Zandra Klippel

Carfilzomib as salvage therapy in Waldenstrom macroglobulinemia: a case series

Waldenstrom macroglobulinemia (WM) is an incurable disease with frequent relapse after frontline therapy [1]. With one approved agent (ibrutinib) and no standard of care [1,2], new treatment option...

Validation of claims algorithms for Progression to Metastatic cancer in Patients with Breast, non-small cell lung, and colorectal cancer

Background Validated algorithms for identifying progression to metastatic cancer could permit the use of administrative claims databases for research in this area. Objective To identify simple algorithms that could accurately detect cancer progression to metastatic breast, non-small cell lung, and colorectal cancer (CRC) using medical and pharmacy claims data. Methods Adults with stage I–III breast, non-small cell lung cancer (NSCLC), or CRC in the Geisinger Health System from 2004 to 2011 were selected. Evidence of progression was extracted via manual chart review as the reference standard. In addition to secondary malignancy diagnosis (ICD-9 code for metastases), diagnoses, procedures, and treatments were selected with clinician input as indicators of cancer progression. Random forests models provided variable importance scores. In addition to codes for secondary malignancy, several more complex algorithms were constructed and performance measures calculated. Results Among those with breast cancer [17/502 (3.4%) progressed], the performance of a secondary malignancy code was suboptimal [sensitivity: 64.7%; specificity: 86.0%; positive predictive value (PPV): 13.9; negative predictive value (NPV): 98.6%]; requiring malignancy at another site or initiation of immunotherapy increased PPV and specificity but decreased sensitivity. For NSCLC [61/236 (25.8%) progressed], codes for secondary malignancy alone (PPV: 47.4%; NPV: 84.8%; sensitivity: 60.7%; specificity: 76.6%) performed similarly or better than more complex algorithms. For CRC [33/276 (12.0%) progressed], secondary malignancy codes had good specificity (92.7%) and NPV (92.3%) but low sensitivity (42.4%) and PPV (43.8%); an algorithm with change in chemotherapy increased sensitivity but decreased other metrics. Conclusion Selected algorithms performed similarly to the presence of a secondary tumor diagnosis code, with low sensitivity/PPV and higher specificity/NPV. Accurate identification of cancer progression likely requires verification through chart review.

Utilization of stored autologous PBSCs to support second autologous transplantation in multiple myeloma patients in the era of novel agent therapy.

Outcomes in multiple myeloma (MM) have improved significantly with novel agent therapy and autologous stem cell transplantation (ASCT). ASCTs are typically planned as either tandem or a single transplant with additional stored PBSCs available for a second salvage transplant. To accommodate these strategies, many centers routinely collect and store adequate PBSCs for two ASCTs. We analyzed the cost associated with this practice by determining the expenses of PBSC collection, cryopreservation and storage, and the ultimate use of additional cryopreserved PBSCs in patients who had undergone at least one ASCT. There were 889 MM patients transplanted between 1993 and 2011 at our center. Most (N=726) had residual PBSCs in storage after their first ASCT (ASCT1). Only 135 patients underwent a second ASCT within a median of 14 months after ASCT1. The percentage of patients receiving a second ASCT declined over time. The resources required to collect and store unused PBSCs added up to 336 extra patient days of apheresis and 41 587 extra patient months of cryopreservation, translating into an average extra cost per patient of US

A systematic literature review of the efficacy, effectiveness, and safety of filgrastim

4981.12. A reconsideration of conventional PBSC collection and storage practices would save significant cost for the majority of MM patients who never undergo a second ASCT.

A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Pegfilgrastim in Patients Receiving First-Line FOLFOX/Bevacizumab or FOLFIRI/Bevacizumab for Locally Advanced or Metastatic Colorectal Cancer: Final Results of the Pegfilgrastim and Anti-VEGF Evaluation Study (PAVES)

PurposeFilgrastim (NEUPOGEN®) is the originator recombinant human granulocyte colony-stimulating factor widely used for preventing neutropenia-related infections and mobilizing hematopoietic stem cells. This report presents findings of a systematic literature review and meta-analysis of efficacy and safety of originator filgrastim to update previous reports.MethodsA literature search of electronic databases, congress abstracts, and bibliographies of recent reviews was conducted to identify English-language reports of clinical trials and observational studies evaluating filgrastim in its US-approved indications up to February 2015. Two independent reviewers assessed titles/abstracts and full texts of publications, and extracted data from studies that compared originator filgrastim vs placebo or no treatment. For outcomes with sufficient homogeneous data reported across studies, meta-analysis was performed and relative risk (RR) determined. Data were summarized descriptively for all other evaluated outcomes.ResultsA total of 1194 unique articles evaluating originator filgrastim were identified, with 25 meeting eligibility criteria for data extraction: 18 randomized controlled trials, 2 nonrandomized clinical trials, and 5 observational studies. In chemotherapy-induced neutropenia (CIN), filgrastim vs placebo or no treatment significantly reduced febrile neutropenia incidence (RR 0.63, 95% CI 0.53–0.75) and grade 3 or 4 neutropenia incidence (RR 0.50, 95% CI 0.37–0.68). The most commonly reported adverse event (AE) with filgrastim was bone pain (RR 2.61, 95% CI 1.29–5.27 in CIN). Additional efficacy and safety outcomes are described within indications.ConclusionsThis systematic literature review and meta-analysis confirms and updates previous reports on the efficacy and safety of originator filgrastim. Bone pain was the commonly reported AE associated with filgrastim use.

Relationship between severity and duration of chemotherapy-induced neutropenia and risk of infection among patients with nonmyeloid malignancies

Micro‐Abstract In a phase III, double‐blind trial, 845 patients with advanced colorectal cancer receiving bevacizumab plus first‐line chemotherapy (FOLFOX [leucovorin), 5‐fluorouracil, oxaliplatin] or FOLFIRI [leucovorin, 5‐fluorouracil, irinotecan]) were randomized to pegfilgrastim versus placebo. Pegfilgrastim significantly reduced grade 3/4 febrile neutropenia, with no differences in tumor response rates, survival outcomes, or nonhematologic toxicities observed between the 2 arms. Background: Pegfilgrastims role in reducing the risk of febrile neutropenia (FN) in patients with colorectal cancer (CRC) receiving chemotherapy plus bevacizumab was not previously evaluated in a prospective study. The present phase III, double‐blind trial evaluated the efficacy of pegfilgrastim versus placebo in reducing the incidence of grade 3/4 FN in patients with advanced CRC receiving bevacizumab combined with first‐line chemotherapy (FOLFOX [leucovorin, 5‐fluorouracil, oxaliplatin] or FOLFIRI [leucovorin, 5‐fluorouracil, irinotecan]). Patients and Methods: Patients aged ≥ 18 years with locally advanced or metastatic CRC were randomized 1:1 to placebo or 6 mg of pegfilgrastim ˜24 hours after receiving chemotherapy plus bevacizumab every 14 days. The study treatment period included 4 cycles, but patients could continue treatment for ≤ 60 months. The primary endpoint was incidence of grade 3/4 FN in the first 4 cycles. The secondary endpoints included the objective response rate (ORR), overall survival, and progression‐free survival, analyzed at the end of the long‐term follow‐up period. Results: A total of 845 patients were randomized from November 2009 to January 2012 (422, pegfilgrastim; 423, placebo). Pegfilgrastim significantly reduced the incidence of grade 3/4 FN in the first 4 treatment cycles (pegfilgrastim, 2.4%; 95% confidence interval [CI], 1.1%‐4.3%; placebo, 5.7%; 95% CI, 3.7%‐8.3%; odds ratio [OR], 0.41; P = .014). No significant differences were observed between the 2 arms in ORR (OR, 1.15; P = .330), overall survival (hazard ratio, 0.94; P = .440), and progression‐free survival (hazard ratio, 0.93; P = .300). Conclusion: Pegfilgrastim reduced the FN incidence in patients with advanced CRC receiving chemotherapy and bevacizumab. Administration of pegfilgrastim was tolerable and did not negatively affect the tumor response or survival in this patient population.

A Randomized, Single-Blind Study Evaluating the Effect of a Bone Pain Education Video on Reported Bone Pain in Patients with Breast Cancer Receiving Chemotherapy and Pegfilgrastim

PurposeChemotherapy-induced neutropenia (CIN) may increase infection risk for cancer patients; however, there is limited understanding on the quantitative relationships between severity and duration of CIN and infection risk.MethodsThis study combined individual data from adult cancer patients receiving no granulocyte colony-stimulating factor during the first chemotherapy cycle in six trials. We used area over the curve (AOC) of absolute neutrophil count (ANC) time-response curve (below different thresholds) to measure the combined effect of severity and duration of CIN. Time-dependent Cox proportional hazards models quantified the hazard of first infection associated with duration of grade 4 or grade 3/4 CIN and the hazard associated with AOC.ResultsWe analyzed data from 271 patients who had small cell lung cancer, non-Hodgkin’s lymphoma, head and neck cancer, or breast cancer; 63.8 % of the patients had advanced cancer, and 77.5 % received chemotherapy regimens with high risk of febrile neutropenia. In the first cycle, 18.8 % of the patients had infection-related hospitalizations. Each additional day patients had grade 3/4 or grade 4 CIN was associated with 28 % (95 % CI 7, 51 %) and 30 % (95 % CI 10, 54 %) increased risk of infection-related hospitalization, respectively. Each unit increase in AOC (day × 109/L ANC), with threshold of ANC < 0.5 × 109/L, was associated with a significantly increased risk of infection-related hospitalization (hazard ratio 1.98; 95 % CI 1.35, 2.90).ConclusionsInfection risk increases dramatically with each additional day of grade 3 or 4 CIN. Interventions limiting CIN severity and duration are of critical importance to reduce infection risk in cancer patients receiving chemotherapy.

A Study of Novel Febrile Neutropenia Risk Factors Related to Bone Marrow or Immune Suppression, Barrier Function, and Bacterial Flora

Abstract: Background: Mild‐to‐moderate bone pain is the most commonly reported adverse event associated with pegfilgrastim. Aims: To investigate the effect of bone pain education on pegfilgrastim‐related bone pain in patients with breast cancer receiving chemotherapy and pegfilgrastim. Design: Randomized, single‐blind study. Settings: Forty‐eight community oncology clinics throughout the United States. Participants: Three hundred women ≥18 years of age with newly diagnosed stage I ‐III breast cancer, who were planning ≥4 cycles of neoadjuvant or adjuvant chemotherapy with pegfilgrastim support starting in cycle 1. Methods: Patients were randomized 1:1 to view a general education DVD on chemotherapy side effects (GE‐DVD) or a DVD on bone pain following chemotherapy and pegfilgrastim (BP‐DVD). Patients recorded severity of bone pain on a scale of 0–10, location of pain, and use of bone pain medications (i.e., analgesics, antihistamines, and nonsteroidal anti‐inflammatory drugs) for 5 days, beginning on the day of pegfilgrastim administration, in each of the first four chemotherapy cycles. Results: Patient‐reported maximum bone pain was similar in the two groups (GE‐DVD vs BP‐DVD: cycle 1, 3.2 vs. 3.5, p = .3479; across all cycles, 4.1 vs. 4.6, p = .2196). Other measures of bone pain were also similar between the groups. Bone pain was highest in cycle 1 but decreased and then remained stable in subsequent cycles. Bone pain medication use was similar in both groups and was highest in cycle 1. Conclusions: The bone pain‐specific education evaluated here did not improve perceptions of bone pain reported in this patient population.

Value of incorporating newly identified risk factors into risk prediction for chemotherapy‐induced febrile neutropenia

Background: Previously identified patient-level risk factors for chemotherapy-induced febrile neutropenia (FN) indicate several potential underlying pathogenic mechanisms, including bone marrow suppression, impaired neutrophil function, or disturbances of barrier function. This study evaluated whether additional clinical characteristics related to these pathogenic mechanisms were risk factors for FN. Patients and Methods: The study population included patients diagnosed with non-Hodgkins lymphoma or breast, lung, colorectal, ovarian, or gastric cancer between 2000 and 2009 at Kaiser Permanente Southern California and treated with myelosuppressive chemotherapy. Those who received prophylactic granulocyte colony-stimulating factor or antibiotics were excluded. Potential risk factors of interest included surgery, radiation therapy, selected dermatologic/mucosal conditions, and use of antibiotics and corticosteroids. All data were collected using electronic medical records. Multivariable Cox models were used to evaluate associations between these factors and risk of FN in the first chemotherapy cycle, and adjusted using propensity score-based functions. Results: A total of 15,971 patients were included. Of these, 4.3% developed FN in the first chemotherapy cycle. Use of corticosteroids was significantly associated with increased risk of FN (adjusted hazard ratio [aHR], 1.53; 95% CI, 1.17-1.98). Selected dermatologic/mucosal conditions and intravenous antibiotic use were marginally associated with increased risk of FN (aHR, 1.40; 95% CI, 0.98-1.93, and 1.35; 95% CI, 0.97-1.87, respectively). Surgery, radiation therapy, and oral antibiotic use were not statistically significantly associated with FN. Conclusions: Dermatologic or mucosal conditions that might affect barrier integrity and use of corticosteroids and intravenous antibiotics prior to chemotherapy may increase risk of FN and should be considered in prophylaxis use and FN prediction modeling.

Pre-transplantation novel agent induction predicts progression-free survival for patients with immunoglobulin light-chain amyloidosis undergoing high-dose melphalan and autologous stem cell transplantation.

Several comorbidities have recently been shown to affect risk of chemotherapy‐induced febrile neutropenia (FN). Here, we evaluated the added predictive value of these comorbidities beyond established FN risk factors. A retrospective cohort study was conducted among adult patients diagnosed with cancer and treated with chemotherapy at Kaiser Permanente Southern California between 2000 and 2009. The study cohort was equally split into training and validation datasets to develop and evaluate the performance of FN risk prediction models in the first chemotherapy cycle. A reference model was developed based on the model proposed by Lyman et al (Cancer 2011;117:1917). A new model was developed by incorporating the newly identified comorbidities such as rheumatoid conditions and thyroid disorders into the reference model. Area under the receiver operating characteristic curve (AUROCC), risk reclassification, and integrated discrimination improvement (IDI) were used to evaluate the potential improvement of FN risk prediction by incorporating comorbidities. A total of 15 279 patients were included; 4.2% experienced FN in the first chemotherapy cycle. Including comorbidities in FN risk prediction did not improve AUROCC (reference model 0.71 vs new model 0.72). A significant improvement in individual‐level FN risk prediction was indicated by IDI (P = .02). However, significant improvement in risk reclassification was not observed overall (although 6% of all patients were more accurately classified for their FN risk level, 5% were less accurately classified) or when examining predicted FN risk among patients who did and did not develop FN. Incorporating several new comorbidities into FN prediction led to improved FN risk prediction in the first chemotherapy cycle, although the observed improvements were small and might not be clinically relevant.