Phase III clinical trial data presented at the 53rd Annual Meeting of the American Society of Hematology (ASH) in San Diego, CA, shows growing evidence that adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase who are treated withnilotinib (Tasigna?, Novartis) have deeper levels of response compared to those treated with imatinib mesylate(Glivec?/Gleevec?, Novartis)[1],[2].

The findings are from the ENEST (Evaluating Nilotinib Efficacy and Safety in clinical Trials) clinical research program, the first exploratory randomized trial to investigate the impact of switching adult patients with residual disease after a minimum of two years of treatment with imatinib to nilotinib to determine if a deeper level of response could be achieved[1].

The study showed that twice as many patients switched to nilotinib 400 mg twice a day achieved undetectable Bcr-Abl levels by 12 months compared to imatinib (23% taking nilotinib 400 mg twice daily and 11% taking imatinib 400 mg or 600 mg once daily; p= 0.0202). The primary endpoint, which is more stringent than conventional measures, is undetectable Bcr-Abl level in two consecutive samples. Samples with any detectable level were not considered to be in complete molecular response (CMR). The lowest detected Bcr-Abl value was 0.00073%. This endpoint showed a two-fold difference in confirmed undetectable CMR for 13% of patients on nilotinib versus 6% of patients on imatinib, although statistical significance was not achieved (p=0.108). The study has a planned follow-up of four years[1].

More patients achieved CMR
After 36 months of follow-up, data from the open-label, randomized, prospective, multi-center Phase III ENESTnd clinical trial in adult patients with newly diagnosed Ph+ CML in chronic phase continued to show significantly more patients achieved CMR, defined in this study as at least a 4.5 log reduction from baseline or a trace amount of 0.0032% or less of Bcr-Abl compared to imatinib (32% taking nilotinib 300 mg twice daily and 15% taking imatinib 400 mg once daily). The ENESTnd study also continued to show that first-line treatment with nilotinib resulted in significantly fewer patients progressing to advanced phase and blast crisis (AP/BC) stages of disease compared to imatinib, leading to a significantly lower number of CML-related deaths in patients taking nilotinib versus imatinib (p=0.0356)[2].

“Data from both ENESTnd and ENESTcmr reinforce that patients taking Tasigna have a greater chance of achieving CMR, the deepest level of response measurable today, compared to those taking Glivec,” said Timothy P. Hughes, MD, ENEST study investigator and Clinical Professor at the University of Adelaide, Australia. “We are encouraged by what we saw in ENESTcmr and further follow-up on both trials should help to determine if more patients can reach undetectable levels of CML over time, which could have important implications for determining criteria for future studies on discontinuation of therapy.”

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Philadelphia chromosome
CML is a disease in which the body produces cancerous white blood cells. Almost all patients with CML have an abnormality known as the Philadelphia chromosome, which is comprised of a protein called Bcr-Abl that causes malignant white blood cells to proliferate[3]. The success of treatment for CML can be measured by a test called real-time quantitative polymerase chain reaction (RQ-PCR). A molecular response means RQ-PCR shows a reduction in Bcr-Abl in the blood. A CMR means no Bcr-Abl is detected[4],[5]. In recent investigator-initiated studies, select patients who achieved durable CMR have been able to cease therapy without relapse for trial periods lasting from six months to a year[6-8].

“Data from the ENESTnd 36-month update and the ENESTcmr trial at ASH continue to reinforce the benefits of Tasigna over Glivec, and support the use of Tasigna for adult patients with chronic-phase Ph+ CML,” said Herv? Hoppenot, President, Novartis Oncology. “We look forward to even more progress in the future as we observe the impact of achieving deep and sustained molecular response with Tasigna for people living with this cancer.”

Worldwide, CML is responsible for approximately 10% to 15% of all adult cases of leukemia, with an incidence of one to two cases per 100,000 people per year[9],[10].

[1] Hughes TP, Lipton JH, Leber B et al. Complete Molecular Response (CMR) Rate With Nilotinib in Patients (pts) With Chronic Myeloid Leukemia in Chronic Chase (CML-CP) Without CMR After ? 2 Years on Imatinib: Preliminary Results From the Randomized ENESTcmr Trial of Nilotinib 400 mg Twice Daily (BID) vs Imatinib. Abstract no. 606. December 12, 2011.
[2] Saglio G, le Coutre PD, Pasquini R et al. Nilotinib Versus Imatinib in Patients (pts) With Newly Diagnosed Philadelphia Chromosome-Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP): ENESTnd 36-month (mo) Follow-up. Abstract no. 452. December 12, 2011.
[3] National Cancer Institute. General Information About Chronic Myelogenous Leukemia(PDQ). Last accessed November 2011.
[4] Baccarani M, Pane F, Saglio G. Monitoring treatment of chronic myeloid leukemia. Haematologica. 2008 Feb;93(2):161-9.
[5] NCCN Clinical Practice Guidelines in Oncology. Chronic Myelogenous Leukemia. Version 2.2012
[6] Rousselot P, Huguet F, Rea D et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood. 2007 Jan 1;109(1):58-60.
[7] Ross DDM, Grigg A, Schwarer A, et al. The majority of chronic myeloid leukaemia patients who cease imatinib after achieving a sustained complete molecular response (CMR) remain in CMR, and any relapses occur early. ASH Annual Meeting Abstracts 2008 112: 1102.
[8] Mahon FX, R?a D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010 Nov;11(11):1029-35.
[9] American Cancer Society. Detailed Guide: CML. What are the key statistics about CML? (06/23/2011 Revision) Last accessed November 2011.
[10] Central European Leukemia Study Group. About CML. Last accessed November 2011.

For more information:
– Treatment Pathway Connections Ties Clinicians and Care Managers to Support Treatment
Nilotinib ApprovalGives Patients With Newly Diagnosed Ph+ Chronic Myeloid Leukemia New Medical Option
– Nilotinib (Tasigna?) Demonstrates Major Treatement Advance Over Imatinib(Glivec?) For Newly Diagnosed Chronic Myeloid Leukemia Patients.

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