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Pazopanib is approved in Latin America as first targeted therapy for patients with metastatic renal cell carcinoma (mRCC). A retrospective chart review of adult patients with mRCC who initiated pazopanib as first targeted therapy between January 2011 and March 2016 was conducted among oncology care centers in Argentina, Brazil, Chile, Colombia, and Mexico. Patient characteristics, treatment patterns, overall survival (OS), progression-free survival (PFS), and adverse events were summarized. A total of 156 charts of patients with mRCC receiving first-line pazopanib were reviewed (29, 54, 27, 28, and 18 patients from Argentina, Brazil, Chile, Colombia, and Mexico, respectively). The mean age at initial mRCC diagnosis was 61.6 years, 73.7% were male, and 51.3% were Hispanic. The median dose of pazopanib was 800 mg and the median time from initial mRCC diagnosis to pazopanib start was 2.2 months. The median time on treatment was 10.0 months. At the time of data extraction, 16.7% of patients remained on pazopanib, with clinical progression listed as the main reason for discontinuation. Subsequent therapy was received by 25.6% of patients; the most common were everolimus (9.6%) and axitinib (5.8%). Overall, median PFS and OS were 10.8 and 16.9 months, respectively, and varied across countries. The most common all-grade adverse events were diarrhea (44.9%), asthenia/fatigue (43.6%), and nausea (28.8%). Pazopanib was used for first-line mRCC treatment in a clinically diverse patient population across Latin America. Real-world PFS and tolerability were similar to clinical studies of pazopanib. Novartis Pharmaceuticals Corporation, Inc.

4574Background: PRINCIPAL (NCT01649778) was the largest prospective real-world effectiveness and safety study of pazopanib (PAZ) in patients (pts) with renal cell carcinoma (RCC). Methods: Pts with...

4561Background: Although pazopanib (PAZ) has been evaluated in clinical trials of patients (pts) with renal cell carcinoma (RCC), limited real-world data on the effectiveness and safety of PAZ exis...

648 Background: EVE following failure of sorafenib or sunitinib for RCC was first approved by the FDA in 2009. CATChEz (NCT01545817) was designed to test the activity of EVE following first-line PAZ in pts with advanced or metastatic RCC who had not received prior systemic therapy. Methods: From 2012 to 2016, pts received first-line PAZ followed by EVE until progressive disease (PD), death, unacceptable toxicity, consent withdrawal, or study termination. Pts with PD during or within 6 months of stopping PAZ were eligible for EVE. Pts off study treatment were evaluated for PD, survival, and updates on anticancer treatment every 8 weeks until death or end of study. The primary efficacy endpoint was median progression-free survival (mPFS) for the second-line EVE treatment period; secondary endpoints included other survival measures, and safety evaluations were for second-line EVE and grade 3/4 toxicities attributable to PAZ and EVE. Results: Of 74 pts who started first-line PAZ, 38 received ≥1 dose of second-line EVE. The primary endpoint of mPFS from the start of second-line EVE and the secondary endpoint of mPFS with first-line PAZ (Table) were consistent with previous reports; no unexpected adverse events (AEs) were reported. All pts had ≥1 treatment-emergent AE, 83.8% had grade ≥3 AEs, and 71.6% had serious AEs. Of 34 total deaths, 29 were due to PD and 5 were due to AEs (2 related to EVE [lower respiratory tract infection; pulmonary sepsis]; 3 unrelated to study treatment). Conclusions: Efficacy and safety outcomes were consistent with published phase III data. The CATChEz study supports sequential first-line use of PAZ followed by EVE for the treatment of pts with advanced or metastatic RCC. Clinical trial information: NCT01545817. [Table: see text]

4574 Background: COMPARZ was a randomized, controlled, open-label, phase 3 trial that demonstrated comparable efficacy of first-line PAZ and SUN, but favorable safety and quality of life profiles for PAZ in patients (pts) with mRCC (NEJM 2013;369:722). We evaluated the relationship between dosing, safety, and efficacy in PAZ- and SUN-treated pts who did or did not undergo dose reduction or interruption resulting from adverse events (AEs) and other reasons. Methods: The AEs and median progression-free survival (mPFS) of PAZ and SUN were evaluated for pts with no, any, 1, and ≥2 dose reductions or dose interruptions lasting ≥7 days. Results: Similar percentages of pts in the PAZ and SUN groups had a dose interruption (44% vs 49%, respectively) or reduction (44% and 51%, respectively). The incidence of AEs in pts from the PAZ and SUN groups with dose modifications was higher compared to those with no dose modifications. Longer mPFS was observed in pts with dose modification (Table). Pts treated with PAZ or SUN with no dose reductions had mPFS of 7.3 months (mos) and 5.5 mos, respectively, whereas pts with any dose reduction had mPFS of 12.5 mos and 13.8 mos, respectively. Similarly, pts treated with PAZ or SUN with no dose interruptions lasting ≥7 days had mPFS of 8.2 mos and 5.6 mos, respectively, whereas those with any dose interruption lasting ≥7 days had mPFS of 12.6 mos and 13.8 mos, respectively. Pts with 2 or more dose interruptions or reductions had mPFS > 16 mos with both SUN and PAZ. Conclusions: Consistent with previous data for SUN, the current analyses showed longer mPFS with PAZ and SUN when dose modification is required to manage toxicity, suggesting that pts are not disadvantaged by such dose reductions or interruptions. Pts not requiring dose modification may have sub-optimal therapeutic drug exposure. Clinical trial information: NCT00720941. [Table: see text]

4572 Background: COMPARZ (NCT00720941) was a phase 3, randomized, controlled, open-label trial that demonstrated comparable efficacy of first-line PAZ and SUN, but favorable safety and quality of life profiles for PAZ in 1110 patients with mRCC (NEJM 2013;369:722). The objectives of this study were to identify patients from COMPARZ who exhibited a long-term response (LTR) to PAZ and SUN, determine time to response, and describe the clinical characteristics of patients who achieved LTR. Methods: Patients in the intention-to-treat population of COMPARZ were analyzed for differences in LTR (≥10 months [mos]) as measured by responder rate with either complete response or partial response (CR/PR) and PFS rate, and time to response. We also compared the clinical characteristics between long-term and shorter-term responders within and between each treatment arm. Results: The overall percentage of long-term responders with CR/PR (PAZ = 14%, SUN = 13%) and PFS (PAZ = 31.4%, SUN = 33.6%) in the PAZ and SUN groups were similar. This similarity was observed regardless of the cut-off for long-term duration of response. However, a shorter time to achieve CR/PR was observed in the overall population with PAZ (11.9 weeks [95% CI, 11.3–12.1] vs 17.4 weeks; [95% CI, 12.7–18.0]). Analysis conducted to identify baseline clinical characteristics that may be related to LTR will be reported. Conclusions: These exploratory subanalyses in long-term responders support the overall efficacy results with PAZ and SUN, which were reported in the COMPARZ trial. However, the results here demonstrate that the time to response was shorter with PAZ versus SUN. Clinical trial information: NCT00720941.

Background: The cytogenetic hallmark of chronic myeloid leukemia (CML) is a translocation, t(9;22)(q34;q11), resulting in the Philadelphia (Ph) or derivative 22 chromosome. Cytogenetic studies indicate that 90-95% of cases have the Ph chromosome or recognized variant (Ph+ CML), with the remaining 5-10% having a normal or near normal karyotype despite the presence of the BCR-ABL fusion (Ph-negative, BCR-ABL-positive CML). Tyrosine kinase inhibitors (TKIs) have been approved for the treatment of patients with Ph+ CML. The effect of TKIs in patients with Ph- CML has not been described in detail. Objective: ENEST1st (Evaluating Nilotinib Efficacy and Safety in clinical Trials as First-Line Treatment) sub-group analysis was planned to explore the effect of nilotinib in patients with Ph- CML. Patients and Methods: ENEST1st (NCT01061177) is a phase 3b, multicenter, open-label study of nilotinib 300 mg twice daily (BID) in adults with newly diagnosed BCR-ABL+ CML-CP. Patients with confirmed Ph- CML-CP were included in the sub-analysis. Primary endpoint was rate of MR4 (defined as BCR-ABL ≤ 0.01% on the International Scale [BCR-ABLIS] or undetectable BCR-ABL in cDNA with ≥ 10,000 ABL transcripts) at 18 mo. Results: Of the 1089 patients included in ENEST1st study, 30 patients (2.7%) were Ph- (only one of those had a cytogenetic aberration [del9q34]), 983 patients (90.3%) were Ph+ and 76 (7.0%) patients had an unknown karyotype at baseline. Among these patients, 28 pts (2.7%) Ph- and 952 pts (90.5%) Ph + with b2a2 and/or b3a2 BCR-ABL transcripts and treated with imatinib for ≤ 3 mo were analyzed for molecular response (MR). Median age of patients with Ph- CML was 51.5 years (range, 21.0 to 75.0). EUTOS score was low in 86.7% and high in 6.7% of patients (6.7% missing). Sokal risk score was low, intermediate, and high in 33.3%, 30.0%, and 23.3% of patients, respectively (13.3% missing). In Ph+ CML patients, the median age was 53.0 years (range, 18.0 to 91.0). EUTOS score was low in 82.0% and high in 9.2% of pts (8.9% missing). Sokal risk score was low, intermediate, and high in 34.8%, 37.2%, and 18.1% of pts, respectively (9.9% missing). The MR4 rate at 18 mo in Ph- population was 39.3% (95% CI, 21.2% - 57.4%). The cumulative incidence of MR4 by18 mo was60.7% (95% CI, 42.6% - 78.8%). Rates of cumulative MMR (BCR-ABLIS ≤0.1%) and MR4.5 (BCR-ABLIS ≤0.0032%) by 18 mo were 85.7% (95% CI, 72.8% - 98.7%) and 46.4% (95% CI, 28.0% - 64.9%), respectively. For the Ph+ CML population, the MR4 rate at 18 mo was 38.1% (95% CI, 35.0% - 41.2%). The cumulative incidence of MR4 by 18 mo was48.1% (95% CI, 44.9% - 51.3%). Rates of cumulative MMR (BCR-ABLIS ≤0.1%) and MR4.5 (BCR-ABLIS ≤0.0032%) by 18 mo were 76.8% (95% CI, 74.1% - 79.5%) and 31.4% (95% CI, 28.5% - 34.4%), respectively. Rates of MMR, MR4, and MR4.5 at 18 and 24 mo among Ph- population and the Ph+ CML population are summarized in the Table. The 3-month BCR-ABL level has been shown to be predictive of MR in the Ph+ CML population. Among Ph- population not pretreated with imatinib (n = 14), 85.7% achieved BCR-ABLIS ≤ 1%, no patients had BCR-ABLIS > 1% to ≤ 10% and > 10% at 3 mo. Two patients did not have the assessment at 3 mo. Among patients with Ph+ CML not pretreated with imatinib (n = 802), 70.0% , 17.0%, and 2.7% of patients achieved BCR-ABLIS ≤ 1% , > 1% to ≤ 10%, and >10% respectively. Eighty-five patients did not have the assessment at 3 mo. Most common AEs experienced by the Ph- population were hypophosphatemia (25%), rash (18%), pruritus (14%), nasopharyngitis (14%), alanine aminotransferase increase (14%), and blood bilirubin increase (14%). In the Ph+ population, the list of most common AEs includes rash (22%), pruritus (17%), headache (16%), and fatigue (14%). Conclusions: The MR rates observed in Ph- CML subgroup are similar to the rates observed in Ph+ CML patients. These results indicate that nilotinib is active in this previously unexplored population as well and larger studies should be conducted to confirm the results. The safety results observed in Ph-CML patients are similar to the ones observed in the Ph+ CML pts. aCML patients with typical b2a2 and/or b3a2 BCR-ABL transcripts and ≤3 mo of prior imatinib Figure 1. Figure 1. Disclosures Hochhaus: ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Mahon:Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Coriu:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ossenkoppele:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Cross:Ariad: Consultancy, Honoraria, Research Funding; Qiagen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Müller:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding. Rea:Pfizer: Honoraria; Ariad: Honoraria; BMS: Honoraria; Novartis: Honoraria. Steegmann:Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria, Research Funding. Castagnetti:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria. Hellmann:Novartis: Research Funding; BMS: Research Funding. Rosti:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau. Gattermann:Novartis: Honoraria, Research Funding. Gutierrez: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; PFIZER: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tubazio:Novartis: Employment. Pellegrino:Novartis: Employment. Dezzani:Novartis: Employment. Giles:Novartis: Consultancy, Honoraria, Research Funding.

[Graphic][1] Background : The incidence of CML increases with age and also the disease characteristics vary with age. However, whether age has any impact on molecular response (MR) with TKIs or not has not been clearly established. Objective: To assess the effect of age on MR and adverse events (AEs) with nilotinib (NIL) in patients (pts) with CML in the ENEST1st ([NCT01061177][2]) phase 3b trial. Patients and Methods: ENEST1st is an open-label study of NIL 300 mg BID in adults with newly diagnosed CML-CP. Treated pts with typical transcripts and ≤ 3 months of prior imatinib (IM) therapy were included in the sub-analysis and were stratified according to age (> 65 years and ≤ 65 years). Primary endpoint was rate of MR4 (defined as BCR-ABL ≤ 0.01% on the International Scale [BCR-ABLIS ] or undetectable BCR-ABL in cDNA with ≥ 10,000 ABL transcripts) at 18 months. Results: Of the 1089 pts (median age, 53 years; range, 18 - 91 years) enrolled into the study, 1052 had b2a2 and/or b3a2 BCR-ABL transcripts and were treated with IM for ≤ 3 months. Sokal risk scores were low, intermediate, and high in 34.9%, 37.5%, and 18.1% of pts, respectively (9.5% missing). The rate of MR4 at 18 months in all treated pts with typical transcripts and ≤ 3 months of prior IM (n = 1052) was 38.4% (95% CI, 35.5% - 41.3%). The cumulative rates of MR at 24 months are shown in the figure. At 12 months the rates of MR4 and MR4.5 were 30.8% and 15.3% respectively. Among pts who were in MR4 and MR4.5 at 12 months, 60.8% and 33.9% pts were able to maintain continuous MR4 and MR4.5 until Month 24, with no documented loss of MR4 and MR4.5 between 12 and 24 months, respectively. Among all pts treated (n=1089), six pts (0.6%) progressed to accelerated phase/blast crisis (AP/BC) on study; 13 pts (1.2%) died by 24 months, including one due to CML progression (16 month after study drug discontinuation). The most common AEs of any cause were rash (21.4%), pruritus (16.5%), and headache (15.2%). Subgroup-analysis by age: As per the WHO guidelines, pts > 65 years are defined as older. Accordingly, for this sub-analysis, pts with typical transcripts and treated with IM for ≤ 3 months (n = 1052) were stratified into two subgroups: 851 pts (80.9%) were ≤ 65 years of age and 201 pts (19.1%) were > 65 years old at the time of enrollment. The median age at enrollment was 71 (range 66 - 91) and 48 (range 18 - 65) years in the old and young group, respectively. Among old pts, Sokal risk scores were low, intermediate, and high in 4.5%, 61.2%, and 23.4% of pts, respectively (10.9% missing). Among young pts, Sokal risk scores were low, intermediate, and high in 42.1%, 32.0%, and 16.9% of pts, respectively (9.0% missing). Cumulative incidence of MR4 by 18 months was 48.8% (95% CI, 45.4% - 52.1%) among younger pts and 48.3% (95% CI, 41.4% - 55.2%) in older pts. Rate of MR4 by 18 months among younger pts with low, intermediate, and high Sokal score was 53.6%, 45.2%, and 35.4%, respectively. Rate of MR4 by 18 months among older pts with low, intermediate, and high Sokal score was 44.4%, 49.6%, and 44.7%, respectively. The incidence rate of MR4.5 by 18 months in younger pts and older pts was 32.5% and 28.4%, respectively. Most common AEs experienced by younger patients were rash (23%), headache (17%), pruritus (16%), and fatigue (14%). In older population, the list of most common AEs includes pruritus (19%), nausea (18%), and rash (14%) (Table). Conclusions : In this study, frontline NIL yielded equivalent rates of molecular responses in older and younger pts with a similar safety profile. | Adverse Event | Patients ≤65 years (n = 851) % | Patients >65 years (n = 201) % | | ---------------- | ------------------------------------- | ------------------------------------- | | Rash | 23.2 | 13.8 | | Headache | 17.1 | 7.6 | | Pruritus | 16.0 | 18.6 | | Fatigue | 14.0 | 13.3 | | Thrombocytopenia | 11.0 | 7.6 | | Nasopharyngitis | 10.8 | 8.6 | | Alopecia | 10.8 | 9.5 | | Nausea | 9.8 | 17.6 | | Diarrhea | 8.0 | 11.4 | | Asthenia | 8.4 | 11.0 | | Anemia | 5.1 | 10.5 | | Abdominal pain | 6.9 | 10.5 | | Dry skin | 8.2 | 10.0 | Table. ![Figure 1.][3] Figure 1. Disclosures Giles: Novartis: Consultancy, Honoraria, Research Funding. Rea: Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Baccarani: NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cross: Ariad: Consultancy, Honoraria, Research Funding; Qiagen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Steegmann: Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Griskevicius: Novartis: Honoraria, Research Funding. Coriu: PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ossenkoppele: Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Mahon: Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Muller: Ariad: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Hellmann: BMS: Research Funding; Novartis: Research Funding. Porkka: Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Brummendorf: Novartis: Consultancy, Patents & Royalties, Research Funding. Gastl: AOP Orphan: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Tubazio: Novartis: Employment. Pellegrino: Novartis: Employment. Dezzani: Novartis: Employment. Rosti: Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Hochhaus: Novartis: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. [1]: /embed/inline-graphic-2.gif [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01061177&atom=%2Fbloodjournal%2F126%2F23%2F479.atom [3]: pending:yes

TPO, the primary regulator of megakaryopoiesis, is produced at a constant rate and is removed from the circulation by adsorption to specific receptors on platelet and megakaryocyte surfaces. An inverse relationship between platelet count and TPO therefore exists in healthy subjects. However, a few studies in patients with reactive thrombocytosis identified levels of the hormone higher than expected, and suggested that TPO behaves as an acute-phase protein and was responsible for increased platelet count. At the opposite, other studies did not find any significant rise of the hormone in patients who similarly developed reactive thrombocytosis. To gain further information on this topic, we compared TPO levels and platelet counts in two series of hospitalized patients: one (53 patients aged 73 ± 17 years) with strong elevation of both erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and the other (28 age-matched control patients) with normal values. All subjects had been admitted to hospital for acute illnesses: infections, cancer, heart failure or ischemia, stroke, deep vein thrombosis or pancreatitis. Within the group of subjects with high ESR and CRP, 38 had normal platelet counts, while 15 had thrombocytosis at the admittance (n=9) or developed it during their stay (n=6). No thrombocytosis was observed in control patients. Patients with high acute phase indexes had significantly higher TPO levels (R&D Systems, Minneapolis, USA) and platelet counts than control patients (TPO 189.55pg/ml ± 139 vs 62.04pg/ml ± 83, p