Biosimilars: Hope and concern.

As patents of the first introduced biologic therapeutics in oncology have begun to expire, competing pharmaceutical companies are allowed to produce and market the same protein as the original agent. These products are called biosimilars. Upon patent expiration, biosimilars would hopefully be a cheaper alternative to the original agent and that is the main reason for their existence. Although the financial aspect is similar to generics, the complex nature of these products generates the need for a distinct regulatory environment. Biosimilars are produced by DNA technology in bacteria, plant cells, or animal cells, while generics are produced by chemical synthesis. Details in the process of synthesis, selection of the microorganism, protein extraction, purification and manufacturing, affect the precise nature of the end product. Monoclonal antibodies are large proteins with four polypeptide chains and interact variably with each other and with the environment. It is important for payors to realize that biosimilars are different from generics; therefore, they need to develop different set of rules for approving, registering, and dispensing biosimilars. Regulators ought to respect the physicians' request for non-interchangeability and facilitate in any possible way of traceability. Such regulations along with a rigorous pharmacovigilance program will satisfy the concerns for true equivalence in activity and long-term safety. This is the only way to accumulate over time reliable safety information for new biosimilars. In conclusion, the wish born by the medical community and the society for a more affordable health system triggers the emergence of biosimilars, which could meet that goal if properly regulated.

Feasibility of rapid infusion of the initial dose of bevacizumab in patients with cancer.

PURPOSE: Bevacizumab is a monoclonal antibody against vascular endothelial growth factor (VEGF) widely used in clinical oncology. Bevacizumab is commonly co-adminis- tered with chemotherapy. It is recommended that the first infusion of the antibody last 90 min, the second 60 and all subsequent 30 min. Since there is no clear rationale for the proposed schedule of administration, our study assessed the feasibility of a 30 min initial infusion. METHODS: Cancer patients eligible for de novo bevacizumab treatment were enrolled. All patients received standard bevacizumab dose of 5, 7.5 or 10 mg/kg according to the indication, diluted in 250 ml normal saline, as a 30-min intravenous infusion. RESULTS: Thirty two patients were enrolled: male 18, female 14, median age 58 years, range 42-78. Oncologic diagnosis: lung cancer 16, colorectal 4, breast 3, ovarian 7, renal 2. All patients tolerated the infusion well. No hypersensitivity reactions were noted. Mean systolic and diastolic blood pressures were 122 and 73 mm/Hg respectively prior to the infusion and 125 and 75 mm/Hg 15 min after the infusion (p=0.3). During the observation period of 1 hour, blood pressure did not change. Transient grade 3 systolic hypertension was noted in 1 patient, with spontaneous regression in 45 min. CONCLUSION: Rapid administration of bevacizumab in 30 min, rather than the recommended in the package insert 90 min is feasible and safe. Such a practice limits the time of confinement in the treatment area to patients' satisfaction and would result in cost savings by reducing health resource utilization.

Prognostic Role of Circulating Tumor Cells in Patients with Metastatic Castration-Resistant Prostate Cancer Receiving Cabazitaxel: A Prospective Biomarker Study.

RATIONAL: Circulating tumor cells (CTCs) appear to be a promising tool for predicting the clinical outcome and monitoring the response to treatment in patients with solid tumors. The current study assessed the clinical relevance of monitoring CTCs in patients with metastatic castration resistant prostate cancer (mCRPC) treated with cabazitaxel. PATIENTS AND METHODS: Patients with histologically confirmed mCRPC who were previously treated with a docetaxel-containing regimen and experienced disease progression were enrolled in this multicenter prospective study. CTC counts were enumerated using the CellSearch system at baseline (before cabazitaxel initiation), after one cabazitaxel cycle (post 1st cycle) and at disease progression (PD). Patients were stratified into predetermined CTC-positive and CTC-negative groups. The phenotypic characterization was performed using double immunofluorescence staining with anti-CKs and anti-Ki67, anti-M30 or anti-vimentin antibodies. RESULTS: The median PFS and OS were 4.0 (range, 1.0-17.9) and 14.5 (range, 1.2-33.9) months, respectively. At baseline, 48 out of 57 (84.2%) patients had ≥1 CTCs/7.5 mL of peripheral blood (PB) and 37 (64.9%) had ≥5 CTCs/7.5 mL of PB. After one treatment cycle, 30 (75%) out of the 40 patients with available measurements had ≥1 detectable CTC/7.5 mL of PB and 24 (60%) ≥ 5CTCs/7.5 mL of PB; 12.5% of the patients with detectable CTCs at the baseline sample had no detectable CTCs after one treatment cycle. The detection of ≥5CTCs/7.5 mL of PB at baseline and post-cycle 1 was associated with shorter PFS and OS (p = 0.002), whereas a positive CTC status post-cycle 1 strongly correlated with poorer OS irrespective of the CTC cut-off used. Multivariate analysis revealed that the detection of non-apoptotic (CK+/M30-) CTCs at baseline is an independent predictor of shorter OS (p = 0.005). CONCLUSIONS: In patients with mCRPC treated with cabazitaxel, CTC counts both at baseline and after the first cycle retain their prognostic significance, implying that liquid biopsy monitoring might serve as a valuable tool for predicting treatment efficacy and survival outcomes.

Front-Line Bevacizumab plus Chemotherapy with or without Maintenance Therapy for Metastatic Breast Cancer: An Observational Study by the Hellenic Oncology Research Group.

Front-line bevacizumab (BEV) in combination with taxanes offers benefit in progression-free survival (PFS) in metastatic breast cancer (mBC). The medical records of mBC patients, treated with front-line BEV-based chemotherapy, were retrospectively reviewed in order to generate real life safety and efficacy data. Patients with human epidermal growth factor receptor 2 (HER2)-negative mBC treated with front-line BEV in combination with chemotherapy were eligible. Maintenance therapy with BEV and/or hormonal agents was at the physicians' discretion. Among the 387 included patients, the most common adverse events were anemia (61.9%, mainly grade 1), grade 3/4 neutropenia (16.5%), grade 1/2 fatigue (22.3%), and grade 1/2 neuropathy (19.6%). Dose reductions were required in 164 cycles (7.1%) and toxicity led to treatment discontinuation in 21 patients (5.4%). The median PFS and the median overall survival (OS) were 13.3 (95% CI: 11.7-14.8) and 32.3 months (95% CI: 27.7-36.9), respectively. Maintenance therapy, with hormonal agents (ET) and/or BEV, was associated with longer OS versus no maintenance therapy (47.2 versus 23.6 months; p < 0.001) in patients with hormone receptor (HR)-positive disease and BEV maintenance offered longer OS versus no maintenance in patients with HR-negative disease (52.8 versus 23.3; p = 0.023). These real-life data show that front-line BEV-based chemotherapy in HER2-negative mBC patients is an effective treatment with an acceptable toxicity profile. The potential benefit of maintenance treatment, especially ET, is important and warrants further research.

Long-term outcomes to fludarabine and rituximab in Waldenström macroglobulinemia.

We report the long-term outcome of a multicenter, prospective study examining fludarabine and rituximab in Waldenström macroglobulinemia (WM). WM patients with less than 2 prior therapies were eligible. Intended therapy consisted of 6 cycles (25 mg/m(2) per day for 5 days) of fludarabine and 8 infusions (375 mg/m(2) per week) of rituximab. A total of 43 patients were enrolled. Responses were: complete response (n = 2), very good partial response (n = 14), partial response (n = 21), and minor response (n = 4), for overall and major response rates of 95.3% and 86.0%, respectively. Median time to progression for all patients was 51.2 months and was longer for untreated patients (P = .017) and those achieving at least a very good partial response (P = .049). Grade 3 or higher toxicities included neutropenia (n = 27), thrombocytopenia (n = 7), and pneumonia (n = 6), including 2 patients who died of non-Pneumocystis carinii pneumonia. With a median follow-up of 40.3 months, we observed 3 cases of transformation to aggressive lymphoma and 3 cases of myelodysplastic syndrome/acute myeloid leukemia. The results of this study demonstrate that fludarabine and rituximab are highly active in WM, although short- and long-term toxicities need to be carefully weighed against other available treatment options. This study is registered at clinicaltrials.gov as NCT00020800.

Update on the association of hepatitis B with intrahepatic cholangiocarcinoma: Is there new evidence?

Intrahepatic cholangiocarcinoma (iCCA) is a subgroup of cholangiocarcinoma that accounts for about 10%-20% of the total cases. Infection with hepatitis B virus (HBV) is one of the most important predisposing factors leading to the formation of iCCA. It has been recently estimated based on abundant epidemiological data that the association between HBV infection and iCCA is strong with an odds ratio of about 4.5. The HBV-associated mechanisms that lead to iCCA are under intense investigation. The diagnosis of iCCA in the context of chronic liver disease is challenging and often requires histological confirmation to distinguish from hepatocellular carcinoma. It is currently unclear whether antiviral treatment for HBV can decrease the incidence of iCCA. In terms of management, surgical resection remains the mainstay of treatment. There is a need for effective treatment modalities beyond resection in both first- and second-line treatment. In this review, we summarize the epidemiological evidence that links the two entities, discuss the pathogenesis of HBV-associated iCCA, and present the available data on the diagnosis and management of this cancer.

Effect of type-specific human papillomavirus incidence on screening performance and cost.

BACKGROUND: Implementation of human papillomavirus (HPV) vaccination is expected to change the epidemiology of HPV infection. METHODS: Using age-dependent (inhomogeneous) Markov chains, we tested the effect of type-specific (ie, HPV-16/HPV-18 and other high-risk HPV types) HPV incidence on 3 screening strategies in a cohort of 100,000 women, starting screening at the age of 25 years and continuing until the age of 34 years. All the strategies started with an HPV test; if the result was positive, the next step was triage with cytology (strategy 1), cytology and colposcopy together (strategy 2), or colposcopy only (strategy 3). Published background data were used for the models. RESULTS: Strategy 2 had the highest sensitivity; the absolute number of missed cervical intraepithelial neoplasia (CIN)3+ cases was associated with HPV incidence in all the strategies, but their relative sensitivity remained unaffected. Strategy 2 was cheaper per diagnosed CIN3+ for very low HPV incidence rates, but this changed for higher incidence rates. For any given pair of HPV-16/HPV-18 and other high-risk-type incidence, the cost of the triage and the total cost of screening was highest in screening 2 and lowest in screening 1. For each screening strategy, the cost per diagnosed CIN3+ was mainly determined by the incidence of HPV-16/HPV-18, and the cost of the triage and the total screening cost by the incidence of other high-risk types. CONCLUSIONS: Type-specific HPV incidence affects the absolute number of missed CIN3+ cases and the cost of screening in a mathematically describable way and can be used for prediction of changes in these outcomes with changing HPV epidemiology.

Extended resections for the treatment of patients with T4 stage IIIA non-small cell lung cancer (NSCLC) (T4N0-1M0) with or without cardiopulmonary bypass: a 15-year two-center experience.

BACKGROUND: Stage IIIA non-small cell lung cancer (NSCLC) is a heterogeneous group of patients, often requiring variable and individualized approaches. The dilemma to operate or not frequently arises, since more than 75% of the cases of NSCLC are diagnosed in advanced stages (IIIA). The main objective of this study was to assess whether the benefits outweigh surgical risks for the T4N0-1M0 subgroup. METHODS: Data from 857 patients with locally advanced T4 NSCLC were retrospectively collected from two different institutions, between 2002 and 2017. Clinical data that were retrieved and analyzed, included demographics, comorbidities, surgical details, neoadjuvant or/and adjuvant therapy and postoperative complications. RESULTS: Twelve patients were in the cardiopulmonary bypass (CPB) group and thirty in the non-CPB. The most common types of lung cancer were squamous cell carcinoma (50.0%) and adenocarcinoma (35.7%). The most frequent invasion of the tumor was seen in main pulmonary artery and the superior vena cava. Significantly more patients of the CPB group underwent pneumonectomy as their primary lung resection (P=0.006). In all patients R0 resection was achieved according to histological reports. The overall 5-year survival was 60%, while the median overall survival was 22.5 months. Analysis revealed that patient age (P=0.027), preoperative chronic obstructive pulmonary disease (COPD) (P=0.001), tumor size (4.0 vs. 6.0 cm) (P=0.001), postoperative respiratory dysfunction (P=0.001) and postoperative atelectasis (P=0.036) are possible independent variables that are significantly correlated with patient outcome. CONCLUSIONS: We suggest that in patients with stage IIIA/T4 NSCLC, complete resection of the T4 tumor, although challenging, can be performed in highly selected patients. Such an approach seems to result in improved long-term survival. More specific studies on this area of NSCLC probably will further enlighten this field, and may result in even better outcomes, as advanced systemic perioperative approaches such as modern chemotherapy, immunotherapy and improvements in radiation therapy have been incorporated in daily practice.

The effects of oxaliplatin, an anticancer drug, on potassium channels of the peripheral myelinated nerve fibres of the adult rat.

Oxaliplatin is a novel chemotherapeutic agent which is effective against advanced colorectal cancer, but at the same time causes severe neuropathy in the peripheral nerve fibres, affecting mainly the voltage-gated sodium (Na(+)) channels (VGNaCs), according to literature. In this study the effects of oxaliplatin on the peripheral myelinated nerve fibres (PMNFs) were investigated in vitro using the isolated sciatic nerve of the adult rat. The advantage of this nerve-preparation was that stable in amplitude evoked compound action potentials (CAP) were recorded for over 1000min. Incubation of the sciatic nerve fibres in 25, 100 and 500microM oxaliplatin, for 300-700min caused dramatic distortion of the waveform of the CAP, namely broadening the repolarization phase, repetitive firing and afterhyperpolarization (AHP), related to the malfunction of voltage-gated potassium (K(+)) channels (VGKCs). At a concentration of 5microM, oxaliplatin caused broadening of the repolarization phase of the CAP only, while the no observed effect concentration was estimated to be 1microM. These findings are indicative of severe effects of oxaliplatin on the VGKCs. In contrast, the amplitude and the rise-time of the depolarization of the CAP did not change significantly, a clear indication that the VGNaCs of the particular nerve preparation were not affected by oxaliplatin. The effects of oxaliplatin on the PMNFs were similar to those of 4-aminopyridine (4-AP), a classical antagonist of VGKCs. These similarities in the pattern of action between oxaliplatin and 4-AP combined with the fact that the effects of oxaliplatin were more pronounced and developed at lower concentrations suggest that oxaliplatin acts as a potent VGKCs antagonist.

Phase I trial of toll-like receptor 9 agonist PF-3512676 with and following rituximab in patients with recurrent indolent and aggressive non Hodgkin's lymphoma.

PURPOSE: PF-3512676 (formerly CpG 7909) is a novel Toll-like receptor 9-activating oligonucleotide with single-agent antitumor activity that augments preclinical rituximab efficacy. This Phase I trial was designed to investigate the safety, tolerability, and preliminary antitumor activity of PF-3512676 in combination with rituximab. EXPERIMENTAL DESIGN: Patients with relapsed/refractory CD20+ B cell non-Hodgkin's lymphoma received i.v. rituximab (375 mg/m2/week for 4 weeks) and PF-3512676 weekly for 4 weeks either i.v. (0.04, 0.16, 0.32, or 0.48 mg/kg) or s.c. (0.01, 0.04, 0.08, or 0.16 mg/kg). An additional extended-treatment cohort received 4 weeks of 0.24 mg/kg s.c. PF-3512676 in combination with rituximab followed by s.c. PF-3512676 alone weekly for 20 weeks. RESULTS: Patients (N = 50) had received a median of three prior therapies (range, 1-11) including rituximab in 80% of patients. Treatment-related adverse events occurred in 11 of 19 (58%) i.v. patients, 15 of 19 (79%) s.c. patients, and all 12 patients in the extended-treatment cohort. Most common adverse events were mild to moderate systemic flu-like symptoms and injection-site reactions (s.c. cohorts only). Grade 3/4 neutropenia occurred in four patients. Objective responses occurred in 12 of 50 (24%) patients overall and in 6 of 12 (50%) patients in the extended-treatment cohort, including 2 patients with rituximab-refractory disease. CONCLUSION: Brief or extended-duration PF-3512676 can be safely administered in combination with rituximab in patients with relapsed/refractory non-Hodgkin's lymphoma.

Palifermin for oral mucositis after intensive therapy for hematologic cancers.

BACKGROUND: Oral mucositis is a complication of intensive chemotherapy and radiotherapy with no effective treatment. We tested the ability of palifermin (recombinant human keratinocyte growth factor) to decrease oral mucosal injury induced by cytotoxic therapy. METHODS: This double-blind study compared the effect of palifermin with that of a placebo on the development of oral mucositis in 212 patients with hematologic cancers; 106 patients received palifermin (60 microg per kilogram of body weight per day) and 106 received a placebo intravenously for three consecutive days immediately before the initiation of conditioning therapy (fractionated total-body irradiation plus high-dose chemotherapy) and after autologous hematopoietic stem-cell transplantation. Oral mucositis was evaluated daily for 28 days after transplantation. RESULTS: The incidence of oral mucositis of World Health Organization (WHO) grade 3 or 4 was 63 percent in the palifermin group and 98 percent in the placebo group (P<0.001). Among patients with this degree of mucositis, the median duration of mucositis was 6 days (range, 1 to 22) in the palifermin group and 9 days (range, 1 to 27) in the placebo group. Among all patients, regardless of the occurrence of mucositis, the median duration of oral mucositis of WHO grade 3 or 4 was 3 days (range, 0 to 22) in the palifermin group and 9 days (range, 0 to 27) in the placebo group (P<0.001). As compared with placebo, palifermin was associated with significant reductions in the incidence of grade 4 oral mucositis (20 percent vs. 62 percent, P<0.001), patient-reported soreness of the mouth and throat (area-under-the-curve score, 29.0 [range, 0 to 98] vs. 46.8 [range, 0 to 110]; P<0.001), the use of opioid analgesics (median, 212 mg of morphine equivalents [range, 0 to 9418] vs. 535 mg of morphine equivalents [range, 0 to 9418], P<0.001), and the incidence of use of total parenteral nutrition (31 percent vs. 55 percent, P<0.001). Adverse events, mainly rash, pruritus, erythema, mouth and tongue disorders, and taste alteration, were mild to moderate in severity and were transient. CONCLUSIONS: Palifermin reduced the duration and severity of oral mucositis after intensive chemotherapy and radiotherapy for hematologic cancers.

Front-line bevacizumab in combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study.

PURPOSE: To evaluate the efficacy and the toxicity of front line FOLFOX4 combined with bevacizumab in patients with metastatsic CRC (mCRC). PATIENTS AND METHODS: Chemotherapy-naïve patients with mCRC, received bevacizumab (5 mg/kg every 2 weeks d1), oxaliplatin (85 mg/m2 on d1), leucovorin (200 mg/m2) on days 1 and 2 and 5-Fluorouracil (400 mg/m2 as i.v. bolus and 600 mg/m2 as 22 h i.v. continuous infusion on days 1 and 2) every 2 weeks. RESULTS: Fifty three patients (46 with a PS 0-1) were enrolled. Complete and partial response was achieved in eight (15.1%) and 28 (52.8%) patients, respectively (ORR: 67.9%; 95% C.I.: 53.8%-92%); 11 (20.7%) patients had stable disease and six (11.3%) progressive disease. With a median follow up period of 13.5 months, time to tumor progression was 11 months while the median survival has not yet been reached; the probability of 1-, 2- and 3- year survival was 79.8%, 63.8% and 58.3%, respectively; Two patients relapsed during the follow up period. Eight (15%) patients underwent metastasectomy with R0 resections. Grade 3-4 neutropenia occurred in 15.1% of patients and one (1.9%) of them presented febrile neutropenia. Non-hematologic toxicity included grade 3 diarrhea (7.6%) and grade 2 and 3 neurotoxicity in 16.9 and 15.1% of patients, respectively. One (1.9%) patient presented pulmonary embolism and one (1.9%) cardiac ischaemia. There was one (1.9%) sudden death after the first cycle. CONCLUSION: The combination of FOLFOX4/bevacizumab appears to be highly effective, well tolerated and merits further evaluation in patients with mCRC.

Current treatment options in follicular lymphoma: science and bias.

Follicular lymphoma is a disease usually characterized by sensitivity to treatment but a pattern of multiple recurrences. Over the last decades, a single optimal therapeutic approach could not be identified and agreed upon. As a result, the selection of the treatment employed for a given patient was both a result of clinical science and bias. The outcomes have been recently improved substantially with the implementation of rituximab, an antiCD20 antibody. Randomized studies have documented repeatedly the clinical benefit conferred by its use, both in combination with chemotherapy, as well as monotherapy applied after remission induction. Although such studies have resulted in important conclusions that help formulate a widely accepted model of treatment sequences for patients with follicular lymphoma, there still remains a considerable area of uncertainty, open for speculation and biased choices. The current review intends to describe the current status of follicular lymphoma treatment, making also an effort to distinguished firm knowledge from reasonable speculation.

Weight-based dosing of Yttrium 90 ibritumomab tiuxetan in patients with relapsed or refractory B-cell non-Hodgkin lymphoma.

BACKGROUND: Ibritumomab tiuxetan radioimmunotherapy produces durable remissions in patients with relapsed/refractory indolent non-Hodgkin lymphoma. The dosing of Yttrium 90 (90Y)-ibritumomab tiuxetan is based on patient weight and platelet count: 0.4 mCi/kg in patients with a count >or= 150 x 10(9)/L, to a maximum dose of 32 mCi. Patients weighing > 80 kg with platelet counts of >or= 150 x 10(9)/L receive a lower dose per unit of body weight. We evaluated whether this influences the safety or efficacy of treatment. PATIENTS AND METHODS: Data on efficacy and safety in patients in 3 registration trials who were treated with 90Y ibritumomab tiuxetan at 0.4 mCi/kg (patients weighing 80 kg) were collected. RESULTS: Clinical responses were evaluated in 103 patients weighing 80 kg (median, 95 kg). Sex (41% female vs. 73% male) was the only significantly different characteristic between the patients weighing 80 kg, respectively. The overall response rates were 79% ( 80 kg), and the complete response rates were 28% and 34%, respectively. Median times to progression were 8.9 months ( 80 kg). There were no significant differences in efficacy measures or in the incidences of grade 3/4 nonhematologic adverse events, neutropenia, thrombocytopenia, or anemia. CONCLUSION: The dose of 90Y ibritumomab tiuxetan was < 0.4 mCi/kg in 39% of patients, owing to the 32-mCi dose cap, but the efficacy or safety of 90Y ibritumomab tiuxetan in patients > 80 kg was not affected.

A phase 2 study of rituximab in combination with recombinant interleukin-2 for rituximab-refractory indolent non-Hodgkin's lymphoma.

PURPOSE: The incidence of non-Hodgkin's lymphoma (NHL), the fifth most common malignancy in the United States, has increased over 70% in the last 30 years. Fifty percent to 75% of patients with low-grade or follicular NHL respond to rituximab therapy. However, responses are generally of limited duration, and complete responses are rare. Preclinical work suggests that human recombinant interleukin-2 (rIL-2; aldesleukin, Proleukin) enhances rituximab efficacy. Antibody-dependent cellular cytotoxicity (ADCC) is an important mechanism of action of rituximab. rIL-2 induces expansion and activation of Fc receptor (FcR)-bearing cells, thereby enhancing ADCC. Therefore, a large, multicenter phase 2 trial to assess the effects of rIL-2 on rituximab therapy in patients with rituxumab-refractory low-grade NHL was conducted. EXPERIMENTAL DESIGN: The combination of rituximab and rIL-2 was studied in 57 patients with rituximab-refractory low-grade NHL (i.e., patients must have received a single-agent course of rituximab and showed no tumor response, or had a response lasting <6 months). I.V. rituximab was given at 375 mg/m(2) (weeks 1-4). S.C. rIL-2 was given thrice a week at 14 MIU (weeks 2-5) and at 10 MIU (weeks 6-9). RESULTS: Rituximab plus rIL-2 combination therapy was safe and generally well tolerated, but responses were low. Fifty-seven patients were enrolled with 54 evaluable for response; however, only five responses (one complete and four partial) were observed. Correlative data indicate that rIL-2 expanded FcR-bearing cells and enhanced ADCC. However, other factors, such as FcgammaR polymorphisms in patients refractory to single-agent rituxumab and heterogeneous tumor biology, may have influenced the lack of clinical efficacy seen with this combination therapy. CONCLUSIONS: rIL-2 expands FcR-bearing cellular subsets in vivo and enhances in vitro ADCC of rituxumab. However, these findings do not directly translate into meaningful clinical benefit for patients with rituxumab-refractory NHL.

Safety and efficacy of yttrium-90 ibritumomab tiuxetan in older patients with non-Hodgkin's lymphoma.

OBJECTIVE: Treatment-related complications are more common in older patients with non-Hodgkin's lymphoma (NHL), often leading to chemotherapy modifications that can compromise efficacy. We analyzed data from clinical trials of yttrium-90-ibritumomab tiuxetan (Zevalin); Biogen Idec, Cambridge, MA) to determine its safety and efficacy in older patients with NHL. DESIGN AND METHODS: Data on safety and efficacy from four clinical trials of (90)Y-ibritumomab tiuxetan in 211 patients with NHL were pooled and analyzed by ages of <60, 60-69, and > or =70 years. RESULTS: Patients > or =70 years had a similar incidence of grade 3 or 4 neutropenia (68% vs. 66%), thrombocytopenia (68% vs. 70%), anemia (8% vs. 22%), and nonhematologic adverse events (23% vs. 19%) as that observed in patients <60 years. Response rates (range, 71%-80%) and the durations of response (median of 9.9, 11.0, and 9.4 months) were similar in the three groups. CONCLUSIONS: Yttrium-90-ibritumomab tiuxetan produces high rates of clinical response (up to 80%) and durable remissions in patients with NHL, and can be given at standard doses in older patients. The favorable safety profile of the regimen makes it an effective treatment for older patients, who may not otherwise tolerate the adverse events associated with chemotherapy.

Phase I/II study of galiximab, an anti-CD80 antibody, for relapsed or refractory follicular lymphoma.

PURPOSE: This multicenter, dose-escalation study evaluates the safety, pharmacokinetics, and efficacy of galiximab (anti-CD80 monoclonal antibody) in patients with relapsed or refractory follicular lymphoma. PATIENTS AND METHODS: Patients had follicular lymphoma that had relapsed or failed to respond to primary therapy; the majority (90%) presented with stage III or IV disease. Four weekly intravenous infusions of galiximab were administered at doses of 125, 250, 375, or 500 mg/m2. RESULTS: Thirty-seven patients received galiximab treatment and were evaluated for safety; 35 were assessable for response. Antibody infusions were safe and well tolerated with no dose-limiting toxicities. A total of 22 (60%) of 37 patients experienced adverse events related to galiximab. All but one of the events were grade 1 or 2; the most common were fatigue, nausea, and headache. Cytopenias were rare; only one patient experienced anemia and febrile neutropenia, which were unrelated to galiximab and resolved after treatment. No patient developed antigaliximab antibody formation. The mean serum half-life ranged from 13 to 24 days. The overall response rate was 11% (two complete responses and two partial responses). Time to best response was delayed (months 3, 6, 9, and 12). Twelve patients (34%) maintained stable disease. Nearly half of all patients (49%) had a decrease in indicator lesions. Two responders remain on study without progression (22 and 24.4 months). CONCLUSION: The favorable safety profile of galiximab and evidence of single-agent biologic activity and dose-dependent pharmacokinetics support further evaluation of galiximab as a treatment for follicular lymphoma, possibly in combination with other lymphoma therapies.

Polymorphisms in FcgammaRIIIA (CD16) receptor expression are associated with clinical response to rituximab in Waldenström's macroglobulinemia.

PURPOSE: Rituximab is an important therapeutic for Waldenstrom's macroglobulinemia (WM). Polymorphisms in FcgammaRIIIA (CD16) receptor expression modulate human immunoglobulin G1 binding and antibody-dependent cell-mediated cytotoxicity, and may therefore influence responses to rituximab. PATIENTS AND METHODS: Sequence analysis of the entire coding region of FcgammaRIIIA was undertaken in 58 patients with WM whose outcomes after rituximab were known. RESULTS: Variations in five codons of FcgammaRIIIA were identified. Two were commonly observed (FcgammaRIIIA-48 and FcgammaRIIIA-158) and predicted for amino acid polymorphisms at FcgammaRIIIA-48: leucine/leucine (L/L), leucine/arginine (L/R), and leucine/histidine (L/H). Polymorphisms at FcgammaRIIIA-158 were phenylalanine/phenylalanine (F/F), phenylalanine/valine (F/V), and valine/valine (V/V). A clear linkage between these polymorphisms was detected and all patients with FcgammaRIIIA-158F/F were always FcgammaRIIIA-48L/L, and patients with either FcgammaRIIIA-L/R or -L/H always expressed at least one valine at FcgammaRIIIA-158 (P < or = .001). The response trend was higher for patients with FcgammaRIIIA-48L/H (38.5%) versus -48L/R (25.0%) and LL (22.0%), and was significantly higher for patients with FcgammaRIIIA-158V/V (40.0%) and -V/F (35%) versus -158F/F (9.0%; P = .030). Responses for patients with FcgammaRIIIA-48L/L were higher when at least one valine was present at FcgammaRIIIA-158 (P = .057), thereby supporting a primary role for FcgammaRIIIA-158 polymorphisms in predicting rituximab responses. With a median follow-up of 13 months, no significant differences in the median time to progression and progression-free survival were observed when patients were grouped according to their FcgammaRIIIA-48 and -158 polymorphisms. CONCLUSION: The results of these studies therefore support a predictive role for FcgammaRIIIA-158 polymorphisms and responses to rituximab in WM.

Treatment with yttrium 90 ibritumomab tiuxetan at early relapse is safe and effective in patients with previously treated B-cell non-Hodgkin's lymphoma.

Yttrium 90 ((90)Y) ibritumomab tiuxetan (Zevalin), a radiolabeled monoclonal antibody against the CD20 antigen, is indicated for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma (NHL), including patients with rituximab-refractory follicular NHL. Data on 211 patients treated in four clinical trials were analysed to compare the efficacy and safety of (90)Y ibritumomab tiuxetan when it was used after the first relapse of NHL and when it was used after two or more prior therapies. Sixty-three patients (30%) were treated with (90)Y ibritumomab tiuxetan after their first relapse and 148 (70%) after two or more prior therapies. Demographics, disease characteristics and the frequency of adverse events were similar in all groups, with the exception of a higher rate of marrow involvement in first-relapse patients than in patients with two or more prior therapies (57% vs. 39%; P < 0.05). The complete response rate [confirmed (CR) and unconfirmed (Cru)] was higher in first-relapse patients (49% vs. 28%; P < 0.01), and the median time to progression (TTP) was longer (12.6 vs. 7.9 months; P < 0.05). In patients with follicular NHL, the differences were even more pronounced (CR/CRu: 51% vs. 28%; P < 0.01; TTP: 15.4 vs. 9.2 months; P < 0.05). (90)Y ibritumomab tiuxetan has substantial clinical benefits as a second-line therapy, especially in patients with follicular NHL. The quality of disease remissions obtained when (90)Y ibritumomab tiuxetan is administered after first relapse appears to be comparable with that observed with most chemotherapy regimens in first-relapse patients.

Sorafenib in breast cancer treatment: A systematic review and overview of clinical trials.

AIM: To evaluate the current role of sorafenib, an oral multikinase inhibitor in the treatment of breast cancer. METHODS: An extensive search of the literature until March 2016 was carried out in Medline and clinicaltrials.gov, by using the search terms "sorafenib" and "breast cancer". Papers found were checked for further relevant publications. Overall, 21 relevant studies were found, 18 in advanced breast cancer (16 in stage IV and two in stages III-IV) and three in early breast cancer. RESULTS: Among studies in advanced breast cancer, there were two trials with sorafenib as monotherapy, four trials of sorafenib in combination with taxanes, two in combination with capecitabine, one with gemcitabine and/or capecitabine, one with vinorelbine, one with bevacizumab, one with pemetrexed and one with ixabepilone, three trials of sorafenib in combination with endocrine therapy and two trials in women with brain metastases undergoing whole brain radiotherapy. In addition, there was one trial of sorafenib added to standard chemotherapy in the adjuvant setting, and two trials in the neoadjuvant setting. In general, sorafenib was well tolerated in breast cancer patients, though its dosage had to be adjusted in some trials, and discontinuation rates were high, particularly for the combination of sorafenib with anastrozole. Sorafenib monotherapy and combinations with taxanes, bevacizumab and ixabepilone showed inadequate efficacy, while efficacy results from combinations with gemcitabine and/or capecitabine and possibly tamoxifen were more promising. CONCLUSION: At present, sorafenib should not be used for the treatment of breast cancer outside of clinical trials and more clinical data are needed in order to support its standard use in breast cancer therapy.