High Grade Non Research Articles

Background and Update for ECOG-ACRIN EA8212: A Randomized Phase 3 Trial of Intravesical Bacillus Calmette-Guérin (BCG) Versus Intravesical Docetaxel and Gemcitabine Treatment in BCG-naïve High-grade Non–muscle-invasive Bladder Cancer (BRIDGE)

EA8212 BRIDGE is a phase 3 randomized trial comparing BCG vs GemDoce for BCG naïve high-risk non-muscle-invasive bladder cancer. This article provides an explanation for the rationale of the clinical trial and details the study design.

Sarcopenia Predicts Disease Progression in Patients with T1 High-grade Non–muscle-invasive Bladder Cancer Treated with Adjuvant Intravesical Bacillus Calmette-Guérin: Implications for Decision-making?

BackgroundSkeletal muscle loss (sarcopenia) has been linked to cancer cachexia and can predict survival in several tumors, including advanced genitourinary malignancies. ObjectiveTo investigate the predictive and prognostic role of sarcopenia in patients with T1 high grade (HG) non-muscle invasive bladder cancer (NMIBC) treated with adjuvant intravesical Bacillus Calmette-Guerin (BCG). Design, setting, and participantsOncological outcomes were evaluated for 185 patients with T1 HG NMIBC treated with BCG at two European referral centers. Sarcopenia, identified from computed tomography scans performed within 2 mo after surgery, was defined as a skeletal muscle index of <39 cm2/m2 for women and <55 cm2/m2 for men. Outcome measurements and statistical analysisThe main endpoint was the association between sarcopenia and disease recurrence and progression. Kaplan-Meier curves and multivariable Cox models were built, and the clinical value of any association was assessed using Harrell’s C index and decision curve analysis (DCA). Results and limitationsSarcopenia was present in 130 patients (70%). On multivariable Cox regression analyses that accounted for the effect of standard clinicopathological prognosticators, sarcopenia was independently associated with disease progression (hazard ratio 3.41; p = 0.02). Addition of sarcopenia to a standard model for prediction of disease progression improved the discrimination of the model from 62% to 70%. DCA revealed superior net benefits for the proposed model in comparison to the strategies of treating all or no patients with radical cystectomy, and in comparison to the existing predictive model. Limitations are inherent to the retrospective design. ConclusionsWe demonstrated the prognostic role of sarcopenia in T1 HG NMIBC. Pending external validation, this tool could be easily incorporated into existing nomograms for prediction of disease progression to improve clinical decision-making and patient counseling. Patient summaryWe looked at the role of loss of skeletal muscle (sarcopenia) as a factor in predicting prognosis for stage T1 high-grade non–muscle-invasive bladder cancer. We found that sarcopenia is a ready-to-use, cost-free marker that could be used to guide treatment and follow-up in this disease, although the results need to be confirmed in other studies.

Prognostic and Predictive Value of Fibroblast Growth Factor Receptor Alterations in High-grade Non–muscle-invasive Bladder Cancer Treated with and Without Bacillus Calmette-Guérin Immunotherapy

BackgroundLimited data are available on the prognostic and predictive value of fibroblast growth factor receptor alterations (FGFRa) relative to clinical outcomes in patients with non–muscle-invasive bladder cancer (NMIBC). ObjectiveTo determine whether FGFRa may be clinically useful in stratifying for treatment response in a real-world cohort of patients with pT1 NMIBC treated and untreated with bacillus Calmette-Guérin (BCG) instillation therapy. Design, setting, and participantsA pooled dataset of matched clinical and genomic data (1992–2015) for pT1 NMIBC patients was assessed by the Bladder Cancer Research Initiative for Drug Targets in Germany consortium. Outcome measurements and statistical analysisKey efficacy outcomes were recurrence-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS), which were estimated by Kaplan-Meier analysis, with hazard ratios calculated using a multivariate Cox proportional-hazard model. Results and limitationsIn this retrospective study of 263 patients with high-grade NMIBC, at a median follow-up of 63 mo, 32% showed recurrence and 15% progressed to muscle-invasive bladder cancer. FGFRa were found in 43% of patients, including 39% mutations and 5.7% fusions. FGFRa were associated with lower rates of concomitant carcinoma in situ. Among patients with or without FGFRa, there was no significant difference in PFS, RFS, and DSS in those who were BCG treated or BCG naive, or in the overall population. Limitations include the retrospective design from a single-center setting. ConclusionsIn patients with high-risk NMIBC, FGFRa were frequently observed. Patients with FGFRa who often exhibit recurrence/relapse after BCG treatment have a high unmet need. Patient summaryOur retrospective study suggests that fibroblast growth factor receptor alterations (FGFRa) occur frequently in non–muscle-invasive bladder cancer (NMIBC). Outcomes were similar with or without FGFRa in patients with NMIBC, both overall and for standard bacillus Calmette-Guérin (BCG) treatment.

Phase 1/2 Study of Orociep All Oral Regimen with Idarubicin, Cyclophosphamide, Etoposide, Prednisolone in Combination to Intravenous Rituximab in Elderly Patients with Disseminated High Grade Non Hodgkin Lymphoma. Final Analysis

Background. CHOP, recently combined to the first in class anti CD20immunotherapy, is the leading regimen worldwide for the treatment of high grade B cell non Hodgkin lymphoma (DLBCL). Over the years, improvement have been made to CHOP in order to enhance its efficacy, although no development were made to improve its convenience, indeed, most of the CHOP chemotherapy are IV based. We sought to demonstrate that oral topoisomerase inhibitors III (idarubicin, I) in combination with oral cyclophosphamide (C), etoposide (E, celltop), and prednisolone (P) would prove similar efficacy with an improved convenience to patients.Patients and Methods: This phase 1/2 study was performed to determine the maximum-tolerated dose (MTD) of oral idarubicin in combination with oral C, E, P keeping IV rituximab (R). The patients were to be previously untreated DLBCL stage III or IV, aged 60 to 80 years old. Secondary objectives included evaluation of toxicity and efficacy. The MTD was defined as the dose level at which at least 2 of 3, and if none then 3 of 6 patients experienced a DLT. Dose-limiting toxicity (DLT) was defined as grade 4 neutropenia lasting at least 4 days or grade 4 thrombopenia or more than grade 2 extra hematological toxicity.I was administrated on day 1 at 20, 30, 40mg/m2. No intrapatient dose escalatation was allowed. C and E were given on day 1 to 3 at the fixed dose of 150 mg/m2 and 100 mg/m2 respectively. P was given at the fixed dose of 50 mg/m2 on day 1 to 5. R was administrated IV on day 1 at the fixed dose of 375 mg/m2. G-CSF was systematically used from day 6 to hematological reconstitution. Eight cycles were planned at 3 week-intervals.Results: Twenty six pts were recruited, median age 71 (range 62-80). Overall, 180 cycles at 3 different I dose levels were administered. Although no DLT was observed at dose level 1 (20 mg/m2), 2 of 6 patients developed a DLT at dose level 2 (30 mg/m2), and eventually, all first 3 patients developed a DLT at level 3 (40 mg/m2) which was then considered as MTD. Fourteen patients were then enrolled for the phase 2 portion at the RP2D of 30mg/m². Main toxicity results are summarized in the table below. No toxic related mortality was observed. Two patients stopped treatment because of toxicity and 10 patients received a decreased dose of ID. Overall response rate and complete response rate were 80% and 73%, respectively. With a median follow-up of 4.5 years (9.5 years for alive patients), the 5-year overall survival and event free survival were 65% (95%CI: 41;81) and 65% (95%CI: 42;81), respectively.Conclusion. This study shows that all oral OroCIEP regimen for elderly disseminated DLBCL demonstrated similar efficacy (Coiffier et al, NEJM 2002) with improved convenience to patients, especially elderly as studied in our trial. Subcutaneous anti-CD20 antibody treatment will represent a future improvement towards an all ‘at home’ regimen. This data needs validation in a larger cohort. [Display omitted] DisclosuresLeleu:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

BCG versus Cystectomy for High Risk, High Grade Non Muscle Invasive Bladder Cancer.

BCG versus Cystectomy for High Risk, High Grade Non Muscle Invasive Bladder Cancer.

Treatment of High-grade Non–muscle-invasive Bladder Carcinoma by Standard Number and Dose of BCG Instillations Versus Reduced Number and Standard Dose of BCG Instillations: Results of the European Association of Urology Research Foundation Randomised Phase III Clinical Trial “NIMBUS”

BackgroundIntravesical instillation of bacillus Calmette-Guérin (BCG) is an accepted strategy to prevent recurrence of non–muscle-invasive bladder cancer (NMIBC) but associated with significant toxicity. ObjectiveNIMBUS assessed whether a reduced number of standard-dose BCG instillations are noninferior to the standard number and dose in patients with high-grade NMIBC. Design, setting, and participantsA total of 345 patients from 51 sites were randomised between December 2013 and July 2019. We report results after a data review and safety analysis by the Independent Data Monitoring Committee based on the cut-off date of July 1, 2019. InterventionThe standard BCG schedule was 6 wk of induction followed by 3 wk of maintenance at 3, 6, and 12 mo (15 instillations). The reduced frequency BCG schedule was induction at wks 1, 2, and 6 followed by 2 wk (wks 1 and 3) of maintenance at 3, 6, and 12 mo (nine instillations). Outcome measurements and statistical analysisThe primary endpoint was time to first recurrence. Secondary endpoints included progression to ≥ T2 and toxicity. Results and limitationsIn total, 170 patients were randomised to reduced frequency and 175 to standard BCG. Prognostic factors at initial resection were as follows: Ta/T1: 46/54%; primary/recurrent: 92/8%; single/multiple: 57/43%; and concomitant carcinoma in situ: 27%. After 12 mo of median follow-up, the intention-to-treat analysis showed a safety-relevant difference in recurrences between treatment arms: 46/170 (reduced frequency) versus 21/175 patients (standard). Additional safety analyses showed a hazard ratio of 0.40 with the upper part of the one-sided 97.5% confidence interval of 0.68, meeting a predefined stopping criterion for inferiority. ConclusionsThe reduced frequency schedule was inferior to the standard schedule regarding the time to first recurrence. Further recruitment of patients was stopped immediately to avoid harm in the reduced frequency BCG arm. Patient summaryAfter surgical removal of the tumour, patients with high-grade non–muscle-invasive bladder cancer are treated with bacillus Calmette-Guérin to prevent recurrence and progression. This is associated with significant side effects. We report the results of a clinical trial showing a reduction in the number of instillations (from 15 to nine in total) being inferior to the standard protocol. From today’s perspective, complete tumour resection and a standard number of instillations remain the standard of care.

Oral CHOP-like Chemotherapy in Elderly Patients with High-Grade Non Hodgkin B Cell Lymphoma

Background. The Doxorubicin based R-CHOP regimen remains the standard of care for the upfront treatment of DLBCL. The advent of oral idarubicin permitted to develop an all-oral ambulatory oro-CIEP regimen. We hypothesized this regimen would improve the treatment of elderly DLBCL.Methods. We have performed a phase 1/2 study to determine the MTD of idarubicin in the oro-CIEP regimen. Idarubicin was orally administrated on day 1 with starting dose at 20mg/m2 and escalated per 10mg/m2 increment.Results. Twenty-six newly diagnosed patients were enrolled, median age of 71 years (range, 62-80). All first 3 patients developed a DLT at level 3 (40mg/m2), and 14 patients were then enrolled at RP2D 30mg/m² in the phase 2. The most significant hematological toxicities were thrombocytopenia grade 3 or 4 (3.3%) and neutropenia grade 3 or 4 (26%); and extra-hematological toxicities were infectious disease (5% grade 3 or 4). No toxic related death was observed. ORR and CR rates were 85% and 77%, respectively. The 5-year overall survival and event free survival were 65% (95%CI 41;81) and 65% (95%CI 42;81), respectively.Conclusion. This analysis shows that oral idarubicin at the MTD of 30 mg/m2 is safe and active in elderly DLBCL. The results we have observed, particularly overall survival seemed to be superimposable to previous publications with the regular CHOP-like regimens for this population. Further improvements in the protocol will be introduced with the subcutaneous anti-CD20 immunotherapy approach. This data needs to be confirmed in the context of a larger study. DisclosuresLeleu:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Utilization and Outcomes of Radical Cystectomy for High-grade Non-muscle-invasive Bladder Cancer in Elderly Patients.

Radical cystectomy (RC) represents a treatment option for patients with high-grade non-muscle-invasive bladder cancer (HG-NMIBC); however, perioperative morbidity is not insignificant, particularly in elderly patients. We sought to evaluate the associations of age with utilization and outcomes of RC for HG-NMIBC. Patients with HG-NMIBC diagnosed between 2004 and 2013 were identified in the National Cancer Database and stratified by age:≤ 60, 61-70, 71-80, and > 80 years. Association between age and treatment with RC was assessed by multivariable logistic regression. Associations between age and overall survival were assessed using the Kaplan-Meier method. A multi-institutional analysis was performed to evaluate the associations of age with perioperative outcomes and survival among patients managed with RC for HG-NMIBC. On multivariable analysis, age was associated with RC utilization, with the lowest usage in patients > 80 years (2.1%; P< .01). Upstaging at RC occurred in 40% of patients with HG-NMIBC, and no association of age with upstaging risk was noted. Significantly inferior overall survival was observed in the patients who were upstaged across age strata (all P< .01). In the multi-institutional cohort, age was not associated with risks of upstaging, receipt of transfusion, 30-/90-day complications, or recurrence-free or cancer-specific survival (all P > .05), whereas upstaging was associated with inferior recurrence-free and cancer-specific survival regardless of age. RC for HG-NMIBC is used less frequently in older adults, despite similar risks of pathologic upstaging. As upstaging is associated with inferior survival regardless of age, these data suggest that elderly patients with HG-NMIBC may be at risk for undertreatment.

Renal Tuberculosis Following Intravesical Bacillus Calmette-Guérin for High-grade Non–muscle-invasive Bladder Cancer

A 47-year-old man presented to the urology department with visible hematuria. He was found to have a high-grade non-muscle-invasive transitional cell carcinoma of the bladder and was subsequently treated with intravesical Bacillus Calmette-Guérin instillations. On routine surveillance computed tomography scan following treatment, he was found to have multiple rounded areas of low density in the right kidney, suspicious for renal malignancy. He underwent renal biopsy that revealed necrotizing granulomatous inflammation suggestive of mycobacterial infection. He was successfully treated with antituberculosis therapy.

A phase ii study of doxorubicin, vincristine, cyclophosphamide, prednisolone (CHOP) chemotherapy with intathecal (IT) methotrexate and prophylactic cranial irradiation in a patients with high grade non Hodgkin`s lymphoma (NHL)

Objective: The objective of this phase II study was to evaluate the efficacy and toxicity of (CHOP) chemotherapy with intrathecal methotrexate and prophylactic cranial irradiation in patients with high-grade Non Hodgkin`s lymphoma. Method: From January 2002 to December 2002 tewenty consecutive patients with histopathologically and immunohistochemically confirmed high grade NHL with Ann Arbor stage III &amp; IV were enrolled. ECOG performance status of 0 or 1 was required. Written informed consent was obtained from all patients. Patients with symptomatic meningeal or brain involvement were excluded from the study. Cyclophosphamide 750 mg /m2, vincristine 1.4 mg / m2 (maximum 2 mg), doxorubicin 50 mg / m2 was given I/V on D1 and prednisolone 100 mg PO was given from D1 - D5. Cycles were repeated after every 21 days. Intrathecal methotrexate was given at a dose of 12 mg once during 3rd week, twice weekly on 5th &amp; 6th week and once during 7th week. A total dose of 1800 cGy was given to whole brain in 10 fraction s with a daily tumor dose of 180 cGy using a Cobalt 60. Common Toxicity Criteria was used for evaluation of toxicity and WHO criteria for response evaluation. Result: All 20 patients were able to complete the planned therapy. Grade IV neutropenia was observed in 45% (9/20) of patients. Episodes of febrile neutropenia were seen in 20%(4/20). Grade II diarrhea was seen in 25%(05/20). 20%(4/20) had grade II cutaneous toxicity. No immediate radiation related toxicity was seen except grade II nausea and vomiting. Overall response was found in 75%(15/20) of patients, CR in 60%(12/20) and PR in 15%(03/20). 15%(03/20) patients showed stable disease and 10%(02/20) had progressive disease. Conclusion: This combined modality treatment of CHOP chemotherapy with intrathecal methotrexate and prophylactic cranial irradiation has been feasible and effective with acceptable toxicity in this group of patients with high-grade Non Hodgkin`s lymphoma.

PA03.13. Effect of triphaladi rasayana along with yoga therapy on low grade non hodgkins lymphoma and resistant intermediate and high grade non hodgkins lymphoma

Purpose:1. To find out the effect of Thriphaladi Rasayana along with Yoga Therapy on low grade Non Hodgkins Lymphoma and resistant intermediate and high grade NonHodgkins Lymphoma. 2. To apply a less costly, less morbid, well accepted method of treatment on NHL. 3.To find a simple method to increase the immunity. 4.To try a drug which is easy to prepare?Method:Purposive sampling technique was used for the study. Sample of 30 patients age range 25 75 years with histologicaly proven NonHodgkins lymphoma, attending the M.O.I.O.P of the regional cancer centre during a period of 18 months. Groups1) Low grade NonHodgkins Lymphoma 2) Resistant intermediate &High grade NonHodgkins lymphoma (failed chemotherapy) were taken. Procedure : 2 groups were given Triphaladhi Rasayana (15 grams of powder with ghee and honey) twice dailymorning& at bed time with milk as anupana for period of 1month along with selected yoga asanas and niyama?Result:Symptoms included were fever, night sweats, weight loss, lymph nodes enlargement, splenomegaly, and hepatomegaly. In low grade symptom relief was noted in almost all cases. Lymph node changes notedLow grade5 2% (complete remission), 38% (partial remission), 10% (no change), intermediate35% (CR), 52% (PR) & 13% (NC), High grade67% (CR), 33%(PR). Hepatomegaly changes :ve in low grade92.86%, intermediate 90.9% & high grade100%. Splenomegaly changes :ve in low grade92.86%, intermediate72.72% & high grade80% Over all remission status of 30 patientscomplete remission30%, partial remission 30% & no change30%?Conclusion:Thriphaladirasayana along with Yoga therapy is very effective in Low grade NonHodgkins lymphoma and resistant intermediate and high grade Non hodgkins Lymphoma?

1069PD - Predicting Response Rates of High Grade Non Hodgkin's Lymphoma: A Comparative Study of International Prognostic Index (IPI) with Subjective Global Assessment (SGA)

ABSTRACT Introduction Malnutrition is common in patients with cancer and no study has co- related the effect of malnutrition on outcomes of non Hodgkins Lymphoma (NHL) from India. Besides, there are no studies validating the international prognostic index (IPI) from India. This study was done to compare the prognostic abilities of IPI and subjective global assessment (SGA) for early outcomes in NHL. Methods This is a prospective observational study set in the lymphoma clinic of Tata Memorial Hospital, Mumbai between January to December 2010. All patients were screened for malnutrition at entry using a modified SGA tool. Baseline clinical factors of prognostic importance including IPI scores were recorded. Univariate and multivariate comparison were made using SPSS or EpiInfo 2000 software. Results There were 401 patients with high grade NHL. The analysis of 389 patients with all information available showed that the IPI scores were low risk, low intermediate risk, intermediate high risk, high risk in 133 (34.3%), 95 (24.4 %), 91 (23.4%) and 70 (17.9 %) patients respectively. The SGA scores were A, B, and C in 188 (48.6%), 129 (33.2%) and 72 (18.2 %) patients respectively. Early outcomes included CR in 241 (62.6 %), EFS in 73% and overall survival in 81% patients at 1-year. Univariate analysis revealed that the SGA scores were significantly associated with the IPI variables - age, serum LDH, performance status (ECOG), stage (Ann Arbor), extranodal sites as well as hemoglobin, response rates, one year survival and disease progression. Multivariate analysis revealed that SGA was a highly significant independent predictor of all early outcome parameters. Some IPI scores lost significance in the multivariate model. Conclusions The SGA is a highly significant and independent predictive biomarker (for CR) and a prognostic biomarker (for 1-year OS and PFS) with good discriminative function in patients with NHL. Disclosure All authors have declared no conflicts of interest.

Polyamine-modulated Factor-1 Methylation Predicts Bacillus Calmette-Guérin Response in Patients with High-grade Non–muscle-invasive Bladder Carcinoma

BackgroundBacillus Calmette-Guérin (BCG) is a standard treatment to reduce tumor recurrence and delay progression of high-risk non–muscle-invasive (NMI) bladder tumors. However, it is not clear yet which patients are more likely to respond to BCG. ObjectiveThe aim was to evaluate the role of polyamine-modulated factor-1 (PMF-1) methylation in predicting clinical outcome of T1 high-grade (T1HG) bladder tumors treated with BCG. Design, setting, and participantsIn a retrospective design, PMF-1 methylation was analyzed on tumor specimens belonging to 108 patients with T1HG NMI bladder cancer undergoing BCG treatment. Median follow-up was 77 mo (range: 5–235 mo). Outcome measurements and statistical analysisPMF-1 methylation was assessed by methylation-specific polymerase chain reactions. Recurrence, progression into muscle-invasive tumors, and disease-specific survival rates were analyzed using competing risks regression analysis. Results and limitationsAmong the 108 patients analyzed, 35 had recurring disease (32.4%), 21 progressed (19.4%), and 16 died of disease (14.8%); 71.3% of tumors had PMF-1 methylation. Univariate analyses using cumulative incidence curves revealed that an unmethylated PMF-1 was significantly associated with increased recurrence (p=0.026), progression (p=0.01), and shorter disease-specific survival (log-rank, p=0.03). Multivariate analyses indicated that among sex, age, focality, tumor size, and concomitant carcinoma in situ, only PMF-1 methylation provided significant hazard ratios (HRs) for recurrence of (HR: 2.032; p=0.042), and progression (HR: 2.910; p=0.020). Limitations of the study include its retrospective design, lymphovascular invasion status not available, short maintenance BCG, and that a second transurethral resection was not performed. ConclusionsEpigenetic analyses revealed that the methylation status of PMF-1 was associated with the clinical outcome of patients with T1HG tumors undergoing BCG treatment. An unmethylated PMF-1 correlated to recurrence and progression in T1HG disease using univariate and multivariate analyses. Thus, assessing the methylation status of PMF-1 may serve to distinguish patients responding to BCG from those who may require more aggressive therapeutic approaches.

Hormone Receptor Status Rather Than HER2 Status Is Significantly Associated With Increased Ki-67 and p53 Expression in Triple-Negative Breast Carcinomas, and High Expression of Ki-67 but Not p53 Is Significantly Associated With Axillary Nodal Metastasis in Triple-Negative and High-Grade Non–Triple-Negative Breast Carcinomas

Triple-negative (TN) breast carcinoma is associated with a higher recurrence rate and shorter survival and lacks the benefit of specific therapy. TN tumors usually express high levels of Ki-67 and p53 that are considered prognostic markers for breast cancer. We compared Ki-67 and p53 expression between TN and high-grade non-TN invasive carcinomas in a total of 214 cases and investigated an association between their expression and axillary nodal metastasis in these tumors. Our findings demonstrate that TN tumors are associated with significantly higher expression of Ki-67 and p53 compared with non-TN tumors, which may contribute to the poorer prognosis in TN tumors. Hormone receptor negativity rather than HER2 negativity is associated with the significantly increased Ki-67 and p53 expression in TN tumors. Furthermore, a high expression level of Ki-67 but not p53 is more likely to be associated with axillary nodal metastasis in these cases.

CNS Disease In Younger Patients (

AbstractAbstract 112 Background:CNS involvement by aggressive lymphoma carries a poor prognosis. Little is known about the frequencies of CNS relapse or progression, risk factors, and the efficacy of prophylaxis in younger patients (pts) undergoing modern chemoimmunotherapy (R-CHOP). Methods:2.797 younger pts (<= 60 years) with aggressive lymphoma were treated on trials of the DSHNHL and the Mabthera International Trial. Pts with B-cell lymphoma (n=2.196) received 6 or 8 courses of CHO(Etoposid)P ± Rituximab (R) or were treated on the MegaCHOEP + R protocols featuring high doses of C, H, E, and P necessitating repetitive transplantation of autologous stem cells (Schmitz et al., BLOOD 2009, 404 a). Pts with lymphoma in testes, bone marrow, upper cervical nodes, sinuses, or other sites in the cranial region were to receive four i. th. injections of 15 mg MTX for prophylaxis of meningeosis during treatment courses 1 and 2 except for pts on the NHL-A and -B1 trials. In the latter studies, CNS prophylaxis was recommended for pts with lymphoblastic lymphoma only. Results:Overall, sixty-five of 2.797 pts (2.3%) developed meningeal and/or parenchymal CNS relapse (43.1 %) or progressed during therapy (56.9%). Relapse/ progression in the CNS was combined with systemic disease in 20 pts (32.3%) but represented the only site of disease in the majority of cases (67.7 %). Median time to relapse/ progression was 7.2 months (range: 0.2– 85.2 months); median survival after relapse or progression was 4.2 months (0 - 54.0 months).The incidence of CNS relapse/ progression was low in pts with age-adjusted International Prognostic Index (aaIPI) 0 or 1 (High-CHOEP phase III study with 385 pts: CNS events 0.3%; MInT trial with 818 pts: CNS events 1.6 %) but was significantly higher in the 463 pts on the MegaCHOEP phase II/III trials which included pts with aaIPI 2 or 3 only (CNS events: 6.4 % and 7.5 %, respectively).Focusing on 663 pts treated with state-of-the-art chemoimmunotherapy including rituximab, multivariate Cox regression analysis identified LDH>N (relative risk [RR]=4.5, p=0.046) and stage III/IV (RR=6.2, p= 0.016) as significant risk factors for CNS disease. Using this model, 32.7 % of all pts would have been considered “high-risk”; 82.4 % of those pts who developed CNS disease carried both risk factors. However, only 14/217 (6.5%) of the “high-risk” pts defined by elevated LDH and advanced stage actually experienced CNS relapse or progression.Rituximab significantly reduced the risk for CNS disease when all 1.570 pts treated with CHO(E)P- 14/21 were considered (RR= 0.3, p=0.03). In contrast, the addition of R did not reduce the RR in 309 pts treated with MegaCHOEP ± R (RR=0.8, p= 0.54). There was no indication that the addition of etoposide to CHOP (CHOEP) reduced the risk of CNS disease in any patient cohort treated with chemotherapy and R. Conclusions:Pts with aggressive lymphoma and aaIPI 0 or 1 show low frequencies of CNS relapse or progression. Omitting CNS prophylaxis in such pts seems reasonable also because – similar to our recent findings in the elderly (Boehme et al., BLOOD 2009; 113: 3896) – this analysis in younger pts failed to show benefit of prophylaxis with i.th. MTX in any of the risk groups analyzed. CNS disease remains a serious problem in younger pts with aaIPI 2 or 3. We failed to discover clinical or laboratory features to precisely define a “high-risk” group of patients all of whom might benefit from CNS-directed prophylaxis. Unfortunately, neither high-dose therapy including high-doses of etoposide (MegaCHOEP), standard dose etoposide (CHOEP), nor i. th. MTX reduced the incidence of CNS disease. Rituximab reduced the RR of CNS disease in pts with B-cell lymphoma treated with CHO(E)P- 14/21 but failed to do so in pts treated with R-MegaCHOEP. Disclosures:Schmitz:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Glass:Roche: Honoraria, Research Funding. Pfreundschuh:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Phase I/II Study of Escalating Doses of Idarubicin Orally Given with Oral Cyclophosphamide, Etoposide, Prednisolone and Intravenous Rituximab in Elderly Patients with Disseminated High Grade Non Hodgkin Lymphoma.

Abstract 3695Poster Board III-631 IntroductionThis study was performed to determine the maximum-tolerated dose (MTD) of oral idarubicin in combination with oral cyclophosphamide (CY), etoposide (ET), prednisolone (PRED) and intravenous (IV) rituximab (RI) administrated to previously untreated patients (pts) (60-80 years-old) with high grade stage III or IV non Hodgkin lymphoma. Secondary objectives were evaluation of toxicity and efficacy. Patients and MethodsIdarubicin was administrated per os on day 1 with doses starting at 20 mg/m2 and escalated by 10 mg/m2 increments. Each idarubicin dose level included 3 to 6 pts. No intrapatient dose escalatation was allowed. Dose-limiting toxicity (DLT) was defined as grade 4 neutropenia lasting at least 4 days or grade 4 thrombopenia or more than grade 2 extra haematological toxicity. The MTD was defined as the dose level at which at least 2 of 3 or 3 of 6 pts experienced a DLT. CY and ET were given per os on day 1 to 3 at the fixed dose of 150 mg/m2 and 100 mg/m2 respectively. PRED was given at the fixed dose of 50 mg/m2 per os on day 1 to 5. RI was administrated IV on day 1 at the fixed dose of 375 mg/m2. G-CSF was systematically used from day 6 to haematological reconstitution. Eight cycles were planned at 3 week-intervals. ResultsBetween October 2003 and August 2008, 19 immunocompetent pts [median age 70 (range 62-80)] with a new diagnosis of high grade non Hodgkin lymphoma received 128 cycles at 3 different idarubicin dose levels. No DLT was observed at dose level 1 (20 mg/m2), whereas 2 of 6 patients developed a DLT at dose level 2 (30 mg/m2). All 3 pts developed a DLT at level 3 (40 mg/m2) which was considered as MTD. Seven pts were enrolled at level 2 to confirm the results. Main toxicity results are summarized in the table below. No toxicity related mortality was observed. Two pts stopped treatment because of toxicity and 8 pts received a decreased dose. Overall response rate and complete response rate were 79% and 68% respectively. With a median follow-up of 22 months, the 2-year survival rates were 75% (95% CI: 45-90) for all pts and 58 % (95% CI: 21-83) for dose level 2 pts.Idarubicin level: Number of cycles at planned dose (89/128)Haemoglobin G1-G2 G3-G4Platelets <G4 G4<g4 g4<=” td=“”></g4 g4<=“>ANC <G4 G4Infection G1-G2 G3-G4Level 1 (24 cycles)14 012 09 41 0Level 2 (61 cycles)29 29 118 118 3Level 3 (4 cycles)1 22 00 41 2 ConclusionThis first analysis clearly shows that the MTD of oral idarubicin administrated with CY, ET, PRED and RI, is 40 mg/ m2 on day 1 every 21-day cycle. The recommended dose study is ongoing. Overall survival data seems to be similar to previous publications. (Coiffier et al, NEJM 2002). Future development of subcutaneous anti-CD20 antibody could represent a special interest for this new oral chemotherapeutic protocol in order to improve the quality of life of elderly pts. Disclosures:No relevant conflicts of interest to declare.

Phase I Study of Bortezomib in Combination with Gemcitabine in Relapsed/Refractory Intermediate Grade B-Cell and Mantle Cell Non-Hodgkin's Lymphoma.

Abstract 1682Poster Board I-708 BackgroundThe outlook for patients with relapsed or primary progressive intermediate to high grade Non Hodgkin's Lymphoma (NHL) remains problematic. The current best strategy is to to identify potential chemosensitive patients who may respond to autologous transplant, by use of high dose chemotherapy protocols However, approximately fifty percent of those who undergo high-dose therapy, and the majority of patients treated with standard salvage regimens alone, will ultimately show progression or relapse; newer regimens are necessary. In-vitro data in a number of tumor cell types shows enhanced activity of gemcitabine (gem) when combined with the proteasome inhibitor bortezomib (B). MethodsPatients with intermediate to high grade relapsed or refractory B cell NHL or mantle cell lymphoma who had been treated with up to 4 prior regimens including autologous transplant were eligible. Starting dose of gemcitabine was 1000 mg/m2 on days 1 and 8 of a 21 day cycle, with bortezomib starting at 1 mg/m2 on days 1, 4, 8, 11. CT (and PET when possible) were performed after cycle 4 and after cycle 6. Patients were allowed to continue therapy in the event of clinical benefit. Results28 patients were enrolled overall, of whom 24 are evaluable for response. 3 of the patients had mantle cell lymphoma. Median Age was 63 (range 34-77). 20 were male, 8 female. Four patients were enrolled on dose level 1, of whom three were evaluable for toxicity. All 3 showed DLT (neutropenia and thrombocytopenia) so enrollment continued at dose level -1 (gem 800 days 1 and 8, B 1.0 mg/m2 d1, 4, 8, 11). One DLT was seen in the five patients treated. In order to make the regimen more easily tolerable, the regimen was changed to increase the time between doses so that dose escalations would begin from gem 800 given on days 1 and 15 and B 1.0 given on days 1 and 15 only, on a 28 day cycle. Dose escalation to the target dose of gem 1000 mg/m2 and B 1.3 mg/m2 was achieved without DLT, and this level was expanded to six patients. A second group of six patient was treated on this dose level with the addition of rituxan 375 mg/m2 given on days 1 and 15 with no DLT seen. Grade 4 toxicities seen on the study were neutropenia (4 pts), and thrombocytopenia (2). Grade 3 toxicities were neutropenia (6) thrombocytopenia (5) and febrile neutropenia (1). Other toxicities of grade 2 or less included elevated transaminases, fatigue, diarrhea, and peripheral neuropathy (grade 2: 3 pts grade 1: 3 patients). 24 patients were evaluable for response. Complete Remission was seen in 3 patients, one at dose level 1, one at dose level 5B (gem 1000 mg/m2 d1 and 15, B 1.3 mg/m2 d1 and 15) and one at dose level 5B1 (5B plus rituxan 375 mg/m2 d1 and 15). ConclusionThe combination of gemcitabine 1000 mg/m2 combined with bortezomib 1.3 mg/m2 with or without rituxan 375 mg/m2 on a day 1, 15 schedule shows activity in patients with relapsed/refractory B cell NHL, and was well tolerated. A phase II study of this combination is ongoing. DisclosuresOff Label Use: bortezomib in lymphoma.

High-grade B-cell NHL of the brachial plexus followed by infiltration of the spinal cord

Sirs: Primary lymphoma of the central nervous system (CNS) account for about 1–3 % of all primary brain tumors. Involvement of the peripheral nervous system by lymphoma is a rarity, typically secondary, either by direct extension of the neoplasm from an adjacent, involved site or in the context of systemic dissemination. Only a few cases have been reported with the tumor confined to the peripheral nervous system [4]. Most of these cases, however, still have shown concomitant central nervous system involvement with either positive cerebrospinal fluid analysis or leptomeningeal involvement, suggesting that peripheral disease results from secondary spread of tumor cells [4]. We report the case of a 48-yearold woman who presented with progressive numbness and weakness of her right arm. A magnetic resonance imaging (MRI) scan showed a contrast enhancing lesion infiltrating the lower part of the brachial plexus and extending to the entry zone of the C8 spinal root (Fig. 1). An open biopsy of the spinal ganglion C8 revealed unspecific lymphocytic infiltration. Cytological examination of CSF was not diagnostic. A following MRI scan showed a regression of the contrast-enhancing lesion of the right brachial plexus, but also an infiltration of the cervical spinal cord. Four months later a further MRI scan revealed a contrast enhancing lesion of the cervical spinal cord at the C6/C7 level. An open biopsy of this lesion revealed a high grade Non Hodgkin’s B-cell lymphoma (Fig. 2). The patient underwent a combination of systemic and intrathecal chemotherapy following the “Bonn Protocoll” consisting of methotrexate, cytarabine, ifosfamide, cyclophosphamide and steroids [3]. After four cycles of chemotherapy complete tumor response was confirmed. One year later, however, she developed paralysis of the oculomotor and trigeminal nerves. MRI scan revealed a contrast enhancing lesion in the cavernous sinus but no residual tumor in the spinal cord or brachial plexus. The patient LETTER TO THE EDITORS

ABV (doxorubicin [Adriamycin], bleomicin and vincristine) polychemotherapy regimen in HIV Kaposi’s Sarcoma: Uruguaian 10-year experience

9559 Background: Kaposi’s sarcoma is the most common malignancy among HIV patients and is considered to be one of the AIDS defining conditions. This abstract illustrates our 10 year experience with the treatment of 32 Kaposi’s sarcoma HIV patients with the same therapeutic approach. Methods: Between 04/95 and 03/05 we recruited 32 previously untreated patients that were diagnosed with Kaposi’s sarcoma and treated at the Servicio de Oncologia Clinica (Universitary Clinicas Hospital) in Montevideo. All of them received the same iv polychemotherapy plan (Adriamycin 10mg/m2, Bleomycin 10 U/m2 and Vincristine 1.4 mg/m2, every two weeks until tumor progression or severe toxicity). Results: 21 of the patients were good risk ones and the remaining 11 were poor risk patients (AIDS Clinical Trials Group staging classification). CD4 levels varied from 6 to 780/ml and the viral load ranges were 240 to 89000 copies. The patients received an average of 10.2 (4–21) polychemotherapy cycles. Grade 3–4 myelotoxicity was reported in 5 patients delaying the onset of the subsequent cycles. Grade 2 neurotoxicity was seen in 7 patients after 4, 5, 6, 8, 10, 11 and 13 cycles of ABV, changing vincristine for vinblastine (4mg/m2 every two weeks) in these patients. All the patients achieved a partial response with improvements in CD4 levels and viral load. 13/32 patients experienced a relapse (3–29 months after last chemotherapy cycle). 3 patients were retreated with paclitaxel 135 mg/m2 with 2/3 new partial responses of shorter duration. 5 patients received 4 additional ABV cycles achieving a new partial response. 5 patients refused further treatment dying due to progressive disease. One relapsed patient developed a second malignancy (High grade Non Hodgkin lymphoma) dying three months later. Conclusions: These data suggest that ABV regimen is still an effective treatment option for HIV-Kaposi’s sarcoma, specially in the undeveloped countries in which the cost of other better internationally approved options (liposomal doxorubicin and daunorubicin) makes them unaccesible for the majority of the population. No significant financial relationships to disclose.

Echocardiography Identifies Changes in Left Ventricular Cardiac Function after Low Doses of Anthracycline, Particularly in Older Patients.

Anthracyclines remain an essential component of treatment regimes for lymphoma. Increasing numbers of older patients are being offered potentially curative treatment for lymphoma and a corresponding increase in cases of cardiac toxicity might be expected. Upper limits for total doses of anthracycline are published, but there is little information on whether age predicts independently for cardiac susceptibility to anthracyclines. There is also little data on the effect of low doses of anthracycline on the heart. We have prospectively studied cardiac function in patients receiving Doxorubicin (DOX) for High Grade Non Hodgkin's Lymphoma and Hodgkin's disease. 28 patients are included: 18 male, 9 female aged 16 to 89 (median 59) years. Echocardiographic examinations were undertaken before and after patients received DOX at a median dose of 85 mg/m2 (50 mg/m2 to 150 mg/m2). The Left Ventricular (LV) Tei index was calculated in all cases as the sum of the isovolumetric contraction time and isovolumetric relaxation time divided by the ejection time. Higher values represent cardiac dysfunction and a rise post treatment was regarded as deterioration in LV function. For the group, there was a significant post treatment deterioration in LV function as measured by the Tei index: 0.400 ± 0.12 pre-treatment to 0.475 ± 0.16 post treatment (P = 0.0076). Multivariate analysis of age, pre-treatment Tei index and DOX dose (in this low range) revealed age to be the only significant predictor of deterioration in cardiac function after treatment (correlation coefficient 0.69, p < 0.0001).We conclude that measurable changes in cardiac function occur after very low doses of DOX and that these changes are more marked in older patients. Whether these changes will predict for further deterioration after higher doses of DOX and potentially predict for long term symptomatic cardiac dysfunction post therapy will require further study and follow up.