Graciela M. Nogueras-Gonzalez

Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study

BACKGROUND Ibrutinib, an orally administered covalent inhibitor of Brutons tyrosine kinase (BTK), is an effective treatment for relapsed chronic lymphocytic leukaemia (CLL). We investigated the activity and safety of the combination of ibrutinib with the monoclonal antibody rituximab in patients with high-risk CLL. METHODS In this single-arm phase 2 study, we enrolled adult patients with high-risk CLL at the MD Anderson Cancer Center (Houston, TX, USA). All enrolled participants had high-risk cytogenetic abnormalities (deletion 17p, TP53 mutation, or deletion 11q) or a short progression-free survival (PFS <36 months) after previous first-line chemoimmunotherapy. Patients with symptomatic disease requiring therapy received 28-day cycles of once-daily ibrutinib 420 mg together with rituximab (375 mg/m(2), intravenously, every week during cycle 1, then once per cycle until cycle 6), followed by continuous daily single-agent ibrutinib 420 mg until disease progression or until toxicities or complications precluded further treatment. The primary endpoint was progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov number NCT01520519, and is no longer accruing patients. FINDINGS Between Feb 28, 2012, and Sept 11, 2012, we enrolled 40 patients with CLL with high-risk disease features, 20 of whom had deletion 17p (del[17p]) or TP53 mutations (16 previously treated, four untreated), 13 had relapsed CLL with deletion 11q (del[11q]), and seven a PFS less than 36 months after first-line chemoimmunotherapy. 18-month PFS in all patients was 78·0% (95% CI 60·6-88·5), whereas in those with a del(17p) or TP53 mutation it was 72·4% (45·6-87·6) Toxicity was mainly mild to moderate in severity (grade 1-2). Diarrhoea occurred in ten (25%) patients (grade 1 in nine patients and grade 2 in one), bleeding events in 14 (33%) patients (eight grade 1 and five grade 2), nausea or vomiting in 15 patients (38%) (ten grade 1 and five grade 2), and fatigue in seven (18%) patients (four grade 1 and three grade 2). Five patients (13%) had grade 3 infections (two lung infections, one upper respiratory tract infection, one sepsis, and one mucositis), and no grade 4 or 5 infections occurred. One patient had grade 4 neutropenia. INTERPRETATION The encouraging safety and activity of ibrutinib and rituximab in this population of patients with high-risk CLL merits further investigation of this combination. FUNDING Pharmacyclics Inc, Cancer Prevention and Research Institute of Texas, Leukemia and Lymphoma Society, National Cancer Institute, MD Anderson Cancer Center.

Evaluating women with ovarian cancer for BRCA1 and BRCA2 mutations: Missed opportunities

OBJECTIVE: To estimate the incidence of genetic counseling referral for ovarian cancer patients who are at substantial risk for a BRCA1 or BRCA2 mutation. METHODS: An analysis was performed of new ovarian cancer patients who were seen at a comprehensive cancer center from January 1, 1999, through December 31, 2007. Patients at substantial (more than 20–25%) risk for a BRCA1 or BRCA2 mutation were identified and records reviewed for referral to genetic counseling. Time to referral was estimated using the Kaplan-Meier method. RESULTS: A total of 3,765 epithelial ovarian cancer patients were seen during the 9-year period. On average, 23.8% of patients met substantial-risk criteria for BRCA mutations. In 1999, only 12% of patients at substantial-risk were referred. Referral improved over time with 48% referred in 2007 (P<.001). Newly diagnosed patients were more often referred for genetic counseling than new patients with recurrent disease or those seen as second opinions. African-American women meeting substantial-risk criteria were less likely to be referred than were white or Hispanic women (P=.009). CONCLUSION: Although dictated family history was accurate, interpretation of risk for BRCA1 or BRCA2 mutations and subsequent referral to genetic counseling was poor. Although there was significant improvement over time, 50% of substantial-risk patients still were missed. Systematic efforts to identify those ovarian cancer patients at substantial risk for a BRCA1 or BRCA2 are necessary. LEVEL OF EVIDENCE: III

Risk Factor Analysis in a Contemporary Cystectomy Cohort Using Standardized Reporting Methodology and Adverse Event Criteria

PURPOSE Adverse event reporting is poorly classified and nonstandardized in the urological literature. We report adverse event data and associated risk factors using standardized reporting methods and Common Terminology Criteria for Adverse Events, version 3.0 to minimize interpretation bias and allow reliable comparisons with other populations. MATERIALS AND METHODS We retrospectively reviewed consecutive radical cystectomies done for urothelial bladder carcinoma at our institution between January 2004 and September 2006. Adverse events within 90 days postoperatively were recorded. We explored the association of important risk factors with the overall complication rate and specific complications. RESULTS A total of 283 patients were included in the study. Complete 90-day followup data were available on 90% of patients. Median age was 70 years (IQR 62-75). Median body mass index was 26.8 kg/m(2) (IQR 24.4-31.0). At least 1 adverse event was observed in 152 patients (54.0%) and a grade 3-4 adverse event was observed in 40.3%. The most common grade 4 adverse events were myocardial infarction in 3.5% of cases, septic shock in 2.8% and pulmonary embolism in 1.8%. No patient died during followup. An association between body mass index, and any and major adverse events was found after adjusting for confounding variables. CONCLUSIONS More than 50% of patients experience an adverse event after radical cystectomy and 40% are major. Body mass index is independently associated with adverse events in these patients. These findings are important for individualized risk assessment, patient counseling and uniform assessment of quality care.

Age and Body Mass Index Are Independent Risk Factors for the Development of Postoperative Paralytic Ileus After Radical Cystectomy

OBJECTIVES To identify the risk factors that would aid in the identification of patients at the greatest risk of developing postoperative paralytic ileus (POI). POI is a common complication after radical cystectomy and can result in a prolonged hospital stay and delayed recovery. METHODS A retrospective cohort study design was used to analyze data from consecutive patients presenting to our institution for radical cystectomy with pelvic nodal dissection. POI was declared if patients were without evidence of bowel function beyond the anticipated discharge goal of 6 days. The association between several clinical features and the occurrence of POI was examined. RESULTS Of 283 patients, 43 (15.2%) developed POI. Of the 43 patients, 38 (88.4%) were given total parenteral nutrition for nutritional supplementation. No difference in the incidence of POI was observed between the sexes, previous abdominal operations, estimated blood loss, transfusion requirement, operative time, neoadjuvant chemotherapy, or previous radiotherapy. POI was observed in 11.3% of normal and overweight patients (body mass index [BMI] <30.0 kg/m(2)) compared with 25.6% of obese patients (BMI ≥30.0 kg/m(2); P = .005). On multivariate analysis adjusted for the influence of competing variables, increasing age (hazard ratio 1.09, 95% confidence interval 1.02-1.16, P = .008) and BMI (hazard ratio 1.09, 95% confidence interval 1.03-1.17, P = .007) were significantly associated with the presence of POI. CONCLUSIONS Our results showed that increasing age and BMI were significantly associated with the presence of POI in patients undergoing radical cystectomy for bladder cancer.

Accuracy of Colposcopy in the Diagnostic Setting Compared With the Screening Setting

OBJECTIVE: To estimate the accuracy of colposcopy to identify cervical precancer in screening and diagnostic settings. METHODS: As part of a larger clinical trial to evaluate the diagnostic accuracy of optical spectroscopy, we recruited 1,850 patients into a diagnostic or a screening group depending on their history of abnormal findings on Papanicolaou tests. Colposcopic examinations were performed and biopsies specimens obtained from abnormal and normal colposcopic sites for all patients. The criterion standard of test accuracy was the histologic report of biopsies. We calculated sensitivities, specificities, likelihood ratios, receiver operating characteristic curves, and areas under the receiver operating characteristic curves. RESULTS: The prevalence of high-grade squamous intraepithelial lesions (HSIL) or cancer was 29.0% for the diagnostic group and 2.2% for the screening group. Using a disease threshold of HSIL, colposcopy had a sensitivity of 0.983 and a specificity of 0.451 in the diagnostic group when the test threshold was low-grade squamous intraepithelial lesions (LSIL), and a sensitivity of 0.714 and a specificity of 0.813 when the test threshold was HSIL. Using the same HSIL disease threshold, in the screening group, colposcopy had a sensitivity of 0.286 and a specificity of 0.877 when the test threshold was LSIL, and a sensitivity of 0.191 and a specificity of 0.961 when the threshold was HSIL. The colposcopy area under the receiver operating characteristic curve was 0.821 (95% confidence interval 0.79–0.85) in the diagnostic setting compared with 0.587 (95% confidence interval 0.56–0.62) in the screening setting. Changing the disease threshold to LSIL demonstrated similar patterns in the tradeoff of sensitivity and specificity and measure of accuracy. CONCLUSION: Colposcopy performs well in the diagnostic setting and poorly in the screening setting. Colposcopy should not be used to screen for cervical intraepithelial neoplasia. LEVEL OF EVIDENCE: II

Prospective Multicenter Randomized Intermediate Biomarker Study of Oral Contraceptive versus Depo-Provera for Prevention of Endometrial Cancer in Women with Lynch Syndrome

Women with Lynch syndrome have a 40% to 60% lifetime risk for developing endometrial cancer, a cancer associated with estrogen imbalance. The molecular basis for endometrial-specific tumorigenesis is unclear. Progestins inhibit estrogen-driven proliferation, and epidemiologic studies have shown that progestin-containing oral contraceptives (OCP) reduce the risk of endometrial cancer by 50% in women at general population risk. It is unknown whether they are effective in women with Lynch syndrome. Asymptomatic women ages 25 to 50 with Lynch syndrome were randomized to receive the progestin compounds Depo-Provera (depo-MPA) or OCP for three months. An endometrial biopsy and transvaginal ultrasound were conducted before and after treatment. Endometrial proliferation was evaluated as the primary endpoint. Histology and a panel of surrogate endpoint biomarkers were evaluated for each endometrial biopsy as secondary endpoints. A total of 51 women were enrolled, and 46 completed treatment. Two of the 51 women had complex hyperplasia with atypia at the baseline endometrial biopsy and were excluded from the study. Overall, both depo-MPA and OCP induced a dramatic decrease in endometrial epithelial proliferation and microscopic changes in the endometrium characteristic of progestin action. Transvaginal ultrasound measurement of endometrial stripe was not a useful measure of endometrial response or baseline hyperplasia. These results show that women with Lynch syndrome do show an endometrial response to short-term exogenous progestins, suggesting that OCP and depo-MPA may be reasonable chemopreventive agents in this high-risk patient population. Cancer Prev Res; 6(8); 774–81. ©2013 AACR.

Randomized Clinical Trial of Endobronchial Ultrasound Needle Biopsy With and Without Aspiration

BACKGROUND Endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (EBUS-TBNA) is performed with a dedicated 22- or 21-gauge needle while suction is applied. Fine-needle sampling without suction (capillary sampling) has been studied for endoscopic ultrasound and for biopsies at various body sites and has resulted in similar diagnostic yield and fewer traumatic samples. However, the role of EBUS-guided transbronchial needle capillary sampling (EBUS-TBNCS) is still to be determined. METHODS Adults with suspicious hilar or mediastinal lymph nodes (LNs) were included in a single-blinded, prospective, randomized trial comparing EBUS-TBNA and EBUS-TBNCS. The primary end point was the concordance rate between the two techniques in terms of adequacy and diagnosis of cytologic samples. The secondary end point was the concordance rate between the two techniques in terms of quality of samples. RESULTS A total of 115 patients and 192 LNs were studied. Concordance between EBUS-TBNA and EBUS-TBNCS was high, with no significant difference in adequacy (88% vs 88%, respectively [P ± .858]; concordance rate, 83.9% [95% CI, 77.9-88.8]); diagnosis (36% vs 34%, respectively [P ± .289]; concordance rate, 95.8% [95% CI, 92-92.8]); diagnosis of malignancy (28% vs 26%, respectively [P ± .125]; concordance rate, 97.9% [95% CI, 94.8-99.4]); or sample quality (concordance rate, 83.3% [95% CI, 73.3-88.3]). Concordance between EBUS-TBNA and EBUS-TBNCS was high irrespective of LN size (≤ 1 cm vs > 1 cm). CONCLUSIONS Regardless of LN size, no differences in adequacy, diagnosis, or quality were found between samples obtained using EBUS-TBNA and those obtained using EBUS-TBNCS. There is no evidence of any benefit derived from the practice of applying suction to EBUS-guided biopsies. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00886847; URL: www.clinicaltrials.gov

Clinical characteristics and outcomes of therapy-related chronic myelomonocytic leukemia

We sought to describe the clinical features and outcomes of therapy-related chronic myelomonocytic leukemia (t-CMML) and compare with those of de novo CMML. We identified 358 CMML patients, of whom 39 (11%) had t-CMML. Although the groups had similar demographic, hematologic, and molecular alteration profiles, the proportion of patients with intermediate or high CMML-specific cytogenetic risk in the t-CMML was significantly higher than that in the de novo CMML (P = .011). The median latency to develop t-CMML was 6 years. The median overall and leukemia-free survival duration of the t-CMML were shorter than those of the de novo CMML; however, t-CMML itself was not prognostic after adjusting for the effects of other covariates including cytogenetics. These results suggest that compared with de novo CMML, t-CMML is associated with more high-risk cytogenetics that manifest as poor outcomes. We propose that t-CMML be recognized as one of the therapy-related myeloid neoplasms.

Can a Durable Disease-Free Survival be Achieved With Surgical Resection in Patients With Pathological Node Positive Renal Cell Carcinoma?

PURPOSE Patients with isolated regional nodal metastases from renal cell carcinoma are a distinct cohort for which resection of involved lymph nodes may be therapeutic. We assessed the outcomes of patients treated at our institution with pathological node positive renal cell carcinoma without concomitant metastatic disease (T(any)N+M0). MATERIALS AND METHODS A total of 2,521 patients with nonmetastatic renal cell carcinoma (T(any)N(any)M0) of any histological subtype treated with nephrectomy were identified between 1995 and 2009. Pathological regional node positive disease in the absence of clinically detectable metastases (T(any)N(1-2)M0) was present in 68 patients (2.7%) and these patients formed our study cohort. Patients were assessed for timing and location of recurrence, disease specific survival and overall survival. Multivariate Cox regression analysis was performed to define factors predictive of recurrence and overall survival. RESULTS Of the 68 patients with T(any)N(1-2)M0 renal cell carcinoma 22.1% were free of disease at a median followup of 43.5 months. In those patients experiencing recurrence, disease was detected within the first 4 months after surgery in 51% and was most commonly detected at multiple organ sites. The Kaplan-Meier estimated 5-year overall survival and disease specific survival was 37% and 39%, respectively. Predictors of a favorable outcome included an Eastern Cooperative Oncology Group performance status of 0, single node involvement, absence of sarcomatoid features and papillary histology. CONCLUSIONS Nephrectomy with lymph node dissection can provide a durable disease-free survival in a proportion of patients with regionally advanced renal cell carcinoma and limited lymph node metastases.

Molecular Characterization of Gallbladder Cancer using Somatic Mutation Profiling

Gallbladder cancer is relatively uncommon with high incidence in certain geographic locations, including Latin America, East and South Asia and Eastern Europe. Molecular characterization of this disease has been limited and targeted therapy options for advanced disease remain an open area of investigation. In the present study, surgical pathology obtained from resected gallbladder cancer cases (n=72) was examined for the presence of targetable, somatic mutations. All cases were formalin-fixed and paraffin-embedded (FFPE). Two approaches were used: a) mass spectroscopy-based profiling for 159 point (‘hot-spot’) mutations in 33 genes commonly involved in solid tumors and b) next-generation sequencing (NGS) platform that examined the complete coding sequence of in 182 cancer-related genes. Fifty-seven cases were analyzed for hotspot mutations and 15 for NGS. Fourteen hotspot mutations were identified in nine cases. Of these, KRAS mutation was significantly associated with poor survival on multivariate analysis. Other targetable mutations included PIK3CA (N=2) and ALK (N=1). On NGS, 26 mutations were noted in 15 cases. P53 and PI3 kinase pathway (STK11, RICTOR,TSC2) mutations were common. One case had FGF10 amplification while another had FGF3-TACC gene fusion, not previously described in gallbladder cancer. In conclusion, somatic mutation profiling using archival FFPE samples from gallbladder cancer is feasible. NGS, in particular may be a useful platform for identifying novel mutations for targeted therapy.