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Chimeric antigen receptor (CAR) T-cell therapy is an investigational immunocellular therapy that reprograms a patient's cytotoxic T cells to engage and eliminate malignant cells. CAR T-cell therapies targeting the CD19 antigen have demonstrated high efficacy in clinical trials for patients with B-cell malignancies and may potentially be available on a broader scale in the future. CAR T-cell therapy begins with the collection of a sufficient number of T cells from a patient's peripheral blood through leukapheresis. Several factors must be considered when patients undergo leukapheresis for CAR T-cell therapy, including age and prior therapies. The leukapheresis material is shipped to a manufacturing facility, followed by return of the CAR T cells to the treatment center. Careful coordination of a multidisciplinary team composed of physicians, nurses, pharmacists and other hospital personnel is critical for the proper care of the patient before, during and after CAR T-cell therapy. CAR T-cell therapy has been associated with adverse events (AEs) such as cytokine release syndrome, which requires rapid attention by the emergency department, intensive care unit and hospital pharmacy. In this review, we discuss several aspects of institutional preparation for leukapheresis, CAR T-cell infusion and AE management based on our experience with clinical trials of the CD19 CAR T-cell therapy CTL019.

Background: The phase II, exploratory, open-label Exploring Nilotinib BCR-ABL Effects (ENABL) study [ ClinicalTrials.gov identifier: NCT00644878] assessed the impact of switching to nilotinib therapy in patients with chronic myeloid leukemia in chronic phase (CML-CP) who had a suboptimal molecular response with imatinib. Methods: Patients with CML-CP who had previously achieved a complete cytogenetic response (CCyR), but had a suboptimal molecular response, with frontline imatinib therapy ( N = 18) were assigned to receive nilotinib 300 mg twice daily. The primary endpoint was the change in BCR-ABL1 transcript levels from baseline after 12 months; rates of major molecular response (MMR) and safety were also assessed. Results: At 3 months after switching to nilotinib, 10 of 17 (59%) evaluable patients had achieved MMR. At 12 months, 9 of 12 (75%) evaluable patients had achieved MMR, and the median BCR-ABL1 level among all patients remaining in the study was 0.020% on the International Scale (IS), equivalent to a 3.7-log reduction from the standardized IS baseline (primary endpoint). Adverse events (AEs) were typically grade 1/2 and manageable with dose interruptions. A total of three patients experienced serious study drug-related AEs, including pancreatitis, bradycardia, and vertigo. No deaths were reported. Conclusions: Overall, results from this exploratory study suggest that switching to nilotinib due to suboptimal molecular response with imatinib can result in improved molecular response for patients with CML-CP.

We describe the significant technological leap from bench to bedside that was achieved through a strong academic-industry collaboration between dedicated clinicians and researchers at the University of Pennsylvania, the Children’s Hospital of Philadelphia, and Novartis to commercialize the chimeric antigen receptor T cell (CAR-T) therapy tisagenlecleucel (CTL019; Kymriah®; Novartis Pharma AG, Basel, Switzerland). Tisagenlecleucel was the first CAR-T therapy and the first gene therapy to receive US Food and Drug Administration approval in 2017, with an initial indication for pediatric and young adult patients with relapsed or refractory (r/r) acute lymphoblastic leukemia, followed by approval in May 2018 for a second indication in adult patients with r/r diffuse large B cell lymphoma. Subsequent approvals in the European Union, Switzerland, and Canada soon followed. The tisagenlecleucel success story represents the development and commercialization of a first-of-its-kind personalized cellular therapy with a manufacturing process that supports commercial production and ongoing global clinical trials in a growing number of countries.

Real-world treatment and monitoring patterns have not been well documented among imatinib-treated chronic phase chronic myeloid leukemia (CP-CML) patients. Thus, we evaluated these patterns and responses to imatinib in CP-CML patients.This retrospective study, based on the Georgia Cancer Specialists' electronic medical record (EMR) system, identified CP-CML patients initiating treatment with imatinib from 01/01/2002 to 11/01/2011 who were subsequently followed for ≥6 months.A total of 177 patients met the study criteria. Imatinib dose modification occurred in 59 patients (33%). Rates of treatment interruption, discontinuation, and switching to another therapy were 16%, 24%, and 23%, respectively. Of 27 patients discontinuing imatinib for lack of efficacy, 9 (33%) had initial dose escalation; 26 patients (96%) eventually switched to a second-generation tyrosine kinase inhibitor. By 3 months, 168 patients remained on imatinib, of whom 96 (57%) had undergone cytogenetic and/or molecular testing. The frequency of response monitoring fluctuated over time, with rates as high as 28% for cytogenetic and 69% for molecular testing. Cumulative response rates steadily increased; 18 month rates were 47% for complete cytogenetic response and 26% for major or complete molecular response. There were no cases of progression and/or death among 38 patients who were regularly monitored for molecular response within the first 12 months of imatinib. Ten of 98 patients (10%) not regularly monitored had progressed or died.Almost one-third of patients initiating imatinib for CP-CML required dose modification, treatment interruption, or discontinuation. Opportunities for improved monitoring in this setting were identified. Limitations include those inherent to retrospective analyses based on EMR and the uncertain extrapolability of the results.

Monitoring treatment response is an integral part of chronic myeloid leukemia (CML) treatment. The guidelines recommend regular monitoring using standard methods (e.g., real-time quantitative polymerase chain reaction based on the international scale for molecular response) and treatment adjustment when failure is detected among patients treated with imatinib. The objective of this study was to assess the real-world monitoring and therapy adjustment in this patient population in the US.Twenty-nine physicians from community practices across the US participated in an online chart review. Adult patients with chronic phase CML who initiated imatinib as first-line therapy during 2006-2010 were selected. Information was collected up to 36 months after imatinib initiation, including response monitoring, response status, and therapy adjustment upon treatment failure.The study included 297 eligible patients. By 18 months, 47% of patients had received cytogenetic response assessment continuously as recommended by the guidelines. The corresponding proportion was 39% for continuous molecular response assessment. Among patients who experienced treatment failure by 18 months, only 14%-38% of patients switched to a second-generation tyrosine kinase inhibitor as recommended by the National Comprehensive Cancer Network and the European Leukemia Net guidelines.Major limitations included limited generalizability and the inability to accurately assess molecular response due to the variations in testing methods during the study period.Based on the guidelines, the rates of treatment monitoring and switching upon failure were low, demonstrating the need for improvement in CML care in community settings in the US.

BACKGROUND: Postmenopausal breast cancer (BC) patients receiving adjuvant aromatase inhibitor therapy are at risk of progressive bone loss and fractures. Zoledronic acid inhibits osteoclastic bone resorption, is effective in maintaining bone health, and may therefore be beneficial in this setting. METHODS: Overall, 602 postmenopausal women with early, hormone receptor-positive BC receiving adjuvant letrozole were randomized (301 each group) to receive upfront or delayed-start zoledronic acid (4 mg intravenously every 6 months) for 5 years. The primary endpoint was the change in lumbar spine (LS) bone mineral density (BMD) at month 12. Secondary endpoints included changes in LS BMD, total hip BMD, and bone turnover markers at 2, 3, and 5 years; fracture incidence at 3 years; and time to disease recurrence. RESULTS: At month 61, the adjusted mean difference in LS and total hip BMDs between the upfront and delayed groups was 8.9% and 6.7%, respectively (P < .0001, for both). Approximately 25% of delayed patients received zoledronic acid by month 61. Only 1 patient experienced grade 4 renal dysfunction; no confirmed cases of osteonecrosis of the jaw were reported. Fracture rates (upfront, 28 [9.3%]; delayed, 33 [11%]; P = .3803) and Kaplan-Meier disease recurrence rates (upfront, 9.8 [95% confidence interval (CI), 6.0-10.3]; delayed, 10.5 [95% CI, 6.6-14.4]; P = .6283) were similar at month 61. CONCLUSIONS: Upfront zoledronic acid seems to be the preferred treatment strategy versus delayed administration, as it significantly and progressively increases BMD in postmenopausal women with early BC receiving letrozole for 5 years, and long-term coadministration of letrozole and zoledronic acid is well tolerated. Cancer 2012. © 2011 American Cancer Society.

Zoledronic acid, an intravenous (IV) bisphosphonate, is a standard treatment for multiple myeloma (MM) but may exacerbate preexisting renal dysfunction. The incidence of zoledronic acid-induced renal dysfunction may correlate with infusion duration. In this randomized, multicenter, open-label study, 176 patients with MM, at least one bone lesion, and stable renal function with a serum creatinine (SCr) level < 3 mg/dL received zoledronic acid 4 mg (in 250 mL) as a 15- or 30-minute IV infusion every 3-4 weeks. At month 12, 20% (17 patients) in the 15-minute and 16% (13 patients) in the 30-minute arm experienced a clinically relevant but nonsignificant SCr-level increase (P = 0.44). By 24 months, the proportion of patients with a clinically relevant SCr-level increase was similar between arms (15-minute 28% [24 patients] vs 30-minute 27% [23 patients], P = 0.9014). Median zoledronic acid end-of-infusion concentrations were higher with the shorter infusion (15-minute 249 ng/mL vs 30-minute 172 ng/mL), and prolonging the infusion beyond 15 minutes did not influence adverse events related to zoledronic acid. For patients with MM, the safety profile of IV zoledronic acid is similar between those receiving a 15- or 30-minute infusion; therefore, determining the appropriate infusion duration of zoledronic acid should be based on individual patient considerations.

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.

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.

Postmenopausal women with breast cancer receiving adjuvant aromatase inhibitors (AIs) are at risk for accelerated bone loss and subsequent fractures. The ongoing Zometa-Femara Adjuvant Synergy Trial (Z-FAST) is evaluating the efficacy and safety of zoledronic acid in preventing such bone loss.In this multicenter study, postmenopausal women with early hormone receptor-positive breast cancer receiving adjuvant letrozole were randomized to receive up-front or delayed-start zoledronic acid (ZA; 4 mg intravenously every 6 months) for 5 years. Delayed-start ZA was administered if the lumbar spine (LS) or total hip (TH) T score fell below -2.0 or a nontraumatic fracture occurred. The primary endpoint was to compare the change from baseline in LS bone mineral density (BMD) between groups at month 12; secondary endpoints, measured at other predetermined timepoints, included comparing changes in TH BMD, LS BMD, and markers of bone turnover, fracture incidence, and time to disease recurrence. Herein, we report the results of the 36-month interim analysis.Overall, 301 patients were randomized to each group. At month 36, the absolute difference in mean LS and TH BMDs between the up-front and delayed groups was 6.7% and 5.2%, respectively (P.0001 for both). Although this study was not designed to show antifracture efficacy, the incidence of fractures was slightly higher in the delayed group (up-front, 17 [5.7%] vs. delayed, 19 [6.3%]) but not statistically significant (P = .8638). Pyrexia (27 [9%] vs. 6 [2%]; P = .0002) and bone pain (39 [13%] vs. 20 [6.7%]; P = .01) were more common in up-front patients; cough (13 [4.3%] vs. 27 [9%]; P = .03) was more common in delayed patients. No severe renal dysfunction or confirmed cases of osteonecrosis of the jaw were reported. Disease recurrence was reported in 9 up-front (3.0%) and 16 delayed (5.3%) patients (Kaplan-Meier analysis, P = .127), with an absolute decrease of 2.3%.Up-front ZA more effectively prevents AI-associated bone loss in postmenopausal women with early breast cancer than delaying therapy until substantial bone loss or fracture occurs.

Purpose: Zoledronic acid (ZOL) given every 3 to 4 weeks can reduce skeletal-related events (SRE) in patients with bone lesions from multiple myeloma. This study evaluated efficacy and safety of less-frequent ZOL dosing based on bone turnover markers in patients with 1 to 2 years of prior bisphosphonate therapy. Experimental Design: Patients received ZOL (4 mg) every 4 or 12 weeks based on urinary N-telopeptide of type 1 collagen (uNTX) levels (every 4 weeks if uNTX ≥50 nmol/mmol creatinine, every 12 weeks if uNTX < 50). Results: Of 121 patients enrolled (mean age, 63.8 years; median follow-up, 21 months), 4 patients started ZOL every 4 weeks and 117 received ZOL every 12 weeks based on uNTX at study entry. All 4 patients who initiated ZOL every 4 weeks switched to every 12 weeks due to decreased uNTX. Thirty-eight of 117 patients who initiated ZOL every 12 weeks switched to ZOL every 4 weeks due to disease progression (n = 20), increased uNTX (n = 14), and SREs (n = 4). Overall SRE incidence was low; 7 (5.8%) and 5 (4.9%) patients experienced an SRE during years 1 and 2, respectively. Mean (SD) SRE rate at year 2 was 0.01 (0.03) per person-year. The 2-year incidence rate for osteonecrosis of jaw was 3.3%. Four deaths were reported, none related to ZOL. Conclusions: Less frequent ZOL dosing (every 12 weeks over 2 years) maintains a low SRE rate and can be safely administered for up to 4 years. Clin Cancer Res; 22(6); 1378–84. ©2015 AACR. See related commentary by Fonseca and Jain, p. 1301

Comprehensive gene expression analysis of the T cell receptor repertoire of an individual can be very useful in evaluating the immune response in a variety of conditions. Antibody-based analysis methods can detect approximately 60% of the human T cell receptor beta variable (TCRBV) proteins, while gene expression analysis, primarily through employment of the polymerase chain reaction (PCR), has had somewhat greater success in the detection of additional TCRBV families. Many of these previous PCR methods, however, have been unable to detect all 91 alleles of the human TCRBV genes. This is primarily due to either deficiencies in the amplification of all of the variable beta families, subfamilies, and alleles, or the prior lack of a systematic classification of the TCR variable family gene segment sequences. We describe here a real-time reverse transcription polymerase chain reaction-based method, which allows efficient automation and integration of amplification, detection, and analysis with sequence-specific detection of all T cell receptor beta variable gene families, subfamilies, and alleles. This method, which in itself contributes significant improvements over existing technologies through its comprehensiveness and efficiency, also functions independently of variables such as sample source and sample processing and has the ability to run on multiple real-time PCR platforms, affording one the implementation of personal preferences.

IL-6 is involved in the control of differentiation of the acute promyelocytic leukemia cell line, HL-60. However, the participation of protein tyrosine phosphatase (PTP) in the monocytic differentiation activity of IL-6 at low concentrations has not been well clarified. In the present study, we demonstrate that IL-6 (10 ng/ml) alone increased cell growth without differentiation. In the presence of vanadate (10 microM), a PTP inhibitor, IL-6 induced pronounced G0/G1 cell cycle arrest; this effect was associated with CD14+ monocytic differentiation as well as F-actin filament polymerization. Furthermore, vanadate potentiated IL-6-signaling pathway by increasing the tyrosine phosphorylated levels of STAT3 (Tyr705), and Lyn. Such induction of Lyn kinase activity resulted from hypophosphorylated tyrosine (Tyr507) at its negative regulatory site. Vanadate also cooperated with IL-6 to form a protein complex containing Lyn and an actin-associated protein, AFAP110. A complex between Lyn and AFAP110 may serve to regulate F-actin filament polymerization. In conclusion, inhibition of PTP by vanadate promotes hematopoietic differentiation activity of IL-6 through modulating multiple signalings, particularly actin filament polymerization.

The objective of this study was to examine whether CD45 mediates interleukin 6 (IL-6) signaling in human multiple myeloma (MM) cells. We chose U266 MM cells as a study model and isolated cells into CD45+ and CD45- subpopulations. CD45+ and CD45- U266 cells were cocultured with bone marrow stromal cells (BMSCs). IL-6-induced proliferation in CD45+ U266 cells was inhibited by vanadate, a potent protein tyrosine phosphatase inhibitor. However, IL-6-independent CD45- U266 cell growth was not affected by vanadate. CD45+ U266 cells, but not CD45- U266 cells, have the capability of cell adhesion concomitant with actin filament polymerization at the adherent cells. Adhesion of CD45+ U266 cells to BMSCs was impaired by vanadate. We clarified the signaling differences between CD45+ and CD45- U266 cells in response to IL-6. In CD45+ U266 cells, IL-6 increased tyrosine phosphorylation of gp130 and STAT3 and stimulated the level of Mcl-1 protein expression. An association between CD45 and the Src-family protein tyrosine kinase, Lyn, was maintained in the presence of IL-6; the formation of the CD45/Lyn complex was impaired by vanadate. Additionally, IL-6-induced Lyn kinase activity in CD45+ U266 cells was increased by the cross-linking of CD45, and this increase was due to the dephosphorylation of Tyr507 at Lyn. In conclusion, IL-6-dependent MM cells require CD45 to initiate IL-6 signaling and to maintain Lyn kinase activity, both of which are essential for cell proliferation and cell adhesion.

We evaluated the results of high-dose therapy (HDT) and autologous hematopoietic stem cell transplantation (ASCT) in patients with relapsed or primary refractory Hodgkin’s disease (HD), using a previously reported prognostic model based on the presence of three poor prognostic factors at the start of salvage therapy/preparative regimen: B symptoms, extranodal disease and the duration of last complete response of less than 1 year. Based on this model, the patients were divided into low-risk and high-risk groups. Between 1993 and 2001, 24 patients with HD were treated with HDT and ASCT. Eighteen of the 24 patients had 0–1 risk factors (low-risk group) and 6 patients had 2–3 risk factors (high-risk group). Using Kaplan-Meier analysis, after a median follow-up of 40.5 months, the progression-free survival (PFS) was 48%, and the overall survival (OS) was 55%. PFS in the low-risk group was 56%, and in the high-risk group 17% (p < 0.001). OS in the low-risk group was 68% and in the high-risk group it was 18% (p < 0.001). The 100-day transplant-related mortality for the entire group was 16%. Our results are comparable to those reported in previous clinical trials for patients with refractory and relapsed HD treated with HDT and ASCT. The use of a prognostic model appears useful for predicting the outcome of HDT and ASCT for HD patients, and may play an important role in choosing the appropriate therapy for these patients.

Systemic fungal infections are a major problem in bone marrow transplant recipients who have prolonged neutropenia or who receive high-dose corticosteroids. Prophylaxis with Fluconazole or low-dose amphotericin B reduces, but does not eliminate these infections. To determine which prophylactic agent is better, we performed a prospective randomized study. Patients undergoing allogeneic (related or unrelated) or autologous marrow or peripheral stem cell transplantation were randomized to receive Fluconazole (400 mg/day p. o. or i.v.) or amphotericin B (0.2 mg/kg/day i.v.) beginning 1 day prior to stem cell transplantation and continuing until recovery of neutrophils to500/microl. Patients were removed from their study drug for drug-associated toxicity, invasive fungal infection or suspected fungal infection (defined as the presence of fever38 degrees C without positive culture while on broad-spectrum anti-bacterial antibiotics). Proven or suspected fungal infections were treated with high-dose amphotericin B (0.5-0.7 mg/kg/day). Patients were randomized at each institution and stratified for the type of transplant. The primary end-point of the study was prevention of documented fungal infection; secondary endpoints included fungal colonization, drug toxicity, duration of hospitalization, duration of fever, duration of neutropenia, duration and total dose of high-dose amphotericin B and overall survival to hospital discharge. From July 1992 to October 1994, a total of 355 patients entered into the trial with 159 patients randomized to amphotericin B and 196 to Fluconazole. Patient groups were comparable for diagnosis, age, sex, prior antibiotic or antifungal therapy, use of corticosteroids prior to transplantation and total duration of neutropenia. Amphotericin B was significantly more toxic than Fluconazole especially in related allogeneic transplantation where 19% of patients developed toxicity vs 0% of Fluconazole recipients (p0.05). Approximately 44% of all patients were removed from prophylaxis for presumed fungal infection. Proven fungal infections occurred in 4.1% and 7.5% of Fluconazole and amphotericin-treated patients, respectively. Proven fungal infections occurred in 9.1% and 14.3% of related allogeneic marrow recipients receiving Fluconazole or amphotericin B, respectively, and 2.1% and 5.6% of autologous marrow recipients receiving Fluconazole or amphotericin B, respectively (P0.05). In this prospective trial, low-dose amphotericin B prophylaxis was as effective as Fluconazole prophylaxis, but Fluconazole was significantly better tolerated.

A nondestructive fluorescence-imaging assay is described for quantitating the number and size of plaques formed over time by cytotoxic effector cells in a monolayer of target cells. It can also be used to assay the growth of adherent cells toward confluence. The method involves the use of fluorescein conjugated to high molecular weight dextran. The dextran is excluded by adherent cells, thereby making the medium around cells more fluorescent than the cells themselves. The area of the plate that is fluorescent can be determined by confocal fluorescence imaging microscopy. With this new method, changes in the confluency of adherent cells or in the number and area of cytotoxic plaques can be assayed repeatedly over an extended period of time, without manipulation of the cells or of the medium.

Polymorphonuclear neutrophils (PMNs) are essential effector cells in host defense and tissue inflammatory responses. These responses may be initiated after cross-linking of cell surface Fc receptors that bind the constant portion of IgG (FcγR). We evaluated the effect of cross-linking FcγRI or FcγRII on interleukin-6 (IL-6) production by purified PMNs from normal donors or from patients being treated with recombinant human granulocyte colony-stimulating factor (rhG-CSF). In PMNs from normal donors, IL-6 mRNA was detected by reverse transcriptase-polymerase chain reaction only after FcγRI or FcγRII cross-linking. We also found that IL-6 mRNA could be detected in PMNs after either in vitro or in vivo rhG-CSF treatment in the absence of FcγR cross-linking. IL-6 protein was found to be produced intracellularly and secreted by PMNs after cross-linking FcγRI or FcγRII or after rhG-CSF stimulation. Cross-linking FcγRI or FcγRII on PMNs from patients treated with rhG-CSF resulted in a synergistic increase in IL-6 secretion. Upregulation of IL-6 production by PMNs after rhG-CSF treatment may contribute to a clinical engraftment syndrome that occurs during periods of rapid increase in PMN numbers in patients receiving rhG-CSF.

Although bone marrow (BM) karyotyping has been the standard in monitoring patients with chronic myeloid leukemia, peripheral blood (PB) monitoring methods may be more convenient.To conduct post hoc analyses of the Rationale and Insight for Gleevec High-Dose Therapy study to evaluate correlations between results of cytogenetic testing and molecular monitoring from BM and PB during the first 18 months of high-dose imatinib therapy, and between early and late molecular responses.Newly diagnosed patients with chronic-phase chronic myeloid leukemia received imatinib 400 mg twice daily and were monitored quarterly for up to 18 months. Cytogenetic testing was performed by karyotyping using BM or by fluorescence in situ hybridization using PB. Molecular testing was performed by quantitative reverse transcriptase polymerase chain reaction using BM and PB.Significant pairwise correlations were found between results obtained by karyotyping, fluorescence in situ hybridization, and quantitative reverse transcriptase polymerase chain reaction using PB or BM (all pairwise correlations0.8; P.001). At 12 months, cytogenetic response by karyotyping correlated well with response by fluorescence in situ hybridization. A median 2.579-log reduction in BCR-ABL1 level from a standardized baseline correlated with fluorescence in situ hybridization-negative status. Patients with greater than 2-log reduction in BCR-ABL1 level at 3, 6, and 9 months were more likely to achieve major molecular response at 18 months than those with 2-log reduction or less.Our findings support the feasibility of molecular monitoring using PB and suggest that molecular monitoring conducted at a single reliable reference laboratory can adequately track response without invasive BM testing. Our findings are consistent with other work indicating that early response to imatinib predicts favorable long-term outcome.

Molecular monitoring using quantitative polymerase chain reaction (qPCR) of BCR-ABL mRNA transcripts using the international scale (IS) is recommended by the National Comprehensive Cancer Network and the European LeukemiaNet for patients with chronic myelogenous leukemia in chronic phase (CML-CP). This study assessed the impact of the frequency of qPCR testing on progression-free survival (PFS).This retrospective chart review of 402 CML-CP patients on first line imatinib therapy, performed by 38 community-based US physicians, analyzed the impact of the frequency of molecular monitoring on the risk of progression and PFS.Time to progression and progression-free survival.Over the 3 year study, 13.2% of patients did not have any qPCR monitoring and 46.3% had 3-4 qPCR tests per year; 5.7% of CML-CP patients progressed to accelerated/blast phase or died. Compared to patients with no qPCR monitoring, those with 3-4 qPCR tests per year had a lower risk of progression (HR = 0.085; p = 0.001) and longer PFS (HR = 0.088; p = 0.001) after adjusting for potential confounders, as did those patients with 1-2 qPCR tests per year (both p0.02). Results were consistent after adjusting for Sokal score when available.This is the first study to document the clinical impact of frequent molecular monitoring, and the findings underscore the importance of regular molecular monitoring in delivering quality care for CML. These findings could be subject to unobserved confounders.

7002Background: Genetically modified T cells expressing an anti-CD19 CAR result in response rates of 90% in children with r/r CD19+ ALL. Cytokine release syndrome (CRS) is the most significant trea...

Background This study retrospectively compared the risks of skeletal-related events (SREs) and zoledronic acid (ZOL) treatment discontinuation associated with early vs. delayed ZOL therapy for patients with symptomatic multiple myeloma (MM). Patients and Methods Data were collected from a physician-administered medical chart review among US patients with a confirmed diagnosis of symptomatic MM treated after 01/01/2002. Early and delayed ZOL therapy were defined, respectively, as initiating ZOL ≤ 60 days (N = 126) vs. > 60 days (N = 186) after the first symptomatic MM diagnosis. Kaplan-Meier analysis with a log-rank test was performed to compare the risk of SREs between the cohorts. Cox proportional hazard modeling compared the risk of SREs associated with early vs. delayed ZOL treatment, controlling for demographic factors, stage of MM, bone health status, and presence of major comorbidities at diagnosis. Time to ZOL discontinuation was evaluated using the Kaplan-Meier method, following patients from the date of ZOL initiation. Results Time to the first SRE was significantly longer for patients who received early treatment with ZOL ( P = .005). At 2 years after diagnosis, the SRE-free rate was 74.6% vs. 56.5% in the early vs. delayed treatment group, respectively. Early ZOL therapy was associated with a significantly lower risk of any SRE (hazard rate [HR] = .625 vs. delayed ZOL therapy; P = .029). At 2 years from ZOL therapy initiation, rates of ZOL discontinuation were 9.6% vs. 16.4% among patients with early vs. delayed therapy, respectively ( P Conclusion Early treatment with ZOL was associated with significantly reduced risks of SREs and with better treatment persistence compared with delayed treatment.

This study was designed to evaluate the efficacy and safety of combined zoledronic acid and docetaxel/carboplatin in patients with non-small cell lung cancer (NSCLC) as preclinical studies showed synergistic antitumoral activity with bisphosphonates and docetaxel. Patients with inoperable stage IIIB or stage IV NSCLC were randomized 2:1 to receive docetaxel 75 mg/m 2 and carboplatin area under the concentration time curve 6 with (Arm A) or without (Arm B) zoledronic acid 4 mg every 3 weeks for 6 cycles. Patients responding in Arm A were rerandomized to receive monthly zoledronic acid (maximum: 12 months [Arm A1] or no zoledronic acid [Arm A2]). Patients responding in Arm B entered Arm B1 for follow-up evaluation only. The primary endpoint was the proportion of patients without disease progression; secondary endpoints were time to disease progression (TTP), TTP in bone, best overall response rate, 1-year overall survival (OS) time, and safety; study not powered to detect endpoint differences. Of 150 patients, 98 were randomized to Arm A and 52 to Arm B. In the treatment phase, results were similar between groups in the proportion of patients without disease progression (40.9% vs 38.8%; P = .8096) and median TTP (132 d vs 132 d; P = .9622). One-year OS times and best overall response rates were 266 d vs 206 d ( P = .4855) and 64.1% vs 72% ( P = .3423), respectively; the study was not powered to detect differences. In the follow-up phase, TTP and OS time were similar. Adding zoledronic acid to docetaxel/carboplatin in advanced stage NSCLC patients was well tolerated, but provided little to no effect on disease progression endpoints.

Learning Objectives After reading this article, the reader should be able to: Monitor for and treat to prevent bone loss in postmenopausal breast cancer patients receiving an aromatase inhibitor.Describe the methodology of the Z-FAST and ZO-FAST clinical trials.Discuss the effectiveness and tolerability of zoledronic acid when administrated to prevent bone loss associated with aromatase inhibitors. CME This article is available for continuing medical education credit at CME.TheOncologist.com Background. The interim (12-month) results of two similarly designed, ongoing studies (the Zometa®-Femara® Adjuvant Synergy Trials [Z-FAST and ZO-FAST]) suggest that zoledronic acid (4 mg intravenously every 6 months) when initiated with adjuvant letrozole increases bone mineral density (BMD) of the lumbar spine (LS) in postmenopausal women with early-stage breast cancer compared with patients who receive zoledronic acid only when bone loss became clinically significant or a fragility fracture occurred. Methods. An integrated analysis was performed to maximize the value of the large pool of data from the two studies in answering clinically relevant questions. The primary objective was to compare the change in LS BMD at month 12. Secondary objectives included comparing (a) the change in total hip (TH) BMD, (b) changes in bone turnover marker concentrations, (c) time to disease recurrence, and (d) safety at month 12. Findings. The integrated analysis included 1,667 patients. At month 12, LS BMD was 5.2% higher in the upfront group than in the delayed group; TH BMD was 3.5% higher. N-telopeptide and bone-specific alkaline phosphatase concentrations decreased by 21.3% and 12.8% in the upfront group and increased by 21.7% and 24.9% in the delayed group, respectively (p < .0001 for intergroup comparisons). Fewer patients receiving upfront zoledronic acid experienced disease recurrence than patients in the delayed group—seven patients (0.84%) versus 17 patients (1.9%) (p = .0401). Fracture rates were similar. No confirmed osteonecrosis of the jaw was reported. Conclusions. The results of this analysis strengthen the statistical validity of the preliminary results of the Z-FAST and ZO-FAST studies, showing that upfront zoledronic acid prevents aromatase inhibitor–associated bone loss more effectively than delayed-start zoledronic acid in postmenopausal women with early-stage breast cancer receiving letrozole. Additionally, disease recurrence appears to be lower with upfront zoledronic acid, but further follow-up is needed to confirm these interim results.

Allogeneic stem cell transplantation (SCT) is the treatment of choice for selected patients with chronic myeloid leukemia (CML). However, it is associated with a high risk of treatment-related mortality (TRM) and morbidity. To assist in decision making about transplantation, a simple scoring system to assess the risk is needed. We analyzed the utility of a scoring system, first reported by the European Group for Blood and Marrow Transplantation (EBMT). We analyzed the data from 31 patients who underwent allogeneic transplantation at our institution, using the EBMT scoring system. It was based on five pretransplant risk factors: donor type, stage of disease at time of transplantation, age of recipient, sex of donor and recipient, and interval between diagnosis and transplant. Seventeen patients had a risk score of 0–2, and 14 patients had a score of 3–7. Using Kaplan-Meier analysis, the estimated 4-year leukemia-free (LFS) and overall survival (OS) for patients with a score of 0–2 were 47 and 53%, respectively. In contrast, the estimated 4-year LFS and OS for patients with a score of 3–7 were 10.5 and 10.5%, respectively. Four-year TRM was 47% for the low-risk group (0–2), and 85% for the high-risk group (3– 7). This simple scoring system may play an important role in predicting the outcome of allogeneic SCT, and in choosing the appropriate therapy for patients with CML.

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.

We surveyed five academic medical centers to develop a clinical process for patients undergoing cytokine mobilization and leukapheresis prior to autologous peripheral blood stem cell transplantation. Costs were obtained from three centers and applied to each component of the pathway. Costs were divided into three categories: (1) pre-apheresis evaluation; (2) process of apheresis; (3) post-apheresis and peripheral blood stem cells processing. All centers participated in the development of the leukapheresis pathway. Because charges vary greatly among institutions, costs were determined from three of the institutions and a mean was calculated for each of the components of the process. Pre-apheresis costs consisted of central line placement, blood work, and the price of cytokine (rhG-CSF). Costs associated with apheresis included professional fees (for physicians and nurses), leukapheresis with stem cell cryopreservation, storage, sterility testing, analysis of circulating CD34+ cell counts, and 1 day of cytokine therapy. The post-apheresis process included thawing with sterility testing along with CD34+ cell number analysis and the performance of clonogenic assays. Total costs were as follows: (1) pre-apheresis, $2711; (2) apheresis, $2990; and, (3) post-apheresis/stem cell processing, $754. This survey from five academic medical centers provides the average costs associated with three main components of the apheresis procedure. Because many patients require multiple aphereses, interventions to achieve target CD34+ cell collections in as few collections as possible would result in significant cost reduction.

Optimizing chemotherapeutic drug delivery strategies relies, in part, on identification of the most clinically effective sequence, dose, and duration of drug exposure. The combination of dose intensive etoposide (VP-16) followed by cyclophosphamide has clinical efficacy in the treatment of advanced breast cancer. However, molecular mechanisms that underlie the effectiveness of this combination of chemotherapeutic agents have not been investigated. In this study we investigated regulation of BAX and BCL-2 expression by VP-16 and cyclophosphamide as a potential mechanism for the induction of breast cancer cell death induced by this regimen. There was a dose and time dependent increase in BAX expression in the breast cancer cell lines MCF-7, MDA-MB-435S, and MDA-MB-A231 following in vitro treatment with 50-100 microM VP-16. Elevation of BAX protein expression in the presence of VP-16 alone did not correlate with reduced viability or induction of apoptosis in MCF-7, MDA-MB-435S, or MDA-MB-A231. VP-16 did effectively block the breast cancer cell lines evaluated (MCF-7 and MDA-MB-435S) at G2/M phase of the cell cycle, confirming activity of the drug in vitro. MCF-7 and MDA-MB-435S cells that were pre-treated with VP-16 and subsequently exposed to 1.0-12.0 microg/ml 4-hydroperoxycyclophosphamide (4HC), an active metabolite of cyclophosphamide, had markedly reduced viability when compared to matched controls treated with either VP-16 or 4HC individually. Consistent with this loss of viability, exposure of all three cell lines to the combination of VP-16 and 4HC resulted in higher BAX protein levels than those observed following treatment with either single agent. This combination of chemotherapeutic agents also resulted in reduced BCL-2 expression. These observations suggest that combination chemotherapy may derive its efficacy, in part, through coordinated regulation of specific gene products associated with apoptosis. Characterization of molecular events that underlie susceptibility of specific tumor cells to combination chemotherapeutic regimens may lead to additional improvements in treatment strategies for this disease.

Macrophage inflammatory protein-1alpha (MIP-1alpha) is a chemokine that can inhibit the cell cycle progression of both primitive haemopoietic and epidermal progenitor cells. This property could potentially be exploited to attenuate both the myelosuppressive effects of chemotherapy as well as mucositis. We evaluated both the biological and clinical effects of BB-10010, a genetically engineered variant of MIP-1alpha, in patients with malignant lymphoma or breast cancer receiving high-dose etoposide (VP 3.6 g/m2) and cyclophosphamide (Cy 200 mg/kg). 52 patients were randomized to one of three cohorts. Cohort A received no BB-10010; cohorts B and C received 10 microg/kg and 100 microg/kg of BB-10010, respectively. All patients received post-chemotherapy G-CSE BB-10010 was well tolerated. There were no significant differences between groups in recovery to an ANC0.5 x 10(9)/l, 1 x 10(9)/l or 1.5 x 10(9)/l, the number of days with an ANC0.5 x 10(9)/l, days to a platelet count50 x 10(9)/l or 100 x 10(9)/l, or the incidence and severity of mucositis. There was no evidence of any effect of BB-10010 on colony-forming cell (CFC) or long-term culture-initiating cell (LTC-IC) mobilization, cycling activity in the marrow or on chemotherapy-induced changes in CFC or LTC-IC number both of which were in the normal range by 22 d after completion of the chemotherapy. To our knowledge this is the first report of a myelointensive regimen having no apparent long-term effect on the LTC-IC compartment. In summary, BB-10010 is safe when used in patients receiving high-dose therapy but has no effect on reducing the toxicity of such therapy.

7096 Background: The objective was to evaluate the types, frequency and adherence of molecular tests utilized in patients (pts) with CML-CP who initiated 1st-line TKI therapy in the community practice (prac) setting. Methods: A retrospective study of newly diagnosed CML-CP pts; initiating 1st-line TKI during 06/2007 and 03/2011, with ≥18-mo follow-up was conducted. Data was collected from iKnowMed, various local & national labs to evaluate whether qRT-PCR test results was reported in International Scale (IS) or not (non-IS). The proportion (prop) of pts tested for molecular response in 3-mo intervals was tallied. Results: The study identified 189 pts (mean age 57 yrs, 53% male), 15% had no cytogenetic (cyto, FISH included) or molecular test (MT) recorded during 1st-line TKI therapy. The median number of MT was 6 (range: 1-28). In 3-mo intervals, the prop of pts tested for cyto responses were: 0-3 mos (24%), 3-6 mos (21%), 6-9 mos (24%), 9-12 mos (22%), 12-15 mos (10%), and 15-18 mos (7%). The prop of pts had MT in the 3-mo intervals were: 34%, 47%, 54%, 47%, 51% , and 55%. Regional patterns show the Northeast (defined by U.S. census regions) had a higher prop of pts for MT at almost all of these intervals. The number of physicians seeing CML pts correlated with the prop of pts monitored at each interval. Of the 1,226 MT ordered, 25% were reported on IS, 9% were unknown and 69% were on non-IS (Data reported: 48% log reduction, 45% BRC-ABL%, 7% other). Labs in the Midwest report on IS most often (61%), followed by the Northeast, Western (29% for both), and the South (13%). As the prac size increased, so did the utilization of IS. Conclusions: A low prop of CML pts were monitored for cyto and molecular responses. Only a quarter of the MT results were reported in IS. These results suggest gaps in CML management that could be closed with effective educational programs stressing the importance of monitoring and using IS reporting labs.

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 Results: Of 121 pts enrolled, 52 discontinued early: 29 (36.7%) in A and 23 (54.8%) in B. Median time to discontinuation was ∼20 months (mo) in A and ∼24 mo in B. Median time on ZOL on study was 22.5 mo for A and 20.8 mo for B. The mean age was 63.8 years (range, 34–90) with approximately 1:1 male:female ratio. By International Staging System criteria, 81.0% in A and 69.1% in B were Stage I/II, while 15.2% and 19.0% were Stage III. Median time from initial MM diagnosis to enrollment was 18.4 mo in A and 18.6 mo in B. A majority of pts in both groups had ≥1 osteolytic lesions at enrollment (A, 65.8%; B, 76.2%). The median duration of prior IVBP therapy was 13.8 mo in A and 14.4 mo in B. At enrollment, 72.2% in A and 78.6% in B had ≥1 SRE. The baseline mean (standard deviation) for uNTX and calculated CrCl was 19.88 (8.8) nmol/mmol Cr, and 85.1 (31.8) mL/min in A and 24.1 (15.6) nmol/mmol Cr and 84.3 (40.0) mL/min in B. Four pts started ZOL at q4 wk vs 117 pts at q12 wk based on uNTX at study entry. Of 117 pts assigned to q12-wk dosing, 79 stayed on schedule throughout the study; 38 pts switched to q4 wk (14 for increased uNTX, 4 for SREs, and 20 for disease progression). Only 7 pts (5.8%; all in A) had a SRE in study Year 1 (3 pathologic fractures, 3 spinal cord compressions, 4 radiation to bone, 1 surgery to bone, 1 hypercalcemia of malignancy). In Year 2, only 5 pts (4.1%) had a SRE (1 pathologic fracture, 4 radiation to bone). Baseline uNTX (low: Conclusions: The final Z-MARK results show that bone marker-directed dosing is feasible and safe in pts with 1–2 years of prior IVBP therapy. The low incidence of SREs on study shows that less-frequent IVBP dosing beyond 1–2 years continues to reduce the SRE risk and may reflect changing treatment patterns for MM that include therapies with bone protective effects. Baseline uNTX (≥28 nmol/mmol Cr) trended toward significance for predicting SREs. Finally, this study, which prospectively evaluated ONJ beyond 3 years, demonstrated an incidence rate of 3.3%. Further studies and additional follow-up are needed to determine the potential predictive value and long-term benefits of bone marker-directed ZOL dosing in MM pts after standard IVBP treatment. Disclosures: Raje: Amgen: Research Funding; Acetylon: Research Funding; Millenium: Consultancy; Celgene: Consultancy; Onyx: Consultancy; Eli-Lilly: Research Funding; Novartis: Consultancy. Off Label Use: Zoledronic acid (4 mg every 3–4 weeks) is indicated for the treatment of patients with multiple myeloma and patients with bone metastases from solid tumors. Vescio:Novartis Pharmaceuticals Corporation: Speakers Bureau. Hadala:Novartis Pharmaceuticals Corporation: Employment. Warsi:Novartis: Equity Ownership; Novartis: Employment. Ericson:Novartis Pharmaceuticals Corporation: Employment, Stocks Other. Anderson:Novartis Pharmaceuticals Corporation: Consultancy.

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 Methods: Community physicians who treat CML patients were invited to retrospectively submit information on Ph+ CML-CP patients in their practice who were ≥18 years old when started on first-line imatinib between 2006–2011 and who had ≥6 months of follow-up. Patients enrolled in clinical trials were excluded. Clinical characteristics at treatment initiation were collected. For each 3 month period after treatment initiation while the patient was on tyrosine kinase inhibitor (TKI) therapy, information was collected on molecular monitoring performed to assess treatment response. Information on death and progression to accelerated phase or blast crisis was collected over the entire follow-up period. Patients were grouped by the average number of QPCR tests received on TKI therapy (scaled to rate per year): the 0 tests group if they never had a QPCR test; the 1–2 tests group if they had on average more than 0 but 2 or less QPCR tests/year; and the 3–4 tests group if they had on average more than 2 but 4 or less QPCR test/year. Progression, mortality, and combined progression/mortality rates were reported for each group. In addition, Cox proportional hazards models were used to test the association between progression and progression-free survival and the average number of QPCR tests per year, controlling for the average number of cytogenetic tests per year, and for potential confounders including age, race, initial imatinib dose, Sokal score, and enlarged spleen at diagnosis. Results were reported as hazard ratios (HR) with 95% confidence intervals (CI). Results: 38 hematologists and oncologists from community practices throughout the US submitted information on 402 patients initiated on first-line imatinib. Patients were followed retrospectively for a median duration of 36 months. Of these, 52 (13%) had no molecular monitoring, 164 (41%) had 1–2 tests/year, and the remaining 186 (46%) had 3–4 tests/year. The figure below shows progression, mortality, and progression/mortality by frequency of molecular testing. The progression/mortality rates tended to decrease with the number of tests received. Adjusting for cytogenetic testing frequency and potential confounders aside from the Sokal score, a higher average number of QPCR tests per year was significantly associated with a lower rate of progression and longer progression-free survival. Each additional QPCR test per year significantly decreased the risk of progression by 45% (HR=0.55; CI [0.35, 0.87], p=0.011), and progression/mortality by 48% (HR=0.52; CI [0.35, 0.79], p=0.002]. Since 48% of patients did not have a reported Sokal score at diagnosis, a separate analysis was done to also adjust for the Sokal score among those without missing data, with nearly identical results. Conclusions: Ph+ CML-CP patients who underwent QPCR testing every 3–4 months experienced decreased progression and longer progression-free survival compared to those patients monitored less frequently, with the impact of molecular monitoring being independent of the frequency of cytogenetic testing. It is possible that molecular monitoring identifies impending treatment failure earlier and enables adjustment of therapy before hematologic and cytogenetic failure occur. This analysis underscores the value of molecular monitoring every 3 months for Ph+ CML-CP patients on TKI therapy and also demonstrates that a significant number of Ph+ CML-CP patients are not undergoing QPCR at the frequencies recommended in published guidelines. Additional community based education on CML monitoring is needed to assure optimal outcomes. Disclosures: Goldberg: Novartis Oncology: Research Funding, Speakers Bureau. Chen:Novartis Oncology: Employment, Own stock in Novartis Other. Ericson:Novartis Pharmaceuticals Corp: Employment, Own stock in Novartis Other. Macalalad:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Guerin:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Liu:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Kaminsky:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Wu:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding.

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 Results: A total of 177 patients, with a mean age of 61 years, met study criteria. The median duration of imatinib treatment was 35 months. The majority of patients (n = 144, 81%) had an ECOG score of 0–1. Among patients on therapy during the first 3 months (n = 168), most patients (n = 165, 98%) had a hematologic test as recommended by guidelines. The proportion of patients who had a cytogenetic test performed decreased over time for those on imatinib treatment who had not achieved CCyR, from 29% at 3 months to 17% at 18 months. Molecular monitoring frequency varied from 51% at 3 months to 56% at 18 months among those patients that were tested. Among patients who were monitored at least once for cytogenetic response within 18 months of initiating treatment with imatinib (n = 96), 50 patients had documented evidence of achieving CCyR. Among patients who were monitored at least once for molecular response within 18 months of initiating treatment with imatinib (n = 140), 37 patients had documented evidence of achieving MMR or CMR. Among the 37 patients achieving a CMR or MMR within 18 months, 21 (60%) had a subsequent molecular monitoring test within 6 months. Among 73 patients not achieving CMR or MMR by 18 months, there was a follow-up molecular monitoring test within 6 months for 53 (70%) patients. Additionally, patients who were regularly monitored for molecular response (n = 38) within the first 12 months of imatinib initiation did not have any indication of progressive disease, compared to 12% (n = 17) with progression among patients not regularly monitored within first 12 months of initiating imatinib (n = 139). Conclusions: This retrospective review of patients with Ph+ CML receiving imatinib in a community outpatient setting found that there is considerable under-monitoring of treatment response. This may result in under-detection of patients with treatment resistance or suboptimal response which limits the ability to modify or switch TKI treatment accordingly, and ultimately compromises patient outcomes. Results also suggest that compliance to monitoring guidelines may be associated with better clinical outcomes among patients that may experience early resistance to imatinib. Possible limitations of this study may include missing data (e.g., omission of tests or testing results) due to retrospective nature of the chart review. Disclosures: Jackson: Novartis: Received funding from Novartis for research study Other. Chen:Novartis Oncology: Employment, Own stock in Novartis Other. Sail:Novartis: Received funding from Novartis for research study Other. Ericson:Novartis Pharmaceuticals Corp: Employment, Equity Ownership.

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.

Abstract 2781 Background: The WORLD CML Registry, with sites in the US, Latin America, Asia-Pacific, the Middle East, Africa, Russia, and Turkey, is a multinational, prospective registry established to longitudinally assess global clinical practice patterns for the management of patients (pts) with CML. Here, we report updated results for the subgroup of pts at US sites and evaluate alignment of US practice patterns with current National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for CML (http://www.nccn.org). Methods: Pts (≥ 16 y of age) within 6 mo + 2 weeks of confirmed CML diagnosis were enrolled. Baseline demographics and medical history were collected at enrollment. Information on disease status and management was collected approximately every 6 mo or with a change in disease status or management. Adverse events (AEs) were collected only if they resulted in a dose/regimen change, nonadherence to treatment, or death. Results: This analysis includes 377 evaluable pts (those with confirmed informed consent forms and no protocol deviations) of 418 total pts enrolled in the US from February 2008 to December 31, 2010. Median age was 53 y (range, 18–91 y), with 26% ≥ 65 y of age. CML diagnosis was confirmed using hematologic (85%), bone marrow (84%), cytogenetic (82%), and molecular (polymerase chain reaction [PCR]; 52%) assessments. Nearly all pts (96%) were diagnosed in chronic phase (CP; Table). Most pts with CML-CP (73%) were treated with imatinib (Glivec®/Gleevec®) as first-line therapy (additional pts may have received first-line imatinib in a clinical trial). Median duration of imatinib treatment in CML-CP pts was 7.59 mo (range, 0.03–33.54 mo). In CML-CP pts (n = 363), imatinib dose was increased in 29 pts (8%; primary reasons included physician request [4%] and lack of efficacy [7%]), decreased in 32 pts (9%; primary reasons included AEs [5%] and physician request [3%]), and interrupted in 10 pts (3%; primary reasons included AEs [2%]). Regimen was switched from imatinib to nilotinib in 21 pts (6%; primary reasons included lack of efficacy [2%] and AEs [2%]) and to dasatinib in 20 pts (6%; primary reasons included AEs [2%], lack of efficacy [1%], and physician request [1%]). Disease burden over time on imatinib was most commonly assessed using blood counts (Table). Only 16% of pts had a molecular assessment at 3 mo; at later time points, 43%-64% of pts had molecular assessments. Cytogenetics was least common (done in 13% of pts at 3 mo and 25%-34% of pts at later time points). AEs reported in ≥ 1% of all pts in the analysis were nausea (3%), fatigue (2%), rash (2%), diarrhea (2%), headache (2%), thrombocytopenia (2%), neutropenia (1%), and dyspnea (1%). There were 17 deaths (5%) reported; 5 deaths were related to CML progression, 1 was related to CML treatment (necrotizing pneumonia), 7 were unrelated to CML treatment, and 4 had unknown causes. Conclusions: In the US, many pts treated with first-line imatinib did not have routine molecular or cytogenetic assessments, suggesting that many US physicians do not monitor their patients as recommended by the NCCN guidelines. These findings may reflect the lack of readily available molecular testing during part of the time period evaluated by this registry. Disclosures: Hermann: Novartis: Sponsor -paid expenses of reported trial Other. Miller:Novartis: Consultancy, Research Funding, Speakers Bureau, development of educational presentations Other; Incyte: development of educational presentations, development of educational presentations Other. Snyder:Novartis: 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. Ericson:Novartis Pharmaceuticals Corp: Employment, Equity Ownership. Zernovak:Novartis Pharmaceuticals Corp: Employment, Equity Ownership. Juma:Novartis Pharmaceuticals Corp: Employment. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding.

Abstract 3782 Background: A large number of Ph+ CML pts treated with IM experience mild to moderate AEs that can negatively impact QoL. A recent study (Efficace F et al. Ann Hematol. 2012) reported that pts and healthcare professionals ranked several AEs induced by BCR-ABL tyrosine kinase inhibitors (fatigue ranked first) in the top 10 issues that adversely impact QoL in pts. The primary objective of the ongoing ENRICH study is to evaluate improvement of IM-related chronic low-grade nonhematologic AEs at the end of cycle (EOC) 3 (ie, after 12 weeks) in CML-CP pts when switched from IM to NIL because of chronic low-grade AEs. This is a report on 45 evaluable pts who completed EOC 3 as of the data cut-off (6/1/2012). Methods: Pts were eligible if they were treated with IM 400 mg/d for ≥3 mo and had IM-related grade (G) 1/2 nonhematologic AEs persisting '2 mo or recurring ≥3 times and recurring despite best supportive care. The study planned to enroll 50 pts in the US and Canada. Pts received NIL 300 mg twice daily for 1 y (or longer if NIL was not yet commercially available for frontline treatment). Nonhematologic AEs were graded using the Common Terminology Criteria for Adverse Events (version 4.03; 6/14/2010) grading scale. Molecular response was monitored by a central PCR lab monthly for the first 3 mo and then every 3 mo on study. Pt-reported outcomes, measured by 2 QoL questions and the MD Anderson Symptom Inventory (MDASI)-CML, were administered at baseline, EOC 1, EOC 3, and then every 3 mo thereafter. Results: 52 pts were enrolled into the study; enrollment closed in January 2012. The median duration (range) of previous IM treatment (tx) was 24.7 mo (2.3–123.0 mo); median duration (range) of NIL tx was 11.9 mo (0.2–23.7 mo). At baseline 199 IM-related nonhematologic AEs were reported (141 G1; 58 G2). Data for 49 pts were available and included in the safety and molecular response analyses; 45 pts were included in the primary end point analysis since 4 withdrew consent prior to EOC 3. These 45 pts accounted for 183/199 of the baseline IM-related AEs (130 G1; 53 G2); 1 AE evaluation is missing at EOC 3. 130/182 AEs (71.4%) improved by EOC 3 (primary end point): 117 resolved (90, 19, 8 by mo 1, 2, 3, respectively) and 13 improved from G2 to G1 (Table). By EOC 3, 64.1% and 53.8% of pts (n = 39) reported an improvement in global QoL from baseline over the last 24 h and last 7 d, respectively. Mean reductions from baseline in MDASI-CML severity score and interference score, and therefore improvement in symptoms, were 1.1 (n = 40) and 1.4 (n = 39) at EOC 1, and 1.2 (n = 39) and 1.7 (n = 38) at EOC 3, respectively. At baseline, 31/49 (63.3%) pts had major molecular response (MMR, 3-log reduction of BCR-ABL1; ≤0.1% IS); 18 and 10 pts had 4-log (MR4; BCR-ABL1 ≤0.01% IS) and 4.5-log reductions (MR4.5; BCR-ABL1 ≤0.0032% IS) in BCR-ABL1, respectively. After switch to NIL, all pts with a baseline MMR maintained MMR and 14/17 remaining pts without baseline MMR achieved MMR. Deeper responses were reported for 16 pts who reached MR4 after the switch, and 14 reached MR4.5. 20 pts were dose-reduced for NIL-related AEs, 2 of whom did not restart study drug. The other 18 pts were dose-reescalated to the original dose when the AEs improved to G1 or resolved. 40 G3 AEs occurred in 19 pts; of these, 24 AEs were investigator-reported as suspected to be NIL-related (hypophosphatemia, hyperglycemia, hypokalemia, increased bilirubin, increased lipase, arthralgia, pleural effusion, acute pancreatitis, dehydration, bronchitis, pruritus, rash, erythematous rash, exfoliative rash, papular rash, abdominal pain, gastroenteritis, and joint pain). 1 G4 AE (cardiac arrest, NIL-suspected) was reported; the pt recovered from the event but was discontinued from the study. Most AEs were managed by brief dose interruption. 9 pts discontinued study (5 due to AEs; 4 withdrew consent). No QTcF prolongation >500 msec occurred. Conclusions: The majority of IM-related nonhematologic AEs improved within 3 mo after switching to NIL; nearly half of the AEs resolved by EOC 1. More than half of pts experienced improvement in QoL and symptom burden on NIL. In general, pts achieved deeper molecular responses on study and approximately a quarter of pts reached MR4.5 after the switch to nilotinib. Disclosures: Cortes: Bristol-Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding; Ariad Pharmaceuticals: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; ChemGenex Pharmaceuticals: Consultancy, Research Funding; Deciphera Pharmaceuticals: Research Funding. Lipton:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Miller:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Ailawadhi:Millennium Pharmaceuticals: Consultancy, Honoraria. Akard:Cellerant: Research Funding; ChemGenex: Research Funding; Millennium: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria; Bristol Myers-Squibb: Honoraria; Pfizer: Research Funding. Pinilla-Ibarz:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Research Funding. Lin:Novartis Pharmaceuticals: Employment, Equity Ownership. Ericson:Novartis Pharmaceuticals Corp: Employment, Equity Ownership. Mauro:Novartis Pharmaceuticals: Consultancy, Honoraria.

6605 Background: This study update assesses change in chronic LG non-heme AEs in adult Ph+ CML-CP pts switched from IM to NIL. Methods: Pts were eligible if treated with IM 400 mg/d for ≥3 mo, and had IM-related grade (G) 1/2 non-heme AEs persisting ≥2 mo or recurring ≥3 times and persisting despite best supportive care. Pts received NIL 300 mg BID. Primary endpoint is change in IM-related LG non-heme AEs at 3 mo. Disease response was monitored by RQ-PCR and pt-reported outcomes measured by 2 quality-of-life (QoL) questions and MD Anderson Symptom Inventory (MDASI)-CML. Results: 47 pts were enrolled as of data cut-off (11/14/2011). There were 168 baseline IM-related non-heme AEs: 121 G1, 47 G2. 37 pts completed 3 mo NIL, by 3 mo 103 of 154 IM-related AEs (67%) improved (92 resolved, 11 improved from G2 to G1), 47 unchanged, 4 increased in severity. 13 pts were dose reduced for NIL-related AEs; 8 pts re-escalated after AEs recovered to G1 or resolved. 34 G3 AEs occurred in 15 pts; investigators reported 19 AEs as suspected NIL-related (increased bilirubin, lipase, or blood glucose; hypokalemia; hypophosphatemia; pruritus; bronchitis; dehydration; rash; arthralgia; pleural effusion). 8 pts discontinued NIL: 6 for AEs, 2 withdrew consent. No G4 AEs were reported. 32 pts had MMR (3-log reduction of Bcr-Abl; ≤0.1% IS) at entry; 16 additional pts achieved MMR on NIL. At entry, 18 pts had 4-log reduction and 10 pts 4.5-log reduction in Bcr-Abl. 16 and 13 additional pts achieved 4- and 4.5-log reduction, respectively, on NIL. At 3 mo (n=34) 62% and 53% pts reported QoL improvement from baseline in the previous 24 h and 7 d, respectively. Reduction in MDASI-CML severity/interference scores indicates symptom improvement. Mean reductions in MDASI-CML from baseline at 3 mo: severity, 1.21 (n=34); interference, 1.55 (n=33). Conclusions: 3 mo after switching to NIL, ~70% baseline chronic LG non-heme IM-related AEs improved and ≥53% of pts reported improvement in QoL. Molecular responses were maintained or improved in all patients. Switch from IM to NIL in majority of pts reduces IM-related toxicities and preserves/induces molecular response in CML-CP.

6594 Background: The objective of this study is to evaluate compliance to National Comprehensive Cancer Network (NCCN) and European LeukemiaNet (ELN) guidelines regarding monitoring frequency and switching practices in CML patients (pts) treated with IM in community practices. Methods: Physicians treating CML pts were selected from 28 community practices throughout the USA. Each physician reviewed and extracted up to 15 pt charts of CML pts in chronic phase not previously enrolled in clinical trials. Pts were required to have initiated 1st-line IM between 1/2006 - 10/2010. Data on 1st-line IM treatment response monitoring frequency and outcomes, and corresponding therapy switching patterns were extracted. Results: Information was collected on treatment monitoring and response from a total of 297 pt charts. Median IM duration was 320 days. Percentages of pts monitored according to both guidelines are reported. In addition, the proportion of pts who missed milestones and the proportion of pts who did not switch to a 2nd-line tyrosine kinase inhibitor (TKI) when they missed milestones are reported. Conclusions: There is considerable undermonitoring of CML pts receiving IM, which is likely to result in a significant portion of pts with suboptimal response left undetected. The switching rate to 2nd-line TKI among pts with suboptimal response to IM is much lower than recommended by either NCCN or ELN guidelines. [Table: see text]

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.

Abstract 5122 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 Methods: MM patients (N=121) who had started standard monthly IV BP (ZOL or pamidronate, PAM) 1–2 years prior to enrollment and received ≥4 prior doses, with baseline calculated creatinine clearance (CrCl) of ≥30 mL/min, were enrolled. Patients received 4mg IV ZOL q4 or q12 weeks based on their most recent urine NTX (uNTX) measurement (uNTX≥50 nmol/mmol Cr - infusion q4 weeks, uNTX Results: As of the May 9, 2011 data cut-off date, 31.3% (9.6% due to AEs, 14.5% withdrew consent, and 7.2% due to other reasons) in A and 36.8% (15.8% due to AEs, 10.5% withdrew consent, and 10.5% due to other reasons) in B discontinued early. The mean age was 63.8 years, with approximately 1:1 male/female ratio. The baseline mean (SD) for uNTX and calculated CrCl was 21.3 (11.8) nmol/mmol Cr and 84.8 (34.7) mL/min, respectively. Based on the International Staging System, 79.5% of the patients were stage I or II and 14.5% were stage III at enrollment in A. The same in B were 71.1% and 21.1%. The median time from initial MM diagnosis to enrollment was 18.4 months in both groups. In A, 67.5% had ≥1 osteolytic lesions and of these 37.5% had >6; in B, 73.7% had ≥1 and of these 42.9% had >6. In A, 83.1% had received ZOL only, 13.3% had received PAM only; in B, 92.1% had received ZOL only and 2.6% had received PAM only prior to enrollment. The median duration of prior BP therapy was 13.8 in A and 14.8 months in B. In A, 73.5% had ≥1 SREs at enrollment; in B the same was 76.3%. Four patients started study ZOL treatment on the q4-weeks dosing schedule and 117 patients started on the q12-weeks schedule (based on uNTX values at study entry). Thirty four of 117 patients assigned to q12-week dosing were switched to q4 weeks (14 due to increased uNTX, 4 due to SREs, and 16 due to disease progression). In study Year 1, no patient in A had any SRE while 7 patients in B had SREs (3 pathologic fractures, 3 spinal cord compressions, 4 radiations to bone, 1 surgery to bone, 1 hypercalcemia of malignancy). Only 5.8% of patients had any SRE in the first year. In A, 90.4% of patients had any adverse event (AE) while it was 100% in B. The most common AEs were upper respiratory tract infection (23.1%), fatigue (23.1%), cough (19%), diarrhea (19%), pneumonia (18.2%), pyrexia (18.2%), arthralgia (16.5%) and nausea (15.7%). The percentage of patients with any serious AE was 26.5 in A and 57.9 in B. Overall, 14.9% (12.0% in A, 21.1% in B) of patients had an AE leading to ZOL discontinuation. At Week 48, the median % change in uNTX was −11.1 in A and 12.5 in B. For serum Cr, no change in the median was observed in either group at Week 48. One death was reported on study (not suspected to be related to ZOL). There were 3 reports of osteonecrosis of the jaw (ONJ) in A, suspected to be related to ZOL, and no report of ONJ in B; the median time on ZOL was 17.0 months for A and 17.3 months for B. Discussion: These Z-MARK PA results show that bone marker directed dosing is feasible in patients who had 1–2 years of prior IV BP therapy. The low number of SREs observed within 1 year of study follow up is possibly due to the persistent protective effects from IV BP treatment prior to study entry and on study. Additional follow up is needed to determine the potential predictive value and the long-term benefits of bone marker directed dosing of ZOL in MM patients following standard IV BP treatment. Disclosures: Raje: Acetylon: Research Funding; Astra Zeneca: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Zoledronic acid: Studying alternate dosing schedule in multiple myeloma(bone marker directed dosing). Vescio:Novartis Pharmaceuticals Corporation: Speakers Bureau. Tran:Novartis Pharmaceuticals Corporation: Employment. Warsi:Novartis: Employment, Equity Ownership. Argonza-Aviles:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Ericson:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Anderson:Novartis Pharmaceuticals Corporation: Consultancy.