You are here

Dasatinib, Imatinib, Associated With Differing Mutation Patterns in CML

sandy craine's picture
Submitted by sandy craine on Mon, 27/07/2015 - 8:44pm
July 10, 2015 | Chronic Myeloid Leukemia, Hematologic Malignancies, Leukemia & Lymphoma Patients with chronic myeloid leukemia (CML) undergoing treatment with dasatinib had a narrower spectrum of mutations in BCR-ABL1 compared to those treated with imatinib, according to a new study, a finding which could aid in selection of second-line treatments. -

July 10, 2015 | Chronic Myeloid Leukemia, Hematologic Malignancies, Leukemia & Lymphoma

Patients with chronic myeloid leukemia (CML) undergoing treatment with dasatinib had a narrower spectrum of mutations in BCR-ABL1 compared to those treated with imatinib, according to a new study, a finding which could aid in selection of second-line treatments. -

Long-term outcome of a phase 2 trial with nilotinib 400 mg twice daily in first-line treatment of chronic myeloid leukemia.

sandy craine's picture
Submitted by sandy craine on Mon, 27/07/2015 - 8:39pm
Abstract Nilotinib is a second-generation tyrosine kinase inhibitors that has been approved for the first-line treatment of chronic phase chronic myeloid leukemia, based on the results of a prospective randomized study of nilotinib vs. imatinib (ENESTnd). Apart from this registration study, very few data are currently available on nilotinib first-line. We report here the long-term, 6-year, results of the first investigator-sponsored, GIMEMA multicenter phase II, single-arm, trial with nilotinib 400 mg twice daily as first-line treatment in 73 chronic-phase chronic myeloid leukemia patients. Six-year overall survival and progression-free survival were 96%, with one death after progression to blast phase. At 6 years, 75% of the patients were still on nilotinib. The cumulative incidence of major molecular response was 98%; only one patient had a confirmed loss of major molecular response. The cumulative incidence of deep molecular response (MR 4.0) was 76%. Deep molecular response was stable (≥ 2 years) in 34% of these patients. Cardiovascular adverse events, mainly due to arterial thrombosis, occurred in 11/73 patients (15%), after 24 to 76 months of therapy. They were more frequent in elderly patients, and in those with baseline cardiovascular risk factors. None was fatal, although there was a relevant morbidity. This is the study with the longest follow-up of a high dose nilotinib (400 mg twice daily), highlighting the high efficacy and the cardiovascular toxicity of the drug (CTG.NCT.00481052).

Abstract
Nilotinib is a second-generation tyrosine kinase inhibitors that has been approved for the first-line treatment of chronic phase chronic myeloid leukemia, based on the results of a prospective randomized study of nilotinib vs. imatinib (ENESTnd). Apart from this registration study, very few data are currently available on nilotinib first-line. We report here the long-term, 6-year, results of the first investigator-sponsored, GIMEMA multicenter phase II, single-arm, trial with nilotinib 400 mg twice daily as first-line treatment in 73 chronic-phase chronic myeloid leukemia patients. Six-year overall survival and progression-free survival were 96%, with one death after progression to blast phase. At 6 years, 75% of the patients were still on nilotinib. The cumulative incidence of major molecular response was 98%; only one patient had a confirmed loss of major molecular response. The cumulative incidence of deep molecular response (MR 4.0) was 76%. Deep molecular response was stable (≥ 2 years) in 34% of these patients. Cardiovascular adverse events, mainly due to arterial thrombosis, occurred in 11/73 patients (15%), after 24 to 76 months of therapy. They were more frequent in elderly patients, and in those with baseline cardiovascular risk factors. None was fatal, although there was a relevant morbidity. This is the study with the longest follow-up of a high dose nilotinib (400 mg twice daily), highlighting the high efficacy and the cardiovascular toxicity of the drug (CTG.NCT.00481052).

Treatment-Free Remission by Tyrosine Kinase Inhibitor for Patients with Chronic Myeloid Leukemia

sandy craine's picture
Submitted by sandy craine on Mon, 20/07/2015 - 6:34pm
Naoto Takahashi* Department of Hematology, Nephrology, and Rheumatology, Akita University, Japan Published: 08 July 2014 ABBREVIATIONS: CML: Chronic Myeloid Leukemia; TKIs: Tyrosine Kinase Inhibitors; CCyR: Complete Cytogenetic Remission; MMR: Major Molecular Response; ELN; European Leukemia Net; STIM: Stop Imatinib; bcr-abl: breakpoint cluster region-Abelson 1; PCR: Polymerase Chain Reaction; ASH: American Society of Hematology; TFR: Treatment-Free Remission; QOL: Quality Of Life; MRD: Minimal Residual Disease; BCRP: Breast Cancer Resistance Protein; SNPs: Single Nucleotide Polymorphisms; GIST: Gastrointestinal Stromal Tumor; BIM: BCL2-Like INTRODUCTION Treatment of Chronic Myeloid Leukemia (CML) with Tyrosine Kinase Inhibitors (TKIs) such as imatinib has dramatically improved the prognosis of this condition. However, the cessation of TKI treatment is considered impossible, because in vitro assays show that CML stem cells cannot be eliminated [1]. Clinically, neither Complete Cytogenetic Remission (CCyR) nor a Major Molecular Response (MMR) is sufficient to prevent recurrence after the cessation of medication [2,3]. Furthermore, progression from chronic to acute-phase disease is considered a major risk factor for treatment cessation. Such a progression is difficult to treat with TKI alone; the European Leukemia Net (ELN) guidelines and the hematopoietic tumor guidelines of the Japanese Society of Hematology prohibit TKI treatment cessation in daily practice outside planned clinical research settings [4,5]. On the other hand, treatment effects are reported to be sometimes maintained after incidental or planned treatment cessation prompted by side effects or pregnancy [6-11].

Naoto Takahashi*
Department of Hematology, Nephrology, and Rheumatology, Akita University, Japan
Published: 08 July 2014

ABBREVIATIONS: CML: Chronic Myeloid Leukemia; TKIs: Tyrosine Kinase Inhibitors; CCyR: Complete Cytogenetic Remission; MMR: Major
Molecular Response; ELN; European Leukemia Net; STIM: Stop Imatinib; bcr-abl: breakpoint cluster region-Abelson 1; PCR: Polymerase Chain Reaction; ASH: American Society of Hematology; TFR: Treatment-Free Remission; QOL: Quality Of Life; MRD: Minimal Residual Disease; BCRP: Breast Cancer Resistance Protein; SNPs: Single Nucleotide Polymorphisms; GIST: Gastrointestinal Stromal Tumor; BIM: BCL2-Like

INTRODUCTION
Treatment of Chronic Myeloid Leukemia (CML) with Tyrosine Kinase Inhibitors (TKIs) such as imatinib has dramatically improved the prognosis of this condition. However, the cessation of TKI treatment is considered impossible, because in vitro assays show that CML stem cells cannot be eliminated [1]. Clinically, neither Complete Cytogenetic Remission (CCyR) nor a Major Molecular Response (MMR) is sufficient to prevent recurrence after the cessation of medication [2,3]. Furthermore, progression from chronic to acute-phase disease is considered a major risk factor for treatment cessation. Such a progression is difficult to treat with TKI alone; the European Leukemia Net (ELN) guidelines and the hematopoietic tumor guidelines of the Japanese Society of Hematology prohibit TKI treatment cessation in daily practice outside planned clinical research settings [4,5]. On the other hand, treatment effects are reported to be sometimes maintained after incidental or planned treatment cessation prompted by side effects or pregnancy [6-11].

BCR-ABL1 mutation development during first-line treatment with dasatinib or imatinib for chronic myeloid leukemia in chronic phase

sandy craine's picture
Submitted by sandy craine on Fri, 17/07/2015 - 3:09pm
T P Hughes, G Saglio, A Quintás-Cardama, M J Mauro, D-W Kim, J H Lipton, M B Bradley-Garelik, J Ukropec and A Hochhaus BCR-ABL1 mutations are a common, well-characterized mechanism of resistance to imatinib as first-line treatment of chronic myeloid leukemia in chronic phase (CML-CP). Less is known about mutation development during first-line treatment with dasatinib and nilotinib, despite increased use due to higher response rates compared with imatinib. Retrospective analyses were conducted to characterize mutation development in patients with newly diagnosed CML-CP treated with dasatinib (n=259) or imatinib (n=260) in DASISION, with 3-year minimum follow-up. Mutation screening, including patients who discontinued treatment and patients who had a clinically relevant on-treatment event (no confirmed complete cytogenetic response [cCCyR] and no major molecular response [MMR] within 12 months; five-fold increase in BCR-ABL1 with loss of MMR; loss of CCyR), yielded a small number of patients with mutations (dasatinib, n=17; imatinib, n=18). Dasatinib patients had a narrower spectrum of mutations (4 vs 12 sites for dasatinib vs imatinib), fewer phosphate–binding loop mutations (1 vs 9 mutations), fewer multiple mutations (1 vs 6 patients), and greater occurrence of T315I (11 vs 0 patients). This trial was registered at www.clinicaltrials.gov as NCT00481247.

T P Hughes, G Saglio, A Quintás-Cardama, M J Mauro, D-W Kim, J H Lipton, M B Bradley-Garelik, J Ukropec and A Hochhaus

BCR-ABL1 mutations are a common, well-characterized mechanism of resistance to imatinib as first-line treatment of chronic myeloid leukemia in chronic phase (CML-CP). Less is known about mutation development during first-line treatment with dasatinib and nilotinib, despite increased use due to higher response rates compared with imatinib. Retrospective analyses were conducted to characterize mutation development in patients with newly diagnosed CML-CP treated with dasatinib (n=259) or imatinib (n=260) in DASISION, with 3-year minimum follow-up. Mutation screening, including patients who discontinued treatment and patients who had a clinically relevant on-treatment event (no confirmed complete cytogenetic response [cCCyR] and no major molecular response [MMR] within 12 months; five-fold increase in BCR-ABL1 with loss of MMR; loss of CCyR), yielded a small number of patients with mutations (dasatinib, n=17; imatinib, n=18). Dasatinib patients had a narrower spectrum of mutations (4 vs 12 sites for dasatinib vs imatinib), fewer phosphate–binding loop mutations (1 vs 9 mutations), fewer multiple mutations (1 vs 6 patients), and greater occurrence of T315I (11 vs 0 patients). This trial was registered at www.clinicaltrials.gov as NCT00481247.

Tyrosine Kinase Inhibitors and Pregnancy

sandy craine's picture
Submitted by sandy craine on Tue, 07/07/2015 - 11:50am
Elisabetta Abruzzese, Malgorzata Monika Trawinska, Alessio Pio Perrotti, and Paolo De Fabritiis Abstract The management of patients with chronic myeloid leukemia (CML) during pregnancy has become recently a matter of continuous debate. The introduction of the Tyrosine Kinase Inhibitors (TKIs) in clinical practice has dramatically changed the prognosis of CML patients; in fact, patients diagnosed in chronic phase can reasonably expect many years of excellent disease control and good quality of life, as well as a normal life expectancy, including the necessity to address issues relating to fertility and pregnancy. Physicians are frequently being asked for advice regarding the need for, and/or the appropriateness of, stopping treatment in order to conceive. In this report, we will review the data published in terms of fertility, conception, pregnancy, pregnancy outcome and illness control for TKI treated CML patients, as well as how to manage a planned and/or unplanned pregnancy.

Elisabetta Abruzzese, Malgorzata Monika Trawinska, Alessio Pio Perrotti, and Paolo De Fabritiis

Abstract
The management of patients with chronic myeloid leukemia (CML) during pregnancy has become recently a matter of continuous debate. The introduction of the Tyrosine Kinase Inhibitors (TKIs) in clinical practice has dramatically changed the prognosis of CML patients; in fact, patients diagnosed in chronic phase can reasonably expect many years of excellent disease control and good quality of life, as well as a normal life expectancy, including the necessity to address issues relating to fertility and pregnancy. Physicians are frequently being asked for advice regarding the need for, and/or the appropriateness of, stopping treatment in order to conceive. In this report, we will review the data published in terms of fertility, conception, pregnancy, pregnancy outcome and illness control for TKI treated CML patients, as well as how to manage a planned and/or unplanned pregnancy.

Network Meta-Analysis Shows a Significant Advantage of Nilotinib Over Imatinib in Chronic Myeloid Leukemia

sandy craine's picture
Submitted by sandy craine on Mon, 29/06/2015 - 2:50pm
Published in Oncology News · June 12, 2015 June 11, 2015 – Vienna, Austria – A comparison of different first-line treatment strategies for chronic myeloid leukemia in a network meta-analysis has shown a significant and relevant nilotinib advantage over standard imatinib 400 mg. This result, covering a patient population of 6314 patients, was reported at the 20th Congress of the European Hematology Society, from June 11 – 14, 2015.

Published in Oncology
News · June 12, 2015

June 11, 2015 – Vienna, Austria – A comparison of different first-line treatment strategies for chronic myeloid leukemia in a network meta-analysis has shown a significant and relevant nilotinib advantage over standard imatinib 400 mg. This result, covering a patient population of 6314 patients, was reported at the 20th Congress of the European Hematology Society, from June 11 – 14, 2015.

ENESTPath

Randomized Phase III Study to Assess the Effect of Longer Duration of Consolidation Treatment With Nilotinib on TFR in CP CML

Randomized Phase III Study to Assess the Effect of Longer Duration of Consolidation Treatment With Nilotinib on TFR in CP CML

STIM 2

Multicenter Trial Estimating the Persistence of Molecular Remission in Chronic Myeloid Leukaemia in Long Term After Stopping Imatinib

Multicenter Trial Estimating the Persistence of Molecular Remission in Chronic Myeloid Leukaemia in Long Term After Stopping Imatinib

Pages