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Novel Imatinib/Nilotinib Strategy Could Optimize CML Treatment

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Submitted by sandy craine on Tue, 26/05/2015 - 3:43pm
News | March 17, 2015 | Chronic Myeloid Leukemia, Hematologic Malignancies, Leukemia & Lymphoma By Cancer Network Staff A single-arm, open-label trial in Australia found that selective early switching from imatinib to nilotinib is feasible and effective in patients with chronic myeloid leukemia (CML).

News | March 17, 2015 | Chronic Myeloid Leukemia, Hematologic Malignancies, Leukemia & Lymphoma
By Cancer Network Staff
A single-arm, open-label trial in Australia found that selective early switching from imatinib to nilotinib is feasible and effective in patients with chronic myeloid leukemia (CML).

RCC Drug Axitinib Could Treat TKI-Resistant CML

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Submitted by sandy craine on Tue, 26/05/2015 - 3:33pm
News | February 17, 2015 | Chronic Myeloid Leukemia, Hematologic Malignancies, Leukemia & Lymphoma By Cancer Network Staff In a paper that shows the benefits of looking at old drugs in new ways, researchers showed that axitinib could be repurposed as a potentially effective treatment for chronic myeloid leukemia (CML) patients who develop resistance to standard tyrosine kinase inhibitors (TKIs) through a certain molecular mechanism.

News | February 17, 2015 | Chronic Myeloid Leukemia, Hematologic Malignancies, Leukemia & Lymphoma
By Cancer Network Staff

In a paper that shows the benefits of looking at old drugs in new ways, researchers showed that axitinib could be repurposed as a potentially effective treatment for chronic myeloid leukemia (CML) patients who develop resistance to standard tyrosine kinase inhibitors (TKIs) through a certain molecular mechanism.

Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV

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Submitted by sandy craine on Sat, 09/05/2015 - 2:23pm
L Kalmanti, S Saussele, M Lauseker, M C Müller, C T Dietz, L Heinrich, B Hanfstein, U Proetel, A Fabarius, S W Krause, S Rinaldetti, J Dengler, C Falge, E Oppliger-Leibundgut, A Burchert, A Neubauer, L Kanz, F Stegelmann, M Pfreundschuh, K Spiekermann, C Scheid, M Pfirrmann, A Hochhaus, J Hasford, R Hehlmann and for the SAKK and the German CML Study-Group.

L Kalmanti, S Saussele, M Lauseker, M C Müller, C T Dietz, L Heinrich, B Hanfstein, U Proetel, A Fabarius, S W Krause, S Rinaldetti, J Dengler, C Falge, E Oppliger-Leibundgut, A Burchert, A Neubauer, L Kanz, F Stegelmann, M Pfreundschuh, K Spiekermann, C Scheid, M Pfirrmann, A Hochhaus, J Hasford, R Hehlmann and for the SAKK and the German CML Study-Group.

Laboratory recommendations for scoring deep molecular responses following treatment for CML

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Submitted by sandy craine on Sat, 09/05/2015 - 2:16pm
N C P Cross1,2, H E White1,2, D Colomer3, H Ehrencrona4, L Foroni5, E Gottardi6, T Lange7, T Lion8, K Machova Polakova9, S Dulucq10, G Martinelli11, E Oppliger Leibundgut12, N Pallisgaard13, G Barbany14, T Sacha15, R Talmaci16, B Izzo17, G Saglio6, F Pane17,18, M C Müller19 and A Hochhaus20 Abstract Treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors has advanced to a stage where many patients achieve very low or undetectable levels of disease. Remarkably, some of these patients remain in sustained remission when treatment is withdrawn, suggesting that they may be at least operationally cured of their disease. Accurate definition of deep molecular responses (MRs) is therefore increasingly important for optimal patient management and comparison of independent data sets. We previously published proposals for broad standardized definitions of MR at different levels of sensitivity. Here we present detailed laboratory recommendations, developed as part of the European Treatment and Outcome Study for CML (EUTOS), to enable testing laboratories to score MR in a reproducible manner for CML patients expressing the most common BCR-ABL1 variants.

N C P Cross1,2, H E White1,2, D Colomer3, H Ehrencrona4, L Foroni5, E Gottardi6, T Lange7, T Lion8, K Machova Polakova9, S Dulucq10, G Martinelli11, E Oppliger Leibundgut12, N Pallisgaard13, G Barbany14, T Sacha15, R Talmaci16, B Izzo17, G Saglio6, F Pane17,18, M C Müller19 and A Hochhaus20

Abstract
Treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors has advanced to a stage where many patients achieve very low or undetectable levels of disease. Remarkably, some of these patients remain in sustained remission when treatment is withdrawn, suggesting that they may be at least operationally cured of their disease. Accurate definition of deep molecular responses (MRs) is therefore increasingly important for optimal patient management and comparison of independent data sets. We previously published proposals for broad standardized definitions of MR at different levels of sensitivity. Here we present detailed laboratory recommendations, developed as part of the European Treatment and Outcome Study for CML (EUTOS), to enable testing laboratories to score MR in a reproducible manner for CML patients expressing the most common BCR-ABL1 variants.

Bosutinib a Good Fourth-Line Option in CML

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Submitted by sandy craine on Wed, 06/05/2015 - 4:16pm
A small retrospective study of heavily pretreated patients with chronic myeloid leukemia (CML) found bosutinib to be a good option in the fourth-line setting.

A small retrospective study of heavily pretreated patients with chronic myeloid leukemia (CML) found bosutinib to be a good option in the fourth-line setting.

Bosutinib a Good Fourth-Line Option in CML

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Submitted by sandy craine on Sat, 11/04/2015 - 1:58pm
News | April 06, 2015 | Chronic Myeloid Leukemia, Hematologic Malignancies, Leukemia & Lymphoma By Ian Ingram A small retrospective study of heavily pretreated patients with chronic myeloid leukemia (CML) found bosutinib to be a good option in the fourth-line setting.

News | April 06, 2015 | Chronic Myeloid Leukemia, Hematologic Malignancies, Leukemia & Lymphoma
By Ian Ingram

A small retrospective study of heavily pretreated patients with chronic myeloid leukemia (CML) found bosutinib to be a good option in the fourth-line setting.

Interferon alpha 2 maintenance therapy may enable high rates of treatment discontinuation in CML

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Submitted by sandy craine on Sat, 11/04/2015 - 1:52pm
A Burchert1, S Saussele2, E Eigendorff3, M C Müller2, K Sohlbach1, S Inselmann1, C Schütz1, S K Metzelder1, J Ziermann3, P Kostrewa1, J Hoffmann1, R Hehlmann2, A Neubauer1 and A Hochhaus3 Abstract A minority of chronic myeloid leukemia (CML) patients is capable of successfully discontinuing imatinib. Treatment modalities to increase this proportion are currently unknown. Here, we assessed the role of interferon alpha 2a (IFN) on therapy discontinuation in a previously reported cohort of 20 chronic phase CML patients who were treated upfront with IFN alpha plus imatinib followed by IFN monotherapy to maintain cytogenetic or molecular remission (MR) after imatinib discontinuation. After a median follow-up of 7.9 years (range, 5.2–12.2), relapse-free survival was 73% (8/11 patients) and 84% (5/6 patients) for patients who discontinued imatinib in major MR (MMR) and MR4/MR4.5, respectively. Ten patients discontinued IFN after a median of 4.5 years (range, 0.24–9.3). After a median of 2.8 years (range, 0.7–5.1), nine of them remain in ongoing treatment-free remission with MR5 (n=6) and MR4.5 (n=3). The four patients who still administer IFN are in stable MR5, MR4.5, MR4, and MMR, respectively. In conclusion, an IFN/imatinib induction treatment followed by a temporary IFN maintenance therapy may enable a high rate of treatment discontinuation in CML patients in at least MMR when stopping imatinib.

A Burchert1, S Saussele2, E Eigendorff3, M C Müller2, K Sohlbach1, S Inselmann1, C Schütz1, S K Metzelder1, J Ziermann3, P Kostrewa1, J Hoffmann1, R Hehlmann2, A Neubauer1 and A Hochhaus3

Abstract
A minority of chronic myeloid leukemia (CML) patients is capable of successfully discontinuing imatinib. Treatment modalities to increase this proportion are currently unknown. Here, we assessed the role of interferon alpha 2a (IFN) on therapy discontinuation in a previously reported cohort of 20 chronic phase CML patients who were treated upfront with IFN alpha plus imatinib followed by IFN monotherapy to maintain cytogenetic or molecular remission (MR) after imatinib discontinuation. After a median follow-up of 7.9 years (range, 5.2–12.2), relapse-free survival was 73% (8/11 patients) and 84% (5/6 patients) for patients who discontinued imatinib in major MR (MMR) and MR4/MR4.5, respectively. Ten patients discontinued IFN after a median of 4.5 years (range, 0.24–9.3). After a median of 2.8 years (range, 0.7–5.1), nine of them remain in ongoing treatment-free remission with MR5 (n=6) and MR4.5 (n=3). The four patients who still administer IFN are in stable MR5, MR4.5, MR4, and MMR, respectively. In conclusion, an IFN/imatinib induction treatment followed by a temporary IFN maintenance therapy may enable a high rate of treatment discontinuation in CML patients in at least MMR when stopping imatinib.

2nd Generation TKIs prevent disease progression in high-risk (high CIP2A)CML patients

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Submitted by sandy craine on Wed, 25/03/2015 - 4:03pm
C M Lucas1, R J Harris1, A K Holcroft1, L J Scott1, N Carmell1, E McDonald1, F Polydoros2 and R E Clark1 1Section of Haematology, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK 2CR-UK Liverpool Cancer Trials Unit, University of Liverpool High CIP2A protein levels at diagnosis of chronic myeloid leukaemia (CML) are predictive of disease progression in imatinib treated patients. It is not known whether this is true in patients treated with second generation tyrosine kinase inhibitors (2G TKI) from diagnosis, and whether 2G TKIs modulate the CIP2A pathway. Here, we show that patients with high diagnostic CIP2A levels who receive a 2G TKI do not progress, unlike those treated with imatinib (P=<0.0001). 2G TKIs induce more potent suppression of CIP2A and c-Myc than imatinib. The transcription factor E2F1 is elevated in high CIP2A patients and following 1 month of in vivo treatment 2G TKIs suppress E2F1 and reduce CIP2A; these effects are not seen with imatinib. Silencing of CIP2A, c-Myc or E2F1 in K562 cells or CML CD34+ cells reactivates PP2A leading to BCR-ABL suppression. CIP2A increases proliferation and this is only reduced by 2G TKIs. Patients with high CIP2A levels should be offered 2G TKI treatment in preference to imatinib. 2G TKIs disrupt the CIP2A/c-Myc/E2F1 positive-feedback loop, leading to lower disease progression risk. The data supports the view that CIP2A inhibits PP2Ac, stabilising E2F1, creating a CIP2A/c-Myc/E2F1 positive-feedback loop which imatinib cannot overcome.

C M Lucas1, R J Harris1, A K Holcroft1, L J Scott1, N Carmell1, E McDonald1, F Polydoros2 and R E Clark1

1Section of Haematology, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
2CR-UK Liverpool Cancer Trials Unit, University of Liverpool

High CIP2A protein levels at diagnosis of chronic myeloid leukaemia (CML) are predictive of disease progression in imatinib treated patients. It is not known whether this is true in patients treated with second generation tyrosine kinase inhibitors (2G TKI) from diagnosis, and whether 2G TKIs modulate the CIP2A pathway. Here, we show that patients with high diagnostic CIP2A levels who receive a 2G TKI do not progress, unlike those treated with imatinib (P=<0.0001). 2G TKIs induce more potent suppression of CIP2A and c-Myc than imatinib. The transcription factor E2F1 is elevated in high CIP2A patients and following 1 month of in vivo treatment 2G TKIs suppress E2F1 and reduce CIP2A; these effects are not seen with imatinib. Silencing of CIP2A, c-Myc or E2F1 in K562 cells or CML CD34+ cells reactivates PP2A leading to BCR-ABL suppression. CIP2A increases proliferation and this is only reduced by 2G TKIs. Patients with high CIP2A levels should be offered 2G TKI treatment in preference to imatinib. 2G TKIs disrupt the CIP2A/c-Myc/E2F1 positive-feedback loop, leading to lower disease progression risk. The data supports the view that CIP2A inhibits PP2Ac, stabilising E2F1, creating a CIP2A/c-Myc/E2F1 positive-feedback loop which imatinib cannot overcome.

Novel Imatinib/Nilotinib Strategy Could Optimize CML Treatment

sandy craine's picture
Submitted by sandy craine on Wed, 25/03/2015 - 2:52pm
News | March 17, 2015 | Chronic Myeloid Leukemia, Hematologic Malignancies, Leukemia & Lymphoma By Cancer Network Staff A single-arm, open-label trial in Australia found that selective early switching from imatinib to nilotinib is feasible and effective in patients with chronic myeloid leukemia (CML).

News | March 17, 2015 | Chronic Myeloid Leukemia, Hematologic Malignancies, Leukemia & Lymphoma
By Cancer Network Staff

A single-arm, open-label trial in Australia found that selective early switching from imatinib to nilotinib is feasible and effective in patients with chronic myeloid leukemia (CML).

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