Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV
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.
Tyrosine kinase inhibitors (TKI) have changed the natural course of chronic myeloid leukemia (CML). With the advent of second-generation TKI safety and efficacy issues have gained interest. The randomized CML - Study IV was used for a long-term evaluation of imatinib (IM). 1503 patients have received IM, 1379 IM monotherapy. After a median observation of 7.1 years, 965 patients (64%) still received IM. At 10 years, progression-free survival was 82%, overall survival 84%, 59% achieved MR5, 72% MR4.5, 81% MR4, 89% major molecular remission and 92% MR2 (molecular equivalent to complete cytogenetic remission). All response levels were reached faster with IM800 mg except MR5. Eight-year probabilities of adverse drug reactions (ADR) were 76%, of grades 3–4 22%, of non-hematologic 73%, and of hematologic 28%. More ADR were observed with IM800 mg and IM400 mg plus interferon α (IFN). Most patients had their first ADR early with decreasing frequency later on. No new late toxicity was observed. ADR to IM are frequent, but mostly mild and manageable, also with IM 800 mg and IM 400 mg+IFN. The deep molecular response rates indicate that most patients are candidates for IM discontinuation. After 10 years, IM continues to be an excellent initial choice for most patients with CML.
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
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 Remarkably, some of these patients remain in sustained remission when treatment is withdrawn, suggesting that they may be at least operationally cured of their disease.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.
Introduction ...read more
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.
The results of the study were published in the American Journal of Hematology, by Valentín García-Gutíerrez, of the Hospital Universitario Ramón y Cajal in Madrid, and colleagues.
The tyrosine kinase inhibitors (TKIs) imatinib, dasatinib, and nilotinib are currently the three approved first-line treatments for CML, so most patients will receive bosutinib as a fourth-line therapy, according to the authors.
There is very little data on bosutinib for CML in this setting, however. In a phase I/II study of CML patients treated with bosutinib, only 3 out of 188 patients were treated with bosutinib in the fourth-line setting. “The aim of this study was to fill this gap, and analyze the efficacy and safety of fourth-line bosutinib treatment after failure or intolerance to imatinib, dasatinib, and nilotinib,” wrote the authors.
The researchers reviewed the records of 30 chronic-phase CML patients who had relapsed or were intolerant to imatinib, nilotinib, and dasatinib. Patients studied had all received 500 mg bosutinib daily, with dose adjustments made according to physician judgment. With a median follow-up time of 11.5 months, 17 patients (56.6%) were able to achieve or maintain complete cytogenetic response (CCyR) and 11 patients (36.7%) were able to achieve or maintain baseline major molecular response (MMR).
Among patients who did not have a CCyR at baseline, the probabilities of obtaining CCyR, MMR, and deep molecular response (MR4.5) were 13%, 11%, and 14%, respectively. Among patients who had a baseline CCyR, the probabilities of obtaining MMR and MR4.5 were 40% and 20%, respectively. ...read more
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
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.
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.
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).
“The TIDEL-II study aimed to optimize treatment outcomes by maximizing the number of patients reaching [European Leukemia Net] treatment milestones,” wrote study authors led by Timothy P. Hughes, of SA Pathology in Adelaide, Australia. The study built upon TIDEL-I, in which imatinib treatment was intensified based upon early targets.
In the new TIDEL-II study, two sequential cohorts totaling 210 patients with CML were enrolled. All patients in both cohorts began treatment with imatinib 600 mg/day. At 22 days imatinib could be intensified to 800 mg/day if plasma trough levels were below 1,000 ng/ml.
BCR-ABL1 levels (targets included ≤ 10%, ≤ 1%, and ≤ 0.1%) at 3, 6, and 12 months were then used to determine treatment plan. In cohort 1, if patients failed any target they were escalated to imatinib 800 mg/day, and then switched to nilotinib 400 mg twice daily if the same target was failed 3 months later. In cohort 2, failing to hit a target resulted in immediate switching to nilotinib; intolerance or loss of response in either cohort also resulted in switching to nilotinib.
At 12 months, 10% of cohort 1 and 12% of cohort 2 had a confirmed complete molecular response. At 24 months, these rates were 22% and 28%. ...read more
BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from expert panel on behalf of European LeukemiaNet
Simona Soverini1, Andreas Hochhaus2, Franck E. Nicolini3, Franz Gruber4, Thoralf Lange5, Giuseppe Saglio6, Fabrizio Pane7,8, Martin C. Müller9, Thomas Ernst2, Gianantonio Rosti1, Kimmo Porkka10, Michele Baccarani1, Nicholas C. P. Cross11,12, and Giovanni Martinelli1
August 4, 2011;
Blood: 118 (5)
Mutations in the Bcr-Abl kinase domain may cause, or contribute to, resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia patients. Recommendations aimed to rationalize the use of BCR-ABL mutation testing in chronic myeloid leukemia have been compiled by a panel of experts appointed by the European LeukemiaNet (ELN) and European Treatment and Outcome Study and are here reported. Based on a critical review of the literature and, whenever necessary, on panelists' experience, key issues were identified and discussed concerning: (1) when to perform mutation analysis, (2) how to perform it, and (3) how to translate results into clinical practice. In chronic phase patients receiving imatinib first-line, mutation analysis is recommended only in case of failure or suboptimal response according to the ELN criteria. In imatinib-resistant patients receiving an alternative TKI, mutation analysis is recommended in case of hematologic or cytogenetic failure as provisionally defined by the ELN. The recommended methodology is direct sequencing, although it may be preceded by screening with other techniques, such as denaturing-high performance liquid chromatography. In all the cases outlined within this abstract, a positive result is an indication for therapeutic change. Some specific mutations weigh on TKI selection.
There has been substantial interest in intermittent or other alternative scheduling of tyrosine kinase inhibitors in treatment for CML. The success of the drugs has been remarkable, but because of that success and the relative young age of many CML patients, many are forced to take the drugs for many years and even decades. This carries high financial burden, as well as increasing chances of non-compliance. Affirming the safety of intermittent scheduling could ease some of those concerns in CML patients.
The phase II trial included 76 patients who were at least 65 years old, and all had a stable complete cytogenetic response (CCgR) lasting more than 2 years. The intermittent imatinib regimen was a 1 month on, 1 month off schedule. -
January 13, 2015 | Chronic Myeloid Leukemia, ASH 2014, Hematologic Malignancies, Leukemia & Lymphoma
By Dave Levitan
Despite the early termination of a phase III trial due to safety concerns, an analysis suggests that ponatinib offers improved efficacy over imatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CP-CML). That improvement comes at the expense of higher rates of adverse events, according to the EPIC trial.
EPIC was a multinational, multicenter, randomized, open-label trial. It included 307 patients, with a median follow-up of only 5.1 months. The trial was terminated in October 2013 after a signal for increased risk of arterial thrombotic events was observed in the ponatinib treatment arm. Because of that early termination, none of the predefined endpoints could be thoroughly analyzed, but researchers presented other relevant data based on a cutoff of April 1, 2014. The analysis, led by Jeffrey H. Lipton, MD, PhD, of Princess Margaret Cancer Centre at the University of Toronto in Canada, was presented at the American Society of Hematology Annual Meeting in San Francisco in December 2014.