ALBERT

Description: Abstract 2771 Background: NIL is a potent, highly selective Bcr-Abl kinase inhibitor approved for newly diagnosed adult pts with Philadelphia-chromosome positive (Ph+) CML-CP and in Ph+ CML-CP and accelerated-phase pts who are resistant or intolerant to IM. Achieving complete cytogenetic response (CCyR) and major molecular response (MMR, 3-log reduction of Bcr-Abl transcript level from the baseline mean) are favorable prognostic factors for CML. This multicenter, open-label study (ENABL) was designed to explore nilotinib Bcr-Abl effects in pts with CCyR but who have suboptimal molecular response to IM. Methods: This study evaluates change in Bcr-Abl trends in 2 groups of CML-CP pts (total n = 18) who achieved CCyR but have suboptimal molecular response to IM defined as: (Group 1) treated ≥ 1 year with IM, but Bcr-Abl transcript levels did not reach ≤ 0.1% on the international scale (IS) (MMR); or (Group 2) 〉 1-log increase in Bcr-Abl transcript levels from best response regardless of IM treatment duration. Pts are treated with NIL 300 mg twice daily for ≥ 1 year. RQ-PCR analysis is performed by a central lab at screening, then every 3 months (mos) for Group 1. Group 2 pts are monitored by RQ-PCR monthly for the first 3 mos, then every 3 mos. The 1° end point is change in Bcr-Abl transcript levels from a standardized baseline value by RQ-PCR at 12 mos. The data cutoff date for this analysis was June 30, 2011. Results: Eighteen pts (Group 1, n = 17; Group 2, n = 1) have been treated with NIL for a median of 17 mos on study (range 3–34 mos). Thirteen pts have been treated for ≥ 6 mos and 10 for ≥ 12 mos. One pt was deemed ineligible due to lack of evidence of CCyR at baseline but is included in the analysis because there was at least 1 post-baseline evaluation performed. The remaining 17 pts had CCyR at baseline. Before enrollment, pts were treated with at least 400 mg once-daily IM; the mean dose of prior IM treatment was 487 mg/day (range 342–786 mg/day). Median duration of prior IM treatment was 3.4 yrs (range 1.3–10.2 yrs). Three pts had prior interferon treatment. All 18 pts were treated for ≥ 3 mos and had ≥ 1 post-baseline RQ-PCR result. Overall, 15 of 18 evaluable pts (83%) achieved MMR during treatment; 10 pts by 3 mos, 1 pt by 4.5 mos (measured at end of study), 1 pt by 6 mos, 2 pts by 9 mos, and 1 pt by 30 mos (Figure 1). The 3 pts who did not reach MMR at any point were only followed for up to 3 mos before discontinuing from the trial but showed a decreasing Bcr-Abl trend. Overall, pts achieved a median log reduction of PCR transcript levels of 3.1 (0.08% IS) at 3 mos; median 3.3-log reduction (0.05% IS) at 6 mos, and median 3.5-log reduction (0.035% IS) at 9 mos. Four pts had 〉 4-log (≤ 0.01% IS) reduction in Bcr-Abl; of these, 2 pts reached 〉 4.5-log (≤ 0.0032% IS) reduction in Bcr-Abl at least once during the study. Median Bcr-Abl transcript log reduction at 12 mos was 3.6 (0.025% IS, 1° end point) for 10 evaluable pts. All these pts reached MMR during NIL treatment; 9 pts by 12 mos, 1 pt after 30 mos. NIL was well tolerated and brief dose interruptions were sufficient to manage most adverse events (AEs). Seven of 18 pts were dose reduced for NIL-related AEs and re-escalated if the patient recovered from the AEs. Patients were permitted to dose escalate to 400 mg b.i.d. per physician's discretion if MMR was not achieved after 6 mos (n = 1). The Grade 3 AEs reported include 2 cases of rash and 1 case each of pneumonia, squamous cell carcinoma, bladder prolapse, uterine prolapse, bradycardia, hypertension, hyperbilirubinemia and hypophosphatemia. The rashes and bradycardia were suspected to be related to NIL. No Grade 4 AEs were reported. The median dose intensity was 600 mg/day (range 300–683 mg/day). Five pts were discontinued from the study (3 due to abnormal laboratory values, 1 due to an AE, and 1 due to protocol violation). No pts who experienced QTcF changes had differences 〉 33 msec from baseline. No QTcF prolongation 〉 500 msec was observed. Conclusions: NIL treatment results in high molecular response rates in CML-CP pts with suboptimal molecular responses to IM. Overall 83% of pts who switched to NIL achieved MMR, and the median Bcr-Abl log reduction for pts who reached 12 mos on study was 3.6 (0.025% IS). The IRIS study has shown that MMR rates increase with time in pts treated with IM (Hughes Blood 2010); however, this study appears to demonstrate that MMR is achieved relatively quickly in suboptimal molecular IM-treated pts when switched to NIL. Disclosures: Ailawadhi: Novartis Pharmaceuticals: Consultancy, Speakers Bureau. Miller:Incyte: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Akard:Eisai: Speakers Bureau; Bristol Myers-Squibb: Speakers Bureau; Novartis: Speakers Bureau; Millenium: Speakers Bureau; Chemgenex: Consultancy. Ericson:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Lin:Novartis: Employment, Equity Ownership. Radich:Novartis: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau. DeAngelo:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy.

Description: Introduction: Autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy achieves rapid and durable responses in patients with r/r DLBCL, although unique potential toxicities require specialized management. Cytokine release syndrome (CRS) is the most commonly observed adverse event of special interest associated with CAR T-cell therapy. Two CRS grading scales have been used in different clinical trials of CAR T-cell therapy: the Penn scale (Porter, Sci Transl Med, 2015; Porter, J Hematol & Oncol, 2018) and the Lee scale (Lee, Blood, 2014; Neelapu, Nat Rev Clin Oncol, 2017). To better inform management of CRS and develop best practices, we assessed concordance and differences between the two scales by using the Lee scale to regrade observed CRS events in r/r DLBCL patients treated with tisagenlecleucel, who were previously graded per protocol using the Penn scale. Methods: Individual patient level data from the JULIET trial, a single-arm, open-label, multicenter, global phase 2 trial of tisagenlecleucel in adult patients with r/r DLBCL (NCT02445248), were used in this study. Four medical experts who had managed DLBCL patients using different CAR T-cell therapy protocols and products independently reviewed the data, while blinded to the original Penn grading, and re-graded CRS for JULIET patients using the Lee scale. Re-grading assessments and disagreements in the assigned Lee grade were discussed and reconciled among reviewers during a live meeting. As per the investigational charter, the most conservative final assessment of any expert reviewer determined the final grading for any individual case. For example, if an event was graded as 2, 3, 3 and 4, then grade 4 would be the final grading. Results: As of December. 8, 2017, 111 patients with r/r DLBCL were infused with tisagenlecleucel in the JULIET trial. Sixty-four (58%) patients had CRS graded according to the Penn scale and each case was re-graded using the Lee scale based on JULIET data collected prospectively (e.g., CRS-related symptoms, oxygen supplementation, intervention for hypotension, and organ toxicities). Using the Lee scale, 63 (57%) patients were considered to have any grade CRS by investigators, including grade 1 events in 26 (23%), grade 2 in 18 (16%), grade 3 in 10 (9%), and grade 4 in 9 (8%) (Figure 1). One patient with grade 1 per Penn scale was re-graded to grade 0 due to absence of documented fever or symptoms requiring intervention. Compared to Penn grades, the Lee scale provided the same grade for 39 patients, a lower grade for 20 patients, and a higher grade for 5 patients. Among 64 patients re-graded, 59 (92%) had fever, 27 (42%) had oxygen supplementation (3 with grade 1, 6 grade 2, 9 grade 3, and 9 grade 4 per Lee scale) and 7 (11%) had concurrent infections. Of 29 (45%) patients requiring intervention for hypotension (13 with grade 2, 7 grade 3, and 9 grade 4 per Lee scale), 28 had fluid resuscitation and 10 received high dose/combination vasopressors. In addition, 8 of 9 patients re-graded as Lee grade 4 were intubated. As for anti-cytokine therapy, only 17 patients received tocilizumab (1 for grade 1, 2 for grade 2, 5 for grade 3, and 9 for grade 4 CRS per Lee scale) and 12 patients received corticosteroids (2 for grade 2, 1 for grade 3, and 9 for grade 4 CRS per Lee scale). Conclusions: Different CAR-T studies in DLBCL patients have used different approaches (Lee and Penn scales) for grading CRS and had different thresholds for tocilizumab treatment of CRS. Harmonization of grading CRS between studies permits a more accurate comparison of observations and outcomes. In this analysis, patients with r/r DLBCL receiving tisagenlecleucel in the JULIET trial, which used the Penn scale to grade CRS, were re-graded by expert consensus using the Lee scale. Using the Lee scale, more patients were categorized as grade 1 (Lee vs. Penn: 26 vs. 17), fewer patients as grades 2 and 3 (18 vs. 23, and 10 vs. 15, respectively), and the same number of patients as grade 4 (9 vs. 9) compared to the Penn scale. The re-grading of the JULIET CRS data using the Lee scale makes it possible to perform comparative analyses of CRS outcomes from clinical trials using different CAR-T products and could be used to develop best practice guidelines. Disclosures Schuster: Pfizer: Membership on an entity's Board of Directors or advisory committees; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; OncLive: Honoraria; Genentech: Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Physician's Education Source, LLC: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Maziarz:Athersys, Inc.: Patents & Royalties; Kite Therapeutics: Honoraria; Juno Therapeutics: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ericson:Novartis Pharmaceuticals Corporation: Employment. Rusch:Novartis Pharmaceuticals Corporation: Employment. Romanov:Novartis Pharmaceuticals Corporation: Employment. Locke:Cellular BioMedicine Group Inc.: Consultancy; Novartis Pharmaceuticals: Other: Scientific Advisor; Kite Pharma: Other: Scientific Advisor. Maloney:Janssen Scientific Affairs: Honoraria; Roche/Genentech: Honoraria; Seattle Genetics: Honoraria; GlaxoSmithKline: Research Funding; Juno Therapeutics: Research Funding.

Description: CTLO19 cells are CAR-modified T cells which recognize CD19 and produce high durable remission rates for pts with relapsed or refractory acute lymphoblastic leukemia (ALL). Cytokine Release Syndrome (CRS) has emerged as the major treatment related effect from CTL019, with symptoms that include high fevers and malaise but can progress to capillary leak, hypoxia and hypotension. CRS occurs hours to days after CTL019 infusion and correlates with rapid in vivo CTL019 expansion and marked elevation of serum IL6. In most cases, CRS is self-limited or rapidly reversed with anti-cytokine directed therapies. Here we report 3 cases of refractory CRS in adult pts with ALL. Our experience offers insight into clinical and investigational parameters describing this syndrome; highlights the variance of CRS across disease types and illustrates complexities of CRS management during concurrent infectious illness. As of 7/1/14, 97 pts (30 pediatric ALL, 12 adult ALL, 41 CLL, 14 NHL) have been treated with CTLO19. To capture clinical manifestations of CRS across protocols, we developed a novel CRS grading scale which will be described. Severe CRS (Gr 3-5) occurred in 27 (64%) of ALL pts and only 16 (29%) of CLL/NHL pts (p=0.001). 12 adults with ALL received CTL019; 8/9 evaluable pts achieved CR (MRD negative) at 1 month and 1 pt with extramedullary disease had marked reduction of PET avid disease which is maintained at 1 yr. Severe CRS occurred in 11 of 12 adult ALL pts. CRS was self-limited in 2 pts, rapidly reversed with anti-IL6 directed therapy in 6 pts and was refractory to therapy, contributing to death in 3 pts who were not evaluable for disease response. No baseline attributes differentiate these 3 pts from the 9 adult ALL pts with manageable Gr1-4 CRS. We have shown however that ALL disease burden correlates with CRS severity (in press) and all 3 pts had significant disease burden at baseline. All received lymphodepleting chemotherapy with cyclophosphamide 300 mg/m2 q12h x 6 followed by infusion of CTLO19 cells. These 3 pts each received 6.50E+06, 6.70E+06 and 8.45E+06 CTLO19 cells/kg compared to median CTL019 dose of 3.62E+06 in the 9 adult ALL pts with manageable CRS. Pt 21413-03 developed CRS 12 hrs after infusion and tested positive for influenza B on D3. Despite broad spectrum antimicrobials (including oseltamivir) and anticytokine directed therapy with tocilizumab (4mg/kg x 2) and steroids, he died with refractory hypotension on D5. Pt 21413-06 had extensive disease after 2 prior allogeneic SCTs and developed CRS within 12 hrs of infusion. In addition to broad spectrum antibiotics, she received tocilizumab 8mg/kg (D 3, 6 and 12); intermittent high dose steroids (D 4-15) and etanercept (D14). She died D15 with hypotension, hypoxic respiratory failure and concurrent MDR pseudomonas sepsis and pneumonia. Pt 21413-11 developed CRS within 24 hrs of infusion. He received tocilizumab 8mg/kg (D3&4); siltuximab (D5&15) and intermittent high dose steroids (D 4-15). After an initial response, he developed recurrent fever, pulmonary infiltrates and blood cultures positive for stenotrophomonas. He died D15 with refractory hypoxia and hypotension. All 3 pts’ clinical CRS correlated with marked in vivo CTL019 expansion and progressive serum cytokine elevations (data to be shown). CONCLUSIONS: CRS is the major toxicity of CTL019 therapy and its clinical course varies depending on disease type (more frequent and severe in ALL) and disease burden (in ALL). The 3 refractory CRS cases described here (of 97 total pts treated) have all occurred in adult ALL pts with significant disease burden who received relatively high doses of CTL019 cells. In addition, all 3 had significant infectious complications which potentially fueled underlying CRS and/or were made more virulent due to impairment of immunity with administration of anti-cytokine directed therapies. Future protocol modifications will be made goal of limiting severity of CRS while maintaining high durable remission rates. Further exploration is planned to better correlate timing and choice of anticytokine directed therapy in relation to clinical and investigation parameters of CRS. Disclosures Frey: Novartis: Research Funding. Off Label Use: USe of CART19 cells to treat CLL. Levine:Novartis: Patents & Royalties, Research Funding. Lacey:Novartis: Research Funding. Grupp:Novartis: Consultancy, Research Funding. Schuster:Novartis: Research Funding. Hwang:NVS: Research Funding. Leung:Novartis: Employment. Shen:Novartis: Employment. Ericson:Novartis: Employment. Melenhorst:Novartis: Research Funding. June:Novartis: Patents & Royalties, Research Funding. Porter:Novartis: Patents & Royalties, Research Funding.

Description: Abstract 2971 Background: Standard monthly infusions of 4 mg zoledronic acid (ZOL) have been proven effective at reducing the risk of skeletal complications in patients with multiple myeloma (MM). It is hypothesized that patients with normal bone metabolism may not require as intense a treatment schedule as patients with accelerated bone resorption. The Z-MARK study evaluates whether patients who have been treated with IV bisphosphonates (BP) for 1–2 years can safely be treated long-term with less frequent dosing of ZOL based on bone turnover markers. Materials and Method: One hundred twenty one patients with MM who had started standard monthly IV BP (ZOL or pamidronate, PAM) 1–2 years prior to enrollment and received at least 4 prior doses, with baseline calculated creatinine clearance of ≥30 mL/min, were enrolled. Patients received 4mg IV ZOL every 4 or 12 weeks based on their most recent urine NTX (uNTX) measurement (uNTX≥50 nmol/mmol creatinine - infusion q4 weeks, uNTX

Description: Abstract 1685 Background: Molecular monitoring is recognized as an important part of evaluating treatment response in Philadelphia chromosome positive chronic myelogenous leukemia in chronic phase (Ph+ CML-CP). The latest guidelines from the National Comprehensive Cancer Network (NCCN) recommend quantitative polymerase chain reaction (QPCR) testing in the first 3 months with a goal of

Description: Introduction: CAR-T cell therapy has demonstrated prompt and durable clinical responses in patients with r/r DLBCL, but is associated with unique toxicities such as cytokine-release syndrome (CRS) and neurotoxicity (NT). NT is the second most common unique toxicity frequently attributed to CAR-T therapy and is present in boxed warnings for all approved CD19 targeted therapies. Similar to other organ toxicities, NT is graded using the Common Terminology Criteria for Adverse Events (CTCAE). However, the CTCAE grading system does not adequately characterize the severity, timing and spectrum of CAR-T related NT. New grading tools are needed for this syndrome-specific AE. The CARTOX working group introduced a novel system for CAR-T Related Encephalopathy Syndrome (CRES), i.e. the CRES grading (Neelapu, Nat Rev Clin Oncol, 2017). To better understand CAR-T related NT and move towards harmonized toxicity reporting, this study retrospectively assessed concordance and variances between the CTCAE and a modified version of the CRES (mCRES) grading system among JULIET patients. Methods: Patient level data from case report forms collected for JULIET, a single-arm, open-label, multicenter, global phase 2 trial of tisagenlecleucel in adult patients with r/r DLBCL (NCT02445248) were used. Four medical experts with experience treating DLBCL patients with different CAR-T therapy products independently reviewed the data and definitions of NT proposed by the FDA using CTCAE and mCRES system. Patients were graded using these two systems; however, only NT attributable to CAR-T therapy were considered. For example, headache without temporal association or evidence of cognitive impairment was graded 0. The CARTOX group's CRES grading criteria were modified in this study since the CARTOX-10 questionnaire, a new tool to assess overall cognitive function, was not prospectively utilized. Hence, mCRES grades 1 and 2, distinguished by CARTOX-10 score, could not be distinctly defined and were assigned based upon investigator report of cognitive or attention dysfunction by CTCAE. Results were discussed and reconciled among all medical experts in a live meeting. As per the research group charter, the highest grading by any of the four experts would determine the final grading for an individual event. Graded results were also compared with those in the FDA label of tisagenlecleucel, in which NT was broadly defined as the occurrence of any CTCAE graded neurological or psychiatric AE (e.g., anxiety, dizziness, headache, peripheral neuropathy, and sleep disorder). Results: Among 111 patients infused with tisagenlecleucel (as of December 2017), 68 who had NT per FDA definition were graded. With the CTCAE grading system, the medical experts identified 50 (45%) patients as having experienced CAR-T related NT, including 34 with grade 1/2, 11 with grade 3, and 5 with grade 4; the mCRES system identified 19 (17%) patients, 5 of whom were grade 1/2, 6 were grade 3, and 8 were grade 4 (Figure 1). Among the subgroup of 64 patients who experienced CRS, the CTCAE and the mCRES systems identified 30 (47%) and 15 (23%) patients with any grade NT, respectively (grade ≥3: CTCAE vs. mCRES: 11 vs. 10). For 47 patients without CRS, the CTCAE and the mCRES systems identified 20 (43%) and 4 (9%) patients with NT, respectively (grade ≥3: 5 vs. 4; Table 1). These grades by medical experts also varied from those reported by FDA: among 106 patients receiving tisagenlecleucel (as of September 2017), 62 (58%) had NT including 19 (18%) with grade ≥3. Conclusions: This exploratory study is the first to retrospectively apply a modified version of the new CARTOX-CRES grading system for CAR-T related NT. Using data from JULIET patients, medical experts were able to achieve consensus NT grading using both the CTCAE and the mCRES grading systems. Using the mCRES system, 19 (17%) patients had any grade NT (5 with grade 1/2, 6 with grade 3, and 8 with grade 4) versus the CTCAE system, which identified 50 (45%) patients as having NT (34 with grade 1/2, 11 with grade 3, and 5 with grade 4). The differences between the two grading systems and the NT grading the FDA reported highlight how the same patient data can be represented variably on different scales and highlight the divergent focus of each system, where encephalopathy is the principal focus of CARTOX-10. These results raise an urgent need for broader consensus on a specific grading scale for CAR-T related NT. Disclosures Maziarz: Athersys, Inc.: Patents & Royalties; Kite Therapeutics: Honoraria; Juno Therapeutics: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schuster:Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Research Funding. Romanov:Novartis Pharmaceuticals Corporation: Employment. Rusch:Novartis Pharmaceuticals Corporation: Employment. Ericson:Novartis Pharmaceuticals Corporation: Employment. Maloney:Janssen Scientific Affairs: Honoraria; Juno Therapeutics: Research Funding; Roche/Genentech: Honoraria; Seattle Genetics: Honoraria; GlaxoSmithKline: Research Funding. Locke:Novartis Pharmaceuticals: Other: Scientific Advisor; Kite Pharma: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy.

Description: Abstract 3179 Introduction: Imatinib mesylate has been a standard first-line treatment for newly diagnosed chronic phase chronic myeloid leukemia (CP-CML) patients at a recommended initial dose of 400mg. Dose escalation of imatinib has been shown to overcome imatinib resistance in some patients; however, recent National Comprehensive Cancer Network (NCCN) guidelines recommend switching to second generation tyrosine kinase inhibitors (TKIs) for imatinib resistant or intolerant CP-CML patients. Limited evidence exists regarding the real-world treatment patterns among CP-CML patients initiating treatment with imatinib. Thus, the objectives of the study were to evaluate treatment patterns including dosing patterns and reasons for dose modification; rates of treatment interruption (i.e., drug holiday), discontinuation, and switching to second generation TKIs; and investigate the reasons for treatment interruption, and discontinuation among newly diagnosed CP-CML patients initiating treatment with imatinib in the real-world setting. Methods: We conducted a retrospective study utilizing the Georgia Cancer Specialist (GCS) electronic medical record system. CP-CML patients initiating treatment with imatinib from 01-01-2002 to 11-01-2011 were identified. Patients in clinical trials, diagnosis with accelerated/blast crisis, having less than 6-month follow-up time or receiving concurrent treatment for other primary cancers were excluded. Data on imatinib dosing, rates of treatment interruption, discontinuation defined as patients with no record of resuming imatinib treatment, switching, with corresponding reasons for the observed patterns were extracted through comprehensive chart reviews and summarized using standard descriptive statistics. Results: A total of 177 patients with CP-CML initiating treatment with imatinib between 01-01-2002 and 11-01-2011 met study inclusion criteria. The median duration of treatment with imatinib was 35 months. The average age of patients treated with imatinib was 61 years and the majority (n = 144, 81%) had a good (0–1) Eastern Cooperative Oncology Group (ECOG) performance status score. Hypertension (n = 52, 29%) was the most common comorbidity in this cohort followed by diabetes mellitus (n = 17, 9.6%). Dose modification was noted for 33% (n = 59) of the patients. The initial dose for patients with a dose modification was 400 mg for the majority (n = 55, 93%) of patients. Major reasons for dose modification among the 59 patients with dose modification included lack of efficacy as documented in the physician notes (n = 20, 34%), leading to a dose increase for all 20 patients, and intolerance (n = 23, 39%), leading to a dose reduction in more than half of the patients who did not tolerate imatinib (n = 13, 56%). Rates of treatment interruption, discontinuation and switching to another therapy were 16% (n = 29), 24% (n = 43), and 23% (n = 41), respectively. The major reason for treatment interruption among the 29 patients with treatment interruption was intolerance (n = 15, 52%) due to side effects such as rash, pancytopenia and myalgia. Primary reasons for treatment discontinuation among the 43 patients discontinuing imatinib treatment included lack of efficacy (n = 27, 63%) and intolerance to imatinib (n = 13, 30%). Of the 27 patients discontinuing imatinib treatment due to lack of efficacy, 9 patients (33%) had an initial dose escalation to 600mg or 800 mg and most patients (n = 26, 96%) eventually switched to a second generation TKI. Among the 41 patients who switched therapies, 23 (56%) switched to dasatinib while 18 (44%) switched to nilotinib over a median time of 14 months (range: 1.3 – 94.9 months). Conclusions: This retrospective review of patients with CP-CML receiving imatinib in a community outpatient setting found that almost a quarter to one-third of patients initiating treatment with imatinib experienced changes in treatment that included dose modification, treatment interruption, or discontinuation. These changes were primarily due to lack of efficacy or intolerance. Although imatinib is highly effective and generally well tolerated as a first-line treatment for CP-CML, alternative and more effective second generation TKIs could be considered as first-line therapy, or alternative to high dose imatinib among those who are resistant to imatinib. Disclosures: Sail: Novartis: Received funding from Novartis for research study Other. Chen:Novartis Oncology: Employment, Own stock in Novartis Other. Jackson:Novartis: Received funding from Novartis for research study Other. Ericson:Novartis Pharmaceuticals Corp: Employment, Equity Ownership.

Description: Abstract 4077 Introduction: Treatment with zoledronic acid (ZOL, 4mg) has proven effective for reducing the risk of skeletal-related events (SREs) in patients (pts) with multiple myeloma (MM), with a SRE incidence rate as low as 27% after 3.7 years' median follow-up (Morgan G, et al. Lancet Oncology 2011;12:743-52). Pts with normal bone metabolism may not require as intense a treatment schedule as pts with accelerated bone turnover. The Z-MARK study evaluated if pts with 1–2 years of prior intravenous (IV) bisphosphonate (BP) therapy can be treated safely long-term with less-frequent ZOL dosing based on bone turnover markers. Methods: MM pts (N=121) who started IVBP therapy (ZOL or pamidronate) 1–2 years before enrollment and received ≥4 prior doses, with baseline calculated creatinine clearance (CrCl) of ≥30 mL/min, were enrolled. Pts received 4mg IV ZOL every (q) 4 or 12 weeks (wk) based on their most recent urinary N-telopeptide of type I collagen (uNTX) levels (q4 wk if uNTX ≥50 nmol/mmol Cr, q12 wk if uNTX

Description: Abstract 4422 Background: Nilotinib is a potent, highly selective Bcr-Abl kinase inhibitor approved for newly diagnosed adult patients (pts) with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) and for adult pts with imatinib-resistant or -intolerant Ph+ CML-CP and CML-AP (accelerated phase). This ongoing study assesses the change in chronic low-grade (LG) non-heme adverse events (AEs) when pts are switched from imatinib (IM) to nilotinib. Methods: Adult CML-CP pts were eligible for the study if they were treated with imatinib 400 mg/d for ≥3 months (mos) and had imatinib-related Grade 1 or 2 non-heme AEs persisting ≥2 mos or recurring ≥3 times and recurring despite best supportive care. Pts are treated with nilotinib 300 mg twice daily on study for up to 1 year. The primary end point is to measure the improvement of imatinib-related LG non-heme AEs at the end of cycle (EOC) 3 after switching to nilotinib therapy. Disease response was monitored and patient-reported outcomes measured by 2 quality-of-life (QoL) questions and the MD Anderson Symptom Inventory (MDASI)-CML. Results: Thirty-eight pts were enrolled as of the data cut-off date (6/27/11) and were included in this analysis. The median time of nilotinib treatment was 7.2 mos. A total of 155 imatinib-related non-heme AEs were reported at baseline; 113 AEs were Grade 1 and 42 AEs were Grade 2. A total of 30 pts completed EOC 3 by the data cut-off date. These pts accounted for 126 of the baseline imatinib-related LG non-heme AEs (Grade 1 = 93, Grade 2 = 33). The median number of IM-related LG non-heme AEs at baseline was 3 per patient. Twenty-one pts reported 1–4 baseline IM-related AEs, 6 pts reported 5–9 IM-related AEs, and 3 pts reported 10–12 IM-related AEs. Of these AEs, 81 (64%) improved (primary end point) by EOC 3; 71 IM-related AEs resolved (51, 15, 5 resolved by mos 1, 2, 3, respectively) and 10 IM-related AEs decreased from Grade 2 to 1. Forty-two AEs were unchanged across 18 pts (20 of which were reported by 3 pts). Three AEs increased in severity by month 3. Overall, 31 (82%) pts had major molecular response (MMR) at entry. MMR is defined as a 3-log reduction of Bcr-Abl from a standardized baseline (Bcr-Abl ≤0.1% IS). All pts maintained MMR after switching to nilotinib on study. The remaining 7 pts achieved MMR during the study. At baseline, 15 pts had a 4-log reduction in Bcr-Abl (Bcr-Abl ≤0.01% IS) and 7 pts with complete molecular response (CMR = Bcr-Abl ≤0.0032% IS). Twelve additional pts achieved a 4-log reduction on study and 9 went on to achieve CMR. Patients completed 2 global QoL questions and the MDASI-CML questionnaire during the study. The MDASI-CML is a patient-reported outcome measure of symptom burden in patients with CML. These were administered at baseline, EOC 1, EOC 3, and then every 3 mos thereafter while on study. Compared to baseline, 68% and 62% of pts (n=34) reported an improvement in global QoL over the last 24 hours and last 7 days, respectively, by EOC 3. The mean reductions from baseline in MDASI-CML severity score and interference score, and therefore improvement in symptoms, were at EOC 1: 1.2 (n=26) and 1.5 (n=25) and at EOC 3: 1.2 (n=24) and 1.6 (n=23), respectively. Thirteen pts were dose reduced for nilotinib-related AEs and subsequently dose re-escalated if the AEs recovered to Grade 1 or resolved. Twenty-seven Grade 3 AEs occurred in 12 pts; of these, 17 AEs were investigator reported and suspected to be nilotinib related (increased bilirubin, hyperglycemia, hypokalemia, hypophosphatemia, increased lipase, pruritus, bronchitis, dehydration, exfoliative rash, rash erythematous, rash, and arthralgia). No pt had a Grade 4 AE. Most AEs were managed by brief dose interruption. A total of 5 pts discontinued, 4 for AEs, and 1 pt withdrew consent. No QTcF prolongation 〉500 msec occurred. Conclusions: In this analysis, at EOC 3, 64% of the chronic LG non-heme IM-related AEs showed improvement after switching to nilotinib. Twenty-eight of 30 pts who completed 3 mos on study had at least 1 LG non-heme IM-related AE improve after switching to nilotinib. At least 62% of pts improved in QoL. In addition, an overall improvement of symptoms as measured by MDASI-CML was seen by the reduction of severity scores. Disclosures: Lipton: Novartis Canada: Consultancy, Research Funding, Speakers Bureau. Mauro:Novartis Oncology: Consultancy, Research Funding, Speakers Bureau. Ailawadhi:Novartis Pharmaceuticals: Consultancy, Speakers Bureau. Miller:Novartis: Consultancy, Research Funding, Speakers Bureau. Busque:Bristol-Myers Squibb: Consultancy; Novartis Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau. Akard:Eisai: Speakers Bureau; Bristol Myers-Squibb: Speakers Bureau; Novartis: Speakers Bureau; Millenium: Speakers Bureau; Chemgenex: Consultancy. Pinilla-Ibarz:Novartis Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau. Ericson:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Shah:Novartis Pharmaceuticals: Employment, Equity Ownership. Cortes:Bristol-Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding; Ariad Pharmaceuticals: Consultancy, Research Funding; ChemGenex Pharmaceuticals: Consultancy, Research Funding; Pfizer: Research Funding; Deciphera Pharmaceuticals: Research Funding.

Description: Abstract 2066 Introduction: Monitoring treatment response to tyrosine kinase inhibitor (TKI) therapy is critical in the management of patients with chronic myeloid leukemia (CML) to assess suboptimal response and detect resistance. This study aimed to evaluate the monitoring patterns and treatment response of CML patients treated with imatinib in a community setting. Methods: A retrospective study was conducted utilizing the Georgia Cancer Specialist (GCS) electronic medical record system. Patients with Ph+ chronic phase CML (CP-CML) initiating imatinib from 01-01-2002 to 11-01-2011 were included, while patients in clinical trials, with