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IMATINIB (IM) 400MG IN PATIENTS WITH CML1ST CP RESULTS IN A HIGHER MOLECULAR RESPONSE RATE AT 6 MONTHS COMPARED TO IM/ HYDROXYUREA. FINAL RESULTS OF THE CML2004 STUDY. NCT 02480608.
Author(s):
Thoralf Lange
,
Thoralf Lange
Affiliations:
Klinik für Hämatologie und Onkologie,Krankenhaus Weißenfels,Weißenfels,Germany;Abteilung Hämatologie und Onkologie,Universität Leipzig,Leipzig,Germany
Rainer Krahl
,
Rainer Krahl
Affiliations:
Abteilung Hämatologie und Onkologie,Universität Leipzig,Leipzig,Germany
Ulrich von Grünhagen
,
Ulrich von Grünhagen
Affiliations:
Gemeinschaftspraxis Hämatologie und Onkologie,Cottbus,Germany
Haifa Kathrin Al-Ali
,
Haifa Kathrin Al-Ali
Affiliations:
Abteilung Hämatologie und Onkologie,Universität Leipzig,Leipzig,Germany;Universitätsklinik und Poliklinik für Innere Medizin IV, Universität Halle,Halle,Germany
Andreas Schwarzer
,
Andreas Schwarzer
Affiliations:
Gemeinschaftspraxis für Hämatologie und Onkologie,Leipzig,Germany
Renate Uhle
,
Renate Uhle
Affiliations:
Gemeinschaftspraxis für Hämatologie und Onkologie,Magdeburg,Germany
Claudia Spohn
,
Claudia Spohn
Affiliations:
Gemeinschaftspraxis für Hämatologie und Onkologie,Halle,Germany
Volker Lakner
,
Volker Lakner
Affiliations:
Gemeinschaftspraxis für Hämatologie und Onkologie,Rostock,Germany
Michael Assmann
,
Michael Assmann
Affiliations:
MVZ Elblandpolikliniken GmbH,Riesa,Germany
Christian Junghanss
,
Christian Junghanss
Affiliations:
Medizinische Klinik III,Universität Rostock,Rostock,Germany
Markus Pfirrmann
,
Markus Pfirrmann
Affiliations:
Institut für medizinische Informationsverarbeitung, Biometrie und Epidemiologie (IBE),Ludwig-Maximilians-Universität München,München,Germany
Arthur Gil
,
Arthur Gil
Affiliations:
Institut für medizinische Informationsverarbeitung, Biometrie und Epidemiologie (IBE),Ludwig-Maximilians-Universität München,München,Germany
Rüdiger Hehlmann
,
Rüdiger Hehlmann
Affiliations:
III. Medizinische Klinik,Universität Heidelberg, Medizinische Fakultät,Mannheim,Germany
Michael Deininger
,
Michael Deininger
Affiliations:
Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute,The University of Utah,Salt Lake City,United States
Dietger Niederwieser
Dietger Niederwieser
Affiliations:
Abteilung Hämatologie und Onkologie,Universität Leipzig,Leipzig,Germany
(Abstract release date: 05/18/17) EHA Library. Lange T. 05/18/17; 182533; PB1819
Thoralf Lange
Thoralf Lange
Contributions
PDF Abstract
Abstract

Abstract: PB1819

Type: Publication Only

Background

Imatinib (IM) monotherapy remains an acceptable option to treat newly diagnosed patients with chronic myeloid leukemia (CML) in the chronic phase (CP). Hydroxyurea (HU) is effective in controlling elevated white blood cell counts and has been widely used to treat CML prior to the era of tyrosine kinase inhibitors (TKIs). The combinations of IM and HU have been tested in vitro and showed a additive suppression of CML CFU-GM cells. Combinations of IM and cytotoxic agents such as cytarabine have been tested also in vivo, but no data are available for the combination of IM and HU in CML.

Aims

The East German Study Group conducted a phase I study to identify the dose of HU in combination with standard dose IM (400mg daily) that would result in mild myelosuppression (white blood cell count 3,000-4,000/mL). Starting dose of HU was 500mg daily which was increased by 500mg every 3 weeks to a maximum of 3,000 mg daily. According to protocol, 500mg HU was identified as the starting dose for the randomized phase II study which tested the combination vs. standard dose IM, with the rate of major molecular response (MMR) at 18 months as the primary endpoint.

Methods

Starting in 2002, 20 adult patients with newly diagnosed CP-CML were included in the phase I study. Additional 93 patients were enrolled in the phase II of the study, 5 of whom were excluded. With ratio 2:1 in phase II, 88 patients were randomized to the IM/HU (n=59) and IM (n=29) arm, respectively. Three patients (2 IM/HU, 1IM) were lost to follow-up. As prospectively designed, all available IM/HU patients (n=77) were analyzed together. According to the study protocol, patients from the CML IV study were to be added to obtain equal numbers for analysis. To arrive at a total of 77 IM patients, from study IV another 49 patients were selected by propensity score matching. The median age of the 154 patients was 55 years (range 18 – 82). The ELTS prognostic score was available for 141 patients and was high in 8 (5.7%), intermediate in 35 (24.8%) and low in 98 (69.5%), with no significant differences between treatment groups.

Results
The 5-year overall survival (OS) / progression-free survival (PFS) probabilities were 90.4 and 86.7 % in the IM/HU and twice 84.9% in the IM arm (p=not significant). With IM/HU, the probabilities of complete cytogenetic response (CCR) at 6, 12, and 18 months were 54.3, 84.0, and 93.7%. In the IM arm, the corresponding numbers were 70.4, 84.9, and 83.3% (p=not significant). Primary endpoint was MMR rate at 18 months. There was no significant difference between IM/HU (65.8%) and IM (66.0%). At 6 months, MMR rates were 21.6 (IM/HU) vs. 41.1% (p=0.0383) and at 12 months 41.9 (IM/HU) vs. 58.9% (not significant). Time to event analyses of OS and PFS did not result in significant differences; neither did group comparisons between the probabilities of CCR and MMR. The median HU dose was 500mg (range 152-3000); the median IM dose was 400 mg (range 145-617mg) in both arms. The gross numbers of adverse events in general or of adverse events of grade 4 were not different between the two arms, but cumulative incidences showed an earlier occurrence in the IM/HU than in the IM arm (p= 0.0343, Gray test)

Conclusion
Compared to Imatinib only, the combination of Imatinib and HU resulted in a lower MMR rate at 6 months but a similar MMR rate at 18 months. Furthermore, IM/HU was associated with more early adverse events. There was no indication of a beneficial effect in the treatment of CML patients in 1st chronic phase using the combination of IM with HU.

Session topic: 8. Chronic myeloid leukemia - Clinical

Keyword(s): Chronic myeloid leukemia, imatinib, Hydroxyurea

Abstract: PB1819

Type: Publication Only

Background

Imatinib (IM) monotherapy remains an acceptable option to treat newly diagnosed patients with chronic myeloid leukemia (CML) in the chronic phase (CP). Hydroxyurea (HU) is effective in controlling elevated white blood cell counts and has been widely used to treat CML prior to the era of tyrosine kinase inhibitors (TKIs). The combinations of IM and HU have been tested in vitro and showed a additive suppression of CML CFU-GM cells. Combinations of IM and cytotoxic agents such as cytarabine have been tested also in vivo, but no data are available for the combination of IM and HU in CML.

Aims

The East German Study Group conducted a phase I study to identify the dose of HU in combination with standard dose IM (400mg daily) that would result in mild myelosuppression (white blood cell count 3,000-4,000/mL). Starting dose of HU was 500mg daily which was increased by 500mg every 3 weeks to a maximum of 3,000 mg daily. According to protocol, 500mg HU was identified as the starting dose for the randomized phase II study which tested the combination vs. standard dose IM, with the rate of major molecular response (MMR) at 18 months as the primary endpoint.

Methods

Starting in 2002, 20 adult patients with newly diagnosed CP-CML were included in the phase I study. Additional 93 patients were enrolled in the phase II of the study, 5 of whom were excluded. With ratio 2:1 in phase II, 88 patients were randomized to the IM/HU (n=59) and IM (n=29) arm, respectively. Three patients (2 IM/HU, 1IM) were lost to follow-up. As prospectively designed, all available IM/HU patients (n=77) were analyzed together. According to the study protocol, patients from the CML IV study were to be added to obtain equal numbers for analysis. To arrive at a total of 77 IM patients, from study IV another 49 patients were selected by propensity score matching. The median age of the 154 patients was 55 years (range 18 – 82). The ELTS prognostic score was available for 141 patients and was high in 8 (5.7%), intermediate in 35 (24.8%) and low in 98 (69.5%), with no significant differences between treatment groups.

Results
The 5-year overall survival (OS) / progression-free survival (PFS) probabilities were 90.4 and 86.7 % in the IM/HU and twice 84.9% in the IM arm (p=not significant). With IM/HU, the probabilities of complete cytogenetic response (CCR) at 6, 12, and 18 months were 54.3, 84.0, and 93.7%. In the IM arm, the corresponding numbers were 70.4, 84.9, and 83.3% (p=not significant). Primary endpoint was MMR rate at 18 months. There was no significant difference between IM/HU (65.8%) and IM (66.0%). At 6 months, MMR rates were 21.6 (IM/HU) vs. 41.1% (p=0.0383) and at 12 months 41.9 (IM/HU) vs. 58.9% (not significant). Time to event analyses of OS and PFS did not result in significant differences; neither did group comparisons between the probabilities of CCR and MMR. The median HU dose was 500mg (range 152-3000); the median IM dose was 400 mg (range 145-617mg) in both arms. The gross numbers of adverse events in general or of adverse events of grade 4 were not different between the two arms, but cumulative incidences showed an earlier occurrence in the IM/HU than in the IM arm (p= 0.0343, Gray test)

Conclusion
Compared to Imatinib only, the combination of Imatinib and HU resulted in a lower MMR rate at 6 months but a similar MMR rate at 18 months. Furthermore, IM/HU was associated with more early adverse events. There was no indication of a beneficial effect in the treatment of CML patients in 1st chronic phase using the combination of IM with HU.

Session topic: 8. Chronic myeloid leukemia - Clinical

Keyword(s): Chronic myeloid leukemia, imatinib, Hydroxyurea

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