Search

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.

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.

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

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.

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.

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.

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 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 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.

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]

6615 Background: IM cross-intolerance on NL is rare (4% in the NL registration study). This ongoing study assesses change in chronic LG non-heme AEs when pts are switched from IM to NL. Methods: Pts were eligible after treatment with IM 400 mg/d ≥3 months (mos) and IM-related G 1/2 non-heme AEs persisting ≥2 mos or recurring ≥3 times and persisting despite best supportive care. Pts received NL 300 mg BID. Primary endpoint was change in IM-related LG non-heme AEs after 3 mos on NL. Disease response was monitored and patient reported outcomes measured by Quality of Life (QoL) questionnaire and MD Anderson Symptom Inventory (MDASI)-CML. 23 pts enrolled as of data cut-off (11/30/10) were analyzed. Results: Median time on NL was 3.57 mos. Of 105 baseline IM-related non-heme AEs, 33 were G2, 72 were G1. 15 pts completed cycle 3 by data cut-off; 45 of 75 IM-related AEs improved (30, 7, 3 resolved by mos 1, 2, 3, respectively; 5 decreased from G2 to G1), 27 were unchanged, 3 increased in severity. 20 pts had MMR ...

Background: Aromatase inhibitor (AI) therapy effectively increases disease-free survival in postmenopausal women (PMW) with ER+ and/or PR+ breast cancer (BCa). However, the use of AIs results in nearly complete ablation of estrogen production which can lead to accelerated bone loss and increased fracture risk. The Z-FAST study evaluated the efficacy and safety of zoledronic acid (ZOL) in preventing AI associated bone loss in PMW with early breast cancer (EBC) who received adjuvant letrozole (LET).Material and Methods: 602 PMW with stage I-IIIa ER+ and/or PR+ BCa starting LET (2.5 mg qd x 5 yrs) were randomized (1:1) to upfront ZOL (4 mg IV q 6 mos) vs delayed ZOL. The delayed arm (D) received ZOL when either the post-baseline T-score decreased to -1), and no U pts as compared to 4.9%(4) D pts became severely osteopenic (T Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4083.

Abstract #2067 Background: Changes in biochemical markers of bone turnover are expected to be predictors of long-term changes in bone mineral density (BMD). We studied the potential of bone-specific alkaline phosphatase (BSAP) and serum N-telopeptide (sNTX) at 6 and 12 months (mo) in predicting BMD of the lumber spine (LS) and total hip (TH) at 48 mo in Z-FAST study. Methods: Postmenopausal women with ER+ and/or PR+ early stage breast cancer were randomized 1:1 into Up-front (U) or Delayed (D) arms (N=301 in each). Patients (pts) in U received zoledronic acid (ZOL) 4 mg IV q6 mo starting at baseline; pts in D started ZOL q6 mo when their LS or TH T-score fell below -2. All pts started Letrozole 2.5 mg/day for 5 years. Levels of BSAP and sNTX were assessed at screening and every 6 mo on a subset of pts. LS and TH BMD were assessed by dual-energy x-ray absorptiometry (DEXA) at screening, 6 mo and every 12 mo thereafter for all available pts. This is an exploratory analysis to investigate the correlation between short-term % changes from baseline in BSAP and sNTX and long-term % changes from baseline in BMD. Pearson correlations and Receiver Operating Characteristics (ROC) analysis were performed. We report the results based on 48 mo data. Results: The Pearson correlations between % change in BSAP at 6 mo and LS BMD at 48 mo were -0.13 [(N=38, not significant (NS)] and -0.17 (N=39, NS) in arms U and D respectively. The correlations between % change in BSAP at 12 mo and LS BMD at 48 mo were -0.15 (N=39, NS) in U and -0.43 (N=38, p=0.0077) in D. Very similar correlations were obtained for % change in sNTX at 6, 12 mo and LS BMD at 48 mo in D, but in U the correlations were smaller and positive. The correlations between % change of both markers at 6, 12 mo and TH BMD at 48 mo were all NS at 0.05. ROC analysis showed that at best performance (maximum of sensitivity plus specificity), for any increase in sNTX at 12 mo, the sensitivity (SE), specificity (SP), positive predictive value (PPV) and negative predictive value (NPV) to predict LS BMD loss at 48 mo was 74%, 77%, 85% and 63% in D. For BSAP change of 3%, the four ROC parameters were 71%, 71%, 81% and 59% respectively. For prediction of TH BMD loss, the SE, SP and NPV were lower for both markers with higher PPV. In U, the SE, SP and PPV were all much lower with very high NPV for both markers and BMD loss. Conclusion: Interim results of Z-FAST data show that short-term changes in BSAP and sNTX have the potential for predicting long-term bone loss. The weaker correlations in U also suggest that zoledronic acid may have a direct preventive effect on bone loss independent of changes in the markers. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2067.

6553 Background: Allogeneic stem cell transplantation is used to treat different types of hematologic malignancies. The target stem cell dose typically is based on the recipient’s ideal body weight (IBW) with CD34 dose of 2.0–5.0 ×106/Kg. The dose of CD3 in the infusate is typically not taken into account in a stem cell product, except in T-depleted transplantation. The dose of T-cells in peripheral blood stem cell collections has been found to be at least 10-fold more than that in a bone marrow harvest product. Combined CD4+ and CD25+ cells infused have been directly correlated with increased incidence of GVHD. Methods: This is a retrospective study reporting the correlation of the CD34 and CD3 doses of stem cell transplant with incidence of acute GVHD in 67 consecutive patients who were treated between 2003 and 2005. All patients were followed up for at least 100 days following the stem cell transplant. Results: Among the 67 patients, 35 patients developed acute GVHD, while 32 patients had no evidence of acute GVHD. The CD3 and CD34 doses did not correlate. The correlation coefficient was 0.14 (P value: 0.27). Using t-test, there was NO statistical difference between the mean CD34 dose when comparing the group of patients who developed acute GVHD with the group that did not develop acute GVHD (P value: 0.31). Those who developed acute GVHD (n = 35) received a mean CD3 dose of 41.9 × 107/kg IBW (95% CI: 35.9–47.9). Those who did NOT develop acute GVHD (n= 32) received a mean CD3 dose of 33.5 × 107/kg IBW (95% CI: 27.3–39.8). By using the t-test, the P value for the different means was 0.0575. However, using a CD3 dose cutoff value of 30 × 107/kg IBW, the incidence of acute GVHD was statistically significantly less among those who received CD3 dose < 30 × 107/kg IBW. The Chi Square P value was 0.04. Conclusions: In our series, CD3 dose less than 30 × 107/kg IBW was associated with reduced risk of acute GVHD (P value: 0.04). There was no correlation between CD3 and CD34 counts in peripheral stem cell product. In addition, the CD34 dose did not influence the incidence of acute GVHD. These data suggest that, in addition to considering CD34 dose required for engraftment in allogeneic transplant, the CD3 dose will need to be considered to try to minimize the risk of acute GVHD. No significant financial relationships to disclose.