent ,Clinical Trials and Supportive Activities ,Oncology and Carcinogenesis ,Article ,Disease-Free Survival ,Drug Administration Schedule ,Dose-Response Relationship ,Young Adult ,Sex Factors ,chronic myeloid leukemia ,Clinical Research ,Predictive Value of Tests ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Humans ,Oncology & Carcinogenesis ,Protein Kinase Inhibitors ,Aged ,Analysis of Variance ,Dose-Response Relationship, Drug ,Evaluation of treatments and therapeutic interventions ,Survival Analysis ,Good Health and Well Being ,Multivariate Analysis ,Chronic-Phase ,BCR-ABL Positive ,Myelogenous - Abstract
BackgroundTyrosine kinase inhibitors (TKIs) significantly improve survival in patients with chronic myeloid leukemia in chronic phase (CML-CP). Conditional probability provides survival information in patients who have already survived for a specific period of time after treatment.MethodsCumulative response and survival data from 6 consecutive frontline TKI clinical trials were analyzed. Conditional probability was calculated for failure-free survival (FFS), transformation-free survival (TFS), event-free survival (EFS), and overall survival (OS) according to depth of response within 1 year of the initiation of TKIs, including complete cytogenetic response, major molecular response, and molecular response with a 4-log or 4.5-log reduction.ResultsA total of 483 patients with a median follow-up of 99.4 months from the initiation of treatment with TKIs were analyzed. Conditional probabilities of FFS, TFS, EFS, and OS for 1 additional year for patients alive after 12 months of therapy ranged from 92.0% to 99.1%, 98.5% to 100%, 96.2% to 99.6%, and 96.8% to 99.7%, respectively. Conditional FFS for 1 additional year did not improve with a deeper response each year. Conditional probabilities of TFS, EFS, and OS for 1 additional year were maintained at >95% during the period.ConclusionsIn the era of TKIs, patients with chronic myeloid leukemia in chronic phase who survived for a certain number of years maintained excellent clinical outcomes in each age group. Cancer 2016;122:238-248. © 2015 American Cancer Society.
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- 2015
32. Targeting IL11 Receptor in Leukemia and Lymphoma: A Functional Ligand-Directed Study and Hematopathology Analysis of Patient-Derived Specimens
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Karjalainen, Katja, Jaalouk, Diana E, Bueso-Ramos, Carlos, Bover, Laura, Sun, Yan, Kuniyasu, Akihiko, Driessen, Wouter HP, Cardó-Vila, Marina, Rietz, Cecilia, Zurita, Amado J, O'Brien, Susan, Kantarjian, Hagop M, Cortes, Jorge E, Calin, George A, Koivunen, Erkki, Arap, Wadih, and Pasqualini, Renata
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Urologic Diseases ,Lymphoma ,Cell Survival ,Pediatric Cancer ,Molecular Sequence Data ,Oncology and Carcinogenesis ,Antineoplastic Agents ,Ligands ,Drug Screening Assays ,Cell Line ,Inhibitory Concentration 50 ,Rare Diseases ,Clinical Research ,Receptors ,Humans ,Amino Acid Sequence ,Oncology & Carcinogenesis ,Cancer ,Pediatric ,Tumor ,Leukemia ,Prostate Cancer ,Antitumor ,Hematology ,Interleukin-11 ,Orphan Drug ,Peptides - Abstract
PurposeThe IL11 receptor (IL11R) is an established molecular target in primary tumors of bone, such as osteosarcoma, and in secondary bone metastases from solid tumors, such as prostate cancer. However, its potential role in management of hematopoietic malignancies has not yet been determined. Here, we evaluated the IL11R as a candidate therapeutic target in human leukemia and lymphoma.Experimental design and resultsFirst, we show that the IL11R protein is expressed in a variety of human leukemia- and lymphoma-derived cell lines and in a large panel of bone marrow samples from leukemia and lymphoma patients, whereas expression is absent from nonmalignant control bone marrow. Moreover, a targeted peptidomimetic prototype (termed BMTP-11), specifically bound to leukemia and lymphoma cell membranes, induced ligand-receptor internalization mediated by the IL11R, and resulted in a specific dose-dependent cell death induction in these cells. Finally, a pilot drug lead-optimization program yielded a new myristoylated BMTP-11 analogue with an apparent improved antileukemia cell profile.ConclusionsThese results indicate (i) that the IL11R is a suitable cell surface target for ligand-directed applications in human leukemia and lymphoma and (ii) that BMTP-11 and its derivatives have translational potential against this group of malignant diseases.
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- 2015
33. Relative survival in patients with chronic-phase chronic myeloid leukaemia in the tyrosine-kinase inhibitor era: analysis of patient data from six prospective clinical trials
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Sasaki, Koji, Strom, Sara S, O'Brien, Susan, Jabbour, Elias, Ravandi, Farhad, Konopleva, Marina, Borthakur, Gautam, Pemmaraju, Naveen, Daver, Naval, Jain, Preetesh, Pierce, Sherry, Kantarjian, Hagop, and Cortes, Jorge E
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Myeloid ,Adult ,Male ,Adolescent ,Clinical Trials and Supportive Activities ,Clinical Sciences ,and over ,Cardiorespiratory Medicine and Haematology ,Young Adult ,Rare Diseases ,Clinical Research ,80 and over ,Humans ,Prospective Studies ,Protein Kinase Inhibitors ,Cancer ,Aged ,Clinical Trials as Topic ,Leukemia ,Evaluation of treatments and therapeutic interventions ,Hematology ,Middle Aged ,Survival Rate ,6.1 Pharmaceuticals ,Chronic-Phase ,Female - Abstract
BackgroundTyrosine-kinase inhibitors improve overall survival in patients with chronic myeloid leukaemia in chronic phase (CML-CP). Survival compared with the general population by age, response, and type of tyrosine-kinase inhibitor is not known. With use of data from trials of tyrosine kinase inhibitors, we compared overall survival in patients with newly diagnosed CML-CP to that of general population.MethodsIn this cohort analysis, we included data from patients with CML-CP enrolled in six consecutive or parallel prospective clinical trials of tyrosine-kinase inhibitors at a single institution from July 30, 2000, to Sept 17, 2012. We analysed data for response and survival with the Kaplan-Meier method. For estimated overall survival in the general population, we obtained data from national vital statistics reports and matched to patients with CML-CP by age, sex, ethnicity, and year at diagnosis. We assessed numbers and causes of death within 1 year of beginning treatment by age group and by response to therapy. We then did univariate analysis and multivariate analysis to investigate factors associated with survival probability.FindingsOur analysis included 483 patients, 271 received imatinib, 105 received nilotinib, and 107 received dasatinib. Most patients were younger than 65 years, and no patients were older than 85 years. Median follow-up was 99·4 months (IQR 44·9-121·6), by which time 53 (11%) patients had died. The most common causes of death were progression to advanced disease stage, including complications of stem-cell transplantation (17 [4%] patients), secondary malignancies (nine [2%] patients), and cardiovascular causes (nine [2%] patients). 5-year overall survival in patients with CML-CP decreased in older age categories. For the whole population of patients with CML-CP, 5-year survival was only slightly lower than that of the matched general population (relative survival 94·7% [95% 92·1-97·4]). Individuals of all ages with a report of complete cytogenetic response to treatment or deeper within 1 year had a 5-year survival similar to that of the general population.InterpretationIn the era of treatment with tyrosine-kinase inhibitors, patients diagnosed with CML-CP can expect a 5-year survival that is only slightly lower than that of the general population. With access to tyrosine-kinase inhibitors, most patients with chronic myeloid leukaemia could enjoy a near normal life expectancy.FundingMD Anderson Cancer Center, National Cancer Institute.
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- 2015
34. RAS mutation acquisition at transformation from myelodysplastic syndrome to acute myeloid leukemia to predict poor outcome
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Talha Badar, Cortes, Jorge E., Jabbour, Elias, Borthakur, Gautam, Konopleva, Marina, Kadia, Tapan M., Bohannan, Zach, Pierce, Sherry, Ravandi, Farhad, Keyur Patel, Rajyalakshmi Luthra, Hagop M. Kantarjian, Garcia-Manero, Guillermo, I Need To Change My DOI, Thanks, and Talha
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- 2015
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35. New tool for monitoring molecular response in chronic myeloid leukemia
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Talha Badar, Hagop M. Kantarjian, Jabbour, Elias, Borthakur, Gautam, Naval Guastad Daver, Xuelin Huang, Singh, Rajesh, Alvarez, Brittany, Morrison, Tom, and Cortes, Jorge E.
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- 2015
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36. Phase II, multicenter, randomized trial of CPX-351 (cytarabine:daunorubicin) liposome injection versus intensive salvage therapy in adults with first relapse AML
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Cortes, Jorge E, Goldberg, Stuart L, Feldman, Eric J, Rizzeri, David A, Hogge, Donna E, Larson, Melissa, Pigneux, Arnaud, Recher, Christian, Schiller, Gary, Warzocha, Krzysztof, Kantarjian, Hagop, Louie, Arthur C, and Kolitz, Jonathan E
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Amsacrine ,Adult ,Male ,Myeloid ,Acute Myeloid Leukemia ,Pediatric Cancer ,Childhood Leukemia ,Clinical Trials and Supportive Activities ,Oncology and Carcinogenesis ,Kaplan-Meier Estimate ,Acute ,Chemotherapy Intervention ,Risk Assessment ,Disease-Free Survival ,Antibodies ,Injections ,Rare Diseases ,Recurrence ,Clinical Research ,Antineoplastic Combined Chemotherapy Protocols ,Monoclonal ,Humans ,Oncology & Carcinogenesis ,Humanized ,Etoposide ,Aged ,Cancer ,Salvage Therapy ,Pediatric ,Leukemia ,First Relapse ,Daunorubicin ,Remission Induction ,Cytarabine ,Evaluation of treatments and therapeutic interventions ,Hematology ,Middle Aged ,Gemtuzumab ,Phase II ,Aminoglycosides ,Treatment Outcome ,6.1 Pharmaceuticals ,Liposomes ,Public Health and Health Services ,Cladribine ,Female ,Mitoxantrone ,Vidarabine - Abstract
BackgroundCPX-351 is a liposome-encapsulated fixed-molar-ratio formulation of cytarabine and daunorubicin that exploits molar ratio-dependent drug-drug synergy to enhance antileukemic efficacy.MethodsThis phase II study randomized 125 patients 2:1 to CPX-351 or investigators' choice of first salvage chemotherapy. Patients with acute myeloid leukemia (AML) in first relapse after initial Complete Remission (CR) lasting ≥1 month were stratified per the European Prognostic Index (EPI) into favorable, intermediate, and poor-risk groups based on duration of first CR, cytogenetics, age, and transplant history. Control salvage treatment was usually based on cytarabine and anthracycline, often with 1 or more additional agents. Survival at 1 year was the primary efficacy end point.ResultsPatient characteristics were well balanced between the 2 study arms. Improvements in efficacy outcomes were observed following CPX-351, but did not meet prospectively defined statistical criteria for 1-year survival improvement in the overall population. Subset analyses of the EPI-defined poor-risk strata demonstrated higher response rates (39.3% vs 27.6%) and improvements in event-free survival (HR, 0.63; P = .08) and overall survival (HR, 0.55; P = .02). Also, 60-day mortality was lower in the CPX-351 study arm for poor-risk patients (16.1% vs 24.1%).ConclusionsTaken together, the data suggest possible improved outcomes in CPX-351-treated first relapse AML patients with EPI-defined poor-risk disease.
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- 2015
37. Augmented Berlin-Frankfurt-Münster therapy in adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL)
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Rytting, Michael E, Thomas, Deborah A, O'Brien, Susan M, Ravandi-Kashani, Farhad, Jabbour, Elias J, Franklin, Anna R, Kadia, Tapan M, Pemmaraju, Naveen, Daver, Naval G, Ferrajoli, Alessandra, Garcia-Manero, Guillermo, Konopleva, Marina Y, Cortes, Jorge E, Borthakur, Gautham, Garris, Rebecca, Cardenas-Turanzas, Maria, Schroeder, Kurt, Jorgensen, Jeffrey L, Kornblau, Steven M, and Kantarjian, Hagop M
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Adult ,Male ,Philadelphia chromosome-negative ALL ,Pediatric Research Initiative ,Adolescent ,Childhood Leukemia ,Pediatric Cancer ,Oncology and Carcinogenesis ,acute lymphoblastic leukemia ,Dexamethasone ,Maintenance Chemotherapy ,Cohort Studies ,Young Adult ,Rare Diseases ,Antineoplastic Combined Chemotherapy Protocols ,pediatric-based therapy ,Humans ,Asparaginase ,Prospective Studies ,Oncology & Carcinogenesis ,pediatric-based regimens ,Thioguanine ,Cyclophosphamide ,Cancer ,Pediatric ,Mercaptopurine ,Daunorubicin ,Cytarabine ,Evaluation of treatments and therapeutic interventions ,augmented Berlin-Frankfurt-Münster ,Induction Chemotherapy ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Stem Cell Research ,Consolidation Chemotherapy ,Methotrexate ,Treatment Outcome ,Orphan Drug ,Vincristine ,Doxorubicin ,6.1 Pharmaceuticals ,Public Health and Health Services ,Female - Abstract
BackgroundVarious trials have reported improved outcomes for adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) who received treatment with pediatric-based regimens. Those reports prompted the current investigation of the pediatric augmented Berlin-Frankfurt-Münster (ABFM) regimen in AYA patients. The results were compared with those from a similar population that received the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) regimen.MethodsEighty-five patients ages 12 to 40 years who had Philadelphia chromosome (Ph)-negative ALL received the ABFM regimen from October 2006 through April 2012. Their outcome was compared with outcomes in 71 historic AYA patients who received hyper-CVAD from the authors' institution. Patient and disease characteristics, as well as minimal residual disease status, were analyzed for their impact on outcomes.ResultsThe complete response rate with ABFM was 94%. The 3-year complete remission duration (CRD) and overall survival (OS) rates were 70% and 74%, respectively. For patients aged ≤21 years, the 3-year CRD and OS rates were 72% and 85%, respectively; and, for patients ages 21 to 40 years, the respective rates were 69% and 60%. The initial white blood cell count was an independent predictive factor of OS and CRD. The minimal residual disease status on days 29 and 84 of therapy also were predictive of long-term outcomes. Severe regimen toxicities included transient hepatotoxicity in 35% to 39% of patients, pancreatitis in 11% of patients, osteonecrosis in 11% of patients, and thrombosis in 22% of patients. The 3-year OS rate was 74% in the ABFM group versus 71% in the hyper-CVAD group, and the corresponding 3-year CRD rate was 70% versus 66%, respectively.ConclusionsABFM was tolerable in AYA patients with ALL but was not associated with significant improvements in CRD and OS compared with hyper-CVAD.
- Published
- 2014
38. Design, development, and validation of a high-throughput drug-screening assay for targeting of human leukemia
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Karjalainen, Katja, Pasqualini, Renata, Cortes, Jorge E., Kornblau, Steven M., Lichtiger, Benjamin, O'Brien, Susan, Kantarjian, Hagop M., Sidman, Richard L., Arap, Wadih, and Koivunen, Erkki
- Subjects
bone marrow ,Oncology and Carcinogenesis ,Drug Screening Assays ,chemical library ,Article ,Small Molecule Libraries ,Rare Diseases ,blood ,Humans ,tumor microenvironment ,drug screening ,Oncology & Carcinogenesis ,Cancer ,screening and diagnosis ,Leukemia ,leukemia targeting ,hypoxia ,Antitumor ,Hematology ,High-Throughput Screening Assays ,4.1 Discovery and preclinical testing of markers and technologies ,Oxygen ,Detection ,Orphan Drug ,Good Health and Well Being ,5.1 Pharmaceuticals ,Public Health and Health Services ,Drug Screening Assays, Antitumor ,Development of treatments and therapeutic interventions ,Biotechnology - Abstract
BackgroundThe authors developed an ex vivo methodology to perform drug library screening against human leukemia.MethodsThe strategy for this screening relied on human blood or bone marrow cultures under hypoxia; under these conditions, leukemia cells deplete oxygen faster than normal cells, causing a hemoglobin oxygenation shift. Several advantages were observed: 1) partial recapitulation of the leukemia microenvironment, 2) use of native hemoglobin oxygenation as a real-time sensor/reporter, 3) cost-effectiveness, 4) species specificity, and 5) a format that enables high-throughput screening.ResultsFor a proof of concept, a chemical library (size, approximately 20,000 compounds) was screened against human leukemia cells. Seventy compounds were identified ("hit" rate, 0.35%; Z-factor = 0.71) that had activity, and 20 compounds were examined to identify 18 true-positive compounds (90%). Finally, the results demonstrated that carbonohydraxonic diamide group-containing compounds are potent antileukemia agents that induce cell death in leukemia cells and in patient-derived samples.ConclusionsThe current results indicated that this unique functional assay can identify novel drug candidates and can help with the development of future applications in personalized drug selection for patients with leukemia.
- Published
- 2014
39. Imatinib-induced postoperative periorbital purpura: GASP (Gleevec-Associated Surgical Purpura) in a woman with imatinib-treated chronic myelogenous leukemia
- Author
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Anzalone, C Lane, Cohen, Philip R, Kurzrock, Razelle, and Cortes, Jorge E
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hemic and lymphatic diseases ,edema, Gleevec, imatinib, periorbital, postoperative, purpura ,neoplasms - Abstract
Background: Imatinib mesylate is a selective tyrosine kinase inhibitor used in the treatment of chronic myelogenous leukemia. Ocular side effects of imatinib include periorbital edema, which may become so severe as to obstruct the visual field. Purpose: The purpose of this case study is to describe the clinical characteristics of imatinib- induced postoperative periorbital purpura. Materials and methods: We retrospectively reviewed the medical literature using PubMed, searching the terms edema, Gleevec, imatinib, periorbital, postoperative and purpura. Patient reports and previous reviews of the subject were critically assessed and the salient features are presented. Results: Three patients have undergone surgery to reduce the imatinib-induced periorbital edema; two of these individuals have developed imatinib-induced postoperative periorbital purpura. Conclusion: We recommend discontinuing imatinib usage one week prior to periorbital surgery and not resuming therapy until the eighth postoperative day.
- Published
- 2014
40. A phase II Open-label Study of the Intravenous Administration of Homoharringtonine in the treatment of Myelodysplastic syndrome
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Daver, Naval, Vega-Ruiz, Arturo, Kantarjian, Hagop M., Estrov, Zeev, Ferrajoli, Alessandra, Kornblau, Steve, Verstovsek, Srdan, Garcia-Manero, Guillermo, and Cortes, Jorge E.
- Subjects
Aged, 80 and over ,Male ,Harringtonines ,Pilot Projects ,Middle Aged ,Article ,Drug Administration Schedule ,Treatment Outcome ,hemic and lymphatic diseases ,Myelodysplastic Syndromes ,Hematinics ,Humans ,Female ,Homoharringtonine ,Infusions, Intravenous ,Aged - Abstract
Homoharringtonine is an alkaloid inhibitor of protein synthesis with activity in myeloid malignancies. We report a phase II pilot study of homoharringtonine in myelodysplastic syndrome (MDS). Induction consisted of homoharringtonine at 2.5 mg/m(2) via continuous infusion for 7 days. Maintenance was given every 4 weeks. Nine patients were enrolled: five with refractory anaemia with excess blasts, two with refractory anaemia with excess blasts in transformation, one each with refractory anaemia and chronic myelomonocytic leukaemia respectively. Median age was 70 years (55-84) and 6 (66%) were male. Per International Prognostic Scoring System (IPSS) two patients were intermediate-1, five intermediate-2 and two high-risk. Median chemotherapy courses were one (1-3). One patient (11%) responded with complete haematological and cytogenetic remission after one course. Eight patients did not respond (four had stable disease, two progressed to acute leukaemia and two died during induction - from aspergillus pneumonia and intracerebral haemorrhage respectively). Grade 3/4 myelosuppression seen in 56% (5/9). Serious non-haematological toxicities included one case of grade 4 left bundle branch heart block and one grade 3 nephrotoxicity. Median time between courses was 42 days (35-72 days). In conclusion homoharringtonine might have clinical activity in some patients with MDS.
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- 2013
41. Ponatinib in refractory Philadelphia chromosome-positive leukemias
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Cortes, Jorge E, Kantarjian, Hagop, Shah, Neil P, Bixby, Dale, Mauro, Michael J, Flinn, Ian, O'Hare, Thomas, Hu, Simin, Narasimhan, Narayana I, Rivera, Victor M, Clackson, Tim, Turner, Christopher D, Haluska, Frank G, Druker, Brian J, Deininger, Michael WN, and Talpaz, Moshe
- Subjects
Adult ,Male ,Pediatric Cancer ,bcr-abl ,Drug Resistance ,Antineoplastic Agents ,Medical and Health Sciences ,Dose-Response Relationship ,Structure-Activity Relationship ,Rare Diseases ,Clinical Research ,General & Internal Medicine ,80 and over ,Humans ,Chronic ,Aged ,Cancer ,Pediatric ,Leukemia ,Imidazoles ,Fusion Proteins ,Evaluation of treatments and therapeutic interventions ,Lipase ,Hematology ,Middle Aged ,Protein-Tyrosine Kinases ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Pyridazines ,Pancreatitis ,6.1 Pharmaceuticals ,Amylases ,Mutation ,Neoplasm ,Female ,BCR-ABL Positive ,Drug ,Follow-Up Studies ,Myelogenous - Abstract
BackgroundResistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) is frequently caused by mutations in the BCR-ABL kinase domain. Ponatinib (AP24534) is a potent oral tyrosine kinase inhibitor that blocks native and mutated BCR-ABL, including the gatekeeper mutant T315I, which is uniformly resistant to tyrosine kinase inhibitors.MethodsIn this phase 1 dose-escalation study, we enrolled 81 patients with resistant hematologic cancers, including 60 with CML and 5 with Ph-positive ALL. Ponatinib was administered once daily at doses ranging from 2 to 60 mg. Median follow-up was 56 weeks (range, 2 to 140).ResultsDose-limiting toxic effects included elevated lipase or amylase levels and pancreatitis. Common adverse events were rash, myelosuppression, and constitutional symptoms. Among Ph-positive patients, 91% had received two or more approved tyrosine kinase inhibitors, and 51% had received all three approved tyrosine kinase inhibitors. Of 43 patients with chronic-phase CML, 98% had a complete hematologic response, 72% had a major cytogenetic response, and 44% had a major molecular response. Of 12 patients who had chronic-phase CML with the T315I mutation, 100% had a complete hematologic response and 92% had a major cytogenetic response. Of 13 patients with chronic-phase CML without detectable mutations, 100% had a complete hematologic response and 62% had a major cytogenetic response. Responses among patients with chronic-phase CML were durable. Of 22 patients with accelerated-phase or blast-phase CML or Ph-positive ALL, 36% had a major hematologic response and 32% had a major cytogenetic response.ConclusionsPonatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations. (Funded by Ariad Pharmaceuticals and others; ClinicalTrials.gov number, NCT00660920.).
- Published
- 2012
42. Treatment-free remission in chronic myeloid leukemia
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Molica, Matteo, Naqvi, Kiran, Cortes, Jorge E., Shilpa Paul, Kadia, Tapan M., Breccia, Massimo, Kantarjian, Hagop, and Jabbour, Elias J.
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Recurrence ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Fusion Proteins, bcr-abl ,Humans ,Protein Kinase Inhibitors - Abstract
Tyrosine kinase inhibitors (TKIs) represent a major breakthrough in the treatment of chronic myeloid leukemia (CML). Thanks to these agents, CML has been transformed from a disease with limited treatment options and a dismal prognosis into a more indolent disease with survival comparable to that of the general population. The need for ongoing TKI therapy remains controversial for several reasons, including cost and toxicity. Studies in CML patients with a sustained deep molecular response have demonstrated that stopping TKI therapy is feasible and safe. Given the heterogeneity of results reported in clinical trials, practice guidelines for optimal patient selection and proper monitoring after discontinuation of TKIs are proposed outside of clinical trials. Current data available show that 40% to 60% of patients who stop therapy relapse; molecular relapses typically occur within 6 months, but nearly all relapsing patients regain response upon reinitiation of the TKI. Several factors that predict for relapse have been investigated. Duration of prior TKI therapy, achievement of deep molecular response, depth of molecular response, prior interferon treatment, and Sokal risk score have been shown to be potential predictors for relapse. Leukemia stem cells that are resistant to TKIs, and that persist despite undetectable BCR/ABL1 transcript levels, likely are responsible for disease relapse after discontinuation. Efforts geared toward better identification of low levels of BCR/ABL1 transcript using new techniques such as digital polymerase chain reaction, along with eradicating CML clones using combination therapies with agents such as pegylated interferon or venetoclax with TKIs, will hopefully lead to a functional cure of this disease.
43. Effect of early blood counts on overall survival (OS) following glasdegib plus LDAC in newly diagnosed AML: BRIGHT AML 1003 post hoc analysis
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Wang, Eunice S., Heuser, Michael, Sekeres, Mikkael A., Papayannidis, Cristina, anna candoni, Merchant, Akil, Brown, Andrew, O Connell, Ashleigh, Ma, Wendy, Chan, Geoffrey, and Cortes, Jorge E.
44. Effect of Early Blood Counts on Response and Overall Survival Following Glasdegib Plus LDAC in Newly Diagnosed AML: BRIGHT AML 1003 Post Hoc Analysis
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Wang, Eunice S., Heuser, Michael, Sekeres, Mikkael A., Papayannidis, Cristina, anna candoni, Merchant, Akil, Brown, Andrew M., O Connell, Ashleigh, Ma, Weidong Wendy, Chan, Geoffrey, and Cortes, Jorge E.
45. Treatment-free remission (TFR) in patients with chronic myeloid leukemia (CML) following the discontinuation of tyrosine kinase inhibitors
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Haddad, Fadi, Jabbour, Elias, Issa, Ghayas C., Garcia-Manero, Guillermo, Ravandi, Farhad, Kadia, Tapan M., Cortes, Jorge E., Konopleva, Marina, Pemmaraju, Naveen, Valero, Yesid Alvarado, Yilmaz, Musa, Borthakur, Gautam, Dinardo, Courtney Denton, Jain, Nitin, Daver, Naval Guastad, Short, Nicholas James, Kantarjian, Hagop M., and Koji Sasaki
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Cancer Research ,Oncology - Abstract
7050 Background: Tyrosine kinase inhibitors (TKIs) discontinuation in patients (pts) with CML is increasingly considered. We evaluated the outcome of pts with CML who discontinued TKIs and determined the factors associated with differences in the success rates of TFR. Methods: We reviewed data from 284 pts with CML treated with TKIs at our institution between October 1999 and February 2017 and who subsequently discontinued therapy. Major molecular response (MMR) was defined as a BCR-ABL1/ABL1 transcripts ratio ≤0.1% as determined by real time (RT)-PCR, MR4 as a ratio ≤0.01% IS, and MR4.5 as a ratio ≤0.0032%. TFR failure was defined as the loss of MMR on any single test. We analyzed TFR rates according to duration and depth of response and conducted a multivariate analysis for factors associated with loss of MMR. Results: Median age was 63 years (range, 25-93). 199 pts (70%) had electively discontinued their TKI while 70 pts (24%) stopped therapy because of adverse events. 92 pts (32%) had switched ≥1 TKI prior to discontinuation due to drug intolerance or resistance. The median time from the initiation of frontline TKI to discontinuation was 117 months (range, 16-242). The median duration of MR4 and MR4.5 before TKI discontinuation was 74 months (range, 2-207) and 64 months (range, 0-207), respectively. At a median follow-up of 36 months (95% CI, 32-40) after TKI discontinuation, 53 pts (19%) lost MMR, translating into a 5-year TFR rate of 79%. 50 pts (94%) resumed TKI therapy and, among 47 evaluable pts, all but one pt regained MMR, with 41 pts (88%) achieving MR4.5. The estimated 5-year TFR rates were 91%, 76% and 70% in pts achieving MR4.5 for ≥6 years, between 5 and 6 years, and < 5 years, respectively (P < 0.0001). The estimated 5-year TFR rates were higher with MR4 and MR4.5 ≥5 years, compared with MR4 < 5 years (87% vs 92% vs 64%; P < 0.0001). Pts who remained on their frontline TKI at the time of discontinuation had a 5-year TFR rate of 82%, compared with 75% and 72% among pts who switched to a second line TKI or beyond because of intolerance or resistance, respectively (P = 0.417). TFR rates did not vary according to the type of frontline TKI used (P = 0.761). By multivariate analysis, only durations in MR4 or MR4.5 ≥5 years before stopping treatment were associated with a lower risk of loss of MMR, with hazard ratios of 0.37 (95% CI, 0.18-0.76; P = 0.007) and 0.20 (95% CI, 0.09-0.45; P < 0.0001), respectively. We evaluated the impact of the frequency of molecular monitoring on the success rate of TFR. The estimated 5-year TFR rate was 79% for pts monitored monthly compared with 85% for pts monitored every 6-8 weeks following discontinuation (P = 0.263). Conclusions: Our findings suggest that achieving MR4 for ≥5 years was associated with a very high probability of maintaining TFR, and that less frequent molecular monitoring could be more cost-effective without any negative impact on outcomes.
46. Treatment with PF-04449913, an oral smoothened antagonist, in patients with myeloid malignancies: a phase 1 safety and pharmacokinetics study
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Rachel Courtney, Vivian G. Oehler, Wendy J. Levin, Michele Baccarani, Naveed Shaik, Catriona Jamieson, Xiaoxi Zhang, Jerald P. Radich, Hagop M. Kantarjian, Giovanni Martinelli, Cristina Papayannidis, Jorge E. Cortes, Ashleigh O'Connell, Karen McLachlan, Xianxian Zheng, Martinelli, Giovanni, Oehler, Vivian G., Papayannidis, Cristina, Courtney, Rachel, Shaik, M. Naveed, Zhang, Xiaoxi, O'Connell, Ashleigh, Mclachlan, Karen R., Zheng, Xianxian, Radich, Jerald, Baccarani, Michele, Kantarjian, Hagop M., Levin, Wendy J., Cortes, Jorge E., and Jamieson, Catriona
- Subjects
medicine.medical_specialty ,Myeloid ,Maximum Tolerated Dose ,Administration, Oral ,Pharmacology ,Gastroenterology ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Internal medicine ,medicine ,Clinical endpoint ,Humans ,Adverse effect ,Myelofibrosis ,business.industry ,Phenylurea Compounds ,Standard treatment ,Hematology ,medicine.disease ,United States ,Dysgeusia ,Leukemia, Myeloid, Acute ,Treatment Outcome ,medicine.anatomical_structure ,Italy ,Tolerability ,Primary Myelofibrosis ,Myelodysplastic Syndromes ,Pharmacodynamics ,Benzimidazoles ,medicine.symptom ,business ,Half-Life - Abstract
Summary Background Activation of the Hedgehog signalling pathway contributes to cancer progression and the development of myeloid leukaemia stem cell therapeutic resistance. We aimed to identify the maximum tolerated dose (MTD) and the recommended phase 2 dose of the selective Hedgehog antagonist PF-04449913 in myeloid malignancies. Methods We undertook an open-label, dose-finding, standard 3+3 design phase 1 study of PF-04449913 in adult patients with acute myeloid leukaemia, chronic myeloid leukaemia, chronic myelomonocytic leukaemia, myelodysplastic syndrome, or myelofibrosis who were refractory, resistant, or intolerant to previous treatments, at three centres in the USA and one in Italy. Patients who had newly diagnosed, untreated disease were included if they were not eligible for standard treatment options or if standard treatments were not deemed appropriate. Patients received PF-04449913 once daily continuously until disease progression, unacceptable toxic effects, or patient withdrawal for up to 12 28-day cycles. Additional cycles were given if patients showed evidence of clinical benefit. The starting dose was 5 mg and was increased by 100% until the first dose-limiting toxic effect (DLT) and by 50% thereafter, in keeping with a 3+3 clinical trial statistical design. The primary endpoint was first-cycle DLTs. Secondary endpoints were safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. This trial is registered with ClinicalTrials.gov, number NCT00953758. Findings Between March 24, 2010, and Sept 7, 2012, 47 patients were enrolled and included in the study: 28 with acute myeloid leukaemia, six with myelodysplastic syndrome, five with chronic myeloid leukaemia (two with chronic-phase and three with blast-phase disease), one with chronic myelomonocytic leukaemia, and seven with myelofibrosis. Patients received PF-04449913 once daily at 5 mg (n=3), 10 mg (n=3), 20 mg (n=4), 40 mg (n=4), 80 mg (n=8), 120 mg (n=3), 180 mg (n=3), 270 mg (n=5), 400 mg (n=9), and 600 mg (n=5). Two patients experienced DLTs (one each in the 80 mg and 600 mg dose groups). The MTD for PF-04449913 was established to be 400 mg once daily. Of the 47 patients enrolled, 28 (60%) experienced treatment-related adverse events, three of which were grade 4 in severity. The most common treatment-related adverse events included dysgeusia (13 [28%] patients), decreased appetite (nine [19%]), and alopecia (seven [15%]). None of the 15 deaths reported were treatment related. Pharmacokinetics seemed to be dose proportional. The mean half-life was 23·9 h (SD 14·0) in the MTD group. Some suggestion of clinical activity was noted in 23 (49%) of 47 patients with haematological malignancies. Based on these results, the recommended phase 2 dose was 200 mg or lower once daily. Interpretation Based on these findings, PF-04449913 is being tested in phase 2 studies in patients with myelodysplastic syndrome, acute myeloid leukaemia, and myelofibrosis. Funding Pfizer.
- Published
- 2015
47. Long-term response to imatinib is not affected by the initial dose in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: final update from the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) study
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Jerald P. Radich, Lidia Mongay, Dong-Wook Kim, Michele Baccarani, Christine Elke Ortmann, Brian J. Druker, Hagop M. Kantarjian, Timothy P. Hughes, Susan Branford, Jorge E. Cortes, François Guilhot, Manisha Mone, Fabrizio Pane, Baccarani, Michele, Druker, Brian J., Branford, Susan, Kim, Dong Wook, Pane, Fabrizio, Mongay, Lidia, Mone, Manisha, Ortmann, Christine Elke, Kantarjian, Hagop M., Radich, Jerald P., Hughes, Timothy P., Cortes, Jorge E., and Guilhot, François
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medicine.medical_specialty ,Time Factors ,Myeloid ,Time Factor ,medicine.drug_class ,Fusion Proteins, bcr-abl ,Tyrosine kinase inhibitor ,Protein Kinase Inhibitor ,Phases of clinical research ,Antineoplastic Agents ,Gastroenterology ,Piperazines ,Tyrosine-kinase inhibitor ,Follow-Up Studie ,Antineoplastic Agent ,Benzamide ,Phase 3 clinical trial ,Internal medicine ,medicine ,Humans ,BCR-ABL ,Piperazine ,Protein Kinase Inhibitors ,Hematology ,business.industry ,Medicine (all) ,Chronic myeloid leukemia ,Myeloid leukemia ,Imatinib ,medicine.disease ,Surgery ,Leukemia ,Pyrimidines ,Treatment Outcome ,Imatinib mesylate ,medicine.anatomical_structure ,Pyrimidine ,Benzamides ,Leukemia, Myeloid, Chronic-Phase ,Imatinib Mesylate ,business ,Human ,Follow-Up Studies ,medicine.drug - Abstract
The TOPS trial evaluated high- (800 mg/day; n = 319) versus standard-dose (400 mg/day; n = 157) imatinib in patients newly diagnosed with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase. Patients had a minimum follow-up of 42 months or discontinued early. Major molecular response (MMR) rates were similar between arms at (51.6 vs 50.2 % for 400 and 800 mg/day, respectively; P = 0.77) and by (75.8 vs 79.0 %; P = 0.4807) 42 months. There were no differences in event-free survival (EFS), progression-free survival(PFS), or overall survival (OS) between arms. The estimated rates of PFS on treatment and OS at 42 months were significantly higher in patients with MMR at 6, 12, and 18 months compared with those without MMR.Adverse events were more frequent with high-dose imatinib. Patients with B1 treatment interruption (vs [1) and those able to maintain imatinib C600 mg/day (vs\600 mg/day) in the first year of treatment had faster and higher response rates, but no improvement in EFS or PFS. Adherence to prescribed dose without interruption may be more important than initiation of therapy with higher doses of imatinib. Achievement of MMR correlated with longterm clinical outcomes.
- Published
- 2014
48. Overall survival with ponatinib versus allogeneic stem cell transplantation in Philadelphia chromosome-positive leukemias with the T315I mutation
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Nicolini, FE, Basak, GW, Kim, DW, Olavarria, E, Pinilla-Ibarz, J, Apperley, JF, Hughes, T, Niederwieser, D, Mauro, MJ, Chuah, C, Hochhaus, A, Martinelli, G, DerSarkissian, M, Duh, MS, McGarry, LJ, Kantarjian, HM, Cortes, JE, Nicolini, Franck E., Basak, Grzegorz W., Kim, Dong-Wook, Olavarria, Eduardo, Pinilla-Ibarz, Javier, Apperley, Jane F., Hughes, Timothy, Niederwieser, Dietger, Mauro, Michael J., Chuah, Charle, Hochhaus, Andrea, Martinelli, Giovanni, DerSarkissian, Maral, Duh, Mei Sheng, McGarry, Lisa J., Kantarjian, Hagop M., Cortes, Jorge E., Imperial College Trust, Imperial College Healthcare NHS Trust- BRC Funding, and National Institute for Health Research
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Male ,Cancer Research ,Hematologic Malignancies ,Kaplan-Meier Estimate ,RESISTANT ,Blast Crisi ,Antineoplastic Agent ,Retrospective Studie ,hemic and lymphatic diseases ,Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph plus ALL) ,Philadelphia Chromosome ,ponatinib ,Multivariate Analysi ,MARGINAL STRUCTURAL MODELS ,Transplantation, Homologou ,Imidazoles ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Pyridazines ,Survival Rate ,allogeneic stem cell transplantation (allo-SCT) ,Treatment Outcome ,Oncology ,Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph+ ALL) ,Female ,Original Article ,Pyridazine ,Life Sciences & Biomedicine ,Human ,Adult ,Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) ,Antineoplastic Agents ,PHASE-2 ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,threonine to isoleucine mutation at codon 315 (T315I) ,Humans ,Transplantation, Homologous ,Oncology & Carcinogenesis ,chronic myeloid leukemia (CML) ,CHRONIC MYELOID-LEUKEMIA ,Imidazole ,ACUTE LYMPHOBLASTIC-LEUKEMIA ,Aged ,Proportional Hazards Models ,Retrospective Studies ,Science & Technology ,Original Articles ,Multivariate Analysis ,Mutation ,Proportional Hazards Model ,Disease Site ,INHIBITORS ,Blast Crisis ,1112 Oncology And Carcinogenesis ,allogeneic stem cell transplantation (allo‐SCT) ,Stem Cell Transplantation - 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., In patients who have chronic‐phase chronic myeloid leukemia (CML) with the Philadelphia chromosome threonine to isoleucine mutation at codon 315, single‐agent ponatinib is associated with significantly longer overall survival compared with allogenic stem cell transplantation. In those who have accelerated‐phase CML, blast‐crisis CML, and Philadelphia chromosome‐positive acute lymphoblastic leukemia with the T315I mutation, single‐agent ponatinib is associated with similar or shorter overall survival compared with stem cell transplantation.
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- 2016
49. Compound mutations in BCR-ABL1 are not major drivers of primary or secondary resistance to ponatinib in CP-CML patients
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J. Graeme Hodgson, Moshe Talpaz, Jin Li, Tim Clackson, Victor M. Rivera, François Guilhot, Franck E. Nicolini, Stephanie Lustgarten, Simona Soverini, Timothy P. Hughes, Michael W. Deininger, Susan Branford, Michele Baccarani, Frank G. Haluska, Hagop M. Kantarjian, Martin Müller, Jorge E. Cortes, Dong-Wook Kim, Neil P. Shah, Wendy T Parker, Andreas Hochhaus, Deininger, Mw, Hodgson, Jg, Shah, Np, Cortes, Je, Kim, Dw, Nicolini, Fe, Talpaz, M, Baccarani, M, Müller, Mc, Li, J, Parker, Wt, Lustgarten, S, Clackson, T, Haluska, Fg, Guilhot, F, Kantarjian, Hm, Soverini, S, Hochhaus, A, Hughes, Tp, Rivera, Vm, Branford, S., Deininger, Michael W, Hodgson, J Graeme, Shah, Neil P, Cortes, Jorge E, and Branford, Susan
- Subjects
0301 basic medicine ,Myeloid ,DNA Mutational Analysis ,Fusion Proteins, bcr-abl ,Drug resistance ,medicine.disease_cause ,Biochemistry ,RECOMMENDATIONS ,chemistry.chemical_compound ,KINASE-INHIBITOR THERAPY ,0302 clinical medicine ,DOMAIN ,hemic and lymphatic diseases ,Sanger sequencing ,Mutation ,european leukemianet ,Ponatinib ,CHROMOSOME-POSITIVE LEUKEMIAS ,Imidazoles ,High-Throughput Nucleotide Sequencing ,Myeloid leukemia ,Hematology ,kinase-inhibitor therapy ,Neoadjuvant Therapy ,chromosome-positive leukemias ,Pyridazines ,Leukemia ,medicine.anatomical_structure ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Leukemia, Myeloid, Chronic-Phase ,symbols ,CHRONIC PHASE ,Tyrosine kinase ,Immunology ,bcr-abl mutations ,Biology ,IMATINIB ,03 medical and health sciences ,symbols.namesake ,BCR-ABL MUTATIONS ,EUROPEAN LEUKEMIANET ,medicine ,Humans ,CHRONIC MYELOID-LEUKEMIA ,Protein Kinase Inhibitors ,chronic phase ,chronic myeloid-leukemia ,Cell Biology ,medicine.disease ,030104 developmental biology ,Amino Acid Substitution ,chemistry ,imatinib ,Drug Resistance, Neoplasm ,MUTANT ,Cancer research - 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 (containingmutations 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. Refereed/Peer-reviewed
- Published
- 2016
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