ALBERT

Description: BACKGROUND: PVF contribute significantly to MM morbidity and disability but are poorly characterized at the population level. We studied the inpatient outcomes for a population-based sample of MM patients to better describe the burden of PVF and patterns of acute management, including use of newer vertebral augmentation (VA) techniques such as vertebro-/kyphoplasty. Methods: Using data from the Nationwide Inpatient Sample and ICD-9CM diagnosis codes, we identified adult PVF cases among MM admissions (N = 54,790) to all US hospitals in calendar year 2005. Admissions were described by patient (age, gender, race, adjusted Charlson comorbidity score, primary payer) and hospital type (control, location, teaching status, bedsize). Admissions complicated by spinal cord injury (SCI) were identified and described, but excluded from further analyses. Data regarding therapeutic interventions was extracted for radiotherapy, chemotherapy, spinal surgery, and VA using ICD-9CM procedure coding. We then examined hospital costs (charges transformed using Medicare cost-to-charge ratios), length of stay (LOS) and mortality by intervention. Factors influencing use of VA technology were explored in multivariate logistic regression models. All analyses were sample weighted. Results: A group of 3641 PVF admissions was extracted. Mean LOS was 8.9 days (95%CI 8.2–9.7) and mean costs were $19,290 (95%CI $16,395–22,184). Summary statistics for the uncomplicated group, including rates for therapeutic interventions, are given in the table. Intervention N (%) [95% CI] Mean LOS in Days [95% CI] Mean Costs in $US [95% CI] Radiotherapy 299 (8.3%) [224–374] 11.1 [9.1–13.1] $19,671 [$15,352–23,989] Spinal Surgery 217 (6.0%) [122–313] 11.9 [6.5–17.3] $40,976 [$25,784–56,169] Vertebral Augmentation 1063 (29.5%) [436–1690] 6.8 [5.8–7.9] $19,201 [$17,316–21,088] SCI complicated only 32 (

Description: Abstract 1233 Poster Board I-255 Introduction Cytogenetic analysis has become a routine part of the evaluation of patients with chronic lymphocytic leukemia (CLL) because specific chromosomal aberrations have been shown to assist in predicting disease progression, treatment efficacy, and overall survival. One such abnormality is del(17p13.1), which has been found to be associated with a need for early therapy, poor response to conventional treatment, and shortened survival. Identification of recurring abnormalities in this region represents great interest to identify genes relevant to CLL progression and poor prognosis. Patients and Methods We performed an extensive review of 1213 patients undergoing metaphase cytogenetics study at our institution and identified 16 (1.3%) with a recurrent unbalanced translocation between the p arms of chromosomes 17 and 18 that results in a dicentric chromosome with loss of much of 17p and 18p. The clinical features of these patients were characterized. Results A total of 16 patients were identified to have dic(17;18)(p11.2;p11.2) representing a 1.3% occurrence rate. The median age at diagnosis of these patients was 57 years (range 37-68). The dic(17;18)(p11.2;p11.2) was associated with a complex (3 or more unrelated cytogenetic abnormalities) karyotype in 12 patients (75%) at the time that the abnormality was first identified, and eventually associated with a complex karyotype in 94% of patients. This abnormality was associated with trisomy 12 in 7 patients (44%) and with del(13q) in 5 patients (31%) with no overlap between these two abnormalities. IgVH mutational analysis was un-mutated in 88% of cases. Except for one patient who was diagnosed with CLL incidentally during a workup for metastatic tonsillar cancer, all patients identified with dic(17;18)(p11.2;p11.2) met criteria for disease treatment, with a median time from diagnosis to first treatment of 15 months. Of the 12 patients who received fludarabine-based therapy, 7 (58%) were refractory. Three patients have received stem cell transplant for recurrent/refractory disease, and 4 are currently undergoing chemotherapy. With a mean follow-up of 54 months, 4 patients have died, 21, 42, 49, and 92 months after diagnosis. Conclusions Our study combined with small series reported by others demonstrate that dic(17;18)(p11.2;p11.2) is a novel recurrent cytogenetic abnormality in CLL. Here we demonstrate the clinical significance of this recurring abnormality that is associated with young age at diagnosis, accelerated disease progression, decreased response to fludarabine, and shortened overall survival. The dic(17;18)(p11.2;p11.2) is frequently accompanied by other negative prognostic markers including a complex karyotype and unmutated IgVH status. Additional studies to further characterize the prevalence of this abnormality and genes that are disrupted by the translocation are warranted. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 3725 Poster Board III-661 CD19 is a lineage-specific B-cell antigen, expressed at a high density on CLL cells, that contributes to B-cell receptor signaling but to date has not been effectively targeted with therapeutic monoclonal antibodies. XmAb5574 is a novel engineered anti-CD19 monoclonal antibody with a modified Fc-domain designed to enhance binding of FcγRIIIa that is predominately expressed on Natural Killer (NK)-cells. Utilizing freshly isolated chronic lymphocytic leukemia (CLL) patient B-cells we demonstrate that XmAb5574 lacks significant internalization seen with other anti-CD19 antibodies [maximum internalization for XmAb5574 was only 27.9% at 30-minutes (95%CI 14.5%, 41.4%)], thereby enhancing its ability to induce potent antibody-dependent cellular cytotoxicity (ADCC). Annexin V/PI flow cytometry analysis revealed that XmAb5574 mediates modest direct cytotoxicity not significantly different from Rituximab (0.6% increase, 95%CI -10.5%, 11.7%, p=0.91), and no complement mediated cytotoxicity (CDC) against primary CLL B-cells. Multi-color flow cytometry and monocyte derived macrophages (MDM) were used to assess XmAb5574 antibody dependent cellular phagocytosis (ADCP) against CLL cells and revealed no significant impact of the Fc-domain modification on MDM induced ADCP against CLL cells as compared to the wild type parental anti-CD19 antibody (12.37% vs. 10.51%, p=0.58). Interestingly, utilizing NK-cells and CLL cells isolated from normal donors and CLL patients, and employing autologous and allogeneic effector-target (E:T) conditions, XmAb5574 was found to mediate significantly higher ADCC when compared to the control humanized anti-CD19 non-engineered antibody (26.9% higher at E:T 25:1, p=0.0004 for allogeneic conditions, and 23.6% higher, p=0.004 for autologous conditions). ADCC mediated by XmAb5574 was also significantly higher as compared to Rituximab (33.5% higher at E:T 25:1, p

Description: Allogeneic hematopoietic stem cell transplantation (ASCT) may produce long-term remissions in patients with CLL, however toxicity has limited the success of myeloablative regimens. We pursued a strategy of reduced intensity conditioning (RIC) allogeneic stem cell transplantation (ASCT) in patients (pts) with heavily pretreated relapsed and/or refractory CLL. Twenty-seven pts with advanced CLL underwent ASCT following RIC at our institution between March 2002 and May 2008. There were 20 male and 7 female pts with a median age of 52 years (range 43–69 yrs).Median number of prior therapies was 3 (range 2–11). 26 pts (96%) had previously received fludarabine (F) based chemotherapy. 55% (n=15) had chemorefractory disease. Karyotype assessment by FISH (Fluorescent in situ hybridization) revealed high-risk cytogenetics in 55% (n=15) of the pts (−17p13.1 or −11q22–23). Donors were matched siblings (n=14) or unrelated volunteers (n=13). Stem cell source was peripheral blood (n=26) or bone marrow (n=1). Minimal residual disease (MRD) was assessed with 4-color flow cytometry on bone marrow biopsy specimens posttransplantation. Conditioning regimens included F/TBI/Campath (n=8), F/Busulfan with (n=9) or without ATG (n=6), and F/Cyclophosphamide (n=4). GVHD prophylaxis consisted of tacrolimus/MMF (n=8) or tacrolimus/methotrexate (n=19). All pts engrafted neutrophils and platelets promptly (median 16 and 20 days, respectively). Following allografting 15 pts (55%) achieved complete remission (CR), while 5 were in partial remission (PR). Overall response rate (CR+PR) was 74%. 13 pts (48%) in CR were MRD negative. Among pts with chemorefractory disease the overall response rate was 73%, with 8 pts achieving CR (7 MRD negative). Compared to pts with high-risk cytogenetics, those with low-risk cytogenetics were more likely achieve MRD negative state (58% vs. 40%). No impact of conditioning regimen or development of chronic GVHD with MRD negative state was seen. Rates of grade II–IV and III–IV acute GVHD were 55% (n=15) and 11% (n=3) respectively. 19 pts (70%) developed chronic GVHD, while extensive chronic GVHD was seen 37% (n=10). Cumulative incidence of relapse was 25%. 4 pts underwent DLI at relapse. Two of these pts remain in CR at +15 months post DLI. A fifth patient received DLI to successfully eradicate MRD. The median follow-up of surviving patients is 15 months (range 3–70 months). Day 100 and overall non-relapse mortality was 0% and 11% (n=3) respectively. At last followup 7 pts have died. Causes of death included disease progression=4, GVHD=1, second malignancy=1, and hepatic failure=1. Rates of overall survival (OS) and progression free survival (PFS) at 2 years are 61% and 41% respectively. On univariate analysis donor type, remission at transplant, and number of prior therapies were not associated with OS or PFS. Pts with high-risk cytogenetics by FISH showed trends towards worse OS (31% vs. 75%; p-value=0.13) and PFS (21% vs. 57%; p-value=0.09). Pts younger than 55yrs had superior OS (p-value=0.05) and PFS (0.005). Pts achieving MRD negative state had superior PFS (57% vs. 29%; p-value=0.01), and trends toward improved OS (67% vs. 57%; p-value=0.13). PFS advantage in MRD negative pts persisted even after adjusting for cytogenetic riskcategories. On multivariate analysis only MRD negative state remained significant for superior PFS (p-value=0.01; 95% CI 0.008–0.61). In conclusion, RIC regimens for ASCT in CLL are associated with low TRM, and approximately half of pts were able to achieved MRD negative status. These pts experienced durable remissions, regardless of cytogenetic risk status. Novel strategies promoting elimination of MRD following allografting, especially in high-risk CLL pts, are warranted.

Description: Abstract 3443 Poster Board III-331 Introduction The first Phase I-II clinical trial of oxaliplatin, fluradabine, cytarabine (Ara-C), and rituximab (OFAR1) demonstrated significant activity in refractory CLL and RS (Tsimberidou et al, J Clin Oncol, 2008;26:196). To enhance the response rate and decrease myelosuppression, the dose of oxaliplatin was increased to 30mg daily, the dose of Ara-C was decreased to 0.5g/m2 daily and the optimal number of days of fluradabine and Ara-C administration was explored (OFAR2). Methods In a Phase I-II study of OFAR2, patients were treated with oxaliplatin 30mg/m2, D1-4; fludarabine 30mg/m2, Ara-C 0.5g/m2; rituximab 375mg/m2, D3; and pelfigrastim 6mg, D6. Fludarabine and Ara-C were given on D2-3 (dose level 1) D2-4 (dose level 2) or D2-5 (dose level 3); courses were repeated every 4 weeks. Patients received prophylaxis for tumor lysis, DNA viruses, and PCP. A “3+3” design was used and the planned number of patients in the Phase II was 90 (CLL, 60; RS, 30). Results Ninety-one patients (CLL, 67; RS, 24) have been treated to date: Phase I, 12 patients (by dose level: 1, n=3; 2, n=6; and 3, n=3). DLTs were noted in 2 of 3 patients on dose level 3 (G4 diarrhea, 1; G4 neutropenic sepsis, 1); thus, dose level 2 was the MTD. Seventy-nine patients (relapsed CLL, 58; RS, 19) have been treated in the Phase II portion of the study. Patient characteristics were as follows: age 〉 60 years, 65%; 17p deletion, 38%; 11q deletion, 13%; 13q deletion, 16%; trisomy 12, 21%; no findings, 12%; unmutated IgVH, 80%; ZAP70-positive, 75%; and CD38 ≥30%, 58%. Response in patients treated in the Phase II recommended dose is shown in Table (evaluable, 67). The overall response rates in patients with 17p and 11q deletions were 48% and 55%, respectively. The median survival duration was 21 months (CLL, 21 months; RS, 9.5 months). At 18 months, the survival rates in patients with 17p and 11q deletions were 66% and 76%, respectively. Twelve patients underwent stem cell transplantation after OFAR2 (as post-remission therapy, n=10; as salvage, n=2). Overall, 196 cycles were administered. Grade 3-4 neutropenia, thrombocytopenia, and anemia were noted in 63%, 72%, and 39% of patients and in 57%, 70%, and 25% of cycles and Grade 3-4 infections in 19% of patients. Conclusion Preliminary results demonstrated that OFAR2 induced response in 40% of patients with RS and 63% of patients with relapsed/refractory CLL. OFAR2 had antileukemic activity in patients with 17p deletion. Clinical outcomes appeared to be superior to those of OFAR1 in refractory CLL, whereas results of OFAR1 appeared to be superior to those of OFAR2 in RS. Accrual is ongoing. Disclosures Tsimberidou: ASCO: ASCO Career Development Award; Sanofi: Research Funding. Off Label Use: Oxaliplatin is used off-label. Wierda:Genentech: Honoraria; Bayer, Sanofi-Aventis, Abbott, GSK: Research Funding; GSK, Trubion, Ligand, Genentech, Medimmune, Abbot: Consultancy; Celgene: Speakers Bureau. Plunkett:Sanofi-Aventis: Research Funding. O'Brien:Genentech: Research Funding; Sanofi: Consultancy. Kipps:NCI: Grant P01CA-81534.

Description: BACKGROUND: The influence of comorbid medical illness on treatment outcome and survival from LM has been well-characterized. Recent reports suggest that optimal management of these comorbidities may also be important. We sought to indirectly determine the effectiveness of outpatient treatment for ACSCs, conditions where good outpatient care can potentially prevent the need for hospitalization, by calculating population-based estimates of hospital admission rates among patients with LM. Methods: Data were obtained from the 2005 Nationwide Inpatient Sample. Using ICD-9CM codes, we identified all adult (age ≥20) admissions to U.S. community hospitals for LM (Hodgkin’s disease, non-Hodgkin’s lymphoma, and multiple myeloma). A comparator group without known diagnosis of cancer was created by excluding records containing any diagnosis code for malignant neoplasm or diagnosis/procedure code for cancer treatment. ACSC admissions, including those for short- and long-term complications of diabetes mellitus (DM), uncontrolled DM, asthma, hypertension (HTN), congestive heart failure (CHF), angina, and hypovolemia, were ascertained using algorithms developed and validated for the U.S. Agency for Health Care Research Quality Prevention Quality Indicators. The 2005 5-year prevalence for LM was obtained from SEER and used as the denominator for rate calculations in that group. A denominator for the no cancer group was created using U.S. Census estimates for the 2005 adult population less the SEER 5-year prevalence for all sites. Mean hospital charges were extracted for each admission and transformed into costs using Medicare cost-to-charge ratios. Length of stay, total costs, and in-hospital mortality were compared across groups for each ACSC. All means and proportions were sample weighted. Results: In 2005 there were an estimated 510,300 total LM admissions and 26,700,000 total admissions in the no cancer comparator group. Estimated hospitalization rates for each ASCS and odds ratios for the between group comparisons are detailed below. ACSC Group Admission Rate LM (per 100,000 pop) Admission Rate No Cancer (per 100,000 pop) OR (95% CI) DM Short-term Comp 74.7 33.3 2.25 (1.96–2.57) DM Long-term Comp 286.8 138.6 2.07 (1.93–2.22) DM Uncontrolled 50.4 12.06 4.18 (3.54–4.93) CHF 2360.0 465.5 5.17 (5.04–5.30) HTN 69.3 57.7 1.20 (1.04–1.38) Angina 60.0 21.9 2.74 (2.36–3.20) Asthma 255.4 81.5 3.14 (2.91–3.38) Hypovolemia 1086.5 90.1 12.2 (11.75–12.63) In-hospital mortality did not significantly differ between groups for any ACSC. Mean length of stay and hospital costs were likewise similar with the exception of costs for CHF ($8,957[95%CI 8,260–9,654] v. $7,176 [6,185–8,168]) and length of stay (5.6d [95%CI 4.8–6.3] v. 4.0d [3.9–4.1]) and costs ($8,702 [6,832–10,572] v. $5690[5,373–6,007]) for asthma admissions. Conclusions: Hospitalization of LM patients for ASCSs is common and occurs with odds generally 〉2 times higher than among patients without a cancer diagnosis. Future studies should be conducted to determine factors influencing these findings (e.g. rates of comorbidity, influence of cancer treatment, utilization of primary care services) and to develop potential strategies for preventing hospital admissions.