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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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Tyrosine Kinase Inhibitors and Pregnancy

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

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

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. 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.

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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. more

Interferon Could Help CML Patients Stop TKI Therapy

News | April 07, 2015 | Chronic Myeloid Leukemia, Hematologic Malignancies, Leukemia & Lymphoma
By Cancer Network Staff

Interferon alpha 2a molecule.
Results from a small study suggest that induction treatment with interferon alpha 2a (IFN) along with imatinib, followed by temporary IFN maintenance therapy, could help patients with chronic myeloid leukemia (CML) discontinue imatinib treatment.

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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.

Laboratory recommendations for scoring deep molecular responses following treatment for 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 more

Bosutinib a Good Fourth-Line Option in CML

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. more

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