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Abstracts and notes on CML presentations from ASH 2014 San Francisco

Professor Steve O’Brien, Newcastle University, UK

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Make a fundraising page JustGiving The CML Support Group is an online patient support group for chronic myeloid leukaemia patients, their families and carers. The website has been running since April 2000 and has a lively discussion forum as well as information regarding current therapies for CML.

Dasatinib, Imatinib, Associated With Differing Mutation Patterns in CML

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. -
See more at:
http://www.nature.com/leu/journal/vaop/ncurrent/full/leu2015168a.html

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

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).
Copyright © 2015, Ferrata Storti Foundation.

http://www.ncbi.nlm.nih.gov/pubmed/26113419

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

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].

Previous prospective imatinib cessation trials ...read more

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

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

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.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4010610/

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

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.

Nicole Skoetz, MD, of the University Hospital of Cologne, Germany, explained that the best treatment strategy for patients with chronic myeloid leukemia is a matter of debate. Since the introduction of the BCR-ABL tyrosine kinase inhibitor imatinib in 1998, patients with chronic myeloid leukemia have experienced a significant improvement in overall survival.

Prior to the tyrosine kinase inhibitors, the 10-year survival rate was 20%; hence imatinib 400 mg is now recommended as standard treatment. Published evidence of second-generation tyrosine kinase inhibitors also recommends dasatinib and nilotinib as first-line therapy. Direct head-to-head comparisons of second-generation tyrosine kinase inhibitors, however, are lacking.

Dr. Skoetz assessed the benefits and risks of different initial treatment strategies including tyrosine kinase inhibitors for patients with chronic myeloid leukemia in the chronic phase.

Sensitive search strategies were developed for CENTRAL, MEDLINE, and conference proceedings from 1990 through 2014. Randomized controlled trials that evaluated a regimen including a first-line tyrosine kinase inhibitor in patients with chronic myeloid leukemia in the chronic phase were reviewed. Two authors independently assessed studies for eligibility. ...read more

Novel Imatinib/Nilotinib Strategy Could Optimize CML Treatment

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.

- See more at: http://www.cancernetwork.com/chronic-myeloid-leukemia/novel-imatinib-nil...

RCC Drug Axitinib Could Treat TKI-Resistant CML

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.
The BCR-ABL1 kinase domain gatekeeper mutation known as T315I confers resistance to all approved TKIs except for ponatinib. That drug, unfortunately, led to frequent severe adverse vascular events, resulting in trial terminations and temporary withdrawal from the market. “Therefore, there is a significant, unmet need for safe and effective therapies for BCR-ABL1(T315I)-driven leukemia,” wrote researchers led by Tea Pemovska, MSc, of the University of Helsinki in Finland.
Pemovska and colleagues combined “drug sensitivity and resistance profiling” of ex vivo patient cells to determine that axitinib, a VEGFR TKI currently approved for the treatment of renal cell carcinoma (RCC), could inhibit T315I-mutated BCR-ABL1-driven leukemia. They published a research letter online ahead of print in Nature.
At both biochemical and cellular levels, the authors wrote, axitinib potently inhibited the target. It did this by binding to the active form of ABL1(T315I) in a mutation-selective binding mode. Ex vivo testing using other TKIs showed that dasatinib, imatinib, and nilotinib could not achieve the same efficacy as axitinib or ponatinib.
The researchers then tested axitinib in the T315I CML patient from whom the CML cells had originated. The patient was treated with the approved therapeutic dose of axitinib (5 mg twice daily) for 2 weeks. This treatment “resulted in a rapid clearance of BCR-ABL1(T315I)-positive cells” from bone marrow, suggesting that this drug could produce effective responses in this particular form of the disease. ...read more

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