Does Baseline Health-Related Quality of Life or Symptom Burden Predict Clinical Outcomes in Patients with Newly Diagnosed CML-CP Treated with Nilotinib or Imatinib?

Abstract Abstract 1025 Background: Nilotinib is a more potent and more selective inhibitor of BCR-ABL in-vitro than imatinib. A randomized Phase III study was conducted comparing these two therapies in adult patients with newly diagnosed Philadelphia Chromosome positive (Ph+) chronic myelogenous leukemia (CML) in chronic phase (CP). Aim: To evaluate whether baseline health-related quality of life (HRQL) or symptom scores were predictive of clinical outcome in this phase III trial. Methods: A total of 846 patients were randomized to receive nilotinib 300 mg BID (n=282), nilotinib 400 mg BID (n=281) or imatinib 400mg QD (n=283). For these analyses to evaluate the impact of baseline HRQL on clinical outcomes, the treatment arms were combined. HRQL was assessed using the Functional Assessment of Cancer Therapy–Leukemia (FACT-Leu). The FACT-Leu consists of four general subscales measuring physical, social/family, emotional, and functional well-being and a 17-item leukemia-specific subscale (LeuS). The FACT-G score is the sum of the four general well-being subscales. The questionnaire was administered at baseline, and at 3, 12, and 24 months. Baseline FACT-G and LeuS scores were divided into three equal-sized groups (i.e., tertiles). Patients with high, mid, and low baseline scores were compared on several clinical outcomes: best molecular response by Month 24, best cytogenetic response by Month 24, treatment discontinuation, hospitalization, dose modification of any kind (interruption, increase, or reduction), grade 3 or 4 adverse events, and missed cytogenetic tests. Chi-square tests were used to compare these dichotomous and categorical outcomes between baseline HRQL groups. The relationship between baseline HRQL scores and Sokal Risk groups was evaluated using analysis of variance. Higher scores on the FACT-G and LeuS indicate better HRQL and less symptom burden. Results: Mean baseline FACT-G scores were 97.8, 85.0, and 66.3, and mean baseline LeuS scores were 61.6, 53.8, and 42.2, for the high/mid/low tertile groups, respectively. There was no significant association between best molecular response by Month 24 or cytogenetic response by Month 24 and baseline FACT-G scores (p=0.149 and p=0.094, respectively). There was an association between best molecular response by Month 24 and baseline LeuS scores (p=0.043) but no significant association with best cytogenetic response by Month 24 (p=0.316). There were no significant associations with either dose modifications (p=0.252 for FACT-G, p=0.643 for LeuS), grade 3 or 4 adverse events (p=0.531 for FACT-G, p=0.831 for LeuS), or missed cytogenetic tests (p=0.722 for FACT-G, p=0.374 for LeuS). There was a significant association between treatment discontinuation and baseline FACT-G scores (p=0.007). Only 18% of patients with the highest baseline FACT-G scores discontinued treatment compared to 26% in the middle group and 31% in the group with the lowest baseline FACT-G scores. This relationship was not statistically significant for baseline LeuS scores (p=0.070). Fourteen percent of patients with high baseline FACT-G scores were hospitalized at some point during the study, compared to 15% of patients with mid FACT-G scores, and 22% with low baseline FACT-G (p=0.099). However, 11% of patients with high LeuS scores were hospitalized compared to 20% of patients with mid-range LeuS scores, and 21% of patients with low LeuS scores (p=0.018). The mean baseline FACT-G scores were 81.4, 83.5, and 83.4 (p=0.288), and the mean baseline LeuS scores were 51.1, 53.4, and 52.5 (p=0.042), for patients with high, intermediate, and low Sokal scores, respectively. Conclusions: In patients with newly diagnosed CML-CP, worse general HRQL at baseline was predictive for treatment discontinuation, but not predictive for best molecular response. Leukemia related symptoms at baseline were associated with a greater likelihood of subsequent hospitalization and moderately associated with molecular response. Baseline HRQL was not clearly associated with Sokal scores. These findings suggest that among patients with newly diagnosed CML-CP, examination of baseline HRQL and symptoms may allow patients and clinicians to better anticipate outcomes such as hospitalizations and continuation of therapy. Disclosures: Beaumont: Novartis: Research Funding. Nowinski:Novartis: Research Funding. Coombs:Novartis: Employment, Equity Ownership. Szczudlo:Novartis: Employment, Equity Ownership. Blakesley:Novartis: Employment, Equity Ownership. Gallagher:Novartis: Employment, Equity Ownership. Burns:Novartis: Research Funding. Cella:Novartis: Research Funding.

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Hospitalizations of Patients with Newly Diagnosed CML-CP Treated with Nilotinib or Imatinib: Results From a Randomized Phase III Trial

Blood ◽

10.1182/blood.v116.21.3826.3826 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3826-3826

Author(s):

Jennifer L Beaumont ◽

John Coombs ◽

amsi Bollu ◽

Richard C. Woodman ◽

David Cella

Keyword(s):

Research Funding ◽

Philadelphia Chromosome ◽

Myelogenous Leukemia ◽

Phase Iii ◽

Molecular Response ◽

Newly Diagnosed ◽

Employment Equity ◽

Phase Iii Trial ◽

Equity Ownership ◽

Hospital Days

Abstract Abstract 3826 Background: Imatinib is the current standard of care for chronic myelogenous leukemia (CML). Nilotinib is a highly potent and the most selective inhibitor of BCR-ABL. A Phase III multi-center, open label, randomized study (ENESTnd) was conducted comparing these two therapies in adult patients with newly diagnosed Philadelphia Chromosome positive (Ph+) CML in chronic phase. The primary endpoint analysis at 12 months demonstrated that major molecular response (MMR) was significantly improved with nilotinib 300 mg BID (44%) and nilotinib 400 mg BID (43%) compared to imatinib 400 mg QD (22%; p < 0.001). The discontinuation rate due to adverse events was lowest among the nilotinib 300mg BID treatment arm (5%) compared to 7% in the imatinib arm, and nilotinib 400 mg BID (9%). Based on the results of this clinical trial, nilotinib 300 mg BID was approved for initial use for CML-CP in the US. Aim: To evaluate the occurrence and rate of hospitalizations and time away from usual activities in this phase III trial. Methods: A total of 846 patients were randomized to receive nilotinib 300 mg BID (n=282), nilotinib 400 mg BID (n=281) or imatinib 400mg QD (n=283). Hospitalizations, defined as any visit to the hospital requiring an overnight stay, excluding pre-planned or elective surgery, were assessed throughout the study period. Overdispersed Poisson regression models were used to compare the days hospitalized per 1,000 patient-days on study. Patients were asked to report time-off, defined as average number of hours per week taken away from all usual activities due to CML and side effects of CML treatment over the past 4 weeks, at Baseline and at the end of Months 3 and 12. The Wilcoxon rank-sum test was used to compare the time off from usual activities at each assessment; and t-tests were used to evaluate the within-group changes in time off. Results: There were a total of 57 hospitalizations in the imatinib arm versus 48 hospitalizations in the nilotinib 300 mg BID arm, and 74 hospitalizations in the nilotinib 400 mg BID arm (Table). Descriptive statistics for length of stay (LOS) are presented in the Table. The hospitalization rate, expressed as hospital days per 1,000 patient days, was 47% higher in the imatinib arm compared to the nilotinib 300 mg BID arm (p=0.057) and 8% higher compared to the nilotinib 400 mg BID arm (p=0.68). Patients in the nilotinib 300mg BID arm had fewer stays and shorter LOS than the imatinib arm, whereas patients in the nilotinib 400mg BID arm had more stays than the imatinib arm but shorter LOS on average resulting in fewer total hospital days. The majority of hospitalizations (56%) in all three arms occurred within the first 9 months. Time off from usual activities, which began at an average level of 8–10 hours per week at Baseline, decreased in each arm, but the decrease did not significantly differ between arms (Table). Similar results were observed when patients reporting zero hours of time off were excluded from the analysis. There was no association between time off and age. Summary/conclusions: In patients with newly diagnosed CML-CP, nilotinib resulted in less hospital time compared to imatinib, although this difference did not reach statistical significance. Additionally, patients in all three treatment groups reported significant improvements from baseline in time off from usual activities. Disclosure: Beaumont: Novartis: Research Funding. Coombs:Novartis: Employment, Equity Ownership. Bollu:Novartis: Employment, Equity Ownership. Woodman:Novartis Oncology: Employment. Cella:Novartis: Research Funding.

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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

Blood ◽

10.1182/blood.v118.21.452.452 ◽

2011 ◽

Vol 118 (21) ◽

pp. 452-452 ◽

Cited By ~ 9

Author(s):

Giuseppe Saglio ◽

Philipp D. LeCoutre ◽

Ricardo Pasquini ◽

Saengsuree Jootar ◽

Hirohisa Nakamae ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Philadelphia Chromosome ◽

Safety Data ◽

Molecular Response ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Abstract 452FN2 Background: In ENESTnd, pts treated with nilotinib demonstrated higher and faster rates of major molecular response (MMR, ≤ 0.1% BCR-ABLIS), deeper molecular response (MR4, ≤ 0.01%IS and MR4.5, ≤ 0.0032%IS), and complete cytogenetic responses (CCyR) along with significantly lower rates of progression to AP/BC and fewer CML-related deaths compared with imatinib by 12 and 24 mo. Here, we report data with a minimum follow-up of 24 mo; however, efficacy and safety data based on considerably longer follow-up of ≥ 36 mo will be presented. As demonstrated in IRIS and other imatinib trials, most pts who progress on imatinib do so within the first 3 years of therapy. Thus, this 36-mo update of ENESTnd will be important to further verify the benefits of nilotinib in newly-diagnosed pts. Methods: 846 adult pts with newly-diagnosed Ph+ CML-CP were randomized to nilotinib 300 mg twice daily (BID) (n = 282), nilotinib 400 mg BID (n = 281), or imatinib 400 mg once daily (QD) (n = 283). MMR, MR4, MR4.5, time to progression to AP/BC on treatment, progression-free survival (PFS) on treatment, and overall survival (OS) were evaluated. Results: By 24 mo, both doses of nilotinib demonstrated significantly higher rates of MMR, MR4, and MR4.5 vs imatinib (Table). Nilotinib-treated pts achieved median BCR-ABLIS levels of 0.09% (300 mg BID) and 0.10% (400 mg BID) by 12 mo, while this level of reduction was not observed before 24 mo on imatinib. More pts with CCyR achieved MMR at 12 and 24 mo with either dose of nilotinib vs imatinib (Table). Regardless of Sokal risk, rates of MMR and MR4.5 were higher for nilotinib at both doses vs imatinib (Table). Progression to AP/BC (excluding clonal evolution [CE]) on treatment was significantly lower for nilotinib vs imatinib (2 pts and 3 pts with nilotinib 300 mg BID [P = .0059] and 400 mg BID [P =.0196]), respectively vs 12 pts with imatinib). After achieving CCyR, 4 pts treated with imatinib progressed to AP/BC and 2 pts treated with nilotinib 400 mg BID progressed after achieving both CCyR and MMR (1 also achieved MR4). No pt who achieved MR4.5 progressed at any time. All but 1 pt who progressed to AP/BC on treatment were in the intermediate and high Sokal risk groups; 1 pt treated with nilotinib 400 mg BID progressed in the low Sokal risk group who had an E255V mutation at progression. When considering progression events of pts after discontinuation of treatment, an additional 7, 2, and 6 events (excluding CE) were observed with nilotinib 300 mg BID, nilotinib 400 mg BID and imatinib, respectively. Twice as many pts had emergent mutations on imatinib (n = 20) vs nilotinib (n = 10 on 300 mg BID; n = 8 on 400 mg BID). At 24 mo, OS remained similar in all groups, but there were fewer CML-related deaths in both nilotinib 300 mg BID (5 pts) and nilotinib 400 mg BID (3 pts) arms vs imatinib (10 pts). Both drugs were well tolerated and few new adverse events (AEs) and lab abnormalities were observed between 12- and 24-mo of follow-up. Nilotinib 300 mg BID had the fewest discontinuations due to AEs/lab abnormalities (9% vs 13% and 10% with nilotinib 400 mg BID and imatinib, respectively). Conclusions: With a minimum follow-up of 24 mo, nilotinib continued to demonstrate superiority vs imatinib with faster and deeper molecular responses and a significantly decreased risk of progression. These data support the use of nilotinib as a standard of care option in newly-diagnosed adult pts with Ph+ CML-CP. Disclosures: Saglio: Novartis Pharmaceutical: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Pfizer: Consultancy. Off Label Use: Nilotinib is a safe and effective treatment for patients with CML. LeCoutre:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria. Pasquini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Nakamae:Novartis: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau. Flinn:nOVARTIS: Research Funding. Hochhaus:Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Hughes:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees. Larson:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Gallagher:Novartis: Employment. Yu:Novartis: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding.

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Long-Term Follow-up of a Phase 1 Study of Ponatinib in Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML)

Blood ◽

10.1182/blood.v124.21.4558.4558 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4558-4558 ◽

Cited By ~ 2

Author(s):

Moshe Talpaz ◽

Jorge E. Cortes ◽

Hagop Kantarjian ◽

Neil P. Shah ◽

Dale Bixby ◽

...

Keyword(s):

Research Funding ◽

Phase 1 ◽

Dose Intensity ◽

Cytogenetic Response ◽

Molecular Response ◽

Employment Equity ◽

Duration Of Response ◽

Heavily Pretreated ◽

Equity Ownership

Abstract Background: Ponatinib is a potent oral pan–BCR-ABL tyrosine kinase inhibitor (TKI) active against native and mutated forms of BCR-ABL, and is approved for patients with refractory CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia and those with the T315I mutant. Long-term follow-up of the anti-leukemic activity and safety of ponatinib in patients with CML or Ph+ ALL in this phase 1 clinical trial is reported. Methods: Patients (N=81) with resistant/refractory hematologic malignancies were enrolled in this ongoing, open-label, dose-escalation, phase 1 study (NCT00660920). Ponatinib was dosed once daily (2 mg-60 mg). Intra-patient dose escalation was permitted. The 43 patients who had CP-CML are the focus of this analysis (data as of 6 Jan 2014). Median follow-up for CP-CML patients was 42.5 (1.7-59.1) months. Results: The median age of patients was 55 years; median time since diagnosis was 6.6 years. Patients were heavily pretreated (61% received ≥3 prior TKIs; 37% received 2 prior TKIs). At baseline, 63% of patients had BCR-ABL mutations (28% with T315I). At the time of analysis, 56% of patients remained on study. Significant anti-leukemic activity was observed: major cytogenetic response (MCyR), complete cytogenetic response (CCyR), major molecular response (MMR) and molecular response 4 (MR4) rates were 72%, 65%, 51%, and 40% respectively; 76% of patients with MCyR and 54% with MMR are estimated (Kaplan-Meier [KM]) to maintain response for at least 4 years (3-year KM estimates: 76% MCyR, 70% CCyR, 54% MMR; Figure 1). 15 patients started at a dose of 30 mg or below, and 10 of these patients (67%) achieved MCyR; all were receiving a dose of 30 mg or below at time of response (Table 1). Of 28 patients with CCyR, 22 remained on study (16 with continuous CCyR); of 22 patients with MMR, 19 remained on study (11 with continuous MMR). Adverse events (AEs, 23%) and progression (9%) were the most common reasons for discontinuation. Of the 10 patients that discontinued due to AEs, 5 were in MCyR and, of those, 1 was in MMR. The most common treatment-emergent AEs were rash (63%), fatigue (61%), abdominal pain (58%), headache (56%), and arthralgia (54%). The most common treatment-emergent AEs occurring after 1 year of therapy were fatigue (35%), hypertension (31%), and abdominal pain (30%). Treatment-emergent arterial thrombotic events (AE [SAE]) were observed in 37% [28%] of patients (composite of cardiovascular 28% [19%], cerebrovascular 9% [7%], and peripheral vascular 12% [7%] events), and venous thromboembolic AEs were observed in 5% [no SAEs] of patients. Updated data will be presented. Conclusions: With a median follow-up of 42.5 months in CP-CML patients (maximum follow-up, 59.1 months), ponatinib continues to provide benefit to heavily pretreated patients with limited treatment options. Substantial and durable responses were observed with ponatinib, and responses were observed in patients treated with doses at or below 30 mg. The most common treatment-emergent AEs occurring after one year of therapy were similar to the overall AE profile, albeit with lower incidence rates. Risk and benefit considerations should be evaluated when utilizing ponatinib in this patient population. Figure 1: Duration of Response in CP-CML Patients Figure 1:. Duration of Response in CP-CML Patients aLoss of response is defined as a single time point at which the criteria for response are not met. Table 1: Ponatinib Response Rate for CP-CML Patients by Dose Starting Dose MCyR MMR N (%) Dose intensity*, Median (min, max) N (%) Dose intensity*, Median (min, max) 4 mg, N=3 2 (67) 3.7 (3.5, 3.9) 1 (33) 14.3 (14.3, 14.3) 15 mg, N=7 5 (71) 14.8 (14.7, 23.7) 4 (57) 15.0 (14.7, 36.6) 30 mg, N=5 3 (60) 27.4 (10.6, 29.6) 1 (20) 29.9 (29.9, 29.9) ≤30 mg, N=15 10 (67) 14.8 (3.5, 29.6) 6 (40) 15.0 (14.3, 36.6) 45 mg, N=14 13 (93) 44.5 (23.4, 45.0) 11 (79) 43.5 (16.6, 45.0) 60 mg, N=14 8 (57) 42.6 (14.2, 59.3) 5 (36) 56.5 (14.7, 59.5) *Dose intensity (mg/day) until time of response for responders only Disclosures Talpaz: ARIAD Pharmaceuticals, Inc., BMS, Sanofi, Incyte, Pfizer: Research Funding. Cortes:ARIAD Pharmaceuticals, Inc., BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding. Kantarjian:ARIAD, Pfizer, Amgen: Research Funding. Shah:ARIAD, BMS: Research Funding. Flinn:ARIAD Pharmaceuticals, Inc.: Research Funding. Hu:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Turner:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Haluska:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Druker:BMS: Research Funding; ARIAD Pharmaceuticals, Inc.: PI and co-investigator on clinical trials, PI and co-investigator on clinical trials Other; MolecularMD: Consultancy, Equity Ownership. Deininger:BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding; BMS, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy. Mauro:ARIAD Pharmaceuticals, Inc.: Consultancy.

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High-Resolution Analysis of the Relationship Between Dose and Molecular Response in CP-CML Patients Treated with Ponatinib or Imatinib

Blood ◽

10.1182/blood.v124.21.3153.3153 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3153-3153 ◽

Cited By ~ 1

Author(s):

Justin R. Pritchard ◽

Stephanie Lustgarten ◽

Graeme Hodgson ◽

Michele Baccarani ◽

Jorge E. Cortes ◽

...

Keyword(s):

Research Funding ◽

Molecular Response ◽

Newly Diagnosed ◽

Employment Equity ◽

Daily Dose ◽

Heavily Pretreated ◽

Scatter Plots ◽

Pretreated Patients ◽

Equity Ownership ◽

Dose Levels

Abstract Background: Ponatinib is a potent pan-BCR-ABL tyrosine kinase inhibitor (TKI). The phase 2 PACE study demonstrated that ponatinib is highly active in heavily pretreated CP-CML patients, 58% of whom received ≥3 prior TKIs. The phase 3 EPIC study, in which ponatinib was compared with imatinib, was terminated early due to concerns about arterial thrombotic events observed in the ponatinib development program, though analysis of existing data suggests that ponatinib has improved efficacy over imatinib in newly diagnosed CP-CML patients. Fixed starting doses of ponatinib and imatinib were used in these studies (45 mg and 400 mg once daily, respectively), but the allowance for treatment interruptions and dose reductions, coupled with multiple assessments of molecular response per patient, enables exploration of dose-response relationships. Here we describe a novel approach called BARD (BCR-ABL Response-Dose association) that allows associations between dose, based on patient daily dosing records, and efficacy, based on frequent measurement of BCR-ABL transcript levels, to be examined with high resolution. Methods: BCR-ABL levels were measured every 1-3 months in peripheral blood samples from CP-CML patients in the PACE (N=267) and EPIC studies (N=154 [ponatinib] and 152 [imatinib]), which had median follow-ups of 27.9 and 5.1 months, respectively. The change in BCR-ABL levels (expressed as 1/doubling time [1/DT]) and average daily dose were calculated for every measurement interval (window). Local regression was utilized to smooth scatter plots of 1/DT values across all patients versus dose. Smoothing-adjusted 1/DT values were replotted relative to the average daily dose for each window. Scatter plots of 1/DT values for ranges of dose levels were analyzed for differences by t-test. Average 1/DT values were transformed using an exponential growth/decay model to estimate the number of days required to achieve a 10-fold decrease in BCR-ABL levels. Results: In newly diagnosed patients (EPIC), across all dose levels, BARD analysis showed that the average number of days required to decrease BCR-ABL levels 10-fold was 47.5 (± 3.2) for ponatinib and 89.9 (± 4.6) for imatinib, consistent with the more rapid molecular responses observed in the ponatinib arm. Though increased doses of both ponatinib and imatinib were associated with trends towards more rapid decreases in BCR-ABL levels, the rate of decrease induced by ponatinib was greater overall (Table). Within windows that included only continuous dosing at starting dose levels, 10-fold decreases in BCR-ABL levels were achieved significantly more rapidly (p<0.0001) with 45 mg ponatinib than 400 mg imatinib. Moreover, compared with 400 mg imatinib, 10-fold decreases in BCR-ABL levels were also achieved more rapidly with average ponatinib dose levels <15 mg (p>0.05), 15 to <30 mg (p<0.02) and 30 to <45 mg (p<0.0001). In heavily pretreated patients (PACE), increased doses of ponatinib were also associated with a trend towards more rapid decreases in BCR-ABL levels, although the rate of decrease induced by 45 mg ponatinib (129.9 [± 18.5] days to reduce BCR-ABL levels 10-fold in the first 6 months) was reduced compared with that observed in newly diagnosed patients. Importantly, across the entire PACE study, average daily doses of ponatinib as low as 10 mg were associated with net decreases in BCR-ABL levels. Conclusions: BARD enables a detailed exploration of dose-response relationships in CP-CML. In newly diagnosed patients, ponatinib doses as low as 15 mg induced more rapid decreases in BCR-ABL levels than 400 mg imatinib. Consistent with the possibility that sequential treatment with TKIs increases the degree of BCR-ABL independence, the magnitude of BCR-ABL decreases induced by ponatinib in heavily pretreated patients was reduced compared with newly diagnosed patients. Nonetheless, ponatinib doses as low as 10 mg were still associated with disease control overall. These analyses will help inform the design of future studies aimed at optimizing the benefit/risk of ponatinib treatment for patients with CML. Table. BCR-ABL Response Dose Association (BARD) from EPIC Drug Dose range (mg) Time to 10-fold BCR-ABL decrease (Days) Windows* (N) Ponatinib <15 66.4 ± 23.2 40 15 to <30 55.2 ± 8.2 60 30 to <45 48.1 ± 8.6 136 45 41.5 ± 2.8 184 Imatinib 400 82.8 ± 4.3 374 *Number of BCR-ABL measurement intervals when average dose was within the indicated range Disclosures Pritchard: ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Hodgson:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Baccarani:ARIAD, Novartis, BMS: Consultancy; ARIAD, BMS, Novartis, Pfizer, Teva: Honoraria, Speakers Bureau. Cortes:ARIAD, BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding. Deininger:BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding; BMS, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy. Guilhot:ARIAD Pharmaceuticals, Inc.: Honoraria. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Hughes:Novartis, BMS, ARIAD Pharmaceuticals, Inc.: Honoraria, Research Funding. Shah:ARIAD Pharmaceuticals, Inc., BMS: Research Funding. Talpaz:ARIAD Pharmaceuticals, Inc., BMS, Sanofi, Incyte, Pfizer: Research Funding. Clackson:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Haluska:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Knickerbocker:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership.

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Deep Molecular Response in Patients With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated With Nilotinib: ENESTnext Update

Blood ◽

10.1182/blood.v124.21.1796.1796 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1796-1796

Author(s):

Michael J. Mauro ◽

Shaker Dakhil ◽

Jorge E. Cortes ◽

David A. Rizzieri ◽

Christopher H Keir ◽

...

Keyword(s):

Research Funding ◽

Digital Pcr ◽

Cytogenetic Response ◽

Molecular Response ◽

Newly Diagnosed ◽

Pcr Assay ◽

Transcript Levels ◽

Time Points ◽

Log Reduction ◽

Equity Ownership

Abstract Background: The BCR-ABL tyrosine kinase inhibitor nilotinib elicits faster and deeper molecular responses (MRs) vs imatinib in patients with CML-CP. Achievement of sustained deep MR is associated with improved long-term outcomes and is a key criterion for entry into treatment-free remission (TFR) studies. Given the importance of accurately measuring deep MR in patients with CML, increasingly sensitive techniques are needed for monitoring minimal residual disease. In ENESTnext, MR to nilotinib was assessed using conventional methodology (real-time quantitative reverse transcriptase polymerase chain reaction [RQ-PCR]) and a novel microfluidic digital PCR assay that is > 1 log more sensitive than standard RQ-PCR. Methods: In this single-arm, open-label, multicenter study (NCT01227577), adults with CML-CP diagnosed within 6 months of enrollment were treated with nilotinib 300 mg twice daily (BID) for up to 2 years. Dose escalation to nilotinib 400 mg BID for patients with suboptimal response or treatment failure (per modified European LeukemiaNet 2009 recommendations) was permitted per physician discretion. RQ-PCR evaluation of peripheral blood samples was performed by a central laboratory (monthly for the first 3 months and every 3 months thereafter) according to the International Scale (IS). The primary endpoint is the rate of confirmed (≥ 2 samples taken 3 months apart) MR4.5 (≥ 4.5-log reduction of BCR-ABL transcript levels; BCR-ABLIS ≤ 0.0032%) with 2 years of nilotinib therapy; complete cytogenetic response (CCyR) and major MR (MMR; 3-log reduction of BCR-ABL transcript levels; BCR-ABLIS ≤ 0.1%) were evaluated as secondary endpoints. Per protocol, assessment of cytogenetic response was not required at specified time points for all patients on study. In an exploratory analysis, samples from patients with confirmed MR4.5by conventional RQ-PCR were also evaluated using the more sensitive Fluidigm digital PCR platform. The data cutoff date for this analysis was April 30, 2014. Results: A total of 128 patients were enrolled (median age, 56.5 years [range, 21.0-89.0 years]); 64 patients (50.0%) were male and 103 (80.5%) were Caucasian. As of the data cutoff, 45 patients (35.2%) had completed the study, 49 (38.3%) remained on treatment, and 34 (26.6%) had discontinued early. With a median treatment duration of 12.7 months, 88 (68.8%), 94 (73.4%), and 32 (25.0%) patients achieved CCyR, MMR, and MR4.5, respectively, at any time (Table). Of 32 patients who achieved MR4.5, 14 achieved MR4.5 by 6 months. A total of 169 samples from 32 patients with confirmed MR4.5 by conventional RQ-PCR were analyzed by digital PCR. Using the digital PCR platform, 6 of these patients initially had detectable BCR-ABL transcripts that subsequently became undetectable with continued nilotinib therapy. Of the remaining 26 patients, 12 had BCR-ABL transcripts that were initially undetectable and remained undetectable by digital PCR, 12 had detectable BCR-ABL transcripts that remained detectable, and 2 had undetectable BCR-ABL transcripts that became detectable. The most common (≥ 4 patients) grade 3/4 adverse events (AEs) regardless of relationship to study drug were increased lipase (n = 14), thrombocytopenia (n = 11), neutropenia (n = 8), hypophosphatemia (n = 5), anemia (n = 4), and nausea (n = 4). Reasons for study discontinuation were AEs (n = 15), unsatisfactory therapeutic effect (n = 5), withdrawn consent (n = 4), death (n = 3; causes of death were other malignancy, pneumonia, and not specified/no AE [n = 1 each]), protocol deviation (n = 3), abnormal laboratory values (n = 2), loss to follow-up (n = 1), and administrative problems (n = 1). Conclusions: Frontline treatment with nilotinib 300 mg BID in patients with newly diagnosed CML-CP led to rapid achievement of MR4.5 as assessed with conventional RQ-PCR. As > 40% of samples with at least MR4.5according to standard RQ-PCR were positive using the digital PCR assay, this tool may have potential in evaluating MR to determine eligibility for TFR studies. Table Response CCyRa MMR MR4.5 Patients with response, n (%) 88 (68.8) 94 (73.4) 32 (25.0) Time to response, n (%) < 3 mo 26 (20.3) 21 (16.4) 2 (1.6) 3 to < 6 mo 42 (32.8) 41 (32.0) 12 (9.4) 6 to < 12 mo 16 (12.5) 22 (17.2) 11 (8.6) 12 to < 18 mo 4 (3.1) 9 (7.0) 7 (5.5) ≥ 18 mo 0 1 (0.8) 0 a Cytogenetic response was not assessed in all patients at all time points. Disclosures Mauro: Novartis Oncology: Consultancy; Bristol Myers Squibb: Consultancy; Ariad: Consultancy; Pfizer: Consultancy. Cortes:Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding. Rizzieri:Sanofi: Consultancy; Celgene: Consultancy, Speakers Bureau. Keir:Novartis: Employment, Equity Ownership. Yi:Novartis Pharmaceuticals: Employment. Heinrich:Novartis: Consultancy, Patents & Royalties, Research Funding; MolecularMD: Consultancy, Equity Ownership. Goldberg:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding, Speakers Bureau; Pfizer: Research Funding. Kuriakose:Teva: Speakers Bureau; Alexion: Speakers Bureau. Radich:Novartis: Consultancy, Research Funding; Ariad: Consultancy.

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Efficacy of Bosutinib in Imatinib-Resistant Vs Dasatinib/Nilotinib-Resistant Chronic Phase Chronic Myeloid Leukemia: Results from the Phase 4 BYOND Study

Blood ◽

10.1182/blood-2019-122230 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1650-1650 ◽

Cited By ~ 3

Author(s):

B. Douglas Smith ◽

Tim H Brümmendorf ◽

Gail J. Roboz ◽

Carlo Gambacorti-Passerini ◽

Aude Charbonnier ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Employment Equity ◽

Advisory Committees ◽

Imatinib Resistant ◽

Equity Ownership

Introduction: The tyrosine kinase inhibitor (TKI) bosutinib is approved for patients with Philadelphia chromosome (Ph)+ chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and newly diagnosed patients in chronic phase (CP). Methods: The ongoing phase 4 BYOND study (NCT02228382) is further evaluating the efficacy and safety of bosutinib for CML resistant/intolerant to prior TKIs. Patients were administered bosutinib at a starting dose of 500 mg once daily (QD). Primary results were previously reported. Here, we report the efficacy of bosutinib 500 mg QD in patients with Ph+ CP CML and resistance to imatinib (but not to nilotinib or dasatinib) vs patients with resistance to ≥1 second-generation TKI (dasatinib and/or nilotinib), as well as in patients with intolerance to all prior TKIs. Data are reported at ≥1 year after last enrolled patient; 85% of patients had a minimum follow-up of 2 years. Results: Of 163 patients who received bosutinib, 156 had Ph+ CP CML: 52 had resistance only to imatinib, 31 had resistance to dasatinib/nilotinib, and 73 were intolerant to all prior TKIs. Corresponding median treatment duration (range) was 24.1 (0.2-42.2), 8.9 (0.9-41.6), and 25.3 (0.4-41.9) months, and median dose intensity (range) was 360 (125-500), 431 (195-561) and 292 (80-500) mg/day. In all, 69.2%, 41.9%, and 53.4% of imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively, were still receiving treatment as of the data cutoff date. The main reason for discontinuation was adverse events (AEs), with 10 (19.2%), 8 (25.8%), and 21 (28.8%) imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively, discontinuing due to AEs. Corresponding discontinuations due to insufficient response occurred in 2 (3.8%), 5 (16.1%), and 1 (1.4%) patients. No patient experienced on-treatment transformation to advanced phase CML or discontinued treatment due to disease progression. In the evaluable cytogenetic population, cumulative major cytogenetic response (MCyR) rates were 85.4%, 69.0%, and 88.1% in imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively (Table). The majority of patients, across all cohorts, achieved a complete cytogenetic response (CCyR). In the evaluable molecular population, cumulative major molecular response (MMR) rates were 72.3%, 44.8%, and 82.2% in imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively; the 50th percentile of the cumulative incidence curve was 5.66 months, not reached and 3.22 months, respectively. Correspondingly, 59.6%, 24.1%, and 68.5% achieved molecular response (MR)4, and 48.9%, 17.2%, and 56.2% achieved MR4.5. In imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively, Kaplan-Meier estimated overall survival rates (95% confidence interval) were 96.1% (85.2-99.0), 100% (100-100), and 98.6% (90.5-99.8) at 1 year, and 96.1% (85.2-99.0), 92.6% (73.4-98.1), and 97.2% (89.2-99.3) at 2 years with 4, 3, and 3 deaths occurring on study. Conclusions: Cytogenetic and molecular responses were seen in a high proportion of patients with Ph+ CP CML and TKI-resistance or TKI-intolerance. Response rates were similar between patients with resistance to imatinib and patients who were intolerant to all prior TKIs. Although to a lesser degree, responses were also seen in patients with resistance to second-generation TKIs, including patients achieving MR despite the shorter treatment duration. These results further support bosutinib use for patients with Ph+ CP CML and resistance/intolerance to prior TKIs. Disclosures Smith: Agios: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; Jazz: Consultancy. Brümmendorf:Janssen: Consultancy; Novartis: Consultancy, Research Funding; Ariad: Consultancy; Merck: Consultancy; University Hospital of the RWTH Aachen: Employment; Pfizer: Consultancy, Research Funding. Roboz:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gambacorti-Passerini:Bristol-Meyers Squibb: Consultancy; Pfizer: Honoraria, Research Funding. Charbonnier:Novartis: Consultancy; Pfizer: Consultancy; Incyte: Speakers Bureau. Viquiera:Pfizer: Employment, Equity Ownership. Leip:Pfizer: Employment, Equity Ownership. Giles:Novartis: Consultancy; Epigene Therapeutics Inc: Consultancy, Other: leadership, stock/other ownership ; Actuate Therapeutics Inc: Employment. Ernst:Novartis: Research Funding. Hochhaus:Incyte: Research Funding; MSD: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. Rosti:BMS: Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Nilotinib Demonstrates Superior Efficacy Compared with Imatinib in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase: Results From the International Randomized Phase III ENESTnd Trial

Blood ◽

10.1182/blood.v114.22.lba-1.lba-1 ◽

2009 ◽

Vol 114 (22) ◽

pp. LBA-1-LBA-1 ◽

Cited By ~ 15

Author(s):

Giuseppe Saglio ◽

Dong-Wook Kim ◽

Surapol Issaragrisil ◽

Philipp D. le Coutre ◽

Josy Reiffers ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Chronic Phase ◽

Standard Of Care ◽

Tolerability Profile ◽

Molecular Response ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Abstract LBA-1 Background: Nilotinib is a highly potent and the most selective inhibitor of BCR-ABL, the only proven molecular target for CML therapy. ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) is a phase 3, randomized, open-label, multicenter study comparing the efficacy and safety of 300 or 400 mg bid nilotinib with 400 mg qd imatinib in patients (pts) with newly diagnosed Ph+ CML in chronic phase (CML-CP). Methods: 846 pts with newly diagnosed Ph+ CML-CP, diagnosed within 6 mos, and stratified by Sokal risk score, were randomized 1:1:1 to nilotinib 300 mg bid (n=282), nilotinib 400 mg bid (n=281), and imatinib 400 mg qd (n=283) arms. The primary endpoint was rate of major molecular response (MMR) at 12 months (mos). All pts had a minimum of 12 mos of treatment or discontinued early; median follow-up was 14 mos. MMR was defined as a value of ≤ 0.1% of BCR-ABL/ABL ratio on the International Scale. Molecular response was assessed by RQ-PCR at baseline, monthly for 3 mos and every 3 mos thereafter. Samples were analyzed at a central PCR laboratory. The major secondary endpoint was rate of complete cytogenetic response (CCyR) by 12 mos based on bone marrow cytogenetics. Results: Baseline demographics, disease characteristics, and Sokal scores were well balanced among the 3 arms; pts with high-risk Sokal scores were 28% in all arms. Median dose intensities of nilotinib delivered were 592 mg/day for 300 mg bid and 779 mg/day for 400 mg bid; imatinib dose intensity was 400 mg/day. Overall, 84%, 82%, and 79% of pts remained on the study for 300 mg bid nilotinib, 400 mg bid nilotinib, and 400 mg qd imatinib, respectively. Rates of MMR at 12 mos (Table) were superior for nilotinib 300 mg bid compared with imatinib 400 mg qd (44% vs. 22%,P < .0001) and also for nilotinib 400 mg bid compared with imatinib 400 mg qd (43% vs. 22%,P < .0001). Median time to MMR among pts who achieved MMR was faster for nilotinib 300 mg bid (5.7 mos) and nilotinib 400 mg bid (5.8 mos) compared with imatinib 400 mg qd (8.3 mos). Rates of CCyR by 12 mos were significantly higher for both nilotinib at either 300 mg bid compared with imatinib 400 mg qd (80% vs. 65%,P < .0001) and for nilotinib 400 mg bid compared with imatinib 400 mg qd (78% vs. 65%,P = .0005). Overall, progression to advanced disease was lower for nilotinib 300 mg bid (2 pts) and nilotinib 400 mg bid (1 pt) compared with imatinib 400 mg qd (11 pts). Overall, both drugs were well-tolerated. Rates of discontinuation due to adverse events or laboratory abnormalities were 7% for nilotinib 300 mg bid, 11% for nilotinib 400 mg bid, and 9% for imatinib 400 mg qd. Pts were monitored for QT prolongation and LVEF. No patients in any treatment arm showed a QTcF interval > 500 msec. There was no decrease from baseline in mean LVEF anytime during treatment in any arm. The study is ongoing. Conclusions: Nilotinib at both 300 mg bid and 400 mg bid induced significantly higher and faster rates of MMR and CCyR compared with imatinib 400 mg qd, the current standard of care in pts with newly diagnosed CML. Nilotinib was effective across all Sokal scores. After only one year of treatment, both nilotinib arms resulted in a meaningful clinical benefit compared to imatinib, with reduction of transformation to AP/BC. Nilotinib exhibited a favorable safety and tolerability profile. The superior efficacy and favorable tolerability profile of nilotinib compared with imatinib suggests that nilotinib may become the standard of care in newly diagnosed CML. Disclosures: Saglio: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Off Label Use: Nilotinib is not currently approved for first-line treatment of CML. The presentation will report the results from a randomized study of imatinib versus nilotinib in patients with newly diagnosed Ph+ CML-CP. Kim:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. le Coutre:Novartis: Honoraria, Research Funding; BMS: Honoraria. Reiffers:Novartis: Research Funding. Pasquini:Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees; Schering: Membership on an entity’s Board of Directors or advisory committees. Clark:Novartis: Honoraria, Research Funding, Speakers Bureau. Hughes:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Hochhaus:Novartis: Research Funding. Gallagher:Novartis: Employment, Equity Ownership. Hoenekopp:Novartis: Employment. Dong:Novartis: Employment, Equity Ownership. Haque:Novartis: Employment. Larson:Novartis:

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

Blood ◽

10.1182/blood.v126.23.4048.4048 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4048-4048

Author(s):

Jesus G. Berdeja ◽

Michael Heinrich ◽

Shaker Dakhil ◽

Stuart L. Goldberg ◽

Martha Wadleigh ◽

...

Keyword(s):

Myocardial Infarction ◽

Research Funding ◽

Digital Pcr ◽

Molecular Response ◽

Newly Diagnosed ◽

Employment Equity ◽

Pharmaceutical Corporation ◽

Equity Ownership ◽

Time Point ◽

Advisory Role

Abstract Background : Regular monitoring of MR by real-time quantitative polymerase chain reaction (RQ-PCR) on the International Scale (IS) is critical for proper management of pts with CML-CP, and achievement of deep MR is a key criterion for enrollment in treatment-free remission studies. In addition, newer techniques have been developed for evaluating residual disease below the level of detection of conventional RQ-PCR. The BCR-ABL1 tyrosine kinase inhibitor NIL elicits higher rates of deep MR than imatinib (IM) in pts with newly diagnosed CML-CP. Prior results from ENESTnext in this pt population demonstrated rapid achievement of deep MR by conventional RQ-PCR and further reductions in BCR-ABL1 transcript levels using a microfluidic digital PCR platform in pts who achieved confirmed MR4.5 (BCR-ABL1IS ≤ 0.0032%) with NIL. Final results are presented here. Methods : ENESTnext (NCT01227577) was a single-arm, open-label, multicenter study in adult pts with Philadelphia-chromosome-positive CML-CP (diagnosed within ≤ 6 months of enrollment) treated with NIL 300 mg twice daily (BID) for up to 2 years. The primary endpoint was the rate of confirmed (≥ 2 samples taken 3 months apart) MR4.5 with up to 2 years of NIL therapy. Secondary endpoints included the rate of major MR (MMR; BCR-ABL1IS ≤ 0.1%). RQ-PCR evaluation of peripheral blood samples was performed monthly for the first 3 months and every 3 months thereafter by a central laboratory and according to the IS. In an exploratory analysis, samples from pts with confirmed MR4.5 (limit of detection of the RQ-PCR assay used) were also evaluated using the Fluidigm digital PCR platform (detection limit is approximately 1 positive cell in 1,000,000 negative cells), which is > 1 log more sensitive than conventional RQ-PCR. Samples were analyzed by both digital PCR and RQ-PCR for each pt upon achievement of confirmed MR4.5. Results : A total of 128 pts were enrolled (median age, 56.5 years; male, n = 64 [50.0%]; Caucasian, n = 103 [80.5%]), and 93 pts (72.7%) completed the study per protocol. With up to 2 years of treatment, 94 pts (73.4%) achieved MMR and 34 pts (26.6%) achieved confirmed MR4.5 (Table). Overall, 13 of 94 pts (13.8%) lost MMR and 6 of 34 pts (17.6%) lost MR4.5; among the pts who gained and lost MMR (n = 13) or MR4.5 (n = 6), the mean duration of response was 4.9 and 8.0 months, respectively. All pts who achieved MR4.5 had BCR-ABL1IS ≤ 10% at 3 months. Digital PCR analysis was performed on 195 samples from 33 pts with confirmed MR4.5 by RQ-PCR. Results of digital PCR detection of BCR-ABL1 transcripts in the first and last time point samples from each pt are shown in the Table; among pts for whom both the first and last time point samples showed detectable BCR-ABL1 transcripts by digital PCR, levels decreased over time with continued NIL therapy. The most common (≥ 4 pts) all-cause grade 3/4 adverse events were increased lipase (n = 16), thrombocytopenia (n = 11), neutropenia (n = 8), hypophosphatemia (n = 5), and nausea (n = 5). The most common cardiac disorders were palpitations (6.3%) and atrial fibrillation, myocardial infarction, and tachycardia (2.3% each). Ischemic cardiovascular events included myocardial infarction (2.3%) and cerebrovascular accident and transient ischemic attack (0.8% each). Conclusions : Rapid achievement of MR4.5 was observed in pts with newly diagnosed CML-CP receiving frontline NIL 300 mg BID in ENESTnext; rates of MR were also consistent with those from the ENESTnd study of frontline IM vs NIL with 2 years of follow-up. In ENESTnext, 39% of samples analyzed by digital PCR had detectable levels of BCR-ABL1 transcripts that were not detectable by conventional RQ-PCR, suggesting the potential for detection of even deeper levels of MR using this novel method. Disclosures Berdeja: BMS: Research Funding; Abbvie: Research Funding; Takeda: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Acetylon: Research Funding; MEI: Research Funding; Curis: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Array: Research Funding. Heinrich:BMS: Research Funding; Pfizer: Consultancy, Other: Consulting or Advisory Role; Blueprint Pharmaceuticals: Consultancy, Other: CONSULTING OR ADVISORY ROLE; ARIAD Pharmaceuticals Inc.: Consultancy, Other: Consulting or Advisory Role, Research Funding; Novartis: Consultancy, Other: Consulting & Advisory Role, Research Funding; MolecularMD: Other: Consulting or Advisory Role; MolecularMD: Other: Stock/Shareholder ; Novartis: Other: Expert Testimony; Onyx: Other: Consulting or Advisory Role; Bayer: Research Funding. Goldberg:BMS: Research Funding, Speakers Bureau; Ariad: Research Funding, Speakers Bureau; COTA: Employment, Equity Ownership, Other: Leadership, Stock; Novartis: Research Funding, Speakers Bureau; Pfizer: Research Funding. Kuriakose:Kedrion: Speakers Bureau. Cortes:Astellas: Consultancy, Research Funding; BerGenBio AS: Research Funding; Teva: Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Rizzieri:Novartis: Membership on an entity's Board of Directors or advisory committees. Bonifacio:Novartis Pharmaceutical Corporation: Employment, Equity Ownership. Dautaj:Novartis Pharmaceutical Corporation: Employment. Warsi:Novartis Pharmaceutical Corporation: Employment. Mauro:Ariad: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis Pharmaceutical Corporation: Consultancy, Research Funding; Pfizer: Consultancy.

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Treatment Patterns and Outcomes in Elderly Patients with Newly Diagnosed Multiple Myeloma: Results from the Connect® MM Registry

Blood ◽

10.1182/blood-2019-126205 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3129-3129

Author(s):

Hans C. Lee ◽

Sikander Ailawadhi ◽

Cristina Gasparetto ◽

Sundar Jagannath ◽

Robert M. Rifkin ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Causes Of Death ◽

Age Groups ◽

Treatment Patterns ◽

Age Group ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Background: Multiple myeloma (MM) is common among the elderly, with 35% of patients (pts) diagnosed being aged ≥75 years (y). With increasing overall life expectancy, the incidence and prevalence of newly diagnosed and previously treated MM patients ≥80 y is expected to increase over time. Because elderly pts are often excluded from clinical trials, data focused on their treatment patterns and clinical outcomes are lacking. The Connect® MM Registry (NCT01081028) is a large, US, multicenter, prospective observational cohort study of pts with newly diagnosed MM (NDMM) designed to examine real-world diagnostic patterns, treatment patterns, clinical outcomes, and health-related quality of life patient-reported outcomes. This analysis reviews treatment patterns and outcomes in elderly pts from the Connect MM Registry. Methods: Pts enrolled in the Connect MM registry at 250 community, academic, and government sites were included in this analysis. Eligible pts were adults aged ≥18 y with symptomatic MM diagnosed ≤2 months before enrollment, as defined by International Myeloma Working Group criteria; no exclusion criteria were applied. For this analysis, pts were categorized into 4 age groups: <65, 65 to 74, 75 to 84, and ≥85 y. Pts were followed from time of enrollment to the earliest of disease progression (or death), loss to follow-up, or data cutoff date of February 7, 2019. Descriptive statistics were used for baseline characteristics and treatment regimens. Survival outcomes were analyzed using Cox regression. Time to progression (TTP) analysis excluded causes of death not related to MM. Results: Of 3011 pts enrolled (median age 67 y), 132 (4%) were aged ≥85 y, and 615 (20%) were aged 75-84 y at baseline. More pts aged ≥85 y had poor prognostic factors such as ISS stage III disease and reduced hemoglobin (<10 g/dL or >2 g/dL <LLN) compared with other age groups, although no notable differences between creatinine and calcium levels were observed across age groups (Table). A lower proportion of elderly pts (75-84 and ≥85 y) received triplet regimens as frontline therapy. More elderly pts received a single novel agent, whereas use of 2 novel agents was more common in younger pts (Table). The most common frontline regimens among elderly pts were bortezomib (V) + dexamethasone (D), followed by lenalidomide (R) + D, whereas those among younger pts included RVD, followed by VD and CyBorD (Table). No pt aged ≥85 y, and 4% of pts aged 75-84 y received high-dose chemotherapy and autologous stem cell transplant (vs 61% in the <65 y and 37% in the 65-74 y age group). The most common maintenance therapy was RD in pts ≥85 y (although the use was low) and R alone in other age groups (Table). In the ≥85 y group, 27%, 10%, and 4% of pts entered 2L, 3L, and 4L treatments respectively, vs 43%, 23%, and 13% in the <65 y group. Progression-free survival was significantly shorter in the ≥85 y age group vs the 75-84 y age group (P=0.003), 65-74 y age group (P<0.001), and <65 y age group (P<0.001; Fig.1). TTP was significantly shorter in the ≥85 y group vs the <65 y group (P=0.020); however, TTP was similar among the 65-74 y, 75-84 y, and ≥85 y cohorts (Fig. 2). Overall survival was significantly shorter in the ≥85 y group vs the 75-84 y, 65-74 y, and <65 y groups (all P<0.001; Fig. 3). The mortality rate was lowest (46%) during first-line treatment (1L) in pts aged ≥85 y (mainly attributed to MM progression) and increased in 2L and 3L (47% and 54%, respectively); a similar trend was observed in the younger age groups. The main cause of death was MM progression (29% in the ≥85 y vs 16% in the <65 y group). Other notable causes of death in the ≥85 y group included cardiac failure (5% vs 2% in <65 y group) and pneumonia (5% vs 1% in <65 y group). Conclusions: In this analysis, elderly pts received similar types of frontline and maintenance regimens as younger pts, although proportions varied with decreased use of triplet regimens with age. Considering similarities in TTP across the 65-74 y, 75-84 y, and ≥85 y cohorts, these real-world data support active treatment and aggressive supportive care of elderly symptomatic pts, including with novel agents. Additionally, further clinical studies specific to elderly patients with MM should be explored. Disclosures Lee: Amgen: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Ailawadhi:Janssen: Consultancy, Research Funding; Takeda: Consultancy; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Cellectar: Research Funding. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Jagannath:AbbVie: Consultancy; Merck & Co.: Consultancy; Bristol-Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy. Rifkin:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Narang:Celgene: Speakers Bureau. Terebelo:Celgene: Honoraria; Jannsen: Speakers Bureau; Newland Medical Asociates: Employment. Toomey:Celgene: Consultancy. Hardin:Celgene: Membership on an entity's Board of Directors or advisory committees. Wagner:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; American Cancer Society: Other: Section editor, Cancer journal. Omel:Celgene, Takeda, Janssen: Other: Patient Advisory Committees. Srinivasan:Celgene: Employment, Equity Ownership. Liu:TechData: Consultancy. Dhalla:Celgene: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Abonour:BMS: Consultancy; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

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Specific Drug Transporter Genotypes Are Significantly Associated with Increased Rates of Major and Complete Molecular Responses In Newly Diagnosed Chronic Myeloid Leukemia Patients Treated with Imatinib – A TOPS Correlative Substudy

Blood ◽

10.1182/blood.v116.21.670.670 ◽

2010 ◽

Vol 116 (21) ◽

pp. 670-670

Author(s):

Simona Soverini ◽

Sabrina Angelini ◽

Eleonora Turrini ◽

Matt Burnett ◽

Gloria Ravegnini ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Cumulative Incidence ◽

Myeloid Leukemia ◽

Research Funding ◽

Phase Iii ◽

Molecular Response ◽

Newly Diagnosed ◽

First Line ◽

Favorable Alleles ◽

Summary Measures

Abstract Abstract 670 The availability of multiple options for chronic myeloid leukemia (CML) treatment is not paralleled by the availability of biological predictors of outcome allowing to identify patients (pts) who are more likely to benefit from dasatinib or nilotinib rather than imatinib (IM). Pharmacogenetics has proven a potential source of biomarkers given the known influence of polymorphisms in key genes encoding drug transporters and metabolizing enzymes on drug delivery – hence effectiveness. In CML, only two studies had so far explored this field, but both were conducted in heterogeneous populations including pts at different stages of disease, not all receiving IM first-line. We thus aimed to investigate a panel of 20 single nucleotide polymorphisms (SNPs) in ABCB1, ABCG2, SLC22A1, OATP1A2, OCTN1, CYP3A4 and CYP3A5 genes that can be hypothesized to influence IM transport and metabolism in 189 newly diagnosed CML pts enrolled in the TOPS phase III trial (Cortes et al, J Clin Oncol 2010). Pts selection was exclusively based on availability of written informed consent and sufficient amount of archived material. Median age was 46 years; male to female ratio was 103 to 86; 156 (83%) pts were Caucasian and 23 (12%) were Asian; low, intermediate and high Sokal risk pts were 84 (44.4%), 65 (34.4%) and 40 (21.2%), respectively. Baseline demographic/clinical features did not differ significantly from those of the overall population. Treatment outcomes (complete cytogenetic response [CCyR]; major molecular response [MMR] and complete molecular response [CMR]) were compared according to i) each candidate genotype ii) summary measures based on combinations of SNPs in the same gene and iii) summary measures based on combinations of SNPs in functionally related genes (uptake; efflux). CC genotype in OCTN1 had a favorable impact on the achievement of MMR at 12 months (MMR@12m; P = 0.03). With respect to the summary measures, combination of SNPs in the SLC22A1 gene was significantly correlated with MMR@12m (P = 0.03). When considering summary measures of uptake and efflux, the former was found to be associated with both MMR@12m and CMR@12m (P = 0.003 and P = 0.01, respectively). A separate analysis limited to Caucasian pts (n=156) yielded similar results (Table 1). In addition, the analysis in the Caucasian subgroup evidenced a significant association between the CC genotype in ABCB1 rs60023214 and MMR@12m (P = 0.005) (Table 1). Cumulative incidence plots based on the Kaplan-Meier method were also analyzed in the overall population and in Caucasians, with comparable results. Representative plots are shown in Figure 1. There was evidence for difference among MMR cumulative incidence curves for 2 single SNPs and 2 score measures. Presence of the major allele in OCTN1 (CC) and of the minor allele in CYP3A4 rs2740574 (GG) were associated with increased MMR rate (P = 0.028 and P = 0.042, respectively, in the overall population and P = 0.027 and P = 0.038, respectively, in Caucasians). Similarly, an increase in the number of favorable alleles in the SLC22A1 gene was associated with increased MMR rate (P = 0.030 and P = 0.043 in the overall population and in Caucasians, respectively). In addition, the combination of favorable alleles in the genes involved in IM uptake was associated with increased rates of both MMR and CMR (P = 0.004 and P = 0.015, respectively, in the overall population and P = 0.005 and P = 0.009, respectively, in Caucasians). Our results suggest that SNP genotyping might be helpful in selecting pts who are more likely to benefit from first-line use of more potent inhibitors. Further assessment of the SNPs here identified in larger series of pts is warranted. Supported by Novartis Oncology, Clinical Development, TOPS Correlative Studies Network Disclosures: Hughes: Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria. White:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding. Saglio:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Rosti:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Hatfield:Novartis: Employment. Martinelli:Novartis: Consultancy, Honoraria; BMS: Honoraria; Pfizer: Consultancy.

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