The Value of Pharmaceutical Industry-Sponsored Patient Registries in Oncology Clinical Research.

In May 2019, the US Food and Drug Administration (FDA) released the Framework for FDA's Real-World Evidence (RWE) Program, a draft guidance to evaluate the potential use of real-world data in facilitating regulatory decisions. As a result, pharmaceutical companies and medical communities see patient registries, which are large, prospective, noninterventional cohort studies, as becoming increasingly important in providing evidence of treatment effectiveness and safety in clinical practice. Patient registries are designed to collect longitudinal clinical data on a broad population to address critical medical questions over time. With their large sample sizes and broad inclusion criteria, patient registries are often used to generate RWE in the general and underrepresented patient populations that are less likely to be studied in controlled clinical trials. Here, we describe the value of industry-sponsored patient registries in oncology/hematology settings to healthcare stakeholders, in drug development, and in fostering scientific collaboration.

The Connect CLL Registry: final analysis of 1494 patients with chronic lymphocytic leukemia across 199 US sites.

Optimal treatment of chronic lymphocytic leukemia (CLL) remains unclear. The Connect CLL Registry, a United States-based multicenter prospective observational cohort study, enrolled 1494 patients between 2010 and 2014 from predominantly community-based settings. Patients were grouped by line of therapy (LOT) at enrollment. With a median follow-up of 46.6 months (range, 0-63.0 months), median overall survival (OS) was not reached in LOT1, 63.0 months (95% confidence interval [CI], 46.0-63.0 months) in LOT2, and 38.0 months (95% CI, 33.0-47.0 months) in LOT≥3. Bendamustine and rituximab (BR; 33.5%); fludarabine, cyclophosphamide, and rituximab (FCR; 21.4%); and rituximab monotherapy (18.5%) were the most common regimens across LOTs. Median event-free survival (EFS) was similar in patients treated with BR (59.0 months) and FCR (55.0 months) in LOT1; median OS was not reached. In multivariable analysis, BR or FCR vs other treatments in LOT1 was associated with improved EFS (hazard ratio [HR], 0.60; P < .0001) and OS (0.67; P = .0162). Using the Kaplan-Meier product limit, ibrutinib vs other treatments improved OS in LOT2 (HR, 0.279; P = .009), LOT3 (0.441; P = .011), and LOT≥4 (0.578; P = .043). Prognostic modeling of death at 2 years postenrollment identified 3 risk groups: low (mortality rate, 6.2%), medium (14.5%), and high (27.4%). The most frequent adverse events across LOTs were pneumonia (11.6%) and febrile neutropenia (6.2%). These data suggest that advantages of LOT1 FCR over BR seen in clinical trials may not translate to community practice, whereas receiving novel LOT2 agents improved outcomes. This trial was registered at www.clinicaltrials.gov as NCT01081015.

Nonhematologic toxicity of imatinib mesylate in pediatric patients with chronic myelogenous leukemia: a predominance of musculoskeletal pain.

Therapy with the tyrosine kinase inhibitor imatinib mesylate has become standard initial treatment for adult and pediatric patients with chronic myelogenous leukemia. Long-term follow-up data are now available in the adult population, and the toxicity profile of imatinib mesylate among adults has been extensively studied and reported. Despite its increasing use in the pediatric population, there are limited data regarding adverse event profiles of imatinib mesylate in children, and few reports exist in the literature focusing on nonhematologic toxicity in this population. We reviewed our institutional experience with imatinib therapy for chronic myelogenous leukemia over an 8-year period of time. Nine pediatric patients began therapy with imatinib mesylate and were included in this review. We reviewed the occurrence of nonhematologic toxicity in this cohort and the impact of that toxicity on continuation of therapy. Eight patients experienced nonhematologic toxicity, including nausea/vomiting (44.4%) and musculoskeletal pain (88.9%). Three patients (33.3%) required discontinuation of imatinib therapy due to grade 3/4 musculoskeletal pain, a rate that is significantly higher than that seen in the adult population. As imatinib therapy becomes increasingly widespread in the treatment of pediatric malignancies, there may be different patterns of clinically significant nonhematologic toxicity, including higher grade musculoskeletal pain.

Risk of renal failure in cancer patients with bone metastasis treated with renally adjusted zoledronic acid.

PURPOSE: The purpose of this study was to evaluate the incidence of acute renal failure (ARF) in patients with mild to moderate renal dysfunction, receiving renally adjusted zoledronic acid (ZA) and compare it to patients with normal baseline renal function, receiving standard-dose ZA. METHODS: This was a retrospective study of patients receiving ZA for the treatment of bone metastasis due to cancer. Patients were divided into two groups: (1) normal group with baseline creatinine clearance (CrCl) of greater than 60 mL/min and standard ZA dose; (2) impaired group with baseline CrCl of 30-60 mL/min and renally adjusted ZA dose. Primary endpoint of ARF was defined as an increase in serum creatinine (SCr) of 0.5 mg/dL or 1.0 mg/dL from a baseline SCr of <1.4 mg/dL or ≥ 1.4 mg/dL, respectively. RESULTS: In total, 1,472 evaluable doses of ZA were given to 220 patients. Of these, 184 patients were in the normal group and 36 patients in the impaired group. There were 38 patients (20.7%) who developed ARF in the normal group versus 7 patients (19.4%) in the impaired group. There was no difference in the mean time to the incidence of ARF at 6.1 months in both groups. Incidence of ARF based on CrCl (≥ 25% decline in CrCl) was similar between groups (39.1% vs. 41.7%; p = 0.78). CONCLUSION: The incidence of ARF is similar between patients in the normal group and impaired group when the ZA dose is renally adjusted.

Evaluation of chemotherapy-induced severe myelosuppression incidence in obese patients with capped dosing.

PURPOSE: Clinicians typically cap an obese patient's chemotherapy regimen as a result of concern for excessive toxicity, without adequate clinical evidence. The purpose of this study was to evaluate the incidence of grade 3 or 4 myelosuppression in obese patients versus nonobese patients with capped dosing on the basis of body surface area (BSA). METHODS: A retrospective chart review was conducted comparing obese patients (body mass index [BMI] ≥ 30 kg/m(2)) with capped dosing who received capped chemotherapy doses at a BSA of 2.2 m(2) with nonobese (BMI < 25 kg/m(2)) patients with lung, colorectal, or hormone-refractory prostate cancer. RESULTS: Forty-one obese patients with capped dosing and 244 nonobese patients were included. The obese patient group received on average significantly more cycles of chemotherapy (6 v 4 cycles) compared with the nonobese group. The overall incidence of any chemotherapy-related toxicity was 34% in the obese patient group, compared with 42% in the nonobese patient group (P = .356). The incidence of grade 3 or 4 myelosuppression was lower, but not statistically significant, in obese patients with capped dosing compared with the nonobese patient group (22% v 27%; P = .493). CONCLUSIONS: Overall, obese patients with capped dosing experienced a lower incidence of severe myelosuppression and tolerated more cycles of chemotherapy compared with nonobese patients. The better tolerability of chemotherapy in obese patients with capped dosing suggests that there is room to increase the dose in obese patients above the nationally recognized BSA cap of 2.0 m(2), especially in early-stage lung or colon cancers in which the intention of treatment is curative.

Comparison of the 5-fluorouracil-warfarin and capecitabine-warfarin drug interactions.

STUDY OBJECTIVE: To compare the differences between the 5-fluorouracil-warfarin and capecitabine-warfarin drug interactions in patients receiving therapeutic doses of warfarin. DESIGN: Retrospective medical record review. SETTING: Large academic Veterans Affairs health care system. PATIENTS: Twenty-four patients who received concomitant therapeutic doses of warfarin and at least one dose of a fluoropyrimidine--5-fluorouracil or capecitabine--between January 2004 and May 2008. MEASUREMENTS AND MAIN RESULTS: The primary outcome was mean change in international normalized ratio (INR) from baseline to end of 90-day study period. Only patients who were taking warfarin before starting either fluoropyrimidine-based chemotherapy were included in the primary analysis. Of the 24 eligible patients, 15 (9 receiving 5-fluorouracil, 6 receiving capecitabine) were taking warfarin before receiving either fluoropyrimidine. No significant differences were noted in the average weekly warfarin dose or baseline INR between the 5-fluorouracil and capecitabine groups. The mean change in INR for patients taking warfarin before fluoropyrimidine use was 4.62 in the 5-fluorouracil group compared with 5.11 in the capecitabine group (p=0.87). The capecitabine group had a similar proportion of patients achieving an INR above 9 while taking warfarin compared with the 5-fluorouracil group (17% vs 22%). In those patients who required a warfarin dosage reduction, the dose was reduced by 38% and 41% in the 5-fluorouracil and capecitabine groups, respectively. No significant differences in bleeding events were reported within 90 days of concurrent use of either fluoropyrimidine with warfarin. CONCLUSION: Our study suggests that in patients receiving concomitant warfarin and a fluoropyrimidine, no significant differences in INR elevation or bleeding events were noted with 5-fluorouracil compared with capecitabine.

Retrospective analysis of the consequences of acid suppressive therapy on ketoconazole efficacy in advanced castration-resistant prostate cancer.

BACKGROUND: The area under the curve of a single ketoconazole dose has been shown to decrease significantly when administered with acid suppressive therapy. No published studies have examined the clinical impact of concurrent ketoconazole and acid suppressive therapy in patients with castration-resistant prostate cancer (CRPC). OBJECTIVE: To evaluate the effect of acid suppressive therapy on prostate-specific antigen (PSA) response rate in CRPC patients receiving ketoconazole. METHODS: This retrospective study evaluated CRPC patients treated with ketoconazole 3 times daily between January 1, 1999, and September 30, 2009. Patients included in the analysis had failed androgen deprivation therapy, and were subsequently initiated on ketoconazole. Response (PSA decline ≥50% maintained ≥4 weeks) was evaluated in patients receiving ketoconazole with (group 1 [G1]) or without (group 2 [G2]) concurrent acid suppressive therapy. RESULTS: Thirty patients (G1: 11 patients; G2: 19 patients) were included in the analysis. Mean age in G1 and G2 was 71.8 and 69.6 years, respectively. Most patients had received prior therapy with an antiandrogen (90.9% G1; 100% G2) and fewer patients received antiandrogen withdrawal therapy (27.3% G1; 21.1% G2). Median baseline PSA was 109.4 (G1) and 86.9 ng/mL (G2) (p = 0.55). Median duration of ketoconazole was 7.2 months in G1 and 5.8 months in G2 (p = 0.09). Ketoconazole adherence was 82% (G1) and 100% (G2). Median duration of concurrent acid suppressive therapy was 3.8 months (range 2.0-20.4) in G1. PSA response (72.7% and 47.4%; p = 0.26) and time to PSA response (1.2 vs 0.9 mo; p = 0.53) were statistically similar between G1 and G2, respectively. Median progression free survival was higher in G1 (11.5 vs 6.9 months in G2; p = 0.047). CONCLUSIONS: Use of concurrent acid suppressive therapy and ketoconazole in CRPC patients did not decrease PSA response rate, and progression free survival was unexpectedly higher compared with the non-acid suppressive therapy group. Larger studies are needed to verify the clinical impact of acid suppressive therapy in combination with ketoconazole.