ENESTnd Update: Nilotinib (NIL) Vs Imatinib (IM) In Patients (pts) With Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP) and The Impact Of Early Molecular Response (EMR) and Sokal Risk At Diagnosis On Long-Term Outcomes

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 92-92 ◽  
Author(s):  
Giuseppe Saglio ◽  
Andreas Hochhaus ◽  
Timothy P. Hughes ◽  
Richard E. Clark ◽  
Hirohisa Nakamae ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Eligibility Criterion ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Long Term Outcomes ◽  
Vascular Events ◽  
Advisory Committees ◽  
The Impact

Abstract Introduction Frontline NIL continues to show benefit over IM in pts with Philadelphia chromosome-positive (Ph+) CML-CP, with higher rates of major molecular response (MMR; BCR-ABLIS ≤ 0.1%) and MR4.5 (BCR-ABLIS ≤ 0.0032%), lower rates of progression to accelerated phase (AP)/blast crisis (BC) and fewer new BCR-ABL mutations on treatment in the Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Pts (ENESTnd) trial. Here, we report data with a minimum follow-up (f/u) of 4 y; updated data based on 5 y of f/u will be presented. Methods Adults with newly diagnosed Ph+ CML-CP (N = 846) were randomized to NIL 300 mg twice daily (BID; n = 282), NIL 400 mg BID (n = 281), or IM 400 mg once daily (QD; n = 283). Progression and overall survival (OS) events were collected prospectively during study f/u, including after discontinuation of study treatment. Efficacy in the NIL 300 mg BID and IM arms was evaluated based on achievement of EMR (BCR-ABLIS ≤ 10% at 3 mo). Results At 4 y, ≥ 87% of pts remained on study in each arm and 57%-69% remained on core treatment (Table). Rates of MMR and MR4.5 by 4 y were significantly higher with NIL vs IM. Significantly fewer pts progressed to AP/BC on NIL vs IM (on core treatment: 0.7%, 1.1%, and 4.2%; on study: 3.2%, 2.1%, and 6.7% [NIL 300 mg BID, NIL 400 mg BID, and IM arms, respectively]). Of 17 pts across the 3 arms who progressed on core treatment, 11 (65%) had never achieved complete cytogenetic response and none had achieved MR4.5. Fewer mutations have emerged in the NIL arms vs the IM arm; in y 4, mutations emerged in 2 pts (1 pt with T315I on NIL 300 mg BID; 1 pt with F317L on IM). More pts achieved EMR in the NIL 300 mg BID arm vs the IM arm (91% vs 67%). Pts with EMR had significantly higher rates of progression-free survival (PFS) and OS at 4 y vs pts with BCR-ABL > 10% at 3 mo. Among pts with BCR-ABL > 10% at 3 mo, more progressions to AP/BC occurred in the IM arm (n = 14) vs the NIL 300 mg BID arm (n = 2); half of these pts progressed between 3 and 6 mo. In pts with intermediate or high Sokal risk, PFS and OS at 4 y were higher in both NIL arms vs the IM arm. No new safety signals were detected. Selected cardiac and vascular events were more common on NIL vs IM (by 4 y, peripheral arterial occlusive disease [PAOD] in 4 [1.4%], 5 [1.8%], and 0 pts; ischemic heart disease [IHD] in 11 [3.9%], 14 [5.1%,] and 3 [1.1%] pts; and ischemic cerebrovascular events in 3 [1.1%], 5 [1.8%], and 1 [0.4%] pts in the NIL 300 mg BID, NIL 400 mg BID, and IM arms, respectively). In the NIL 300 mg BID arm, 2 of 11 IHD events occurred between 3 and 4 y (all 4 PAOD events occurred in the first 2 y). In the NIL 400 mg BID arm, 2 of 5 PAOD events and 3 of 14 IHD events occurred between 3 and 4 y. Most pts (7 of 9) with a PAOD event on NIL were at high risk due to a combination of baseline risk factors. Conclusions NIL, a standard-of-care frontline therapy option for newly diagnosed CML-CP pts, affords superior efficacy compared with IM, including higher rates of EMR (which is associated with improved long-term outcomes), higher rates of MR4.5 (a key eligibility criterion for many studies of treatment-free remission), and a lower risk of disease progression. NIL continues to show good tolerability with long-term f/u. While selected cardiac and vascular events (including PAOD) are slightly more frequent on NIL vs IM, no increase in annual incidence of these events over time has been observed. Disclosures: Saglio: ARIAD: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Hochhaus:Ariad: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Hughes:Ariad: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CSL: Research Funding. Clark:Pfizer: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Nakamae:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau, travel/ accomodations/ meeting expenses Other. Kim:BMS, Novartis,IL-Yang: Honoraria; Pfizer: Consultancy, Research Funding. Etienne:Pfizer: Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: 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; Ariad: Membership on an entity’s Board of Directors or advisory committees. Flinn:Novartis: Research Funding. Lipton:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Moiraghi:Bristol Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Fan:Novartis: Employment. Menssen:Novartis: Employment. Kantarjian:Novartis: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding; ARIAD: Research Funding. Larson:Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy.

Enestnd 4-Year (y) Update: Continued Superiority of Nilotinib Vs Imatinib in Patients (pts) with Newly Diagnosed Philadelphia Chromosome–Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1676-1676 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Dong-Wook Kim ◽  
Surapol Issaragrisil ◽  
Richard E Clark ◽  
Josy Reiffers ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Standard Of Care ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Molecular Responses ◽  
The Difference ◽  
The Impact

Abstract Abstract 1676 Background: Pts treated with nilotinib in the ENESTnd phase 3 trial achieved higher and faster rates of major molecular response (MMR, ≤ 0.1% BCR-ABLIS), deeper molecular responses (MR4, ≤ 0.01%IS and MR4.5, ≤ 0.0032%IS), significantly lower rates of progression to accelerated phase/blast crisis (AP/BC), and fewer CML-related deaths compared with imatinib by 1, 2, and 3 y. Here, we report data with a minimum follow-up of 3 y; efficacy and safety data based on longer follow-up of 4 y will be presented to further assess the impact of nilotinib vs imatinib in pts with newly diagnosed Ph+ CML-CP. Methods: Adult pts (N = 846) 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, progression-free survival (PFS), and overall survival (OS) were evaluated. Results: Significantly higher rates of MMR, MR4, and MR4.5 by 3 y were achieved in nilotinib- vs imatinib-treated pts (Table). Nilotinib led to the achievement of higher rates of molecular responses regardless of Sokal risk group or age. The difference in the rates of both MR4 and MR4.5 continued to be significantly higher for nilotinib, with the difference in favor of nilotinib increasing from 1 to 3 y (MR4: 9%-14% difference by 1 y, 18%-24% difference by 3 y; MR4.5: 6%-10% difference by 1 y, 13%-17% difference by 3 y). Among patients who achieved MMR, more pts achieved MR4 or MR4.5 on nilotinib 300 mg BID (68%) and nilotinib 400 mg BID (62%) compared with imatinib (49%). No pt in any arm progressed after achieving MR4.5. Significantly fewer pts progressed to AP/BC on nilotinib vs imatinib (Table). No new progressions occurred on core treatment between the 2-y and 3-y analyses. When events occurring after treatment discontinuation were included, the rates of progression to AP/BC were also significantly lower with nilotinib vs imatinib (Table). Nearly twice as many pts had emergent mutations on imatinib (n = 21) vs either nilotinib arm (n = 11 in each arm), with 5 pts overall developing mutations between 2 and 3 y. OS remained similar in all groups at 3 y, but fewer CML-related deaths occurred in both the nilotinib 300 mg BID (n = 5) and 400 mg BID (n = 4) arms vs imatinib (n = 14). Both drugs were well tolerated. Few new adverse events (AEs) and laboratory abnormalities were observed between 2 and 3 y. Rates of discontinuation due to AEs were 10%, 14%, and 11% in the nilotinib 300 mg BID, nilotinib 400 mg BID, and imatinib arms, respectively. Conclusions: Nilotinib continues to demonstrate superiority vs imatinib, yielding faster and deeper molecular responses and a significantly decreased risk of progression. Results of ENESTnd support the use of nilotinib as a standard of care option in newly diagnosed adult pts with Ph+ CML-CP and should be considered to replace imatinib as the standard-of-care frontline therapy for patients with Ph+ CML-CP. Disclosures: Kantarjian: Novartis: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Kim:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ARIAD: Research Funding; II-Yang: Research Funding. Clark:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Reiffers:BMS: Expense reimbursement for travel expenses Other; Novartis: Expense reimbursement for travel expenses, Expense reimbursement for travel expenses Other. Nicolini:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria. Hughes:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; CSL: Research Funding. Hochhaus:BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding. Kemp:Novartis Pharmaceuticals Corp: Employment. Fan:Novartis Pharmaceuticals Corp: Employment. Waltzman:Novartis Pharmaceuticals Corp: Employment, Equity Ownership. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy. Larson:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy; Ariad: Consultancy, Research Funding.

scholarly journals Differences in Presentation and Survival Outcomes for African American Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5647-5647 ◽  
Author(s):  
Nisha Joseph ◽  
Vikas A. Gupta ◽  
Craig C Hofmeister ◽  
Charise Gleason ◽  
Leonard Heffner ◽  
...  
Keyword(s):  
African American ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Long Term Outcomes ◽  
Advisory Committees ◽  
Entire Cohort ◽  
Significant Difference

Abstract Background : Though the incidence of MM is two- to threefold higher in the African American (AA) population compared to Caucasians, reported long term outcomes are less favorable presumably due to inequities in access to healthcare. Little is known about the biology or disease presentation among AAs. We have conducted a retrospective analysis of our institutional data of 1000 patients treated with RVD induction therapy, specifically assessing differences in presentation, disease biology, and outcomes in AA patients. Methods: A total of 1000 newly diagnosed MM patients were treated with RVD induction therapy [R - 25 mg/day (days 1-14), V - 1.3 mg/m2 (days 1, 4 8, 11) and D - 40 mg once/twice weekly as tolerated every 21 days] from January 1st 2005 until August 31st 2016. Dose-adjustments were made based on the treating physician's discretion and patient tolerability. Demographic and outcomes data for the patients were obtained from our IRB approved myeloma database and responses were evaluated per IMWG Uniform Response Criteria. Results: Of the 1000 patients included in the analysis, 564 (56.4%) of patients were white (W), and 339 (33.9%) were AA, consistent with the demographic representation of the state of GA and our institutional referral population. Median age of this cohort was 61 years (range 16-83), 57 for AA patients (range, 24-83) compared to 62 (range, 16-81) in white patients, suggesting the onset is earlier among AA which has been previously reported in population based studies. Other notable characteristics include: 42.5%M/57.5% F for AA cohort and 61.7%M/38.3%F for white cohort. In regard to stage, AA: 73.9% stage I/II, 26.1% stage III; W: 77.1% stage I/II, 22.9% stage III, showing no difference in prognostic staging at presentation. There was no statistically significant difference in the presenting labs between AA and whites except for hemoglobin, with more AA patients presenting with Hgb≤9.9 g/dL (45.7% AA vs 32.5% W, p <.0001). In terms of prevalence of high-risk cytogenetics, there was no significant difference between the two cohorts in: complex karyotype 16% white/14.4% AA; t(14;16) 2.4% W/2.8% AA; t(4;14) 4.7% W/5.0% AA; t(11;14) 11.7% W/15.9% AA; or del1p 6.5%W/7.8%AA. However, there were significant differences found in the rates of: amp 1q 19.2% W/10.6% AA, (p<.0001), del13 28.3% W/19.6% AA (p=.003), and del17p 11.7% W/7.2% AA (p=.019), all three significantly less frequent in AAs. Median time to transplant for the entire cohort was 5 months (range, 1-124), and median time to best response was 3 months (range, 0-39). There was no significant difference in the number of patients who underwent ASCT (84% W vs 82% AA, p=.241), nor in ≥VGPR rates post-induction and 100 days post-ASCT: 69.9% W vs 64.5% AA (p=.056) and 88.1% W vs 86.7% in AA patients (p=.317), respectively. Median PFS for the entire cohort was 63 months, 62 months (54-69.9) for white patients versus 65 months (53-76.9) for AA patients (p=0.403). At a median follow up of 38 months, median OS has not yet been reached. Conclusions: This is the largest reported cohort of myeloma patients treated with RVD induction, with one-third of the patients representing the AA population. In our dataset, AAs are diagnosed 5 years younger, with lower hemoglobin at presentation and lower rates of amp1q, del13 and del17p when compared to whites. When offered the same induction regimen and opportunity for ASCT, AAs tend to experience the same survival benefits as their white counterparts. The lack of significant difference in PFS or OS suggests standardization and improved access to care could lead to better long-term outcomes in the AA population. Disclosures Hofmeister: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Heffner:Genentech: Research Funding; Pharmacyclics: Research Funding; ADC Therapeutics: Research Funding; Kite Pharma: Research Funding. Boise:AstraZeneca: Honoraria; Abbvie: Consultancy. Kaufman:BMS: Consultancy; Janssen: Consultancy; Karyopharm: Other: data monitoring committee; Abbvie: Consultancy; Roche: Consultancy. Lonial:Amgen: Research Funding. Nooka:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: 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; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Long-Term Outcome of Chronic Phase Chronic Myeloid Leukemia Patients Treated with Nilotinib Front-Line

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 44-45
Author(s):  
Franck E Nicolini ◽  
Vincent Alcazer ◽  
Pascale Cony-Makhoul ◽  
Stephanie Dulucq ◽  
Sandrine Hayette ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Chronic Phase ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Front Line ◽  
Advisory Committees ◽  
Long Term Outcome

Nilotinib (NIL) 600 mg daily has demonstrated its superiority over Imatinib 400 mg daily in terms of response and incidence of deep molecular response in the front-line chronic phase (CP) CML setting. In this observational study we have retrospectively analyzed the outcome of in- and out-study 202 patients (pts) treated in this setting with NIL 600 mg front-line, in "real-life" conditions. All pts with newly diagnosed adult CP-CML receiving NIL 300 mg BID alone front-line between 10/2007 and 06/2020, were eligible for this study. Data were retrospectively collected according to the current French regulations with pts' information. All pts were assessed and followed according to ELN recommendations 2003, 2006, and 2009 along treatment and to the recommendations from the French group of CML (D. Rea et al., Cancer 2018) in case of TFR. In this regard, a TKI was resumed if loss of MMR. All BCR-ABL1 assessments were performed in the 3 reference laboratories, standardised and expressed in % (IS) with ≥32,000 copies of ABL1 as control. The primary endpoints were the rate of molecular responses in the long-term and the (vascular) safety of Nilotinib. Secondary endpoints were the kinetics of molecular response, survival and safety of Nilotinib. Survival (OS, PFS & EFS) was defined according to ELN (J. Guilhot et al. Blood 2012). Two hundred and two patients were reported with 44% females and 56% males with a median age at diagnosis of 50.4 (17.5-83) years, and 26% of them had cardiovascular risk factors at onset (tobacco abuse 11%, hypercholesterolemia 9.3%, diabetes 1.45%, none with past history of cardiovascular events [CVE]). ELTS scores were high in 14%, intermediate in 31% and low in 55% of pts. Twenty-four (12%) pts harboured additional chromosomal abnormalities at diagnosis. The median follow-up after NIL initiation was 61.5 (1-147.5) months. At last follow-up 113 pts (55%) are not on NIL anymore for toxicities, TFR or resistance reasons. Twenty-eight (14%) pts present an arterial event on NIL (18% PAOD, 14% angina pectoralis, 7% myocardial infarction, 14% stroke, 47% others such as atrial fibrillation, cardiomyopathy...), that occurred after a median of 26 (0.6-98.5) months on NIL. Forty-six (22.5%) pts reached TFR criteria and stopped NIL after a median of 58.5 (27-126) months. The cumulative incidence (CI) rates of MMR at 1, 2 and 5 years were 64 (57-71)%, 79.4 (75.45-83.35)% and 95 (92-98.5)% respectively. For MR4, those were 35.5 (29-42)%, 60 (52-67)% and 82 (74.5-89)% respectively; and for MR4.5, were 14 (9-19)%, 31 (24-28)% and 62 (54-70.5)% respectively. The CI of sustained MR4.5 (i. e. patients eligible for TFR: MR4.5 ≥2 years) was observed in 30 (23-37)% at 3 years, 45.5 (36-55)% at 5 years and 52.5 (41.5-64)% at 6 years (Figure). The CI of patients entering TFR was 16.75 (10.5-23)% at 5 years and 51.94 (37.31-66.57)% at 10 years with a survival without MMR loss of 70.7 (58- 86)% at 1 year and 65.26 (50.6-84)% at 5 years. Nine (4.5%) pts progressed towards accelerated phase (4 pts) or BC (2 lymphoid, 3 myeloid) responsible for 5 deaths at latest follow-up. Among NIL resistant patients screened, 15 were harbouring ABL1 mutations (5 Y253H, 3 E255K, 3 T315I, 1 M244V, 1 G250E, 1 F359V, 1 V299L). Overall, 10 patients died (5 from CML, 5 from unrelated causes). The probability of OS was 95.75 [95%CI: 92.9-98.7]% at 2 years and 94.8 [91.5-98.3]% at 5 years, for PFS it was 94.92 [91.7-98.2]% at 2 years and 89.5 [84.7-94.6]% at 5 years, and EFS it was 78 [72.3-84]% at 2 years and 60.25 [53.3-68.1]% at 5 years. Regarding sustained MR4.5, univariate analysis showed that female gender (HR=2.46 [1.50-4.02], p&lt;0.001) and low ELTS (HR=0.41 [0.22-0.76], p&lt;0.004) had a significant impact, while multivariate analysis confirmed the role of these 2 factors (HR=2.31 [1.41- 3.79], p=0.001 and HR= 0.52 [0.30- 0.90], p=0.02) in addition to high ELTS (HR= 0.28 [0.14- 0.58], p&lt;0.001). Univariate and multivariate analyses demonstrated that only age impacted on the CI of CVE (HR= 1.07 [1.04-1.10], p&lt;0.001, and HR=1.07 [1.04-1.10], p&lt;0.001). NIL first-line efficiently limits progression of newly diagnosed CP-CML patients and provides high rates of sustained MR4.5, allowing TFR in a substantial proportion of pts. However, the onset of arterial occlusive events, especially in the elderly is a matter of concern in the choice of this compound at treatment initiation. Disclosures Nicolini: Incyte: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Sun Pharma Ltd: Consultancy. Cony-Makhoul:BMS: Speakers Bureau; Incyte Biosciences: Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy; BMS: Consultancy. Dulucq:Incyte: Speakers Bureau; Novartis: Speakers Bureau. Cayuela:Novartis: Speakers Bureau; Incyte: Speakers Bureau. Rea:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mahon:ARIAD: Honoraria; Pfizer: Honoraria; Novartis Pharma: Honoraria, Research Funding; BMS: Honoraria. Etienne:Pfizer: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau.

Molecular Response at 3 Months On Nilotinib Therapy Predicts Response and Long-Term Outcomes in Patients with Imatinib-Resistant or -Intolerant Chronic Myeloid Leukemia in Chronic Phase (CML-CP).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3292-3292 ◽  
Author(s):  
Susan Branford ◽  
Dong-Wook Kim ◽  
Simona Soverini ◽  
Enrico Gottardi ◽  
Lan Beppu ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Long Term Outcomes ◽  
Advisory Committees ◽  
Imatinib Resistance ◽  
Transcript Levels ◽  
Imatinib Resistant

Abstract Abstract 3292 Poster Board III-1 Background: Nilotinib is a potent and highly selective BCR-ABL kinase inhibitor, approved for the treatment of Philadelphia positive CML patients (pts) in CP or accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib. A recent analysis demonstrated an association between BCR-ABL transcript levels at 3 months (mos) and response in pts treated with second-line tyrosine kinase inhibitors (Branford et al. Blood. 2008). This multi-center analysis was conducted to examine the association specifically between the initial molecular response to nilotinib with response and outcomes. Methods: CML-CP pts (N = 321) with imatinib resistance or intolerance were included and post-baseline BCR-ABL transcript levels were available for 294 patients. Intolerant pts also exhibited some degree of resistance to imatinib and were not eligible for the study if demonstrating major cytogenetic response (MCyR), the primary study endpoint. We aimed to determine if the initial molecular response to nilotinib could predict the response and outcome of patients with or without BCR-ABL mutations at baseline or those with imatinib resistance or intolerance. BCR-ABL transcript levels at 3 mos were used to perform a landmark analysis to assess the association between the initial molecular response and estimated probability of MCyR, major molecular response (MMR), and event-free survival (EFS) at 24 mos. Events were defined as loss of hematologic or cytogenetic response, progression to AP/BC, discontinuation due to progression or death. The analysis excludes patients who had already attained MCyR (n = 111) or MMR [BCR-ABL% (IS) ≤ 0.1%] (n = 28) or who had an event (n = 22) within the first 3 mos of therapy for each respective landmark analysis. Patients censored within the first 3 mos were also excluded. Patients were then grouped according to their level of BCR-ABL% (IS). Results: BCR-ABL% (IS) at 3 mos correlated with MCyR rates at 24 mos; pts with BCR-ABL% (IS) ≤ 10 had better probability of response compared with pts with BCR-ABL% (IS) > 10 (62% vs 35%, respectively). This difference in MCyR rate was most significant for pts with baseline mutations (60% vs 19%, P = .006) and those with imatinib resistance (63% vs 33%, P = 0.0007). A similar trend was observed for patients without baseline mutations (64% vs 47%) and imatinib intolerance (57% vs 40%). BCR-ABL% (IS) at 3 mos was highly predictive of MMR rates at 24 mos (Table). Pts with BCR-ABL% (IS) values > 0.1 - ≤ 1 had significantly higher probability (65%) of achieving MMR for all patient groups, whereas those with BCR-ABL% (IS) > 10 had estimated rates of 10% or less. The BCR-ABL% (IS) value at 3 mos was also found to correlate with EFS at 24 mos (Table). The estimated EFS rate at 24 mos was highest for pts with BCR-ABL% (IS) values of ≤ 1 at 3 mos for each patient group and ranged from 75% to 100%. Patients with BCR-ABL% (IS) values > 10 at 3 mos had the poorest outcome and the estimated EFS rates ranged from 36% for patients with baseline mutations to 57% for those without baseline mutations. Conclusion: BCR-ABL% (IS) at 3 mos predicts response and long-term outcomes of imatinib-resistant and intolerant pts regardless of baseline mutation status at 24 mos on nilotinib therapy. Rapid reduction of BCR-ABL may be important for optimal response and outcome. Pts whose BCR-ABL % (IS) levels decreased below 10% at 3 mos demonstrated a high probability of achieving MMR and MCyR at 24 mos. Pts who achieve early molecular response may also have an increased probability of improved long-term outcomes on nilotinib therapy, while pts with BCR-ABL% (IS) value > 10 at 3 mos may have poorer prognosis. Disclosures: Branford: Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. 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. Haque:Novartis: Employment. Shou:Novartis: Employment. Woodman:Novartis: Employment. Kantarjian:Novartis: Research Funding. Radich:Novartis: Consultancy, Honoraria, Research Funding. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Hochhaus:Novartis: Research Funding.

The Functional Activity of the OCT-1 Protein Is Predictive of Molecular Response and Survival in CP-CML Patients Treated with Imatinib: A 5 Year Update of the TIDEL Trial.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 507-507 ◽  
Author(s):  
Deborah L White ◽  
Verity A Saunders ◽  
Amity Frede ◽  
Phuong Dang ◽  
Stephanie Zrim ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Functional Activity ◽  
Research Funding ◽  
Intracellular Concentration ◽  
Molecular Response ◽  
Advisory Committees ◽  
Significant Difference ◽  
The Impact ◽  
First Time

Abstract Abstract 507 The major active influx protein for imatinib into target BCR-ABL positive cells is the organic cation transporter OCT-1. We have previously demonstrated that the functional activity of the OCT-1 protein (OCT-1 activity) is predictive of molecular response in TIDEL (trial of imatinib 600 mg/day with selective dose intensification in untreated CP-CML) The OCT-1 activity (OA) is measured in mononuclear cells from untreated CML patients by calculating the intracellular concentration of 14-C imatinib less the intracellular concentration in the presence of OCT-1 inhibition. To address the question of whether OA is predicting only the rate of response, we now investigate the impact of OA on response and progression at 5 years. There is a significant difference in the achievement of MMR (p=0.007) and CMR by 60 months (p=0.032) (Table 1). Six patients developed kinase domain mutations over the course of this study. 5/6 had low OA. Significantly, for the first time addressing Event Free Survival (events defined as loss of CHR, MCR or CCR, progression to AP or BC or change of therapy due to unsatisfactory efficacy), we demonstrate that more patients with high OA are event free at 5 years when compared to patients with low OA (Table 1). To determine whether the detrimental effect of low OA on survival was more significant in those patients with OA in the lowest quartile (Q1) we compared the response of Q1 patients to all other patients (Table 2). These data demonstrate importantly, that patients in Q1 have significantly poorer outcomes, than the remainder of the patient cohort. In previous analyses we have shown that the effects of a low OA can be partially overcome by higher imatinib doses. Limiting the analyses to those patients receiving <600mg average daily dose over the first 12 months there was a significant difference in the achievement of MMR (low OA (n=11) 27%: high OA (n=12) 92% p=0.021) and EFS (36% vs 75% p=0.03). In patients receiving ≥600 mg there was no significant difference between the groups, reinforcing the importance of dose. In 45 patients we examined the expression of OCT-1 mRNA for prediction of MMR, CMR, EFS and mutation development. Dividing the patients into low and high OCT-1 expression about the median we found that the level of mRNA is not predictive of MMR (low–60% vs high 78 p=0.241) CMR (low–45% vs high 55 p=0.456) EFS (low–55% vs high 70 p=0.315) or mutation development (low–18% vs high 14% p=0.666). These data indicate that the level of OCT-1 mRNA is not sufficiently discriminating to predict response and progression. While our previous studies demonstrated that OA could predict the rate of decline in BCR-ABL over the first 12-24 months, this update demonstrates for the first time, that this assay can identify nearly all patients (>80%) who fail to achieve MMR in the long term. Most importantly OA is also strongly predictive of resistance and progression events. Functional assessment of OCT-1 Activity provides prognostic information that is more discriminating than assaying the level of OCT-1 mRNA. This long term study reinforces the notion that OA is an important predictive variable in CP-CML patients treated with IM. It provides further evidence that OA is a critical variable to consider in future trials of imatinib and a key factor to enable individualization of imatinib dose to optimize the long term outcome for CML patients. Disclosures: White: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding. Manley:Novartis: Employment. Hughes: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.

scholarly journals Long-Term Outcomes and Organ Responses with Daratumumab Therapy in Previously Treated Patients with AL Amyloidosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1828-1828
Author(s):  
Alfred Chung ◽  
Gregory P. Kaufman ◽  
Surbhi Sidana ◽  
Erik Eckhert ◽  
Stanley Schrier ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cardiac Response ◽  
Al Amyloidosis ◽  
Long Term Outcomes ◽  
Advisory Committees ◽  
Renal Response ◽  
Cardiac Responses ◽  
Previously Treated

Introduction: AL amyloidosis involves deposition of abnormally folded light chains into a wide range of tissues causing end-organ dysfunction, including in the heart and kidney. Daratumumab, a CD38-targeted antibody, has recently demonstrated efficacy in producing hematologic responses in previously relapsed/refractory disease. However, data on long-term outcomes to daratumumab, including organ responses, are lacking. Here we present the largest retrospective study to date on patients with previously treated AL amyloidosis treated with daratumumab. Methods: We conducted a retrospective analysis of relapsed/refractory AL amyloidosis patients treated at Stanford University from January 2016 to January 2019. Patients treated with daratumumab, either as monotherapy with dexamethasone (DMT) or in combination with other plasma-cell directed therapies (DCT) were included. Hematologic and organ responses were assessed by consensus guidelines. Hematologic responses were based on the maximal change in the difference between involved and uninvolved free light chains (dFLC). For cardiac response, a >30% and >300 pg/mL decrease in NT-proBNP for patients with initial baseline NT-proBNP ≥650 pg/mL was considered a response. A graded cardiac response metric was also explored with partial response (PR) representing 30-59% reduction, very good partial response (VGPR) ≥60% reduction, and complete response (CR) NT-proBNP <450 pg/mL as previously reported. For renal response, a >30% decrease (by at least 0.5 g/day) in 24-hour urine protein without worsening in creatinine or creatinine clearance by more than 25% in patients with at least 0.5 g/day pretreatment was considered a response. A graded renal response metric was also explored with PR representing 30-59% reduction in proteinuria, VGPR ≥60%, and CR ≤ 200 mg per 24-hour period. Survival data was analyzed using the Kaplan-Meier method. All time-to-event outcomes, including survival and organ responses, were determined from initiation of daratumumab. Results: Eighty-four patients were identified with baseline characteristics at start of daratumumab shown in Table 1. Median duration of follow-up was 16 months. Two-year overall survival (OS) was 83% and median OS was not reached. Median time-to-next-treatment or death was 31 months. Sixty-seven out of 80 evaluable patients (84%) achieved a hematologic response, with 47 patients (59%) achieving a VGPR or better (Figure 1). Sixty-eight patients (81%) had cardiac involvement, and among the 34 evaluable patients, 18 (53%) of evaluable patients achieved a cardiac response with a median response time of 2 months among responders. In terms of a graded cardiac response, 6 patients (18%) were able to achieve cardiac CR, 5 patients (15%) cardiac VGPR, and 7 patients (21%) PR (Figure 2). The median NT-proBNP percent reduction was 64.5% (IQR: 48.3 - 81.1%) and the median absolute reduction was 2395 pg/mL (IQR 1279.5 - 4089.5 pg/mL). Cardiac responses were associated with an improvement in OS (p<0.001, Figure 3), with landmark analysis for cardiac responses at 6-month trending towards statistical significance (100% vs. 51% at 30 months, p=0.052). Fifty-three patients (63%) had renal involvement, and among the 26 evaluable patients, 12 patients (46%) achieved a renal response with a median initial response time of 6 months among responders. Using graded response, 1 patient (4%) achieved renal CR, 7 patients (27%) renal VGPR, 4 patients (15%) renal PR, and 14 patients had no response, worsening creatinine, or were subsequently started on hemodialysis (54%) (Figure 4). The median percent reduction in proteinuria was 74.1% (IQR: 49.2 - 83.1%) and the median absolute reduction in proteinuria was 3.1 g/24 hours (IQR 2.1 - 4.9 g) among responders. There were no significant differences in OS between renal responders and non-responders. Conclusion: Daratumumab is highly effective in the treatment of previously treated AL amyloidosis, and a significant proportion of patients can achieve durable hematologic responses as well as improvements in organ function. Disclosures Kaufman: Janssen: Other: travel/lodging, Research Funding. Liedtke:Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celator: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding. OffLabel Disclosure: Daratumumab in AL amyloidosis

ENESTnd Update: Continued Superiority of Nilotinib Versus Imatinib In Patients with Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 207-207 ◽  
Author(s):  
Timothy P. Hughes ◽  
Andreas Hochhaus ◽  
Giuseppe Saglio ◽  
Dong-Wook Kim ◽  
Saengsuree Jootar ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Clonal Evolution ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Free Survival ◽  
Superior Efficacy ◽  
Rate Of Progression

Abstract Abstract 207 Background: Results from the phase 3, international, randomized ENESTnd trial have demonstrated the superior efficacy of nilotinib over imatinib with significantly higher rates of major molecular response (MMR), complete cytogenetic response (CCyR), and with significantly lower rates of progression to AP/BC on treatment. Here, we present data with a median follow-up of 18 months. Methods: 846 CML-CP patients were randomized to nilotinib 300 mg twice daily (bid) (n=282), nilotinib 400 mg bid (n=281), and imatinib 400 mg once daily (n=283). Primary endpoint was MMR (≤ 0.1% BCR-ABLIS) rate “at” 12 months, as previously presented. Key secondary endpoint was durable MMR at 24 months. Other endpoints assessed at 24 months include progression to AP/BC (with and without clonal evolution), event-free survival, progression-free survival, and overall survival (OS). Results: With a median follow-up of 18 months, the overall best MMR rate was superior for nilotinib 300 mg bid (66%, P < .0001) and nilotinib 400 mg bid (62%, P < .0001) compared with imatinib (40%). Superior rates of MMR were observed in both nilotinib arms compared with the imatinib arm across all Sokal risk groups (Table). The overall best rate of BCR-ABLIS ≤ 0.0032% (equivalent to complete molecular response, CMR) was superior for nilotinib 300 mg bid (21%, P < .0001) and nilotinib 400 mg bid (17%, P < .0001) compared with imatinib (6%). The overall best CCyR rate was superior for nilotinib 300 mg bid (85%, P < .001) and nilotinib 400 mg bid (82%, P=.017) compared with imatinib (74%). The superior efficacy of nilotinib was further demonstrated using the 2009 European LeukemiaNet (ELN) 12-month milestone in which fewer patients had suboptimal response or treatment failure on nilotinib 300 mg bid (2%, 3%) and nilotinib 400 mg bid (2%, 2%) vs imatinib (11%, 8%). Rates of progression to AP/BC on treatment were significantly lower for nilotinib 300 mg bid (0.7%, P=.006) and nilotinib 400 mg bid (0.4%, P=.003) compared with imatinib (4.2%). The rate of progression on treatment was also significantly lower for nilotinib when including clonal evolution as a criteria for progression (Table). There were fewer CML-related deaths on nilotinib 300 mg bid (n=2), and 400 mg bid (n=1) vs imatinib (n=8). Estimated OS rate (including data from follow-up after discontinuation) at 18 months was higher for nilotinib 300 mg bid (98.5%, P=.28) and nilotinib 400 mg bid (99.3%, P=.03) vs imatinib (96.9%). Both drugs were well-tolerated. Discontinuations due to adverse events or laboratory abnormalities were lowest for nilotinib 300 mg bid (7%) compared with nilotinib 400 mg bid (12%) and imatinib (9%). With longer follow up there has been minimal change in the occurrence of AEs. Minimum 24-month follow-up data for all patients will be presented. Conclusions: With longer follow-up, nilotinib was associated with a significantly lower rate of progression to AP/BC on treatment and lower rates of suboptimal response or treatment failure vs imatinib. Nilotinib resulted in fewer CML-related deaths and a higher OS rate vs imatinib. Nilotinib induced superior rates of MMR, CMR, and CCyR vs imatinib in patients with newly diagnosed CML-CP. Taken together, these data support nilotinib as a new standard of care for patients with newly diagnosed CML. Disclosures: Hughes: Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Meyers Squibb: Honoraria, Research Funding; Ariad: Honoraria. Hochhaus:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Saglio:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Kim:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. le Coutre:Novartis: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau. Reiffers:Novartis: Research Funding. Pasquini:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Clark:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Honoraria, Research Funding. Gallagher:Novartis Pharma AG: Employment, Equity Ownership. Hoenekopp:Novartis Pharma AG: Employment. Haque:Novartis: Employment. Larson:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Kantarjian:Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding.

ENESTxtnd: Impact Of Nilotinib Dose Re-Escalation In Patients (pts) With Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4009-4009
Author(s):  
Jeff H. Lipton ◽  
Luis Meillon ◽  
Vernon Louw ◽  
Carolina Pavlovsky ◽  
Lee-Yung Shih ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Dose Intensity ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3 ◽  
Study Dose ◽  
Dose Reductions

Abstract Background Frontline nilotinib 300 mg twice daily (BID) provides superior efficacy vs imatinib in pts with CML-CP, with good tolerability. Evaluating Nilotinib Efficacy and Safety in Clinical Trials—Extending Molecular Reponses (ENESTxtnd) is evaluating the kinetics of molecular response to frontline nilotinib 300 mg BID in pts with newly diagnosed CML-CP, as assessed in national and local laboratories, and is also the first study to evaluate the safety and efficacy of nilotinib dose optimization (including dose re-escalation in pts who require dose reductions due to adverse events [AEs] and dose increase in pts with less than optimal response). Here, we present results of a preplanned, interim analysis (IA) based on the first 20% of pts who completed 12 mo of treatment or discontinued early. Methods ENESTxtnd (NCT01254188) is an open-label, multicenter, phase 3b clinical trial of nilotinib 300 mg BID in adults with CML-CP newly diagnosed within 6 mo of study entry. The primary endpoint is rate of MMR by 12 mo. Molecular responses were monitored by real-time quantitative polymerase chain reaction (RQ-PCR) at local laboratories at baseline, at 1, 2, and 3 mo, and every 3 mo thereafter. Bone marrow cytogenetic analyses were performed locally at baseline, 6 mo, and end of study. Dose reductions were allowed for grade ≥ 2 nonhematologic AEs and grade 3/4 hematologic AEs. Pts with dose reductions could attempt to re-escalate (successful re-escalation defined as ≥ 4 wk on nilotinib 300 mg BID with no dose adjustments for any AE) and remain on study. Dose increase to nilotinib 400 mg BID was allowed in cases of BCR-ABL > 10% on the International Scale (BCR-ABLIS) at 3 mo or later, no major molecular response (MMR; BCR-ABLIS ≤ 0.1%) at 12 mo, loss of MMR, or treatment failure. Results This IA includes 85 pts treated in 12 countries (Argentina, Australia, Brazil, Canada, Israel, Lebanon, Mexico, Malaysia, Saudi Arabia, Thailand, Taiwan, and South Africa). Median age was 49 y (range, 19-85 y), and 58% of pts were male. Median time since diagnosis was 35 days (range, 2-157 days). Prior to study entry, 64 pts (75%) received hydroxyurea, and 3 pts (4%) received imatinib (all for ≤ 2 wk). At the data cutoff, 68 pts (80%) had treatment ongoing, and the remaining 17 had discontinued due to AEs/laboratory abnormalities (n = 8; nonhematologic AEs [n = 5], biochemical abnormalities [n = 2], and hematologic abnormalities [n = 1]), loss to follow-up (n = 2), administrative problems (n = 2), intolerance to the protocol-proposed dose (n = 2), suboptimal response (n = 1), withdrawal of consent (n = 1), or protocol deviation (n = 1). Median time on treatment was 13.8 mo (range, 1 day-18 mo). Median actual dose intensity of nilotinib was 597 mg/day (range, 165-756 mg/day), and 85% of pts had an actual dose intensity of > 400 mg/day to ≤ 600 mg/day. Of 30 pts with dose reductions due to AEs, 19 (63%) successfully re-escalated to nilotinib 300 mg BID. Nine pts (11%) dose escalated to nilotinib 400 mg BID due to lack of efficacy. The primary endpoint of MMR by 12 mo was achieved by 57 pts (67%; 99.89% CI, 49%-82%). Complete cytogenetic response by 6 mo was achieved by 48 pts (56%). Median BCR-ABLIS decreased over time, with a median value of 0.05% (range, 0.00%-41.36%) at 12 mo (Figure). Most pts (91%) achieved early molecular response (BCR-ABLIS ≤ 10% at 3 mo). Of the 8 pts (9%) with BCR-ABLIS > 10% at 3 mo (4 of whom were then dose escalated), 3 achieved MMR by 12 mo (1 of whom had been dose escalated). By the data cutoff, no pt had progressed to accelerated phase/blast crisis (AP/BC), and there had been no deaths on study. Nilotinib was well tolerated, with a safety profile similar to that seen in other frontline studies. Drug-related nonhematologic AEs (≥ 10% of pts) were rash (31%), constipation (13%), and headache (13%). Newly occurring or worsening grade 3/4 hematologic or biochemical abnormalities (≥ 10% of pts) were neutropenia (17%), thrombocytopenia (17%), increased lipase (13%), and increased bilirubin (12%). Conclusions These results demonstrate that dose-optimized nilotinib affords high rates of molecular response in pts with newly diagnosed CML-CP. Further, they support the feasibility of nilotinib dose re-escalation in pts who require temporary dose reductions due to AEs, with 63% of dose-reduced pts able to successfully re-escalate to nilotinib 300 mg BID and safely continue therapy. Disclosures: Lipton: Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Equity Ownership, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Meillon:Bayer: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria. Louw:Novartis: Congress attendance support Other, Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Congress attendance support, Congress attendance support Other, Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Pavlovsky:Novartis: Research Funding, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Jin:Novartis: Employment. Acharya:Novartis Healthcare Pvt. Ltd.: Employment. Woodman:Novartis: Employment, Equity Ownership. Hughes:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria; CSL: Research Funding. Turkina:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria.

A Randomised 1 Year Study Evaluating the Impact of Vitamin C Supplementation on Systemic Iron Parameters of Iron Overload in Thalassemia Major Patients on Long-Term Treatment with Deferasirox

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1288-1288
Author(s):  
Yesim Aydinok ◽  
Metin Delebe ◽  
Gunes Basol ◽  
Selen Bayraktaroglu ◽  
Nihal Karadas ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Research Funding ◽  
Thalassemia Major ◽  
Average Dose ◽  
Advisory Committees ◽  
Baseline Characteristics ◽  
Labile Iron ◽  
The Impact

Abstract Background Ascorbic acid (AA) supplementation has traditionally been used in iron overloaded patients as means to increase iron chelation efficacy and replenish AA oxidized by labile iron found in those patients. The rationale leaned on AA's ability to render stored iron accessible to chelation, as found in urinary iron excretion following deferoxamine infusion. However, as AA increases labile iron redox-cycling and ensuing toxicity, we set to assess the long term benefits versus toxicity risks of the combined chelator-AA treatment. Objectives Perform a prospective, open-label, randomized and controlled 1 year study on thalassemia patients treated with deferasirox (DFX) in order to assess the effects of AA supplementation on: a. markers of systemic iron overload in selected organs and in plasma and b. markers of plasma labile iron (LPI) as potential contributors to oxidative stress toxicity. Patients and Methods Enrolment: 22 beta thalassemia major (TM) patients ≥10 years treated >2 years with DFX. Exclusion: cardiac dysfunction/arrhythmia or mT2* MRI <6 ms. Study: patients previously unexposed to AA received once-daily DFX (up to 40 mg/kg/d) with or without 125 mg AA for 1 year. All parameters were measured at baseline (BL); serum ferritin (SF) monthly, liver iron (LIC by MRI) and cardiac iron (mT2*MRI) after 1y. e-LPI (surrogate NTBI marker) and LPI (plasma redox-active labile iron marker) were assessed at BL, mo 1 & 6 by FeROS™ (Aferrix, Ltd) and fasting plasma AA at BL and EOS (fluorimetrically). Blood samples were withdrawn on the morning of transfusion day, 24 hours after last DFX (+/- AA) administration. Safety was followed using laboratory and clinical tests. AA levels were also determined in 23 healthy individuals (age and gender matched). Results 22 TM patients were enrolled (mean age 23.5, range 10-34 y). The average dose ± SD of DFX given to all 22 patients was 38±4.5 mg/kg/d. 11 patients were randomised to receive DFX and the others with DFX supplemented with 125 mg AA (mean 2.4±0.5, range 1.9-4.2 mg/kg) for 1 year. At BL, the AA levels were significantly lower in the TM group compared to controls (2.44 ± 3.38 vs 9.60± 4.36 mg/dl respectively, p<0.000001). 11 of 22 patients had AA levels >-2SD of control group whereas the other 11 patients showed normal ranges of AA. The AA deficient patients were those that showed significantly higher SF, LIC and lower mT2* at BL (Table 1). In the DFX+AA arm, 5/11 (45%) patients had subnormal AA levels at BL but attained normal status after 1 year, as did all others on AA. Of the 5/11 (45%) DFX-treated patients that did not receive AA had normal BL AA and only 2/11 maintained normal AA status at EOS. A significant correlation was obtained between BL SF, LIC and mT2* and e-LPI (r 0.49, p 0.025; r 0.57, p 0.01; r -0.43, p 0.057 respectively) but not with LPI. The changes associated with DFX alone or with AA from BL to EOS were subtle for all parameters measured (Table 2). Importantly, eLPI and LPI remained at basal levels throughout 6 months treatment in both arms. With DFX alone, LPI were 0.34±0.30 units (mM iron) (BL) & 0.63±0.58 (6 mo); eLPI: 1.71±1.93 at BL & 2.48±3.11 (6 mo). DFX+AA: LPI were 0.33±0.46 (BL) & 0.35±0.44 (6 mo); eLPI: 2.13±1.71 (BL) & 1.78±1.51 (6 mo). Conclusions TM patients on long term DFX without AA supplementation showed subnormal, AA levels. This was most pronounced in TM patients with higher liver and heart iron. The addition of AA to DFX normalized the AA levels but did not increase the e-LPI and LPI during 6 mo, indicating no apparent risk of iatrogenic toxicity by AA to DFX. Moreover, AA may enhance the efficacy of DFX in cardiac and hepatic iron. The small rise in SF versus fall in LIC in the DFX+AA arm might need further exploration. Table 1 Baseline characteristics of patients based on AA status Table 1. Baseline characteristics of patients based on AA status Table 2 Changes in iron overload markers in patients treated with DFX or DFX+AA over 1 year Table 2. Changes in iron overload markers in patients treated with DFX or DFX+AA over 1 year Disclosures Aydinok: Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cerus: Research Funding; Shire: Research Funding. Cabantchik:Aferrix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Hinoman: Consultancy; Novartis Pharmeceuticals: Honoraria, Speakers Bureau; Apopharma: Honoraria, Speakers Bureau.

scholarly journals Impact of Early Progression on Long Term Outcomes Among Myeloma Patients Receiving Lenalidomide, Bortezomib, and Dexamethasone (RVD) Induction Therapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3302-3302
Author(s):  
Ajay K Nooka ◽  
Jonathan L Kaufman ◽  
Charise Gleason ◽  
Nisha Joseph ◽  
Craig C Hofmeister ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Long Term Outcomes ◽  
Advisory Committees ◽  
Term Survival ◽  
Risk Status ◽  
Early Progression

Abstract Background: The incorporation of modern day induction regimens, autotransplant and continuous maintenance has resulted in better long-term outcomes for myeloma patients. Experience and trials demonstrated that by prolonging 1st progression-free survival (PFS1) and pushing the relapse farther, we can gain the OS advantage (McCarthy et al NEJM 2012). Unfortunately, a subgroup of patients fail to exploit this advantage, either due to their disease biology or due to inadequate therapy and suffer early progression (inferior PFS1) that impacts their long term outcomes. First, we evaluated the predictors of early progression to highlight the modifiable factors that can prevent progression. Next, we quantified the impact of shorter PFS1 (<36 months) on the long-term survival (OS). Methods: Of the 1000 consecutive newly diagnosed myeloma patients treated with homogenous induction therapy (RVD) induction therapy per Richardson et al (Blood 2010) from July 2005 until August 2016, 230 patients progressed within the first 36 months while 96 patients progressed beyond the 36-month mark, at the time of analysis. Median follow up duration was 38 months. Demographic and outcomes data for the pts were collected from myeloma database and responses were evaluated per IMWG Uniform Response Criteria. Results: Median age of the pts is 60 years (range 29-78). 29% of the patients are above the age of 66. M/F 54%/46%; W/AA 60%/32%; ISS III 27% were other patient characteristics. Cytogenetic abnormalities of significance: t(11;14): 13.5%, t(4;14): 7.8%, t(14;16): 5% del 17p: 16%, complex cytogenetics: 29% and high-risk status was conferred to 44% of the patients. 83% of patients underwent an autotransplant and median time to transplant was 6 (2-50) months. 68% of patients received maintenance therapy. Response rates are summarized in Fig 1. The median PFS for early and non-early progressors were 32 months (95% confidence interval (CI), 30.293-33.707) and 101 months (95% CI, 77.14-124.86) months, respectively (P<0.001). The median overall survival (OS) for early progressors was 94 months, and non-early progressors was not reached. (Fig 2). Among the predictors of early relapse, presence of high-risk status, ISS stage 3, inability to achieve ≥VGPR after transplant, non-receipt of transplant and/or maintenance were independent predictors of early progression on the multivariate analysis as illustrated in Table 1. Conclusions: Even with the effective use of the 3-drug induction regimen, these functionally high-risk patients that are early progressors have truncated long term survival. Our analysis advocates for using transplant, deepening the responses with modern drugs such as monoclonal antibodies to achieve ≥VGPR after transplant and intense maintenance strategies to prevent relapse. Disclosures Nooka: Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: 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; GSK: 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; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kaufman:Abbvie: Consultancy; Karyopharm: Other: data monitoring committee; Roche: Consultancy; Janssen: Consultancy; BMS: Consultancy. Hofmeister:Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Boise:AstraZeneca: Honoraria; Abbvie: Consultancy. Heffner:ADC Therapeutics: Research Funding; Kite Pharma: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding. Lonial:Amgen: Research Funding.

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