Prognostic Testing Patterns and Outcomes of Chronic Lymphocytic Leukemia Patients Stratified by Fluorescence In Situ Hybridization/Cytogenetics: A Real-world Clinical Experience in the Connect CLL Registry.

INTRODUCTION: Prognostic genetic testing is recommended for patients with chronic lymphocytic leukemia (CLL) to guide clinical management. Specific abnormalities, such as del(17p), del(11q), and unmutated IgHV, can predict the depth and durability of the response to CLL therapy. PATIENTS AND METHODS: In the present analysis of the Connect CLL Registry (ClinicalTrials.gov identifier, NCT01081015), a prospective observational cohort study of patients treated across 199 centers, the patterns of prognostic testing and outcomes of patients with unfavorable-risk genetics were analyzed. From 2010 to 2014, 1494 treated patients were enrolled in the registry by line of therapy (LOT), and stratified by the results of cytogenetic/fluorescence in situ hybridization (FISH) testing into 3 risk levels: unfavorable (presence of del[17p] or del[11q]), favorable (absence of del[17p] and del[11q]), and unknown. RESULTS: Cytogenetic/FISH testing was performed in 861 patients (58%) at enrollment; only 40% of these patients were retested before starting a subsequent LOT. Of those enrolled at the first LOT, unfavorable-risk patients had inferior event-free survival compared with favorable-risk patients (hazard ratio, 1.60; P = .001). Event-free survival was inferior with bendamustine-containing regimens (P < .0001). Event-free survival did not differ significantly between risk groups for patients treated with ibrutinib or idelalisib in the relapse/refractory setting. The predictors of reduced event-free survival included unfavorable-risk genetics, age ≥ 75 years, race, and treatment choice at enrollment. CONCLUSION: The present study has shown that prognostic cytogenetic/FISH testing is infrequently performed and that patients with unfavorable-risk genetics treated with immunochemotherapy combinations have worse outcomes. This underscores the importance of performing prognostic genetic testing for all CLL patients to guide treatment.

Characterizing and prognosticating chronic lymphocytic leukemia in the elderly: prospective evaluation on 455 patients treated in the United States.

BACKGROUND: Median age at diagnosis of patients with chronic lymphocytic leukemia (CLL) is > 70 years. However, the majority of clinical trials do not reflect the demographics of CLL patients treated in the community. We examined treatment patterns, outcomes, and disease-related mortality in patients ≥ 75 years with CLL (E-CLL) in a real-world setting. METHODS: The Connect® CLL registry is a multicenter, prospective observational cohort study, which enrolled 1494 adult patients between 2010-2014, at 199 US sites. Patients with CLL were enrolled within 2 months of initiating first line of therapy (LOT1) or a subsequent LOT (LOT ≥ 2). Kaplan-Meier methods were used to evaluate overall survival. CLL- and infection-related mortality were assessed using cumulative incidence functions (CIF) and cause-specific hazards. Logistic regression was used to develop a classification model. RESULTS: A total of 455 E-CLL patients were enrolled; 259 were enrolled in LOT1 and 196 in LOT ≥ 2. E-CLL patients were more likely to receive rituximab monotherapy (19.3 vs. 8.6%; p < 0.0001) and chemotherapy-alone regimens (p < 0.0001) than younger patients. Overall and complete responses were lower in E-CLL patients than younger patients when given similar regimens. With a median follow-up of 3 years, CLL-related deaths were higher in E-CLL patients than younger patients in LOT1 (12.6 vs. 5.1% p = 0.0005) and LOT ≥ 2 (31.3 vs. 21.5%; p = 0.0277). Infection-related deaths were also higher in E-CLL patients than younger patients in LOT1 (7.4 vs. 2.7%; p = 0.0033) and in LOT ≥ 2 (16.2 vs. 11.2%; p = 0.0786). A prognostic score for E-CLL patients was developed: time from diagnosis to treatment < 3 months, enrollment therapy other than bendamustine/rituximab, and anemia, identified patients at higher risk of inferior survival. Furthermore, higher-risk patients experienced an increased risk of CLL- or infection-related death (30.6 vs 10.3%; p = 0.0006). CONCLUSION: CLL- and infection-related mortality are higher in CLL patients aged ≥ 75 years than younger patients, underscoring the urgent need for alternative treatment strategies for these understudied patients. TRIAL REGISTRATION: The Connect CLL registry was registered at clinicaltrials.gov: NCT01081015 on March 4, 2010.

The effect of aprepitant and race on the pharmacokinetics of cyclophosphamide in breast cancer patients.

PURPOSE: The prodrug cyclophosphamide is metabolized by cytochrome P450(CYP)2B6 to the active metabolite, 4-hydroxycyclophosphamide (4-OH), and by CYP3A4/5 to toxic chloracetaldehyde and 2-dechloroethylcyclophosphamide (DCE). Since aprepitant is a moderate inhibitor of CYP3A4, the study was designed to determine whether its concurrent use alters the pharmacokinetics (PK) of cyclophosphamide. In addition, we sought to determine the effect of race and pharmacogenomics on cyclophosphamide PK. METHODS: Eighteen patients with localized breast cancer were randomized in this double-blinded cross-over study to receive aprepitant or placebo in addition to cyclophosphamide 600 mg/m(2) and doxorubicin 60 mg/m(2). Blood samples were collected for both PK analysis of cyclophosphamide and metabolites and pharmacogenomic analysis. Single nucleotide polymorphisms genotyped were CYP3A4*1B, CYP3A5*3, and CYP2B6*6. RESULTS: The geometric mean area under concentration-time curve (AUC(0-t) µg/mL h) for cyclophosphamide was 282 following aprepitant and 230 following placebo (ratio 1.23; 90% CI 1.13, 1.33). 4-OH AUC(0-t) (µg/mL h) was 6.80 following aprepitant and 6.96 following placebo (ratio 0.98; 90% CI 0.88, 1.08). DCE AUC(0-t) (µg/mL h) was 6.76 following aprepitant and 9.37 following placebo (ratio 0.72; 90% CI 0.64, 0.81). Genotype analysis was confounded by race. Race was a significant predictor of DCE lnAUC(0-t) (P = 0.0169) as African Americans had approximately a 2-fold higher DCE AUC than Caucasians. CONCLUSIONS: Aprepitant altered the exposure of cyclophosphamide and DCE but not the active 4-OH metabolite, making it unlikely that aprepitant would change the clinical efficacy of cyclophosphamide. African Americans were also found to have altered PK compared with Caucasian patients.

Role of pharmacogenetics as predictive biomarkers of response and/or toxicity in the treatment of colorectal cancer.

Predicting response and limiting drug-induced toxicity are 2 important challenges faced by clinicians in the treatment of colorectal cancer (CRC). The introduction of genetic testing to individualize treatment regimens will hopefully allow better response prediction and limit drug-induced toxicity leading to improved patient outcomes. This review discusses the role of the predictive genetic tests associated with the major therapeutic agents used in the treatment of CRC and their clinical significance in the determination of patient-specific treatment regimens.

Ixabepilone: a new antimitotic for the treatment of metastatic breast cancer.

OBJECTIVE: To evaluate the safety and efficacy of ixabepilone as a new antimitotic chemotherapeutic agent for the treatment of breast cancer. DATA SOURCES: Data were identified by searches of MEDLINE, PubMed, and American Society of Clinical Oncology abstracts from 1966 to March 2008, using the primary search terms ixabepilone, epothilones, BMS-247550, and breast cancer. STUDY SELECTION AND DATA EXTRACTION: Phase 1, Phase 2, and Phase 3 clinical trials examining the safety and efficacy of ixabepilone and its place in cancer treatment were reviewed. Preference was given to large Phase 2 and 3 clinical trials in the breast cancer population. Manufacturer product information was used to supplement data lacking in published trials. DATA SYNTHESIS: Ixabepilone belongs to a novel class of drugs, the epothilones, which are nontaxane microtubule-stabilizing agents. Ixabepilone, in combination with capecitabine, has been approved by the Food and Drug Administration for treatment in patients with metastatic or locally advanced breast cancer that progresses after anthracycline and taxane therapy, or in patients with taxane-resistant cancer with contraindication to further anthracycline therapy. Ixabepilone has also been approved as monotherapy in patients with metastatic and locally advanced breast cancer refractory to taxanes, anthracyclines, and capecitabine. The most common adverse reactions reported by 20% or more of the patients receiving ixabepilone were peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain. The most common hematologic abnormalities seen in more than 40% of the patients include neutropenia, leukopenia, anemia, and thrombocytopenia. Premedication with histamine H(1) and H(2) antagonists is recommended to prevent hypersensitivity reactions. CONCLUSIONS: Based on the clinical trials reviewed here and the current information available, ixabepilone is a welcome addition to the options available for the treatment of patients with metastatic breast cancer refractory to standard therapy.