ENESTnd Study Research Articles

Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis

In the ENESTnd study, with ≥10 years follow-up in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase, nilotinib demonstrated higher cumulative molecular response rates, lower rates of disease progression and CML-related death, and increased eligibility for treatment-free remission (TFR). Cumulative 10-year rates of MMR and MR4.5 were higher with nilotinib (300 mg twice daily [BID], 77.7% and 61.0%, respectively; 400 mg BID, 79.7% and 61.2%, respectively) than with imatinib (400 mg once daily [QD], 62.5% and 39.2%, respectively). Cumulative rates of TFR eligibility at 10 years were higher with nilotinib (300 mg BID, 48.6%; 400 mg BID, 47.3%) vs imatinib (29.7%). Estimated 10-year overall survival rates in nilotinib and imatinib arms were 87.6%, 90.3%, and 88.3%, respectively. Overall frequency of adverse events was similar with nilotinib and imatinib. By 10 years, higher cumulative rates of cardiovascular events were reported with nilotinib (300 mg BID, 16.5%; 400 mg BID, 23.5%) vs imatinib (3.6%), including in Framingham low-risk patients. Overall efficacy and safety results support the use of nilotinib 300 mg BID as frontline therapy for optimal long-term outcomes, especially in patients aiming for TFR. The benefit-risk profile in context of individual treatment goals should be carefully assessed.

Myeloid diseases—Chronic Myeloid Leukemia (CML)—report from ASH 2019 on new developments

The recent American Society of Hematology (ASH) annual meeting, held in Orlando, Florida, in December 2019 was an exciting meeting for researchers and clinicians working in the field of chronic myeloid leukemia (CML), as well as for patients suffering from the disease. Interesting updates were presented on new kinase inhibitors (TKI) demonstrating great potential with low toxicities in heavily pretreated patients. Moreover, the 10-year follow-up data of the ENESTnd Study, comparing 2nd generation (2ndG) TKI nilotinib with imatinib showed a continuous benefit of the 2ndG TKI in achieving deeper molecular responses and less progressions to accelerated phase (AP) and blast crisis (BC), but no benefit in progression-free (PFS) or overall survival (OS). Encouraging data were also presented on the treatment of CML BC by combining conventional chemotherapy (FLAG-IDA) with TKI therapy (Ponatinib). Furthermore, great efforts have been undertaken to be able to predict the likelihood of successful TKI cessation in deep molecular remission for individual CML patients in first chronic phase (CP).

Gene Expression Signature Predicts Deep Molecular Response (DMR) in Chronic Myeloid Leukemia (CML): An Exploratory Biomarker Analysis from ENESTnd

Gene Expression Signature Predicts Deep Molecular Response (DMR) in Chronic Myeloid Leukemia (CML): An Exploratory Biomarker Analysis from ENESTnd

The REL-Protocol PhilosoPhi34 - an Open Label, Single Arm, Phase II Study of Nilotinib 300 Mg BID in Newly Diagnosed Chronic Phase Chronic Myeloid Leukaemia (CML) Patients - Confirms Early Clearance of Bone Marrow CD34+/Lin-Ph+ Cells

Background CML is a clonal disorder characterized by the presence of the Philadelphia (Ph) chromosome which encodes for the bcr-abl tyrosine-kinase (TK). Target therapy with the TK inhibitors (TKIs)) has greatly improved its outcome.Treatment with second generation TKIs - e.g. nilotinib (NIL) - results in deeper and faster responses and prevents disease progression. Sustained responses may enable TKI discontinuation. However, even in the event of qPCR negativity, a fraction of patients (pts) experience disease recurrence possibly due to persistence of quiescent leukemic stem cells (LSCs).Degree and mechanisms of LSCs clearance during TKI treatment are not established yet and conflicting results are reported in the literature. Work from the group of Bocchia (Bocchia 2008; Defina 2012) showed reduction of LSCs during long term imatinib (IM) therapy; moreover, in CCyR pts residual LSCs are more rarely detected after NIL compared to IM therapy and, in a small fraction of pts this occurs after very short-term NIL therapy.This data conflicts with in vitro evidence that NIL is not superior to IM in inducing growth suppression in CML LSCs (Konig, 2008).To verify the in vivo activity and time-course of first-line NIL therapy on bone marrow (BM) Ph+ stem cells (CD34+/lin-) clearance, on behalf of the Rete Ematologica Lombarda (REL) the PhilosoPhi34 study (EudraCT: 2012-005062-34) was designed.Primary efficacy endpoint was to measure the rate of BM residual CD34+/lin-Ph+ cells in CCyR pts at 6 months of treatment.Methods BM cells were collected and stored at diagnosis and at 3,6 and 12 mos of treatment. CD34+/lin- cells were purified using a Diamond CD34 Isolation Kit Miltenyi (97% of purity). FISH analysis of selected unstimulated CD34+/lin- cells was performed according to standard procedures; considering the low sensitivity of the test, in order to define the test as negative at least 200 nuclei were examined.The A'Hern single stage design was chosen for the present study; considering the CCyR results obtained in the ENESTnd study and the anticipated number of un-evaluable tests, a minimun of 87 pts were required.Results Enrolment of the 87 pts was completed by June 2015. Table 1 summarises pts' characteristics and response to treatment. FISH results are as follows:at 3 mos, 8/65 (12,3%; CI 95%: 2,3%-15,7%) evaluable FISH tested positive (10 negative tests not evaluable);at 6 mos 5/71 (7%; CI 95% :2,3-15,7%) evaluable FISH tested positive (7 negative tests not evaluable);at 12 mos, 0/68 (0%; CI95%:0,0-5,2%) evaluable FISH tested positive (9 negative tests not evaluable).At any time point, Sokal score did not predict for FISH results. However, as outlined in Table 2, H-Sokal score pts are less prevalent among pts who achieve a CCyR, a requirement for FISH analysis.Of the 4 pts who failed the treatments' objectives by 12 mos, 1 was in CCyR with detectable residual CD34+/lin-Ph+ cells at 3 mos; 2 were not in CCyR and with residual CD34+/lin-Ph+ cells at 3mos; 1 was in CCyR and with CD34+/lin-Ph- cells at 3 and 6 mos but with increasing qPCR. Only 1 pt with CD34+/lin-Ph- cells at all time points and with optimal molecular response harboured a NIL-resistant mutation at 26 mos of treatment.None of the 22 pts (including 4 H-Sokal score pts = equal proportion of study cohort) in Molecular Response (MR) 3.0 at 3 mos had a positive FISH at 3 and 6 mos or failed treatment at follow-up.Conclusion. Our final results on the whole cohort of pts confirm our preliminary data on the efficacy of NIL 300 g BID in early clearance of BM LSCs (CD34+/lin-Ph+) in newly diagnosed CP-CML patients tested at 3, 6 and 12 mos of treatment. Moreover, according to our data, fast disease debulking seems crucial for obtaining BM LSCs clearance and it can be speculated that the same mechanism responsible for this early MR 3.0 achievement is also capable of preventing H-Sokal risk pts from failing treatment. [Display omitted] [Display omitted] DisclosuresOrlandi:Ariad: Honoraria; BMS: Honoraria; Novartis: Honoraria.

ENESTnext Final Results: Deep Molecular Response (MR) with Nilotinib (NIL) in Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

ENESTnext Final Results: Deep Molecular Response (MR) with Nilotinib (NIL) in Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Updated review of nilotinib as frontline treatment for newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia

Nilotinib, a second-generation tyrosine kinase, is approved for the treatment of newly diagnosed chronic phase chronic myeloid leukemia patients. The drug showed impressive rates of cytogenetic and molecular responses with only few cases of disease progression in Phase II trials. Five years follow-up of Phase III randomized ENESTnd study demonstrated deep molecular responses, lower rate of transformation in the core treatment compared with imatinib (0.7% for nilotinib 300 mg twice daily [BID], 1.1% for nilotinib 400 mg BID and 4.2% with imatinib). ENEST1st study confirmed the activity of nilotinib in first line at the dose of 300 mg BID. Aim of this review is to provide reported evidences on the efficacy and safety of nilotinib when used for the management of early chronic phase chronic myeloid leukemia patients and to discuss about future possible discontinuation.

Five-Year Outcome of 215 Newly Diagnosed Chronic Myeloid Leukemia Patients Treated Frontline with Nilotinib-Based Regimens: A Gimema CML Working Party Analysis

▪Background. Nilotinib (NIL) is a potent and selective BCR-ABL inhibitor approved for the frontline treatment of chronic myeloid leukemia (CML) based on the results of the ENESTnd study. The sustained superiority of NIL vs. imatinib (IM) was confirmed after 5 years of follow-up (Hughes et al, abs. 677, EHA 2014). However, few data are available on patients (pts) treated frontline with NIL outside of Company-initiated trials.Objectives. To analyze the long-term outcome in a large, independent cohort of newly diagnosed CML pts treated frontline with NIL-based regimens.Methods. We analyzed 215 pts, enrolled in 2 multicenter phase II studies conducted by the GIMEMA CML WP (ClinicalTrials.gov. NCT00481052 and NCT00769327) or treated at the Bologna University Hospital, with NIL 300 mg or 400 mg BID as initial treatment; 123 pts received a sequential treatment with NIL and IM (NIL-IM), with a 3-months (mos) rotation period (all patients received NIL in the first 3 mos). The median age was 53 years (range 18–86). Ten out of 215 pts (5%) had a high EUTOS score. The median follow-up was 57 mos (range 36–81 mos). We assessed: the rates of Complete Cytogenetic Response (CCyR) and Major Molecular Response (MMR); the rates of optimal responders at each milestone according to ELN 2013 recommendations; the overall survival (OS; any death included), progression-free survival (PFS; progression to accelerated/blast phase [AP/BP] and deaths for any cause), failure-free survival (FFS; failures according to ELN 2013 recommendations and deaths for any cause), and event-free survival (EFS; events: failures, permanent discontinuation of NIL for any cause, including deaths). All analysis was made according to the intention-to-treat principle.Results. The cumulative rates of CCyR and MMR were 93% and 88%, respectively. At 3 mos, 82% of the pts were in Partial Cytogenetic Response and 90% had a BCR-ABL/ABL (IS) < 10%; at 6 mos, 86% were in CCyR and 83% had a BCR-ABL/ABL (IS) < 1%; at 12 mos, 72% were in MMR; all these pts were optimal responders according to ELN 2013 recommendations. Overall, 80 (37%) pts permanently discontinued NIL: 45 (21%) for adverse events or intolerance; 25 (12%) for failures; 7 (3%) while in stable MR4; 3 (1%) for other reasons. Cardiovascular adverse events (CVAE) were cause of permanent NIL discontinuation, after a median time of 37 mos, in 13 (6%) pts, and included 4 peripheral arterial occlusive diseases and 3 ischemic coronary diseases; only one pt died for CVAE. Nine (4.1%) pts progressed to AP/BP, 8/9 during the 1st year of therapy and one after 25 mos; all pts subsequently died (after a median of 13 mos, range 1-34 mos). NIL-resistant mutations were identified in 6 of these pts (4 T315I; 1 Y253H; 1 F359V); 7/9 progressions occurred in patients receiving NIL-IM. In addition, 6 pts were classified as failures at 3,6, or 12 mos according to ELN 2013 recommendations; afterwards, 10 pts developed a secondary resistance (3 loss of CHR, 3 loss of CCyR, and 4 confirmed loss of MMR). Overall, 17 (8%) pts died, in 7 cases for reasons unrelated to CML progression. The estimated 6-year OS, PFS, FFS, and EFS were 91%, 91%, 83%, and 59%, respectively.Conclusions. Our National experience showed that most pts treated frontline with NIL-based regimens were optimal responders according to ELN recommendations and that 91% of the patients were estimated to be alive and progression-free at 6 years. In particular, NIL alone was highly effective in the prevention of AP/BP. Considering that AP/BP had in most cases an early onset and an extremely poor prognosis, its prevention should be the priority of CML treatment, especially in the firsts 2-3 years. However, afterwards, the relatively high number of CVAE observed, suggests to focus, at least in selected patients, on strategies aimed at the prevention of CVAE (NIL dose reduction? switch to IM?).Acknowledgments. European LeukemiaNet, COFIN, Bologna University, BolognAIL DisclosuresGugliotta:Novartis: Consultancy; Bristol-Myers-Squibb: Consultancy. Castagnetti:Novartis: Consultancy; Bristol-Myers-Squibb: Consultancy. Breccia:novartis: Consultancy; BMS: Consultancy; Celgene: Consultancy. Abruzzese:Novartis: Consultancy. Martinelli:ARIAD: Consultancy; Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Saglio:BMS: Consultancy, Fees for occasional speeches Other; Novartis: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; Pfizer: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; ARIAD: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other. Baccarani:Novartis, BMS, Pfizer, Ariad: Consultancy, Honoraria, Speakers Bureau. Rosti:Novartis: Consultancy; Bristol-Myers-Squibb: Consultancy; Ariad: Consultancy; Pfizer: Consultancy.

Is a cure for CML without allogeneic stem cell transplantation around the corner?

Is a cure for CML without allogeneic stem cell transplantation around the corner?

4-Year Outcome Of 215 Patients With Newly Diagnosed Chronic Myeloid Leukemia (CML) Treated Frontline With Nilotinib In Investigator-Sponsored Studies. A Report From The Gimema CML Working Party

BackgroundNilotinib is a potent and selective BCR-ABL inhibitor approved for the frontline treatment of CML. The latest update (4-yr follow-up) of the ENESTnd study demonstrated sustained superiority of nilotinib vs. imatinib (Hochhaus et al, EHA 2013, abstract 712). The CML Italian Registry of Nilotinib is the largest series of patients treated frontline with nilotinib-based regimens, outside of Company-sponsored trials. Therefore, it represents an important resource for an independent evaluation of the outcome of such patients. Aimsto analyze the response rates and outcome in an independent cohort of patients treated frontline with nilotinib-based regimens in Italy. MethodsThe CML Italian Registry of Nilotinib includes 215 patients, enrolled in 2 multicenter phase II studies conducted by the GIMEMA CML WP (ClinicalTrials.gov. NCT00481052 and NCT00769327) with nilotinib 300 mg or 400 mg BID as initial treatment; 123 patients received a sequential treatment with nilotinib and imatinib, with a 3-mo rotation period. The median age was 53 years (range 18–86). Ten out of 215 patients (5%) had a high EUTOS score. The median follow-up was 43 months (range 18–69 months). We analyzed: the rates of Complete Cytogenetic Response (CCyR) and Major Molecular Response (MMR); the overall survival (OS; any death included), progression-free survival (PFS; progression to accelerated/blast phase [AP/BP] and deaths for any cause), failure-free survival (FFS; failures according to ELN 2013 recommendations and deaths for any cause), and event-free survival (EFS; events: failures, permanent discontinuation of nilotinib for any cause, including deaths). ResultsRates of CCyR were 72% and 92% by 3 months and 12 months, respectively. Rates of MMR were 56% and 83% by 3 months and 12 months, respectively. The cumulative rates of CCyR and MMR were 93% and 92%, respectively. Overall, events were recorded in 64 (30%) patients: 31 (14%) patients permanently discontinued nilotinib for adverse events or intolerance; 22 (10%) patients failed therapy according to ELN 2013 recommendations, including 8 (3.7%) patients that progressed to AP/BP; 11 (5%) patients permanently discontinued nilotinib for other reasons. All progressions to AP/BP occurred within the first year of therapy, and all patients subsequently died. Nilotinib-resistant mutations were identified in 5 of these patients (4 T315I; 1 Y253H). No difference in the rate of progression to AP/BP was observed between patients receiving nilotinib alone or nilotinib and imatinib in sequential schedule. Overall, 15 (7%) patients died, in 7 cases for reasons unrelated to CML progression. The 4-year OS, PFS, FFS, and EFS were 93%, 93%, 86%, and 69%, respectively. ConclusionThese Italian nilotinib registry data provide an independent and unbiased overview of the therapeutic effects of nilotinib, with high and early rates of complete cytogenetic and major molecular response. All progressions (3.7%) to AP or BP occurred within the 1st year of therapy; however, all cases were fatal, emphasizing how crucial is the prevention of AP/BP. With a median follow-up of 43 months, 69% of patients were still on nilotinib, and 93% were alive and progression-free. AcknowledgmentsEuropean LeukemiaNet, COFIN, Bologna University, BolognAIL [Display omitted] Disclosures:Gugliotta:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Castagnetti:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Bocchia:Novartis and Bristol Mayer Squibb: Honoraria. Soverini:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; ARIAD: Consultancy. Saglio:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Cavo:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Baccarani:Novartis: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Pfizer: Honoraria; Ariad: Honoraria. Rosti:Novartis: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Ariad: Consultancy; Roche: Speakers Bureau.

Use Of Nilotinib As a First Line Treatment In Adult Patients With Philadelphia Chromosome-Positive and Chronic Phase Myeloid Leukemia

IntroductionNilotinib, a more potent and selective drug than imatinib, was approved by the FDA and EMA initially for the treatment of chronic and accelerated phase Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) patients resistant or intolerant to prior therapy including imatinib and subsequently for the treatment of newly-diagnosed Ph+ CML patients in the chronic phase (CML-CP). The aim of the present study was to investigate efficacy and safety profile of nilotinib in a Turkish population of newly-diagnosed Ph+ CML-CP patients and to evaluate the effects of these results on prognosis according to current treatment guidelines. MethodsThe study was planned as a multicenter, open-label, one-arm phase II clinical trial. All patients were planned to be treated with nilotinib (AMN107, Tasigna®) 300 mg BID for 24 months. Herein, efficacy results of the patients who completed the first year of the study are presented. ResultsOf the 112 patients included in the study, data for 94 patients who completed 12 months of the study up to April 29, 2013 were analyzed. Of these 94 patients, 16 were excluded within this period and 78 completed the first year of the study within the median 371 days (range, 339-401 days) or median 12.4 months (range, 11.3-13.4 months). General characteristics of the patients are presented in Table 1.Table 1General characteristics of the patientsCharacteristicsAge, year46.5 (range 19-78)Gender (Female/Male)37 (%39.4)/57 (%60.6)Palpable spleen size (maximum distance below the rib margin) (baseline), cm0.0 (0-17)Baseline Leukocyte count (range), K/mm329.2 (1.7-289.4)Baseline Platelet count (range), K/mm3343.0 (75-1,268)Treatment-related characteristics of the patients are presented in Table 2.Table 2Treatment-related characteristics of the patientsN80% Confidence IntervalCumulative MMR rate by 12th month9458 (61.7)54.6-68.4Time to MMR58Days184.8±84.7Months6.2±2.8BCR-ABL level at 3rd month87<%1075 (86.2)80.2-90.8≥%1012 (13.8)9.2-19.8CCyR rate at 6th month8476 (90.5)85.0-94.4CCyR rate at 12th month7467 (90.5)84.6-94.7Data are presented as mean±standard deviation or number (%), where appropriate.MMR (Major molecular rate): BCR-ABL/control gene ratio of ≤%0.1 measured by RQ-PCR as %CCyR (Complete cytogenetic response): Patients with 0% Ph+ metaphasesCumulative MMR rates at 3rd, 6th 9th, and 12th months of the patients are shown in Figure 1. [Display omitted] ConclusionsAccording to the results of interim analysis of this first prospective CML study conducted on Turkish population, the cumulative MMR rate by 12th month (primary endpoint) (61.7%) appears to be similar to that of the ENESTnd study. From the 3rd month, rapid and increasing MMR rates were reported and median time to MMR was 6.5 months. At both 6th and 12th month, high CCyR rates (both 90.5%) were also established. At all landmark evaluations, most of the patients rapidly achieved high rates of cytogenetic and molecular responses to nilotinib assessed by both 2009 and 2013 ELN optimal response criteria, and only one patient had disease progression. These results suggest that more rapid and greater efficacy was achieved with nilotinib during the 1st year of the study in comparison to historical data with imatinib and that nilotinib might improve short-term responses when started in the first-line setting.The rate of patients with BCR-ABL ≤10% at 3rd month, which is very important according to the current treatment guidelines, was 86.2%.The results of the present study revealed that efficacy of nilotinib, which is a licensed alternative for the treatment of newly diagnosed Ph+ CML-CP in Turkey, might provide a new standard of treatment. Disclosures:Saydam:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation, Turkey: Consultancy, Membership on an entity's Board of Directors or advisory committees. Haznedaroglu:Novartis Pharmaceuticals Corporation, Turkey: Honoraria, Research Funding. Yavuz:Novartis Pharmaceuticals Corporation, Turkey: Membership on an entity's Board of Directors or advisory committees. Ali:Novartis Pharmaceuticals Corporation, Turkey: Membership on an entity's Board of Directors or advisory committees. Guvenc:Novartis Pharmaceuticals Corporation, Turkey: Membership on an entity's Board of Directors or advisory committees. Sonmez:Novartis Pharmaceuticals Corporation, Turkey: Membership on an entity's Board of Directors or advisory committees. Akkaynak:Novartis Pharmaceuticals Corporation, Turkey: Employment. Dag:Novartis Pharmaceuticals Corporation, Turkey: Employment.

PHC-016 Nilotinib Versus Imatinib For the Treatment of Patients with Newly-Diagnosed Philadephia Chromosome-Positive, Chronic Myeloid Leukaemia in the Chronic Phase

BackgroundNilotinib is a BCR-ABL inhibitor designed to be more potent and selective than imatinib. Imatinib was the first of a new class of drugs that act by specifically inhibiting a...

Outcome of Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Based On Early Molecular Response and Factors Associated with Early Response: 4-Year Follow-up Data From Enestnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials Newly Diagnosed Patients)

Abstract Abstract 167 Background: In the ENESTnd study, nilotinib significantly reduced progression to accelerated phase/blast crisis (AP/BC) and demonstrated superior rates of deep molecular response vs imatinib. Data from ENESTnd demonstrated that significantly more patients achieved early molecular response of both &lt; 10% and &lt; 1% BCR-ABLIS at both 3 and 6 months on nilotinib vs imatinib. Here, we report landmark analyses based on BCR-ABL transcript levels at 3 and 6 months using data with a minimum follow-up of 3 years and also provide data on factors associated with poor early molecular response; data based on longer follow-up of 4 years will be presented. Methods: The nilotinib 300 mg twice daily (BID; n = 282) and imatinib 400 mg once daily (QD; n = 283) arms from ENESTnd were used for this analysis. Patients were grouped based on BCR-ABL transcript levels of ≤ 1%, &gt; 1% to ≤ 10%, and &gt; 10% at 3 months (n = 258 and n = 264 patients with available PCR samples at 3 months in the nilotinib and imatinib arms, respectively) and at 6 months (n = 257 and n = 256 patients with available PCR samples at 6 months in the nilotinib and imatinib arms, respectively). Rates of major molecular response (MMR; ≤ 0.1% BCR-ABLIS) and molecular response with a 4.5-log reduction in BCR-ABL transcript levels (MR4.5, ≤ 0.0032%IS) as well as rates of progression-free survival (PFS) and overall survival (OS) were evaluated among patients grouped according to their BCR-ABL transcript levels at 3 and 6 months. Data on selected baseline characteristics and dose intensity were also assessed. Results: Among evaluable patients at 3 months, 9% of patients (n = 24) in the nilotinib arm vs 33% (n = 88) in the imatinib arm had BCR-ABL transcript levels of &gt; 10%; among evaluable patients at 6 months, 3% of patients (n = 7) in the nilotinib arm vs 16% (n = 40) in the imatinib arm had BCR-ABL transcript levels of &gt; 10%. Patients with a BCR-ABL transcript level of &gt; 10% had a lower probability of future MMR or MR4.5 as well as poorer PFS and OS compared with patients who had BCR-ABL transcript levels ≤ 10% at 3 months (Table). Results were similar based on 6-month landmark analyses. In patients with &gt; 10% BCR-ABL transcript levels at 3 months, the average dose intensity of nilotinib within the first 3 months was 474 mg/day compared with 600 mg/day for patients with ≤ 10% BCR-ABL transcript levels; the average dose intensity of imatinib within the first 3 months was the same (400 mg/day) for patients with both ≤ 10% and &gt; 10% BCR-ABL levels at 3 months (Table). Patients with &gt; 10% BCR-ABL transcript levels at 3 months were also more likely to have high Sokal risk, larger spleen size, and additional chromosomal abnormalities compared with patients with ≤ 10% BCR-ABL transcript levels at 3 months. Other factors associated with early response and further data on long-term outcomes are being assessed and will be presented with a minimum follow-up of 4 years. Conclusions: Fewer patients in the nilotinib arm vs the imatinib arm had BCR-ABL transcript levels &gt; 10% at 3 and 6 months. Reasons for poor early response appeared to be related, at least in part, to baseline factors and dose intensity. Early molecular response at 3 and 6 months correlated with future MMR and MR4.5as well as an increased probability of PFS and OS. Nilotinib frontline therapy allows more patients to achieve deeper responses earlier, associated with improved long-term outcomes vs imatinib. Disclosures: Hochhaus: BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding. Hughes:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; CSL: Research Funding. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy. Guilhot:Celgene: Consultancy; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Ariad: Honoraria. Al-Ali:Novartis: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Sanofi-Aventis: Consultancy, Honoraria. Rosti:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Speakers Bureau. Kemp:Novartis Pharmaceuticals Corp: Employment. Fan:Novartis Pharmaceuticals Corp: Employment. Hoenekopp:Novartis Pharma AG: Employment, Equity Ownership. Larson:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy; Ariad: Consultancy, Research Funding. Kantarjian:Novartis Pharmaceuticals Corp: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding.

Number Needed to Treat (NNT) and Cost Estimation to Achieve a Major Molecular Response in Newly Diagnosed Chronic-phase cronic Myeloid Leukemia in Brasil: 24-months follow-up

Abstract 4216 Background:The use of imatinib (IM) has greatly improved the outcome of patients with Ph+ chronic myeloid leukemia (CML), with a good balance of potency and exposure that translated into clinical efficacy for many patients. However, patient responses to IM can be variable with factors such as blood plasma levels and OCT-1 transporter activity influencing responses (Larson, 2008; White, 2010). Some patients do not reach complete cytogenetic response (CCyR) and others may have intolerable side effects. Loss of response to IM and disease progression occur mainly in the first 3 years of treatment, and the rate of overall survival is affected as a consequence. Molecular monitoring is the most sensitive measure of CML disease burden and Major Molecular Response (MMR) is associated with an extremely low rate of disease progression (Hughes, 2008). Objectives: (1) To estimate the ‘Number Needed to Treat’ (NNT) to achieve one MMR by 24 months. (2) To provide a relative measure of the cost of attaining treatment objective defined by MMR and hematologic adverse events (AEs) with 2 novel targeted therapies in the treatment of newly diagnosed CP-CML from the Brazilian Public Health Care System (SUS) perspective. Methods: MMR and AE data were evaluated from two phase 3 studies comparing IM 400mg once daily with DAS 100mg (Hochhaus, Haematologica. 2011; abstract 1011) and the other with NIL 300mg twice daily (Hochhaus, Haematologica. 2011, abstract 484) in newly diagnosed CP-CML patients. MMR rates by 24 months were used to calculate the NNT as the inverse of the MMR rate. The costs of managing neutropenia (R$8137), thrombocytopenia (R$599) and anemia (R$232) were estimated from SUS perspective in local currency (2008 BRL) using administrative databases, literature and survey with clinical experts. The costs of managing the AEs were then multiplied by the incidence of the AEs. Results: The number of newly diagnosed Ph+ CML-CP patients needed to treat to achieve 1 MMR with nilotinib (NNT=1,41) is 38% lower than imatinib in the ENESTnd study (Table 1). The dasatinib NNT of 1,56 is 28% lower than imatinib in the DASISION study (table 2). Lower NNT represents more effective therapy. The NNT analysis highlights that CML treatment with NIL600mg or DAS100mg provides greater efficacy when each are compared with IM400mg in the studies, and that Nilotinib NNT of 1,41 in the ENESTnd study is the most efficient in producing MMR among BCR-ABL inhibitors. DASISION study results demonstrate dasatinib produced more hematologic events, resulting in an estimated 14% higher cost of managing these adverse events compared to imatinib (table 2). ENESTnd study results demonstrate nilotinib produced lower incidence of hematologic events than imatinib, providing savings around 40% lower than imatinib in hematologic AE grade 3 or 4 management (table1). Conclusion: Although comparisons between published studies have some limitations, such an approach may be useful in the absence of direct comparative data. The NNT findings in this 24-months analysis and the differential cost of managing AEs in each treatment from this evaluation suggests that nilotinib provides better clinical outcomes and would result in lower costs for hematologic AE management from the perspective of the Brazilian Public Health Care System when compared to Imatinib. [Display omitted] [Display omitted] Disclosures:Alves:Novartis: Employment. Coombs:Novartis: Employment. Ruiz:Novartis: Employment. Valentim:Novartis: Employment. Lemos:Novartis: Employment.

Nilotinib

Nilotinib is an effective first-line treatment for newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia (CML) in chronic phase. It is an aminopyrimidine-based, high-affinity inhibitor of the tyrosine kinase activity of BCR-ABL. It thus decreases ABL-associated cell proliferation and kinase autophosphorylation. At 12 months, a significantly greater proportion of nilotinib 300 mg twice daily recipients experienced a major molecular response (primary endpoint) than those receiving imatinib 400 mg once daily, in the randomized, open-label, multicentre ENESTnd study in adults with newly diagnosed Philadelphia chromosome-positive CML in chronic phase. Moreover, a significantly greater proportion of nilotinib 300 mg twice daily than imatinib recipients had a complete molecular response at 12 months. Complete cytogenetic response rates were also significantly higher in the nilotinib 300 mg twice daily group than in the imatinib group at 12 months. Treatment differences in molecular response rates remained significant in an updated analysis, with data from a minimum follow-up of 24 months. Nilotinib 300 mg twice daily was generally well tolerated in the ENESTnd study. While nilotinib is associated with an increase in corrected QT interval (QTc), the incidence of cardiac-related adverse events in nilotinib recipients in the ENESTnd study was low.

Cost-effectiveness of nilotinib versus imatinib as first-line treatment for newly diagnosed patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in the chronic phase (CML-CP): Swedish perspective.

6572 Background: The ENESTnd study showed that, vs. imatinib (400 mg QD), nilotinib (300 mg BID) results in superior major molecular and complete cytogenetic response and time to disease progression as 1st-line (FL) therapy in newly-diagnosed Ph+ CML-CP patients. The objective was to assess, from a Swedish societal perspective, the direct/indirect cost and quality adjusted life years (QALYs) of FL imatinib v. nilotinib in newly-diagnosed Ph+ CML-CP. Methods: A literature-based Markov model was developed to estimate the lifetime QALYs and costs of Ph+ CML-CP patients initiating therapy with nilotinib or imatinib. A central model feature is the discontinuation rate from FL therapy, which was based on ENESTnd for the first 12 months and, thereafter, on the rate observed in the IRIS study, stratified by initial 12-month FL responses. Patients discontinuing FL therapy were modeled to receive one additional tyrosine kinase inhibitor (TKI). Prognosis after FL discontinuation was modeled using published studies. Clinical outcomes and drug exposure were obtained from the ENESTnd study. Non-TKI-drug costs and productivity loss were assumed to increase as disease progressed. Quality of life varied by disease stage and response. Results: Compared to FL imatinib (Table), FL nilotinib results in increases in net discounted FL drug therapy costs, decreases in other direct medical costs and productivity loss, and gains in discounted survival and QALYs. The discounted incremental cost/LY and cost/QALY are estimated at $21,028 and $22,914, respectively. In probabilistic sensitivity analysis, 95% of model replications cost ≤$56,000/QALY gained. Conclusions: FL nilotinib is cost-effective in Swedish patients with Ph+ CML-CP who are initiating TKI therapy. Imatinib Nilotinib Difference FL drug costs* $602,605 $733,924 $131,319 Other direct medical costs* $227,488 $192,521 -$34,968 Productivity* $647,601 $712,079 $64,478 Net cost difference* - - $31,874 Life Expectancy* 17.3 18.82 1.52 QALY* 14.39 15.78 1.39 Cost/LYG* - - $21,028 Cost/QALY* - - $22,914 Notes: US$1=SEK 6.90. * Discounted at 3%/year.

Long-term estimate of quality-adjusted life expectancy for nilotinib and imatinib as first-line treatment for newly diagnosed patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in the chronic phase (CML-CP).

6570 Background: In the ENESTnd study, the 12-month rates of major molecular (MMR) and complete cytogenetic (CCyR) responses were significantly higher in newly diagnosed Ph+ CML-CP patients initiat...

Nilotinib as frontline therapy for patients with newly diagnosed Ph+ chronic myeloid leukemia in chronic phase: results from the Japanese subgroup of ENESTnd

Recent results from the phase 3 ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) study have demonstrated superiority of nilotinib over imatinib for the treatment of newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in the chronic phase (CML-CP). Here, we report results from the Japanese subset of patients in ENESTnd, and assess whether results in this subpopulation are consistent with the overall study population. Seventy-nine Japanese patients with CML-CP were randomized to receive nilotinib 300 mg twice daily (BID) (n = 30), nilotinib 400 mg BID (n = 24) or imatinib 400 mg once daily (QD) (n = 25). Major molecular response rates at 12 months, the primary endpoint, were at least twice as high for nilotinib 300 mg BID (57%) and nilotinib 400 mg BID (50%) compared with imatinib 400 mg QD (24%). No patient on nilotinib progressed, while one patient progressed on imatinib. Both drugs were generally well tolerated and discontinuations due to adverse events were comparable among treatment arms. The results in the subpopulation of Japanese patients from ENESTnd closely mirror the results of the overall population, and support the use of nilotinib at 300 mg BID in Japanese patients with newly diagnosed CML-CP.

Second-generation tyrosine kinase inhibitors: the future of frontline CML therapy.

All available data from ongoing studies of second-generation tyrosine kinase inhibitors (TKIs) for treatment of patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) were reviewed. In two nilotinib phase 2 trials, the speed and depth of molecular and cytogenetic responses were greater than responses to imatinib. Furthermore, only one patient in each study progressed to accelerated or blastic phase. In the phase 3 ENESTnd study, molecular and cytogenetic responses to nilotinib were superior to imatinib, and more patients achieved undetectable levels of disease with nilotinib. Nilotinib also demonstrated significantly lower progression than did imatinib. In the ongoing phase 2 study of dasatinib, the speed and depth of molecular and cytogenetic responses were higher compared with expected responses to imatinib; no patient to date has progressed. In the phase 3 DASISION study, molecular and cytogenetic responses to dasatinib were superior to those of imatinib and fewer patients progressed. The results suggest that second-generation TKIs have the potential to replace imatinib as the standard of care for patients with early CML-CP. Future CML therapy might include earlier use of these agents to help more patients achieve complete molecular response and may be a path to a CML cure.

Nilotinib is superior to imatinib as first-line therapy of chronic myeloid leukemia: the ENESTnd study

Nilotinib (Tasigna®) is a more potent BCR–ABL inhibitor than imatinib and was designed to overcome imatinib’s deficiencies. Nilotinib has significant efficacy in patients with chronic myeloid leukemia (CML) in chronic phase, accelerated phase and blastic phase, following imatinib failure. Based on the results of the Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Newly Diagnosed Patients (ENESTnd) study, the US FDA has granted accelerated approval of nilotinib for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive CML in chronic phase. Imatinib has changed our perceptions of the therapeutic power of targeted inhibition of a pathologically active kinase. Nilotinib, a designer agent built on the imatinib scaffold, has proven superior to its template agent by every significant surrogate marker we use in monitoring CML. Nilotinib’s clinical superiority over imatinib, as demonstrated by the ENESTnd study, has established it as an agent that we believe is a significant further step towards the cure of CML.

Number Needed to Treat (NNT) and Cost Estimation to Achieve a Major Molecular Response In Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia In Brazil

AbstractAbstract 1520 Background:The use of imatinib (IM) has greatly improved the outcome of patients with Ph+ chronic myeloid leukemia (CML), with a good balance of potency and exposure that translated into clinical efficacy for many patients. However, patient responses to IM can be variable with factors such as blood plasma levels and OCT-1 transporter activity influencing responses (Larson, 2008; White, 2010). Some patients do not reach complete cytogenetic response (CCyR) and others may have intolerable side effects. Loss of response to IM and disease progression occur mainly in the first 3 years of treatment, and the rate of overall survival is affected as a consequence. Molecular monitoring is the most sensitive measure of CML disease burden and Major Molecular Response (MMR) is associated with an extremely low rate of disease progression (Hughes, 2008). Objectives:(1) To estimate the ‘Number Needed to Treat’ (NNT) to achieve one MMR by 12 months. (2) To provide a relative measure of the cost of attaining treatment objective defined by MMR and hematologic adverse events (AEs) with 2 novel targeted therapies in the treatment of newly diagnosed CP-CML from the Brazilian Public Health Care System (SUS) perspective. Methods:MMR and AE data were evaluated from two phase 3 studies comparing IM 400mg once daily with DAS 100mg (DASISION; Kantarjian, 2010) and the other with NIL 300mg twice daily (ENESTnd, Larson, 2010) in newly diagnosed CP-CML patients. MMR rates by 12 months were used to calculate the NNT as the inverse of the MMR rate. The costs of managing neutropenia (R$8137), thrombocytopenia (R$599) and anemia (R$232) were estimated from SUS perspective in local currency (2008 BRL) using administrative databases, literature and survey with clinical experts. The costs of managing the AEs were then multiplied by the incidence of the AEs. Results:The number of newly diagnosed Ph+ CML-CP patients needed to treat to achieve 1 MMR with nilotinib (NNT=1,82) is 50.8% lower than imatinib in the ENESTnd study (Table). The dasatinib NNT of 2.17 is 39.2% lower than imatinib in the DASISION study. The NNT analysis highlights that CML treatment with NIL600mg or DAS100mg provides greater efficacy when each are compared with IM400mg in the studies, and that nilotinib is the most efficient in producing MMR among BCR-ABL inhibitors. DASISION study results demonstrate dasatinib produced more hematologic events, resulting in an estimated 8.2% higher cost of managing these adverse events compared to imatinib. ENESTnd study results demonstrate nilotinib produced lower incidence of hematologic events than imatinib, providing savings around 38.5% lower than imatinib in hematologic AE grade 3 or 4 management. Conclusion:Although comparisons between published studies have some limitations, such an approach may be useful in the absence of direct comparative data. The NNT findings and the differential cost of managing AEs in each treatment from this evaluation suggests that nilotinib provides better clinical outcomes and would result in lower costs for hematologic AE management from the perspective of the Brazilian Public Health Care System.Table:MMR rates and incidence of adverse events reported in ENESTnd and DASISION studiesENESTnd StudyDASISION StudyNIL600mgIM400mgDAS100mgIM400mgMMR rates by 12 months (ENESTnd studies and DASISION)MMR55%27%46%28%NNT (NNT=1/MMR)1.823.702.173.57Incidence of Adverse Events (AE) – Grades 3 or 4Neutropenia12%20%21%20%Thrombocytopenia10%9%19%10%Anemia3%5%10%7% Disclosures:Alves:Novartis Pharmaceuticals: Employment. Coombs:Novartis Pharmaceuticals: Employment, Equity Ownership. Ruiz:Novartis Pharmaceuticals: Employment. Valentim:Novartis Pharmaceuticals: Employment. Lemos:Novartis Pharmaceuticals: Employment.