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435 Background: Quality measurement is one of the four pillars of the Centers for Medicare and Medicaid (CMS) MIPS program. Few MIPS quality measures are specific to oncology. The US Oncology Network (USON) in collaboration with McKesson created a QCDR to align quality improvement reporting with oncology-specific measures to improve cancer care. Methods: The Practice Insights QCDR application was developed and submitted to CMS for approval in 2017. Integrated with an oncology-specific EHR (iKnowMed Generation 2), the QCDR leverages clinical content to automate calculation of quality measures. A multidisciplinary team was created to develop targeted oncology-specific measures that are clinically relevant, improve patient care, and reduce unnecessary healthcare costs. Results: The QCDR has been approved by CMS since 2017 allowing development of oncology-specific measures to monitor critical areas of cancer care. USON practices reported these measures as part of their MIPS participation. CMS established national MIPS program performance benchmarks for 4 measures due to measure feasibility, reporting ease, and high clinician adoption rates. PIMSH4 Pain Improvement (patient-reported outcome) was selected for public reporting through CMS Care Compare. CMS approved all 7 submitted QCDR measures for the 2022 MIPS program year. USON average performance (25 practices, representing 1,787 clinicians) from 2019-2022 YTD demonstrates significant improvement ranging from 4%-10%. Conclusions: Creating an oncologic-specific QCDR allowed USON practices to report more meaningful quality measures through the MIPS program. QCDR measures provide insight for care teams and trends from 2019-2022 YTD demonstrate that USON practices achieved significant performance improvements in key areas of cancer care. Future development will refine and identify new measures that align with our patient care improvement activities to enable clinicians and care teams to focus on measures that matter.[Table: see text]

The purpose of the study was to evaluate the conspicuity of bone metastases on each of the numerous sequences produced by fast Dixon-based multisequence whole-body (WB) magnetic resonance imaging (MRI) scanning in order to determine the most clinically useful sequences overall and per anatomic region.Twenty-seven breast cancer patients with bone metastases were prospectively studied with fast Dixon-based WB MRI including head/neck, chest, abdominal, pelvic, thigh, calf/feet and either cervical, thoracic and lumbar or cervical/thoracic and thoracic/lumbar regions. Sequences included coronal T2, axial T1 without and with intravenous gadolinium (+C), sagittal T1 spine+C, each associated fat-only (FO) and fat-saturated (FS) sequence, axial diffusion-weighted imaging (DWI) and short tau inversion recovery (STIR). Blinded reviewers evaluated lesion conspicuity, a surrogate of clinical utility, on a five-point scale per anatomic region. Sequences were compared using analysis of variance, differences were detected with Tukey's honestly significant difference test, and the four sequences with highest mean conspicuity were compared to the remainder overall and per anatomic region.Overall, a significant lesion conspicuity difference was found (P.0001), and lesion conspicuity was significantly higher on FS T1+C, FO T1+C, T1+C sagittal and FS T1+C axial sequences (P.0001). Per-region results were the same in the head/neck. Other sequences overlapped with these and included the following: chest/abdomen - FO T2, DWI; pelvis - DWI, FO T2; thigh - FS T2, FO T2, FO T1+C; calf/feet - FS T2, DWI, FO T2, STIR.Overall, bone lesions were most conspicuous on FS T1+C sagittal, FO T1+C sagittal, T1+C sagittal and FS T1+C axial fast Dixon WB MRI sequences.

Summary BRCA testing of patients with breast cancer considered at high risk for having a germ-line BRCA mutation usually consists of comprehensive mutational analysis of both BRCA1 and BRCA2 . A more cost-effective strategy of triaging patients for analysis of a single gene could be adopted if tissue-based predictors indicated a high risk specifically for either BRCA1 or BRCA2 . To identify potentially useful tissue-based predictors of BRCA mutation status in breast cancer, we evaluated multiple histopathologic features of invasive breast carcinoma on archival tissue sections from 196 high-risk patients who had undergone BRCA testing, and we analyzed which individual or combination of features was most associated with BRCA mutations. Of the 196 patients with invasive breast carcinoma, there were 44 (22%) with a deleterious BRCA1 mutation and 27 (14%) with a deleterious BRCA2 mutation. For patients with available untreated surgical resection specimens for evaluation (n = 172), estrogen receptor–positive phenotype was inversely associated with the presence of a BRCA1 mutation (odds ratio, 0.243; 95% confidence interval, 0.070-0.840; P = .025), and high mitotic activity (≥25 mitotic figures per 10 high-power fields) was directly associated with the presence of a BRCA1 mutation (odds ratio, 4.222; 95% confidence interval, 1.353-13.18; P = .013). The combination of estrogen receptor–negative phenotype and high mitotic rate had high specificity (99%; 95% confidence interval, 95%-100%) but low sensitivity (43%; 95% confidence interval, 26%-61%) for identifying a deleterious BRCA1 mutation. In patients with breast cancer at high risk for carrying a BRCA mutation, those with estrogen receptor–negative phenotype and high mitotic rate could be triaged specifically for BRCA1 testing instead of initially performing mutational analysis for both BRCA1 and BRCA2.

The purpose of this study is to identify clinical and molecular characteristics of melanoma patients that predict response to high-dose interleukin-2 (HD IL-2) to improve patient selection for this approved but toxic therapy. We reviewed the records of 208 patients with unresectable stage III/IV melanoma treated with HD IL-2 at the University of Texas M.D. Anderson Cancer Center (n=100) and the Beth Israel Deaconess Medical Center (n=108) between 2003 and 2009. The BRAF and NRAS mutation status of the tumors was determined for patients with available tissue samples and the mutation status and clinical characteristics were compared with clinical outcomes. Pretreatment serum lactate dehydrogenase levels were available for most patients (n=194). Tissue was available for mutational analysis on a subset of patients (n=103) and the prevalence of mutations was as follows: BRAF 60%, NRAS 15%, WT/WT 25%. In the subset of patients for which mutational analysis was available, there was a significant difference in the response rate based on the mutation status: NRAS 47%, BRAF 23%, and WT/WT 12% (P=0.05). Patients with NRAS mutations had nonstatistically longer overall survival (5.3 vs. 2.4 y, P=0.30) and progression-free survival (214 vs. 70 d, P=0.13). Patients with an elevated lactate dehydrogenase level had a decreased progression-free survival (46 vs. 76 d, P

Sentinel lymph node (SLN) metastasis size is an important predictor of non-SLN involvement. The goal of this study was to construct a nomogram incorporating SLN metastasis size to accurately predict non-SLN involvement in patients with SLN-positive disease.We identified 509 patients with invasive breast cancer with a positive SLN who underwent completion axillary lymph node dissection (ALND). Clinicopathologic data including age, tumor size, histology, grade, presence of multifocal disease, estrogen and progesterone receptor status, HER2/neu status, presence of lymphovascular invasion (LVI), number of SLN(s) identified, number of positive SLN(s), maximum SLN metastasis size and the presence of extranodal extension were recorded. Univariate and multivariate logistic regression analyses identified factors predictive of positive non-SLNs. Using these variables, a nomogram was constructed and subsequently validated using an external cohort of 464 patients.On univariate analysis, the following factors were predictive of positive non-SLNs: number of SLN identified (P0.001), number of positive SLN (P0.001), SLN metastasis size (P0.001), extranodal extension (P0.001), tumor size (P = 0.001), LVI (P = 0.019), and histology (P = 0.034). On multivariate analysis, all factors remained significant except LVI. A nomogram was created using these variables (AUC = 0.80; 95% CI, 0.75-0.84). When applied to an external cohort, the nomogram was accurate and discriminating with an AUC = 0.74 (95% CI, 0.68-0.77).SLN metastasis size is an important predictor for identifying non-SLN disease. In this study, we incorporated SLN metastasis size into a nomogram that accurately predicts the likelihood of having additional axillary metastasis and can assist in personalizing surgical management of breast cancer.

Background:We evaluated the impact of neoadjuvant chemotherapy (NC) relative to primary surgery (PS) to determine if there was a difference in the total time and number of chemotherapy cycles given in patients with advanced epithelial ovarian cancer.Methods:We identified 263 consecutive women meeting eligibility from 1993 to 2005 for this institutional review board-approved study. Eligible patients in this analysis were those women with advanced disease (stage IIIC-IV) in whom a maximal cytoreductive effort was planned either at PS or after NC. Time to start chemotherapy was defined as follows: (1) NC group: confirmation of diagnosis through biopsy, cytological diagnosis from ascites, and pleural effusion; (2) PS group: confirmation of diagnosis from the date of surgery that confirmed the diagnosis of epithelial ovarian cancer. Total chemotherapy cycles: (1) NC group: NC chemotherapy cycles plus postoperative cycles; (2) PS group: chemotherapy after primary tumor debulking surgery. Clinical information evaluated included chemotherapy type, chemotherapy cycle number, total time to administer frontline chemotherapy, and survival.Results:Median chemotherapy cycles were greater in the NC group compared with the PS group (9 [range, 4-30] vs 6 [range, 3-19];P< 0.01). The PS group was also more likely to undergo chemotherapy regimens involving platinum and taxane treatment compared with the NC group (79% vs 65%;P= 0.017). Total time undergoing primary chemotherapy from initial diagnosis was greater in the NC group compared with PS (223 vs 151 days;P< 0.01). No significant difference was observed in overall survival and progression-free survival in the 2 groups.Conclusions:In patients with advanced ovarian cancer, NC followed by abdominal hysterectomy is associated with improved perioperative outcomes including optimal cytoreduction, decreased blood loss, and decreased inpatient hospitalization. In this cohort, NC was also associated with prolonged chemotherapy treatment intervals and increased chemotherapy cycles without improvement in survival.

Using immunohistochemistry with anti-D2-40 for the detection of lymphovascular invasion (LVI-IHC) in 74 cases of invasive melanoma, we found LVI in 23% (16/74) of the tumors. Data on sentinel lymph node (SLN) biopsy were available for 36 patients. Sixty-seven percent (6/9) of patients with LVI-IHC and 19% (5/27) without LVI-IHC had positive SLN. Follow-up data were available for 60 patients. Data on recurrence/metastasis were available for 60 patients. Twenty-five percent (15/60) had LVI with immunohistochemistry. Fifty-three percent (8/15) of these patients had “distant” metastasis or regional recurrence compared with 11% (5/45) in those without LVI-IHC. Overall and disease-specific survival was shorter for patients with LVI. In both the univariate and multivariate Cox proportional hazards regression models, LVI-IHC in addition to ulceration was statistically significant with respect to overall survival. Specifically, in the reduced multivariate model, compared with patients with no LVI, patients with intratumoral LVI had a hazard ratio (HR) of 5.4 (95% CI 1.6–18.4), while patients with peritumoral LVI had a HR of 3.8 (95% CI 0.7–20.9). In addition, patients with ulceration had an increased hazard of 4.4 (95% CI 1.2–16.8). For the first time, we herein show a positive correlation with LVI in melanoma detected with immunohistochemistry and distant metastasis, overall survival and disease-free survival.

The aim of our study was to retrospectively evaluate whether maximum standardized uptake value (SUVmax), total lesion gylcolysis (TLG), or change therein using 18F-FDG PET/CT performed before and after initial chemotherapy were indicators of patient outcome. Methods: Thirty-one consecutive patients who underwent 18F-FDG PET/CT before and after chemotherapy, followed by tumor resection, were retrospectively reviewed. Univariate Cox regression was used to analyze for relationships between covariates of interest (SUVmax before and after chemotherapy, change in SUVmax, TLG before and after chemotherapy, change in TLG, and tumor necrosis) and progression-free and overall survival. Logistic regression was used to evaluate tumor necrosis. Results: High SUVmax before and after chemotherapy (P = 0.008 and P = 0.009, respectively) was associated with worse progression-free survival. The cut point for SUVmax before chemotherapy was greater than 15 g/mL* (P = 0.015), and after chemotherapy it was greater than 5 g/mL* (P = 0.006), as measured at our institution and using lean body mass. Increase in TLG after chemotherapy was associated with worse progression-free survival (P = 0.016). High SUVmax after chemotherapy was associated with poor overall survival (P = 0.035). The cut point was above the median of 3.3 g/mL* (P = 0.043). High TLG before chemotherapy was associated with poor overall survival (P = 0.021). Good overall and progression-free survival was associated with a tumor necrosis greater than 90% (P = 0.018 and 0.08, respectively). A tumor necrosis greater than 90% was most strongly associated with a decrease in SUVmax (P = 0.015). Conclusion:18F-FDG PET/CT can be used as a prognostic indicator for progression-free survival, overall survival, and tumor necrosis in osteosarcoma.

Background BTZ is approved for the treatment of MM via either SC or IV administration. The observed non-inferior efficacy (overall response rate after 4 cycles) and tolerability with SC administration of BTZ as reported in relapsed/refractory MM (Moreau et al Lancet Oncol 2011) has the potential to impact treatment outcomes in the clinical setting. However, there is a paucity of comparative effectiveness data on SC vs IV BTZ as initial therapy in MM in clinical practice. The main objective of this study was therefore to evaluate the treatment outcomes in NDMM pts who received SC vs IV BTZ in the US community oncology setting. Methods NDMM pts aged ≥18 yrs who received BTZ-based treatment within the McKesson Specialty Health/US Oncology Network between Jan 1 and Dec 31, 2012, and had ≥2 MM-related visits and ≥6 mos' follow-up through Jul 2014, were evaluated. Data were collected via the iKnowMed electronic health records database and supplemented with medical chart reviews. Cohorts stratified by route of administration were matched 2:1 as the Moreau study, and by age, gender, practice region, and performance status. Chi-square analysis (categorical variables), t-tests/non-parametric Mann-Whitney tests (continuous variables), and Kaplan-Meier methodology were employed. Univariate and multivariate Cox models adjusted for clinically relevant covariates were used for associations between cumulative BTZ dose and treatment outcomes. Results 372 NDMM pts who received BTZ were included; 248 received SC and 124 IV BTZ. Similar baseline demographics and clinical characteristics were observed in the SC and IV groups (Table 1). Median BTZ treatment duration was 4.4 and 4.1 mos in the SC and IV groups, respectively (p = 0.21). Among pts receiving SC and IV BTZ, 10% and 13% had dose reductions in the first 16 wks (p = 0.41) and the median time to dose reduction was 49 d in both groups. While observed median relative dose intensities were similar between the SC and IV groups (1.0 [range 0.67-1.2] vs 1.0 [0.5-1.3]; p = 0.89), a higher median cumulative BTZ dose of 25.8 mg/m2 (1.3-208.6) was observed in SC pts, vs 22.9 mg/m2 (1.3-105.9) in IV pts (p = 0.08). When dichotomized by median cumulative BTZ dose (24.7 mg/m2), a numerically greater proportion of SC pts vs IV pts received the higher dose (52% vs 48%, p = 0.38). Higher cumulative dose was associated with longer PFS and better response rate at cycle 4 (12 wks) in multivariate analyses (Table 2). Treatment outcomes were comparable between SC and IV BTZ; 2-yr overall survival (OS) was 81% vs 78% (Fig 1); 2-yr progression-free survival (PFS) was 75% vs 70% (Fig 2). In 204 response-evaluable pts (of 372 in the overall population with a median follow up of 19.1 mos [range 0.1-30.1] in SC pts and 20.8 mos [0.3-30.8] in IV pts), complete response/very good partial response rate was 16% vs 22%. Documented rates of adverse events in the SC vs IV BTZ groups were 34% vs 28% neuropathy (p = 0.27), 13% vs 10% thrombocytopenia (p = 0.57), 10% vs 5% neutropenia (p = 0.09), and 25% vs 24% anemia (p = 0.87). Conclusions The observed non-inferior treatment outcomes between SC and IV BTZ in NDMM pts are consistent with findings from the phase 3 relapsed/refractory MM trial. In addition, SC vs IV BTZ was associated with a trend towards higher cumulative dose, which was associated with improved response rate and PFS. These findings support extended therapy for higher cumulative dosage and better treatment outcomes as demonstrated in a prior phase 3 clinical trial (Benboubker et al NEJM 2014). Table 1. NDMM Pt Baseline Demographics and Clinical Characteristics BTZ SC (N = 248) BTZ IV (N = 124) p value Median age at diagnosis, yrs (range) 66 (32-90+) 68 (36-88) 0.87 Age at diagnosis ≥65 yrs, % 57 60 0.55 Male % 56 56 1.00 IgG / IgA / light chain / other or unknown MM, % 53 / 21 / 22 / 4 41 / 30 / 23 / 6 0.28 Pts with available ISS stage I / II / III disease, % n = 145 22 / 43 / 34 n = 64 17 / 33 / 50 0.12 Peripheral neuropathy, % 4.4 3.2 0.78 Table 2. Regression analyses (RA) for association with cumulative BTZ dose, high vs low (> or < 24.7 mg/m2) Univariate analysis Multivariate analysis OR (95% CI) p value OR (95% CI) p value Objective response* at cycle 4 1.67 (0.86, 3.24) 0.13 2.20 (1.01, 4.80) 0.047 HR (95% CI) HR (95% CI) PFS† 0.41 (0.27, 0.62) Disclosures Rifkin: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ma:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Harrell:McKesson Specialty Health: Employment. Zhu:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Dow:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; Takeda: Equity Ownership. Niculescu:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Bonthapally:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment.

The aim of this study was to evaluate the features of inflammatory breast carcinoma (IBC) on MRI compared with mammography and ultrasound and to better define the role of MRI in patients with this aggressive disease.A retrospective analysis was performed of patients with newly diagnosed IBC evaluated at a single institution between 2003 and 2008. Baseline MRI examinations were performed on a 1.5- or 3-T scanner using contrast-enhanced 3D T1-weighted gradient-echo sequences with parallel imaging. MRI findings were rated in accordance with the BI-RADS MRI lexicon established by the American College of Radiology. All patients underwent concomitant mammography and ultrasound examinations.Eighty women with a clinical diagnosis of IBC were included in the study (median age, 52 years; age range, 25-78 years). MRI detected a primary breast lesion in 78 of 80 symptomatic breasts (98%) compared with 53 of 78 (68%) with mammography (p0.0001) and 75 of 80 (94%) with ultrasound. Of the 78 breasts with a primary lesion, the most common MRI finding was a mass or multiple masses (57/78, 73%). Masses were frequently multiple, small, and confluent (47/57, 82%); mass margins, irregular (43/57, 75%); and internal enhancement pattern, heterogeneous (47/57, 82%). Kinetic analysis revealed a delayed washout pattern in 66 of 78 tumors (85%). MRI showed skin thickening in 74 of 80 breasts (93%), whereas mammography showed skin thickening in 56 of 78 breasts (72%).Multiple small, confluent, heterogeneously enhancing masses and global skin thickening are key MRI features of IBC that contribute to improved detection of a primary breast cancer and delineation of disease extent compared with mammography.

ObjectiveOptimal cytoreduction and response to chemotherapy have been associated with prolonged disease-free survival (DFS), but there are limited data regarding the clinical characteristics of those patients with optimal 5-year DFS (5YrDFS) outcomes.MethodsA case-control study was performed on 32 patients who were progression-free and alive at 5 years with advanced ovarian cancer 5YrDFS from 1993 to 2005 for this institutional review board-approved study. Matching controls were identified from the subset of patients who died or experienced disease progression before 5 years.ResultsOne hundred sixty patients were evaluated. There was no statistical difference between cases and controls in regard to neoadjuvant chemotherapy, grade, race, preoperative cancer antigen-125 level, optimal cytoreduction, operating room time, length of hospital stay, or total chemotherapy cycles in regard to 5YrDFS. If a patient achieved complete response after primary treatment, the likelihood of progression-free survival 5 years or longer is 7 times more likely, (odds ratio = 7.2 [95% confidence interval = 2.3-22.4]; P = 0.0006).ConclusionIn this matched case-control analysis, complete response after primary treatment was the only significant factor associated with 5YrDFS. Further study is needed in patient and tumor characteristics to identify those patients who may have poor or favorable outcomes before treatment completion.

To evaluate the effect of half-dose intravenous gadolinium contrast on the enhancement of bone and soft tissue tumors. This study is HIPAA compliant and informed consent was waived by the institutional review board. An institutional database search was performed over a 1-year period for patients with full- and half-dose MR examinations performed for musculoskeletal oncologic indications. Examination pairs that were identical with regard to field strength and presence or absence of fat saturation were included, resulting in 29 paired examinations. When multiple, the lesion that was best delineated and enhanced well on the first examination in the pair was chosen, yielding 17 bone and 12 soft tissue. Five musculoskeletal radiologists blinded to dosages were asked to assess for a difference in enhancement when comparing the lesion on both examinations and to rate the degree of difference on a three-point scale. They were also asked to identify the examination on which the lesion enhanced less (tallied as low dose). Results were analyzed with the exact binomial test. The readers perceived an enhancement difference in 41% (59/145) of studies (p = 0.03) and the majority were rated as “mild” (66%, 39/59). The readers did not accurately identify the low-dose examinations (54% correctly identified, 32/59, p = 0.60). Half-dose gadolinium enhancement of lesions could not be accurately distinguished from full-dose enhancement upon review of the same lesion imaged at both concentrations.

The World Health Organization classification of tumors of the breast includes a rare variant of invasive ductal carcinoma termed pleomorphic carcinoma. This variant has marked nuclear pleomorphism (6-fold variation in nuclear size by definition, but often10-fold) and characteristically contains multinucleated tumor giant cells. Approximately one-third of the cases in the initial series contained a focal spindle cell metaplastic component. The tumors are reported to have an aggressive behavior, but because some contain a spindle cell metaplastic component, it is unclear whether the metaplastic component or other clinicopathologic features account for the poor clinical outcome. We identified 37 cases of pleomorphic carcinoma of the breast and evaluated the association between clinical outcome and multiple clinicopathologic features. Patients with invasive pleomorphic lobular carcinoma and those without at least a tissue biopsy before chemotherapy were excluded. Patients ranged in age from 23 to 78 years (median, 49 y). Tumor size was5 cm in 12 cases and5 cm in 22. A focal spindle cell component (25% of the tumor) was present in 14 tumors (38%). Clinical follow-up was available for 36 patients (median, 17 mo). In multivariate analysis, when the 2 stage-IV patients were excluded, the presence of a spindle cell component and tumor size5 cm were each independently associated with decreased overall survival. The actuarial 5-year overall survival for patients with and without a metaplastic spindle cell component was 38%+/-15% and 89%+/-7%, respectively. Poor clinical outcome, therefore, is associated with the subset of pleomorphic carcinomas with a spindle cell metaplastic component. As the morphologic features of pleomorphic carcinoma can be seen in primary tumors from other sites, it is important to recognize this tumor as a rare variant of invasive breast carcinoma.

To determine if the location of the point of maximum standardized uptake value (SUVmax) being included in or not included in the histopathologic slab section corresponded to tumor necrosis or survival.Twenty-nine osteosarcoma patients underwent post-chemotherapy [fluorine-18]-fluoro-2-deoxy-D: -glucose (FDG) positron-emission tomography-computed tomography (PET/CT) prior to resection. PET/CT images were correlated with slab-section location as determined by photographs or knowledge of specimen processing. The location of the point of SUVmax was then assigned as being 'in' or 'out' of the slab section. Cox's proportional hazard regression was used to evaluate relationships between the location and value of SUVmax and survival. Logistic regression was employed to evaluate tumor necrosis.No correlation was found between the SUVmax location and survival or tumor necrosis. High SUVmax correlated to poor survival.High SUVmax value correlated to poor survival. Minimal viable tumor (10%) following chemotherapy is a known indicator of poor survival. No correlation was found between the location of SUVmax and survival or tumor necrosis. Therefore, the SUVmax value either does not correspond to a sufficient number of tumor cells to influence tumor necrosis measurement or it was included in the out-of-slab samples that were directed to viable-appearing areas of the gross specimen. Since high SUVmax has been previously found to correspond to poor tumor necrosis, and tumor necrosis is simply an estimate of the amount of viable tumor, SUVmax likely represents many viable tumor cells. Therefore, when not in the slab section, SUVmax was likely included in the tumor necrosis measurement through directed sampling, validating our current method of osteosarcoma specimen analysis.

In this study, we analyzed the long-term outcome of a risk-adapted transplantation strategy for mantle cell lymphoma in 121 patients enrolled in sequential transplantation protocols. Notable developments over the 17-year study period were the addition of rituximab to chemotherapy and preparative regimens and the advent of nonmyeloablative allogeneic stem cell transplantation (NST). In the autologous transplantation group (n = 86), rituximab resulted in a marked improvement in progression-free survival for patients who received a transplant in their first remission (where a plateau emerged at 3-8 years) but did not change the outcomes for patients who received a transplant beyond their first remission. In the NST group, composed entirely of patients who received a transplant beyond their first remission, durable remissions also emerged in progression-free survival at 5 to 9 years. The major determinants of disease control after NST were the use of a peripheral blood stem cell graft and donor chimerism of at least 95%, whereas the major determinant of death was immunosuppression for chronic graft-versus-host disease. Our results show that long-term disease-free survival in mantle cell lymphoma is possible after rituximab-containing autologous transplantation for patients in first remission and after NST for patients with relapsed or refractory disease.

Abstract 2548 Background: The effectiveness of allogeneic NST in CLL has been attributed to a graft-versus-leukemia effect due to elimination of tumor cells by alloimmune effector lymphocytes. In a previous study (Khouri et al, Exp Hematol 2004), we found that when patients with CLL develop relapse after NST, immunomanipulation (IMM) via withdrawal of immunosuppression and DLI with rituximab can induce sustained remissions in some patients. The underlying mechanism of this GVL effect is unknown. The simultaneous presence of the killer-immunoglobulin-like receptor (KIR) 3DL1 and its corresponding human leucocyte antigen (HLA) class I ligands bearing the Bw4 epitope has been described in CLL (Verheyden S, Leukemia 2006). Purpose: Considering that the HLA class I molecules may act as restriction elements for GVL targets after NST in CLL, we investigated the potential association of certain common class I HLA alleles and response to IMM. Methods: We studied all 43 CLL pts who required IMM after NST in sequential phase II protocols at the U.T. MD Anderson Cancer Center from February 1996 to August 2007 because of persistent disease or because of progression. In our analysis, we examined the most common alleles and serotypes expressed in the patients studied. This included HLA-A1, A2, A3, A24, B7, B8, B35, B44, B60, B62, BW4, BW6, CW7. These allele groups are known to be common in most world populations. Rituximab was given at a dose of 375 mg/m2 intravenously followed by 3 weekly doses of 1000 mg/m2. A DLI of 1 × 107 CD3-positive T cells/kg was given after the first two doses of rituximab if no GVHD occurred. An escalated DLI dose was given at 6-week intervals if there was persistent active disease and no GVHD. Results: Median age (range) was 55 years (39-73) and the median Hematopoietic Stem Cell Comorbidity Index was 3 (range, 0–8). The median number of prior chemotherapies was 3. At their transplant, 48% of pts had refractory disease, 90% had Binet stage B/C, and 60% had a beta-2 microglobulin of =/> 3. P53 deletion was detected in 11 of 35 pts (31%) tested. Mixed T-cell chimerism was observed in 60 % of pts at day 90. The median number of DLI infused was 2 (range, 1–6); their median maximal dose was 43.6 (range, 1–200) × 106 CD3+/Kg. In these 43 pts, 20 (47%) experienced complete remission (CR), by CT scans, marrow and flow analysis. Pts characteristics at time of study entry (described above) for NST, and at the time of initiation of IMM (this included white blood cell counts, LDH, % lymphocyte in marrow, % CD5-CD19, lymph node size by computed tomography, maximum dose DLI, number of DLIs, GVHD prior IMM and grade, T-cell chimerism), as well as HLA subtypes were assessed. The major determinants to achieve CR following IMM included receipt of a PBSC graft and achievement of a good (> 90%) donor T-cell chimerism at day 90 (p = 0.035), and having a combination of HLA-A1-positive, HLA-A2-negative, and HLA-B44-negative (p= 0.0009). The rate of CR to IMM was 9%, 36%, 50%, 91% respectively in patients who had none of the HLA factors described, I, 2, and all 3 respectively. There was no statistically significant difference in pts and disease characteristics between HLA-A1-positive or negative, HLA-A2 positive or negative nor between HLA-B44-positive or negative pts. In addition the risks of acute II-IV [Cumulative incidence (CI)=23%) and chronic GVHD (CI=69%) were not different between the respective subtypes. With a median follow-up in surviving pts of 37.2 months (range, 11.4–131.1), the progression-free survival rates at 5-year for patients with HLA-A1+/A2-/B44- vs those who had none of those HLA types were 68% vs 15%, respectively, (p Conclusions: Our results represent the first report showing certain HLA alleles might be predictive for response to GVL and achieving long-term remission in CLL. Verification of our findings in a larger cohort of pts is highly warranted for better selecting pts for IMM for the treatment of recurrent malignancy in CLL. Disclosures: No relevant conflicts of interest to declare.

8597 Background: High dose IL-2 (HD-IL2) is the only FDA-approved treatment that induces durable complete responses (CR) and survival in patients (pts) with metastatic melanoma (MM), but it does so...

Abstract 868 Background: Relapse continues to be the primary cause of treatment failure in patients (pts) with NHL undergoing transplantation. We have previously reported the adverse prognostic value of PET+ in autologous transplants (AUTO) and disease refractoriness in pts undertaking a non-myeloablative allogeneic transplantation (NST). In order to improve outcome, we and others have previously established the feasibility of addition of 90YIT to the transplant conditioning. Herein, we report the long-tem efficacy of this strategy in 74 pts. Methods: Each pt received a single dose of 90YIT (0.4 mCi/kg on day -14) with BEAM as a conditioning regimen in AUTO candidates [relapsed chemosensitive diffuse large cell b-cell (DLBCL); relapsed chemosensitive follicular (FL) if no matched sibling donor was available; mantle cell (MCL) in first remission; age ≤ 65], or with fludarabine, cyclophosphamide and rituximab (Blood 2008:111:5530) in candidates for NST (relapsed chemosensitive or refractory FL and MCL, transformed NHL if not candidates for AUTO, CLL, up to 50% marrow involvement with disease, age ≤ 70). Results: This cohort included 40 pts (DLBCL=25, FL=11, MCL=3, SLL =1). Median age was 53 (range, 31-65) years. Median prior treatments was 2 (range,1-4). At transplant, 21(52.5%) were in CR, 16 (40%) in PR, and 3 pts (7.5%) with DLBCL had stable disease. Nine pts (22.5%) had elevated LDH and 7 of 38 (18%) were PET +. At study entry, median serum rituximab level was 5mcg/ML (range, 0-56.4), and soluble CD20 serum level was 457 nM/L (range, 20.7-1501). Adverse events were similar to those with BEAM alone, and 4 pts (10%) developed secondary malignancies. Median time to >ANC 500 was 9 (range, 7-12) days and to platelet >20,000/mm3 was 11 (range, 2-90) days. At a median follow-up time of 3.6 (range,1.4 - 4.9) years, the 3-year overall (OS) and progression-free survival rates (PFS) were 78% and 64%, respectively. We were not able to identify important determinants of outcome; this included PET+, serum rituximab and soluble CD20. Although histology had no statistically significant impact, a persistent pattern of relapse over time was observed in FL (PFS at 1-,2- and 4-year were 91%, 64% and 45%, respectively), whereas a plateau was observed in DLBCL at 24 months (PFS of 76%). This cohort included 34 pts (FL=11, CLL=20, DLBCL=2, MCL=1). Median age was 59 (range, 29-70). Eight of the 11 pts with FL had high [n=6 (55%)] or intermediate [n=2 (18%)] FLIPI at study entry; 8 (73%) were PET+, and 6 (55%) had refractory disease (non-responding or progressing to at least two lines of therapies such as R-CHOP or RICE). Seven pts with CLL (35%) had refractory disease; 10 of 16 (62.5%) had unmutated IgVH, and 5 of 14(36%) had p53 mutation. Peripheral blood from HLA-compatible sibling donors was the source of graft in all pts. Tacrolimus and methotrexate were used for GVHD prophylaxis. Median time to ANC >500 was 11(range, 8-17) days, and to platelets > 20,000/mm3 was 10 (range, 0-55 days). Median donor T cells at days 30 and 90 were 90% and 100%, respectively. Cumulative incidence (CI) of acute II-IV GVHD was 32% (none had grade 3, one had grade IV), and the CI of extensive chronic GVHD was 44%. With a median follow-up time of 22 (range, 3-73) months, the PFS rates at 3-year for FL and CLL were 100% and 37%, respectively. The causes of failure in CLL were progression (n=6) and complications related to chronic GVHD (n=2). Conclusions: These data provide evidence that combining 90YIT at 0.4mCI/kg with the conditioning improves outcomes in NHL pts undergoing AUTO or NST, but not in CLL. Our results also represent the first report showing that the combination may overcome the negative prognostic value of PET+ in NHL, and that the addition of 90YIT to NST conditioning can induce long-term remission in relapsed refractory FL without added toxicity. Verification of our results in a larger cohort of pts is highly warranted. Disclosures: Khouri: BiogenIDEC: Research Funding. Off Label Use: The use of 90Yttrium Ibritumomab Tiuxetan in stem cell transplantation.

Abstract 2287 Poster Board II-264 Background: The major focus of NST in CLL has been to reduce mortality in this elderly patient (pt) population and attempt to exploit GVL to achieve remission (CR). Donor T cells recognizing host-derived minor histocompatibility antigens presented on the cell surface by MHC class I and II molecules have been implicated in GVL reactions. Purpose: We aimed to analyze predictors of survival after NST in CLL and whether certain HLA alleles are associated with responses to immunomanipulation (IMM)(withdrawal of immunosuppression ± rituximab and step-wise donor lymphocyte infusions (DLI). Methods: We included all 86 CLL pts who had undergone NST in sequential phase II protocols from February 1996 to August 2007. Eligibility criteria included pts aged 19-70 years with CLL who have failed purine analogs + rituximab and had a suitable donor. The preparative regimen used was FCR(fludarabine, 30 mg/m2 , and cyclphosphamide 750 mg/m2, each given intravenously on days –5 to –3 prior to transplant, 375 mg/m2 of rituximab on day –13, and 1000 mg/m2 on days -6, +1, and +8 ). Patients and donors were typed for alleles at HLA-A, B, C, DRB1, DRB3/4/5 and DQB1 by PCR amplification. Donors were matched siblings in 43 (50%) pts, matched unrelated in 30 (35%), and mismatched unrelated in 13 (15%) pts. Graft was from peripheral blood (PBSC) in 61 (71%) of pts, and marrow in 25 (19%) other pts. GVHD prophylaxis consisted of tacrolimus (administered for 6 months) and methotrexate. Pts who underwent non-sibling transplantation also received anti-thymocyte globulin or alemtuzumab (n=28, total dose 45mg). Post-transplant IMM was performed in pts with progressive or residual disease.. Results: Median age (range) was 58 (36-70), and the median Hematopoietic Stem Cell Comorbidity Index (HSCT-CI) was 3 (range, 0-8). Prior to their transplantation, pts were exposed to a median of 3 prior chemotherapies, and 42 pts (48%) had failed alemtuzumab. IgVH was unmutated in 28 (72%) of 39 pts tested, and 15 of 65 (23%) had p53 mutation. The clinical factors used to assess outcome included: recipient and donor age, disease stage, % lymphocytes, %CD5-CD19, b2-microglobulin, LDH, PET-status, number of prior treatments, use of alemtuzumab, HSCT-CI, serum levels of IgG, IgA, IgM, CD4 and CD8, source of graft, # cells (CD34, CD3) infused, chimerism at day 90, acute and chronic GVHD. In addition, IgVH and P53 mutation, and HLA factors were also analyzed. In a multivariate model, the major determinant of survival was the level of immunosuppression as determined by CD4 100/L and IgG level within the normal range vs those whose a CD4 60 years), IgVH and p53 mutation, and HSCT-CI were not found to be important factors in determining survival. Pts had refractory disease at transplantation, and 43 pts required IMM after NST. Of these 43 pts, 20 (47%) achieved CR. Pts characteristics at study entry (described above) for NST, and at the time of initiation of IMM, including number of DLI infused (median 2, range 1-6) and maximal dose (median 43.6, range 1-200, x 106 CD3+/Kg), T-cell chimerism and GVHD, as well as HLA subtypes were assessed. The major determinants to achieve CR following IMM included receipt of a PBSC graft and achievement of a good (≥ 90%) donor T-cell chimerism at day 90 (p=0.035), and having a combination of HLA-A1+/A2-/B44- (p= 0.0009). The rate of CR to IMM was 9%, 36%, 50%, 91% respectively in patients who had none of the HLA factors described, I, 2, and all 3 respectively. There was no statistically significant difference in pts and disease characteristics, nor in the risks of GVHD between the respective HLA-subtypes described. The Current-progression-free survival rates at 5-year for patients with HLA-A1+/A2-/B44- vs those who had none of those HLA types were 68% vs 15%, respectively, (p Conclusions: These data provide first evidence that IgG and CD4 levels may predict survival after NST in CLL. Our results also represent the first report showing certain HLA alleles might be predictive for response to GVL and achieving long-term remission in CLL. Verification of our results in a larger cohort of pts is highly warranted for better selecting pts for IMM for the treatment of recurrent malignancy in CLL. Disclosures: No relevant conflicts of interest to declare.

The abnormal expression of P53 is prognostically important in patients (pts) with CLL treated with conventional chemotherapy. In order to determine its significance upon survival in CLL pts undergoing NST, we analyzed outcome of P53 expression in conjunction with clinical and laboratory parameters in 86 pts transplanted at the MD Anderson Cancer Center between 02/96 and 01/06. Pts were eligible if they had failed conventional chemotherapy and had an HLA-identical or one-antigen mismatched donor. <> Median age (range) was 58 (36–73), the majority (81.4%) were males and the median Hematopoietic Stem Cell Transplantation (HSCT) Co-morbidity score was 3 (range 0–8). Pts were heavily pretreated with advanced disease at time of transplant: 66% had 3 or more lines of chemotherapy regimens, 41 (48%) had failed alemtuzumab, 55/65 (85%) had Binet stage B/C, 19(22%) had experienced transformation to Richter’s, 31 (36%) had progressive disease, and 22 (33%) were gallium/PET positive. Twenty-eight of 39 pts (72%) tested had unmutated IgVH. Immunoglobulin (Ig) G, A and M were below normal in 68%, 78% and 50%, respectively. CD4 and CD8 levels were <> P53 has been commonly tested by FISH methodology. In this report, 37 pts were tested by FISH. As an alternative, immunohistochemistry (IHC) assessing the expression of P53 in the absence of P21 has been suggested as a surrogate for mutated P53 status. IHC was therefore performed using antibodies to P53 (clone DO7; DAKO, Carpinteria, CA), and P21 (clone SX118:BD Pharmingen, San Diego, CA) on paraffin-embedded bone marrow biopsies in 46 pts. Samples were reviewed for expression of P53 and P21 proteins by T.D. and C.B-R., who were blinded as to outcome. Samples were considered positive for P53 mutation only if 20% or more of the malignant cells expressed P53 protein, with less than 5% expressing P21 protein. <> Thirteen of 46 pts (28%) were tested positive for P53+/P21− by IHC, and 10 of 37 (27%) were FISH+. Twenty-one pts were tested by both IHC and FISH: results were concordant in 16 pts (76%); 3 pts were FISH+/IHC−; 2 pts were FISH−/IHC+. <> With a median follow-up time for surviving pts of 37 (range, 12–131) months, the estimated three-year survival of all 86 pts was 53%. Univariate Cox proportional hazards regression for OS that considered P53 results as well all other clinical variables described above showed that IgG level below normal range at transplantation (P=0.001), CD4 =3 (P=0.023), Richter’s transformation (P=0.038), and % lymphocytes in marrow (P=0.039) were significantly associated with time to death. A multivariate analysis that included all the covariates with P values <> NST may overcome the negative predictor significance of P53 mutation. Considering the poor outcome with conventional chemotherapy, these pts may be considered for NST early in the course of their disease, before experiencing further depletion of their immune system as reflected by IgG and CD4 levels.

In order to determine if the addition of rituximab (R) had changed the outcome of autologous stem cell transplantation (AUTO) in patients with mantle cell lymphoma (MCL), we examined the outcome of 86 patients transplanted at the MD Anderson Cancer Center, in first partial or complete remission (frontline AUTO, n=50) or for relapsed / refractory disease (salvage AUTO, n=36). <<>> Among frontline patients, 29 were transplanted in the pre-R era (AUTO-R), and 21 in the post-R era (AUTO+R). AUTO-R patients received homogenous treatment with hyper-CVAD induction and Cy- TBI conditioning. AUTO+R patients were treated with R-hyper-CVAD, hyper-CVAD and R-CHOP induction in 62%, 10% and 29% respectively, and R-Cy-TBI and R-BEAM conditioning in 43% and 52% respectively. Median age (range) at transplantation was 57 (42–66) and 56 (38–73) for the AUTO-R and AUTO+R groups respectively (p=0.91); other baseline characteristics including sex, time from diagnosis, performance status, stage, B-symptoms, B2m, LDH and MIPI were similar. Prior to transplantation, CR or unconfirmed CR (CRu) was present in 38% and 57% of AUTO-R and AUTO+R patients respectively (p=0.18), and 33 of 34 patients were negative on Gallium/PET scan. Following transplantation, CR/CRu was achieved in 93% and 100% patients respectively (p=0.50). Progression free survival (PFS) was similar between AUTO-R and AUTO+R patients for the first 2 years. However, after 2 years a clear difference emerged on the PFS curve with no relapses occurring among 9 AUTO+R patients followed between 30 and 96 months. In contrast, AUTO1-R patients experienced a continuous pattern of relapse (p=0.03 compared with AUTO+R patients). For patients remaining in remission at 2 years, no deaths had occurred in the AUTO+R group, whereas 15 of 22 AUTO-R patients had died. <<>> The 36 salvage patients had similar baseline characteristics as frontline patients, except for the proportion of patients with chemosensitive disease (100% vs 86%, p=0.01) and negative Gallium/PET scans (97% vs 71%, p=0.01), favoring the frontline group. In contrast to the results of frontline patients, no difference was observed in salvage patients by the use of R (p=0.52 and 0.50 for PFS and OS respectively). <<>> Autologous transplantation with rituximab has the potential to cure a proportion of patients with MCL, but only if performed during the first remission. Patients transplanted beyond first remission continued to experience a poor prognosis. Figure Figure

FLIPI is emerging as an important prognostic factor in patients (pts) with FL. In order to determine its significance in FL pts undergoing AUTO, we examined the outcome of 75 consecutive pts transplanted at the MD Anderson Cancer Center between 02/94 and 04/08. Pts were eligible if they had relapsed chemosensitive disease, and had no HLAidentical sibling donor. Twenty-nine pts were transplanted without rituximab (AUTO-R), and 46 pts received high-dose rituximab (AUTO+R) during stem cell mobilization and on days +1 and + 8 after transplantation as previously described (Khouri, JCO, 2005). Median age (range) at AUTO was 54 (33–76) and 49 (35–63) for the AUTO+R and AUTO-R groups respectively (P =0.002). FLIPI was determined at the time of transplantation; more patients had intermediate-high risk in AUTO+R than in AUTO-R (58% vs 27.5%, respectively, P = 0.011). Other patients characteristics were balanced for gender, time from diagnosis, histology subtypes (grades 1,2, 3a, and 3b), disease stage, LDH, bulk, B-symptoms, B-2microglobulin, bone marrow involvement, number of prior chemotherapy regimens received, remission status (CR vs PR), functional imaging, and co-morbidity score. Median follow-up (range) in months was 20 (1–88) for AUTO+R and 70 (4–167) for AUTO-R. Progression-free survival (PFS) was significantly different between AUTO+R and AUTO-R (P = 0.004), with estimated three-year PFS of 48% for AUTO-R and 79% for AUTO+R. Using Cox proportional hazards regression models, the # of prior chemotherapy regimens received (/=3) (P = 0.015) was the only factor associated with PFS in the AUTO+R group, whereas both age (P=0.010), and risk based on FLIPI (P=0.019) were independently associated with PFS in the AUTO-R group. Pts with low-risk vs. intermediate/high-risk had three-year PFS of 62% and 13%, respectively, in the AUTO-R group, whereas in the AUTO+R group, three-year PFS was 90% and 76% in the low-risk and intermediate/high-risk pts, respectively (Figure). Conclusions: These results suggest that the addition of R to the mobilization and conditioning improves the outcome in pts with relapsed chemosensitive FL treated by AUTO. The number of prior chemotherapy regimens received rather than FLIPI score is the most important determinant of outcome in this setting. Figure Figure