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1. Genomic landscape of patients with FLT3-mutated acute myeloid leukemia (AML) treated within the CALGB 10603/RATIFY trial

Author

Jahn, Nikolaus, Jahn, Ekaterina, Saadati, Maral, Bullinger, Lars, Larson, Richard A., Ottone, Tiziana, Amadori, Sergio, Prior, Thomas W., Brandwein, Joseph M., Appelbaum, Frederick R., Medeiros, Bruno C., Tallman, Martin S., Ehninger, Gerhard, Heuser, Michael, Ganser, Arnold, Pallaud, Celine, Gathmann, Insa, Krzykalla, Julia, Benner, Axel, Bloomfield, Clara D., Thiede, Christian, Stone, Richard M., Döhner, Hartmut, and Döhner, Konstanze

Published
2022
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2. Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results

Author

Rücker, Frank G., Du, Ling, Luck, Tamara J., Benner, Axel, Krzykalla, Julia, Gathmann, Insa, Voso, Maria Teresa, Amadori, Sergio, Prior, Thomas W., Brandwein, Joseph M., Appelbaum, Frederick R., Medeiros, Bruno C., Tallman, Martin S., Savoie, Lynn, Sierra, Jorge, Pallaud, Celine, Sanz, Miguel A., Jansen, Joop H., Niederwieser, Dietger, Fischer, Thomas, Ehninger, Gerhard, Heuser, Michael, Ganser, Arnold, Bullinger, Lars, Larson, Richard A., Bloomfield, Clara D., Stone, Richard M., Döhner, Hartmut, Thiede, Christian, and Döhner, Konstanze

Published
2022
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3. Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial

Author

Larson, Richard A., Mandrekar, Sumithra J., Huebner, Lucas J., Sanford, Ben L., Laumann, Kristina, Geyer, Susan, Bloomfield, Clara D., Thiede, Christian, Prior, Thomas W., Döhner, Konstanze, Marcucci, Guido, Voso, Maria Teresa, Klisovic, Rebecca B., Galinsky, Ilene, Wei, Andrew H., Sierra, Jorge, Sanz, Miguel A., Brandwein, Joseph M., de Witte, Theo, Niederwieser, Dietger, Appelbaum, Frederick R., Medeiros, Bruno C., Tallman, Martin S., Krauter, Jürgen, Schlenk, Richard F., Ganser, Arnold, Serve, Hubert, Ehninger, Gerhard, Amadori, Sergio, Gathmann, Insa, Döhner, Hartmut, and Stone, Richard M.

Published
2021
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4. Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results

Author

Rücker, Frank G., primary, Du, Ling, additional, Luck, Tamara J., additional, Benner, Axel, additional, Krzykalla, Julia, additional, Gathmann, Insa, additional, Voso, Maria Teresa, additional, Amadori, Sergio, additional, Prior, Thomas W., additional, Brandwein, Joseph M., additional, Appelbaum, Frederick R., additional, Medeiros, Bruno C., additional, Tallman, Martin S., additional, Savoie, Lynn, additional, Sierra, Jorge, additional, Pallaud, Celine, additional, Sanz, Miguel A., additional, Jansen, Joop H., additional, Niederwieser, Dietger, additional, Fischer, Thomas, additional, Ehninger, Gerhard, additional, Heuser, Michael, additional, Ganser, Arnold, additional, Bullinger, Lars, additional, Larson, Richard A., additional, Bloomfield, Clara D., additional, Stone, Richard M., additional, Döhner, Hartmut, additional, Thiede, Christian, additional, and Döhner, Konstanze, additional

Published
2021
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5. Molecular landscape and prognostic impact of FLT3 -ITD insertion site in acute myeloid leukemia : RATIFY study results

Author

Rücker, Frank G., Du, Ling, Luck, Tamara J., Benner, Axel, Krzykalla, Julia, Gathmann, Insa, Voso, Maria Teresa, Amadori, Sergio, Prior, Thomas W., Brandwein, Joseph M., Appelbaum, Frederick R., Medeiros, Bruno, Tallman, Martin S., Savoie, Lynn, Sierra, Jorge, Pallaud, Celine, Sanz, Miguel A., Jansen, Joop H., Niederwieser, Dietger, Fischer, Thomas, Ehninger, Gerhard, Heuser, Michael, Ganser, Arnold, Bullinger, Lars, Larson, Richard A., Bloomfield, Clara D., Stone, Richard M., Döhner, Hartmut, Thiede, Christian, Döhner, Konstanze, Universitat Autònoma de Barcelona, Rücker, Frank G., Du, Ling, Luck, Tamara J., Benner, Axel, Krzykalla, Julia, Gathmann, Insa, Voso, Maria Teresa, Amadori, Sergio, Prior, Thomas W., Brandwein, Joseph M., Appelbaum, Frederick R., Medeiros, Bruno, Tallman, Martin S., Savoie, Lynn, Sierra, Jorge, Pallaud, Celine, Sanz, Miguel A., Jansen, Joop H., Niederwieser, Dietger, Fischer, Thomas, Ehninger, Gerhard, Heuser, Michael, Ganser, Arnold, Bullinger, Lars, Larson, Richard A., Bloomfield, Clara D., Stone, Richard M., Döhner, Hartmut, Thiede, Christian, Döhner, Konstanze, and Universitat Autònoma de Barcelona

Abstract

In acute myeloid leukemia (AML) internal tandem duplications of the FLT3 gene (FLT3- ITD) are associated with poor prognosis. Retrospectively, we investigated the prognostic and predictive impact of FLT3 -ITD insertion site (IS) in 452 patients randomized within the RATIFY trial, which evaluated midostaurin additionally to intensive chemotherapy. Next-generation sequencing identified 908 ITDs, with 643 IS in the juxtamembrane domain (JMD) and 265 IS in the tyrosine kinase domain-1 (TKD1). According to IS, patients were categorized as JMDsole (n = 251, 55%), JMD and TKD1 (JMD/TKD1; n = 117, 26%), and TKD1sole (n = 84, 19%). While clinical variables did not differ among the 3 groups, NPM1 mutation was correlated with JMDsole (P = 0.028). Overall survival (OS) differed significantly, with estimated 4-year OS probabilities of 0.44, 0.50, and 0.30 for JMDsole, JMD/TKD1, and TKD1sole, respectively (P = 0.032). Multivariate (cause-specific) Cox models for OS and cumulative incidence of relapse using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable identified TKD1sole as unfavorable and HCT as favorable factors. In addition, Midostaurin exerted a significant benefit only for JMDsole. Our results confirm the distinct molecular heterogeneity of FLT3 -ITD and the negative prognostic impact of TKD1 IS in AML that was not overcome by midostaurin.

Published
2021

7. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia

Author

Druker, Brian J., Deininger, Michael W.N., Silver, Richard T., Gathmann, Insa, Kantarjian, Hagop, Gattermann, Norbert, Guilhot, Francois, O'Brien, Stephen G., Rousselot, Philippe; Reiffers, Josy, and Cornelissen, Jan J.

Subjects
Chronic myeloid leukemia -- Drug therapy, Interferon alpha -- Dosage and administration
Abstract

A randomized trial was carried out to compare imatinib with interferon alfa plus cytarabine in the chronic phase of chronic myeloid leukemia (CML) to demonstrate the significant superiority of imatinib in all standard indicators of the disease within a median follow-up of 19 months. After 5 years of follow-up, continuous treatment of chronic-phase CML with imatinib as initial therapy was found to include durable responses in a high proportion of patients.

Published
2006

8. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia

Author

Hughes, Tim P., Kaeda, Jaspal, Branford, Susan, Rudzki, Zbigniew, Hochhaus, Andreas, Hensley, Martee L., Gathmann, Insa, Bolton, Ann E., Hoomissen, Iris C. van, Goldman, John M., and Radich, Jerald P.

Subjects
Chronic myeloid leukemia -- Drug therapy, Chronic myeloid leukemia -- Prognosis
Abstract

The drug imatinib may be more effective than interferon alfa plus cytarabine for treating chronic myeloid leukemia, according to a study of 1,106 patients. Imatinib was much more effective in lowering blood levels of BCR-ABL, an abnormal protein that causes some of the symptoms of this type of leukemia. Patients whose blood level of BCR-ABL was lowered lived longer free of disease than other patients.

Published
2003

9. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia

Author

O'Brien, Stephen G., Guilhot, Francois, Larson, Richard A., Gathmann, Insa, Baccarani, Michele, Cervantes, Francisco, Cornelissen, Jan J., Fischer, Thomas, Hochhaus, Andreas, Hughes, Timothy, Lechner, Klaus, Nielsen, Johan L., Rousselot, Philippe, Reiffers, Josy, Saglio, Giuseppe, Shepherd, John, Simonsson, Bengt, Gratwohl, Alois, Goldman, John M., Kantarjian, Hagop, Taylor, Kerry, Verhoef, Gregor, Bolton, Ann E., Capdeville, Renaud, and Druker, Brian J.

Subjects
Novartis AG -- Product information, Gleevec (Medication) -- Evaluation, Pharmaceutical industry -- Product information, Chronic myeloid leukemia -- Drug therapy
Abstract

The drug Gleevec is more effective than interferon and cytarabine for treating patients with newly diagnosed chronic myeloid leukemia, according to a study of 1,106 patients. Gleevec inhibits an abnormal enzyme that is produced by a chromosomal abnormality. It is the abnormal enzyme that causes the symptoms of this type of leukemia.

Published
2003

11. Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia

Author

Döhner, Konstanze, primary, Thiede, Christian, additional, Jahn, Nikolaus, additional, Panina, Ekaterina, additional, Gambietz, Agnes, additional, Larson, Richard A., additional, Prior, Thomas W., additional, Marcucci, Guido, additional, Jones, Dan, additional, Krauter, Jürgen, additional, Heuser, Michael, additional, Voso, Maria Teresa, additional, Ottone, Tiziana, additional, Nomdedeu, Josep F., additional, Mandrekar, Sumithra J., additional, Klisovic, Rebecca B., additional, Wei, Andrew H., additional, Sierra, Jorge, additional, Sanz, Miguel A., additional, Brandwein, Joseph M., additional, de Witte, Theo, additional, Jansen, Joop H., additional, Niederwieser, Dietger, additional, Appelbaum, Frederick R., additional, Medeiros, Bruno C., additional, Tallman, Martin S., additional, Schlenk, Richard F., additional, Ganser, Arnold, additional, Serve, Hubert, additional, Ehninger, Gerhard, additional, Amadori, Sergio, additional, Gathmann, Insa, additional, Benner, Axel, additional, Pallaud, Celine, additional, Stone, Richard M., additional, Döhner, Hartmut, additional, and Bloomfield, Clara D., additional

Published
2020
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12. Relative response of patients with myelodysplastic syndromes and other transfusion-dependent anaemias to deferasirox (ICL670): a 1-yr prospective study

Author

Porter, John, Galanello, Renzo, Saglio, Giuseppe, Neufeld, Ellis J., Vichinsky, Elliott, Cappellini, Maria Domenica, Olivieri, Nancy, Piga, Antonio, Cunningham, Melody J., Soulières, Denis, Gattermann, Norbert, Tchernia, Gilbert, Maertens, Johan, Giardina, Patricia, Kwiatkowski, Janet, Quarta, Giovanni, Jeng, Michael, Forni, Gian Luca, Stadler, Michael, Cario, Holger, Debusscher, Louisette, Della Porta, Matteo, Cazzola, Mario, Greenberg, Peter, Alimena, Giuliana, Rabault, Bertrand, Gathmann, Insa, Ford, John Malcolm, Alberti, Daniele, and Rose, Christian

Published
2008

13. The prognosis for patients with chronic myeloid leukemia who have clonal cytogenetic abnormalities in philadelphia chromosome-negative cells

Author

Deininger, Michael W. N., Cortes, Jorge, Paquette, Ron, Park, Byung, Hochhaus, Andreas, Baccarani, Michele, Stone, Richard, Fischer, Thomas, Kantarjian, Hagop, Niederwieser, Dietger, Gambacorti-Passerini, Carlo, So, Charlene, Gathmann, Insa, Goldman, John M., Smith, Douglas, Druker, Brian J., and Guilhot, François

Published
2007
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16. A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome–positive acute lymphoid leukemias

Author

Ottmann, Oliver G., Druker, Brian J., Sawyers, Charles L., Goldman, John M., Reiffers, Jose, Silver, Richard T., Tura, Sante, Fischer, Thomas, Deininger, Michael W., Schiffer, Charles A., Baccarani, Michele, Gratwohl, Alois, Hochhaus, Andreas, Hoelzer, Dieter, Fernandes-Reese, Sofia, Gathmann, Insa, Capdeville, Renaud, and O'Brien, Stephen G.

Published
2002
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17. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study: Presented in part at the 43rd Annual Meeting of The American Society of Hematology, Orlando, FL, December 11, 2001.

Author

Sawyers, Charles L., Hochhaus, Andreas, Feldman, Eric, Goldman, John M., Miller, Carole B., Ottmann, Oliver G., Schiffer, Charles A., Talpaz, Moshe, Guilhot, Francois, Deininger, Michael W.N., Fischer, Thomas, O'Brien, Steve G., Stone, Richard M., Gambacorti-Passerini, Carlo B., Russell, Nigel H., Reiffers, Jose J., Shea, Thomas C., Chapuis, Bernard, Coutre, Steven, Tura, Sante, Morra, Enrica, Larson, Richard A., Saven, Alan, Peschel, Christian, Gratwohl, Alois, Mandelli, Franco, Ben-Am, Monique, Gathmann, Insa, Capdeville, Renaud, Paquette, Ronald L., and Druker, Brian J.

Published
2002
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18. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study

Author

Talpaz, Moshe, Silver, Richard T., Druker, Brian J., Goldman, John M., Gambacorti-Passerini, Carlo, Guilhot, Francois, Schiffer, Charles A., Fischer, Thomas, Deininger, Michael W.N., Lennard, Anne L., Hochhaus, Andreas, Ottmann, Oliver G., Gratwohl, Alois, Baccarani, Michele, Stone, Richard, Tura, Sante, Mahon, Francois-Xavier, Fernandes-Reese, Sofia, Gathmann, Insa, Capdeville, Renaud, Kantarjian, Hagop M., and Sawyers, Charles L.

Published
2002
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20. Ratify (Alliance 10603): Prognostic Impact of FLT3 tyrosine Kinase Domain (TKD) and NPM1 Mutation Status in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) Treated with Midostaurin or Placebo Plus Standard Chemotherapy

Author

Voso, Maria Teresa, primary, Larson, Richard A., additional, Prior, Thomas, additional, Marcucci, Guido, additional, Jones, Dan, additional, Krauter, Jürgen, additional, Heuser, Michael, additional, Lavorgna, Serena, additional, Nomdedeu, Josep, additional, Geyer, Susan M., additional, Klisovic, Rebecca, additional, Wei, Andrew H, additional, Sierra, Jorge, additional, Sanz, Miguel A., additional, Brandwein, Joseph M., additional, de Witte, Theo M, additional, Jansen, Joop H., additional, Niederweiser, Dietger, additional, Appelbaum, Frederick R., additional, Medeiros, Bruno C., additional, Tallman, Martin S., additional, Schlenk, Richard F., additional, Ganser, Arnold, additional, Amadori, Sergio, additional, Cheng, Yuan, additional, Gathmann, Insa, additional, Tiecke, Eva, additional, Thiede, Christian, additional, Döhner, Konstanze, additional, Döhner, Hartmut, additional, Stone, Richard M., additional, Bloomfield, Clara D., additional, and Lo-Coco, Francesco, additional

Published
2018
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21. Comprehensive Molecular Profiling of FLT3-Mutated Acute Myeloid Leukemia (AML) Patients Treated within the Ratify Trial (Alliance C10603)

Author

Jahn, Nikolaus, primary, Panina, Ekaterina, additional, Bullinger, Lars, additional, Dolnik, Anna, additional, Herzig, Julia, additional, Blätte, Tamara J., additional, Benner, Axel, additional, Krzykalla, Julia, additional, Gathmann, Insa, additional, Larson, Richard A., additional, Lo-Coco, Francesco, additional, Amadori, Sergio, additional, Prior, Thomas W, additional, Brandwein, Joseph M., additional, Appelbaum, Frederick R., additional, Medeiros, Bruno C., additional, Tallman, Martin S., additional, Tiecke, Eva, additional, Pallaud, Celine, additional, Ehninger, Gerhard, additional, Heuser, Michael, additional, Ganser, Arnold, additional, Stone, Richard M., additional, Thiede, Christian, additional, Döhner, Hartmut, additional, Bloomfield, Clara D., additional, and Döhner, Konstanze, additional

Published
2018
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22. Prognostic Impact of Insertion Site in Acute Myeloid Leukemia (AML) with FLT3 Internal Tandem Duplication: Results from the Ratify Study (Alliance 10603)

Author

Rücker, Frank G., primary, Du, Ling, additional, Blätte, Tamara J., additional, Benner, Axel, additional, Krzykalla, Julia, additional, Gathmann, Insa, additional, Larson, Richard A., additional, Lo-Coco, Francesco, additional, Amadori, Sergio, additional, Prior, Thomas W, additional, Brandwein, Joseph M., additional, Appelbaum, Frederick R., additional, Medeiros, Bruno C., additional, Tallman, Martin S., additional, Geddes, Michelle, additional, Sierra, Jorge, additional, Tiecke, Eva, additional, Pallaud, Celine, additional, Sanz, Miguel A., additional, de Witte, Theo M, additional, Niederwieser, Dietger, additional, Ehninger, Gerhard, additional, Heuser, Michael, additional, Ganser, Arnold, additional, Bullinger, Lars, additional, Bloomfield, Clara D., additional, Stone, Richard M., additional, Döhner, Hartmut, additional, Thiede, Christian, additional, and Dohner, Konstanze, additional

Published
2018
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23. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia : a subanalysis of the IRIS study.

Author

Larson, Richard A, Druker, Brian J, Guilhot, Francois, O'Brien, Stephen G, Riviere, Gilles J, Krahnke, Tillmann, Gathmann, Insa, Wang, Yanfeng, Larson, Richard A, Druker, Brian J, Guilhot, Francois, O'Brien, Stephen G, Riviere, Gilles J, Krahnke, Tillmann, Gathmann, Insa, and Wang, Yanfeng

Abstract

Imatinib at 400 mg daily is standard treatment for chronic myeloid leukemia in chronic phase. We here describe the correlation of imatinib trough plasma concentrations (C(mins)) with clinical responses, event-free survival (EFS), and adverse events (AEs). Trough level plasma samples were obtained on day 29 (steady state, n = 351). Plasma concentrations of imatinib and its metabolite CGP74588 were determined by liquid chromatography/mass spectrometry. The overall mean (+/- SD, CV%) steady-state C(min) for imatinib and CGP74588 were 979 ng/mL (+/- 530 ng/mL, 54.1%) and 242 ng/mL (+/- 106 ng/mL, 43.6%), respectively. Cumulative estimated complete cytogenetic response (CCyR) and major molecular response (MMR) rates differed among the quartiles of imatinib trough levels (P = .01 for CCyR, P = .02 for MMR). C(min) of imatinib was significantly higher in patients who achieved CCyR (1009 +/- 544 ng/mL vs 812 +/- 409 ng/mL, P = .01). Patients with high imatinib exposure had better rates of CCyR and MMR and EFS. An exploratory analysis demonstrated that imatinib trough levels were predictive of higher CCyR independently of Sokal risk group. AE rates were similar among the imatinib quartile categories except fluid retention, rash, myalgia, and anemia, which were more common at higher imatinib concentrations. These results suggest that an adequate plasma concentration of imatinib is important for a good clinical response. This study is registered at http://clinicaltrials.gov as NCT00333840., Bengt Simonsson, Institutionen för medicinska vetenskaper, Medicin (Hematologi) ingår i IRIS Study Group

Published
2008
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24. International Randomized Study of Interferon Vs STI571 (IRIS) 8-Year Follow up: Sustained Survival and Low Risk for Progression or Events in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Imatinib.

Author

Deininger, Michael, primary, O'Brien, Stephen G, additional, Guilhot, François, additional, Goldman, John M, additional, Hochhaus, Andreas, additional, Hughes, Timothy P., additional, Radich, Jerald P., additional, Hatfield, Alan K., additional, Mone, Manisha, additional, Filian, Jeiry, additional, Reynolds, John, additional, Gathmann, Insa, additional, Larson, Richard A., additional, and Druker, Brian J., additional

Published
2009
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25. International Randomized Study of Interferon Versus STI571 (IRIS) 7-Year Follow-up: Sustained Survival, Low Rate of Transformation and Increased Rate of Major Molecular Response (MMR) in Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CMLCP) Treated with Imatinib (IM)

Author

O’Brien, Stephen G, primary, Guilhot, François, primary, Goldman, John M, primary, Hochhaus, Andreas, primary, Hughes, Timothy P, primary, Radich, Jerald P., primary, Rudoltz, Marc, primary, Filian, Jeiry, primary, Gathmann, Insa, primary, Druker, Brian J., primary, and Larson, Richard A., primary

Published
2008
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27. Relative response of patients with myelodysplastic syndromes and other transfusion‐dependent anaemias to deferasirox (ICL670): a 1‐yr prospective study

Author

Porter, John, primary, Galanello, Renzo, additional, Saglio, Giuseppe, additional, Neufeld, Ellis J., additional, Vichinsky, Elliott, additional, Cappellini, Maria Domenica, additional, Olivieri, Nancy, additional, Piga, Antonio, additional, Cunningham, Melody J., additional, Soulières, Denis, additional, Gattermann, Norbert, additional, Tchernia, Gilbert, additional, Maertens, Johan, additional, Giardina, Patricia, additional, Kwiatkowski, Janet, additional, Quarta, Giovanni, additional, Jeng, Michael, additional, Forni, Gian Luca, additional, Stadler, Michael, additional, Cario, Holger, additional, Debusscher, Louisette, additional, Porta, Matteo Della, additional, Cazzola, Mario, additional, Greenberg, Peter, additional, Alimena, Giuliana, additional, Rabault, Bertrand, additional, Gathmann, Insa, additional, Ford, John Malcolm, additional, Alberti, Daniele, additional, and Rose, Christian, additional

Published
2007
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31. Five Year Follow-Up Results of a Phase II Trial in Patients with Late Chronic Phase (L-CP) Chronic Myeloid Leukemia (CML) Treated with Imatinib Who Are Refractory/Intolerant of Interferon-α.

Author

Gambacorti, Carlo, primary, Talpaz, Moshe, additional, Sawyers, Charles L., additional, Druker, Brian J., additional, Hochhaus, Andreas, additional, Schiffer, Charles A., additional, Guilhot, Francois, additional, Niederwieser, Dietger W., additional, Stone, Richard M., additional, Goldman, John M., additional, Mone, Manisha, additional, Krahnke, Tillmann, additional, Gathmann, Insa, additional, and Kantarjian, Hagop M., additional

Published
2005
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37. The comparative efficacy and tolerability of CGP 56697 (artemether+lumefantrine) versus halofantrine in the treatment of uncomplicated falciparum malaria in travellers returning from the Tropics to The Netherlands and France

Author

van Agtmael, Michiel, primary, Bouchaud, Olivier, additional, Malvy, Denis, additional, Delmont, Jean, additional, Danis, Martin, additional, Barette, Stéphane, additional, Gras, Claude, additional, Bernard, Jacques, additional, Touze, Jean-Etienne, additional, Gathmann, Insa, additional, and Mull, Robert, additional

Published
1999
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39. International Randomized Study of Interferon Versus STI571 (IRIS) 7-Year Follow-up: Sustained Survival, Low Rate of Transformation and Increased Rate of Major Molecular Response (MMR) in Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CMLCP) Treated with Imatinib (IM)

Author

O'Brien, Stephen G, Guilhot, François, Goldman, John M, Hochhaus, Andreas, Hughes, Timothy P, Radich, Jerald P., Rudoltz, Marc, Filian, Jeiry, Gathmann, Insa, Druker, Brian J., and Larson, Richard A.

Published
2008
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41. Prognostic Impact of Insertion Site in Acute Myeloid Leukemia (AML) with FLT3Internal Tandem Duplication: Results from the Ratify Study (Alliance 10603)

Author

Rücker, Frank G., Du, Ling, Blätte, Tamara J., Benner, Axel, Krzykalla, Julia, Gathmann, Insa, Larson, Richard A., Lo-Coco, Francesco, Amadori, Sergio, Prior, Thomas W, Brandwein, Joseph M., Appelbaum, Frederick R., Medeiros, Bruno C., Tallman, Martin S., Geddes, Michelle, Sierra, Jorge, Tiecke, Eva, Pallaud, Celine, Sanz, Miguel A., de Witte, Theo M, Niederwieser, Dietger, Ehninger, Gerhard, Heuser, Michael, Ganser, Arnold, Bullinger, Lars, Bloomfield, Clara D., Stone, Richard M., Döhner, Hartmut, Thiede, Christian, and Dohner, Konstanze

Published
2018
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42. Ratify (Alliance 10603): Prognostic Impact of FLT3tyrosine Kinase Domain (TKD) and NPM1Mutation Status in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) Treated with Midostaurin or Placebo Plus Standard Chemotherapy

Author

Voso, Maria Teresa, Larson, Richard A., Prior, Thomas, Marcucci, Guido, Jones, Dan, Krauter, Jürgen, Heuser, Michael, Lavorgna, Serena, Nomdedeu, Josep, Geyer, Susan M., Klisovic, Rebecca, Wei, Andrew H, Sierra, Jorge, Sanz, Miguel A., Brandwein, Joseph M., de Witte, Theo M, Jansen, Joop H., Niederweiser, Dietger, Appelbaum, Frederick R., Medeiros, Bruno C., Tallman, Martin S., Schlenk, Richard F., Ganser, Arnold, Amadori, Sergio, Cheng, Yuan, Gathmann, Insa, Tiecke, Eva, Thiede, Christian, Döhner, Konstanze, Döhner, Hartmut, Stone, Richard M., Bloomfield, Clara D., and Lo-Coco, Francesco

Abstract

Introduction:Mutations localized in the tyrosine kinase domain activation loop of FLT3 (FLT3-TKD), representing point mutations in codon D835/I836 and rarely deletions of codon I836, induce constitutive tyrosine phosphorylation and activation of the receptor tyrosine kinase similarly to FLT3internal tandem duplication (ITD) mutations. However, the prognostic role of FLT3-TKD in AML, particularly in the presence of NPM1mutations, is not well established. The phase 3 RATIFY trial [NCT00651261; Stone et al. N Engl J Med. 2017] showed that in combination with standard chemotherapy, midostaurin (PKC412) improved survival outcomes across all 3 FLT3stratification subgroups (ITD high allelic ratio [≥ 0.7], ITD low allelic ratio [< 0.7], and TKD) vs placebo in patients with newly diagnosed FLT3-mutated AML. Here, we evaluated the prognostic impact of FLT3-TKD and NPM1mutations in a post hoc analysis from the RATIFY trial.

Published
2018
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43. Correlation of Pharmacokinetic Data with Cytogenetic and Molecular Response in Newly Diagnosed Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Imatinib - An Analysis of IRIS Study Data.

Author

Larson, Richard A., Druker, Brian J., Guilhot, Francois, O’Brien, Stephen G., Gathmann, Insa, Riviere, Gilles J., So, Charlene, and Wang, Yanfeng

Abstract

A total of 551 pts with newly diagnosed CML-CP received imatinib (IM) 400 mg orally once daily as part of the IRIS study (O’Brien et al, NEJM 2003). We now summarize the correlation of clinical responses with the steady-state trough plasma concentrations (Cmin) of IM and its major active metabolite CGP74588. Cmin is a reflection of IM clearance and metabolism in CML pts. Trough PK samples (24 hrs post dose) were obtained in IM pts at Day 1 and steady state (Day 29). The plasma concentrations of IM and CGP74588 were determined by liquid chromatography/mass spectrometry. Estimated rates of complete cytogenetic response (CCyR - 0% Ph+) and major molecular response (MMR - ≥ 3 log reduction in BCR-ABL/BCR ratio from a standardized baseline value for untreated pts) were given for the lower and upper quartiles (below Q1=25th percentile, above Q3=75th percentile) and the inter-quartile range of PK trough levels. After 4 weeks of IM at 400 mg, the overall mean (±SD, CV%) steady-state trough levels (Cmin) for IM and CGP74588 (n=351 pts) were 979 (±530, 54.1%) and 242 (±106, 43.6%) ng/mL, respectively. Median (Q1–Q3, min-max) values (in ng/mL) were 879 (647–1170, 153–3910) for IM and 223 (169–291, 50–841) for CGP74588. Times to CCyR and MMR within CCyR pts were significantly different between the three groups of IM plasma exposure (low/intermediate/high; p<0.025). The same was observed for CGP74588, since the parent drug and metabolite levels were highly correlated (0.77, Spearman correlation coefficient). Overall, Cmin of IM was statistically significantly higher in pts who achieved CCyR (1009±544 ng/mL vs. 812±409 ng/mL, p=0.0116). The estimated MMR rate among all pts was significantly lower in pts with low IM levels: only an estimated 59%x43%=25% of all pts with IM levels <647 ng/mL achieved a MMR at 1 year (yr), compared to 40% of all other pts. By 4 yrs an estimated 53% achieved MMR despite low steady state Cmin levels compared with 80% for pts with high Cmin (and 72% for pts within inter-quartile range). CCyR and MMR rates [95% CI] within 1, 2, and 4 yrs by categories of IM trough plasma concentrations measured on Day 29 IM trough level < 647 ng/mL (Q1) N = 87 647–1170 ng/mL N = 178 > 1170 ng/mL (Q3) N = 86 CCyR (%) − 1 yr 59 [48, 70] 71 [64, 78] 73 [63, 83] − 2 yrs 73 [63, 83] 80 [73, 86] 84 [75, 92] − 4 yrs 81 [71, 91] 87 [81, 93] 89 [82, 96] MMR (%) in pts with CCyR − 1 yr 43 [28, 59] 56 [47, 66] 55 [41, 68] − 2 yrs 63 [49, 78] 78 [69, 86] 86 [76, 96] − 4 yrs 65 [50, 80] 83 [75, 91] 90 [81, 100] The trough plasma level following the 1st dose also showed a correlation with CCyR and MMR responses, but appeared to be less predictive than the trough level at steady state. Although all CML-CP pts had received 400 mg qd IM, CCyR and MMR rates at 1 to 4 yrs were depending on their IM trough level (24 hrs after the last dose) after 4 weeks of IM. Similar results were observed for the major active metabolite of IM. These results suggest that achieving and maintaining an adequate plasma concentration of IM is important for a good clinical response, and that therapeutic drug monitoring could be done by measuring trough levels at steady state conditions.

Published
2006
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44. Patients with Chronic Phase CML in the IRIS Study Who Receive Imatinib Mesylate (IM) 2ndLine after Prior IFN/Ara-C Have Sustained Complete Cytogenetic and Major Molecular Response Rates Similar to 1stLine IM Patients.

Author

Kaeda, Jaspal, Hochhaus, Andreas, Radich, Jerald, Branford, Susan, So, Charlene, Gathmann, Insa, Wehrle, Elisabeth, Goldman, John, and Hughes, Timothy

Abstract

The IRIS study compared IM and interferon+cytarabine (IFN/Ara-C) in patients (pts) with newly diagnosed CML-CP (n=553 per arm). IFN/Ara-C pts. could cross over to IM if they satisfied predetermined criteria for disease, either resistance/refractoriness (=resistance), or intolerance of or reluctance to continue the combination (=lack of resistance). Pts who received IM 1stline or 2ndline who achieved a complete cytogenetic response (CCyR) had BCR-ABL transcript levels measured serially by real-time quantitative PCR (RQ-PCR). Results were expressed as log reduction in BCR-ABL/BCR from a standardized baseline value for untreated pts. Yearly rates of 3 log reduction (Major Molecular Response, MMR) from IM treatment starting date were estimated by multiplying the CCyR rate by the MMR rate in CCyR pts at each time point. Overall, of 553 pts who received 1stline IM 82% achieved CCyR, an estimated 69% during the 1styear (yr) of treatment. Of 359 pts who received 2ndline IM, 80% achieved CCyR, 62% during the 1styr; rates were lower in pts with resistance than in those without resistance to prior IFN/Ara-C (75% vs 85% overall, p=0.025, 56% vs 68% within first yr, p<0.01). Best observed and estimated molecular responses for CCyR pts. are summarized in the table. The median follow-up for BCR-ABL evaluation on 1stline vs 2ndline IM was 45 and 35 months, respectively.

Published
2006
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45. Plasma exposure of imatinib and its correlation with clinical response in the Tyrosine Kinase Inhibitor Optimization and Selectivity Trial.

Author

Guilhot F, Hughes TP, Cortes J, Druker BJ, Baccarani M, Gathmann I, Hayes M, Granvil C, and Wang Y

Subjects
Adolescent, Adult, Aged, Benzamides, Female, Humans, Imatinib Mesylate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive blood, Leukemia, Myeloid, Chronic-Phase blood, Male, Maximum Tolerated Dose, Middle Aged, Piperazines pharmacokinetics, Protein Kinase Inhibitors pharmacokinetics, Pyrimidines pharmacokinetics, Remission Induction, Tissue Distribution, Treatment Outcome, Young Adult, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myeloid, Chronic-Phase drug therapy, Piperazines blood, Piperazines therapeutic use, Protein Kinase Inhibitors blood, Protein Kinase Inhibitors therapeutic use, Pyrimidines blood, Pyrimidines therapeutic use
Abstract

Background: This study evaluates the correlation between imatinib trough plasma concentrations (C(min)) and clinical response and safety in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase in the Tyrosine Kinase Inhibitor OPtimization and Selectivity (TOPS) trial., Design and Methods: Patients were randomized 1:2 to 400 mg/day or 800 mg/day imatinib. Imatinib C(min) levels were collected at pre-dose before treatment, and at the end of months 1 (day 29), 6, 9, and 12., Results: Imatinib C(min) were stable over time in the 400 mg/day dose arm, but showed a slight decrease in the 800 mg/day arm due to dose adjustments between months 1-6. The overall median imatinib C(min) levels were 1040, 1200, 1935, and 2690 ng/mL for the actual 300, 400, 600, and 800 mg/day doses, respectively. The rates of major molecular response (MMR) at 3, 6, 9, and 12 months, and complete cytogenetic response (CCyR) at 6 and 12 months were significantly lower among patients with the lowest imatinib C(min) levels at Day 29 (<1165 ng/mL, 25th percentile). There was an apparent association between high imatinib C(min) and the occurrence of grade 3/4 neutropenia and all-grade rash, diarrhea, arthralgia/myalgia, and all-cause edema. Conclusions Imatinib C(min) levels were relatively stable over time and proportional to the dose administered. Patients with an imatinib C(min) above 1165 ng/mL on Day 29 achieved MMR faster and had higher MMR and CCyR rates at 12 months. There appeared to be an association between imatinib C(min) and the frequency of some adverse events. This trial was registered at http://www.clinicaltrials.gov as NCT00124748.

Published
2012
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46. High rates of durable response are achieved with imatinib after treatment with interferon alpha plus cytarabine: results from the International Randomized Study of Interferon and STI571 (IRIS) trial.

Author

Guilhot F, Druker B, Larson RA, Gathmann I, So C, Waltzman R, and O'Brien SG

Subjects
Antineoplastic Combined Chemotherapy Protocols adverse effects, Benzamides, Cross-Over Studies, Cytarabine administration & dosage, Cytarabine adverse effects, Diarrhea chemically induced, Drug Administration Schedule, Edema chemically induced, Humans, Imatinib Mesylate, Interferon-alpha administration & dosage, Interferon-alpha adverse effects, Kaplan-Meier Estimate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive mortality, Muscle Cramp chemically induced, Nausea chemically induced, Piperazines administration & dosage, Piperazines adverse effects, Pyrimidines administration & dosage, Pyrimidines adverse effects, Remission Induction, Survival Rate, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy
Abstract

Background: Imatinib is the standard of care for newly diagnosed chronic-phase chronic myeloid leukemia. The largest randomized clinical trial of imatinib was the multinational IRIS trial in which 1106 patients were randomized to receive either imatinib 400 mg/day or a standard regimen of interferon-alpha plus cytarabine., Design and Methods: Patients were allowed to cross over to the opposite treatment for intolerance, lack of response, disease progression, and, following release of the initial efficacy data, reluctance to remain on therapy with interferon-alpha plus cytarabine. The safety and efficacy of imatinib in patients who crossed over from interferon-alpha plus cytarabine to imatinib is reported here., Results: Of 553 patients originally assigned to interferon-alpha plus cytarabine, 65% crossed over to imatinib, of whom 67% continue to receive treatment. After a median of 54 months of imatinib treatment on study, 93% achieved complete hematologic remission, 86% achieved major cytogenetic remission, and 81% achieved a complete cytogenetic remission as the best observed response. Estimated rates of freedom from progression to accelerated or blast phase and overall survival were 91% and 89%, respectively, at 48 months after starting imatinib., Conclusions: This is the largest analysis to date describing the efficacy of imatinib in patients who have received prior therapies for chronic myeloid leukemia and it demonstrates excellent responses to this treatment. (ClinicalTrials.gov identifier: NCT00006343).

Published
2009
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