Berotralstat for long-term prophylaxis of hereditary angioedema in Japan: Parts 2 and 3 of the randomized APeX-J Phase III trial.

Background: Berotralstat is a once-daily oral inhibitor of plasma kallikrein for the prophylaxis of hereditary angioedema (HAE) in patients ≥12 years. APeX-J aimed to evaluate the efficacy and safety of berotralstat in Japan. Methods: APeX-J was a Phase III trial comprising 3 parts (NCT03873116). Part 1 was a randomized, placebo-controlled evaluation of berotralstat 150 or 110 mg over 24 weeks. Part 2 was a 28-week dose-blinded phase in which berotralstat-treated patients continued the same dose and placebo patients were re-randomized to berotralstat 150 or 110 mg. In Part 3, all patients remaining on study received berotralstat 150 mg in an open-label manner for up to an additional 52 weeks. The primary endpoint of Parts 2 and 3 was long-term safety and tolerability, and secondary endpoints examined effectiveness. Results: Seventeen patients entered Part 2, and 11 continued into Part 3. Treatment-emergent adverse events (TEAEs) were reported by 14/17 patients (82.4%) in Parts 2 or 3; the most common were nasopharyngitis, abdominal pain, cystitis, influenza, and vertigo. One patient (5.9%) experienced a drug-related TEAE (Grade 4 increased hepatic enzyme). No drug-related serious TEAEs were reported. For patients who completed 26 months of treatment with berotralstat 150 mg (n = 5), mean (standard error of the mean) monthly HAE attack rates and on-demand medication use decreased from baseline by 1.15 (0.09) attacks/month and 2.8 (0.64) doses/month, respectively. Sustained improvements were also observed in patient quality of life and treatment satisfaction. Conclusions: Long-term prophylaxis with berotralstat raised no new safety signals and was effective at reducing attacks and improving patient-reported outcomes. Trial registration: ClinicalTrials.gov NCT03873116. Registered March 13, 2019. Retrospectively registered.

Hereditary angioedema outcomes in US patients switched from injectable long-term prophylactic medication to oral berotralstat.

BACKGROUND: Berotralstat, a first-line, once-daily, oral plasma kallikrein inhibitor for long-term prophylaxis of hereditary angioedema (HAE), is an effective and well-tolerated treatment option. OBJECTIVE: To summarize the safety, effectiveness, and impact on treatment satisfaction in patients who switched from injectable long-term prophylactics to oral berotralstat monotherapy (150 mg daily) at US sites in the international open-label APeX-S study. METHODS: APeX-S was an open-label, Phase II study of berotralstat conducted in 22 countries. Here, we focus on APeX-S patients enrolled at US sites who switched from injectable long-term prophylactics to berotralstat 150 mg once-daily monotherapy. RESULTS: A total of 34 patients discontinued lanadelumab (n = 21), subcutaneous C1 esterase inhibitor (n = 11), or intravenous C1 esterase inhibitor (n = 2) and switched to berotralstat 150 mg monotherapy. Vomiting, diarrhea, and upper respiratory tract infection were the most common adverse events (each 11.8%). Mean monthly attack rates were consistently low after the switch to berotralstat. The mean (SEM) monthly attack rate was 0.29 (0.11) at Month 1, 0.48 (0.15) at Month 6, and 0.58 (0.23) at Month 12. The median attack rate was 0 attack/mo throughout 12 months of treatment. Improvements were observed in the Treatment Satisfaction Questionnaire for Medication from baseline to Month 12 after the switch to berotralstat monotherapy, with the greatest improvements in convenience. CONCLUSION: The transition from injectable prophylactic medication to berotralstat was generally well tolerated. Patients switching to berotralstat monotherapy maintained good control of their HAE symptoms and reported improved treatment satisfaction. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03472040.

Once-Daily Oral Berotralstat for Long-Term Prophylaxis of Hereditary Angioedema: The Open-Label Extension of the APeX-2 Randomized Trial.

BACKGROUND: Berotralstat is a first-line, once-daily oral plasma kallikrein inhibitor approved for prophylaxis of hereditary angioedema (HAE) attacks in patients 12 years or older. OBJECTIVE: This analysis examined the safety and effectiveness of long-term prophylaxis with berotralstat. METHODS: APeX-2 was a phase 3, parallel-group, multicenter trial in patients with HAE caused by C1-inhibitor deficiency (NCT03485911). Part 1 was a randomized, double-blind, placebo-controlled evaluation of 150 and 110 mg of berotralstat over 24 weeks. In part 2, berotralstat-treated patients continued the same treatment, and placebo-treated patients were re-randomized to 150 or 110 mg of berotralstat for 24 weeks. In part 3, all patients were treated with open-label berotralstat at 150 mg, which could be continued for up to an additional 4 years. In part 3, the primary endpoint was long-term safety and tolerability. Secondary endpoints included HAE attack rates and quality of life (QoL). RESULTS: Eighty-one patients entered part 3. Treatment-emergent adverse events (TEAEs) occurred in 82.7% of patients, with most being mild or moderate in severity. The most common TEAEs were nasopharyngitis, urinary tract infection, abdominal pain, arthralgia, coronavirus infection, and diarrhea. Drug-related TEAEs occurred in 14.8% of patients, but none were serious. For patients who completed 96 weeks of berotralstat treatment (n = 70), the mean (standard error) change in attack rate from baseline was -2.21 (0.20) attacks/mo. Clinically meaningful improvements in QoL were also observed, with the largest improvements in the functioning domain. CONCLUSION: Berotralstat was generally well tolerated, provided rapid and sustained reductions in HAE attacks and improved QoL over 96 weeks.

Assessment of HAE prophylaxis transition from androgen therapy to berotralstat: A subset analysis of the APeX-S trial.

Background: Given the recent approval of oral berotralstat in several countries for hereditary angioedema (HAE) prophylaxis, transition from long-term androgens to berotralstat may occur in clinical practice. The open-label, Phase II APeX-S trial provided an opportunity to assess the safety and effectiveness of berotralstat in patients previously treated with differing durations of androgens and shorter transition periods. Therefore, we examined the safety, effectiveness, and impact on quality of life of berotralstat after prior androgen use in patients from the APeX-S trial. Alanine aminotransferase (ALT) elevations were also examined because of the association with androgen exposure and hepatic function impairment. Methods: We conducted an analysis of a subset of 39 patients from the APeX-S trial aged ≥12 years with HAE due to C1 inhibitor deficiency (HAE-C1-INH) with prior androgen use who discontinued androgen therapy within <60 days of receiving berotralstat. Patients received daily berotralstat (150 mg) and were divided into subgroups for this analysis based on time between androgen discontinuation and berotralstat commencement (<14 days versus 14 to <60 days). Results: Berotralstat was generally well tolerated, with nasopharyngitis (21%), upper respiratory tract infection (15%), nausea (15%), diarrhea (15%), and abdominal pain (10%) being the most common adverse events occurring in ≥10% of the total subset. Only 7/145 (5%) of all APeX-S study patients with a prior history of androgen therapy experienced ALT elevations, 6 of which were grade 3 or 4 toxicities. All 7 patients recovered without sequelae and belonged to the subgroup of patients who transitioned <14 days after discontinuing androgens (n = 18). A reduction in monthly attack rate versus Month 1 was observed over 12 months for all patients who transitioned from prior androgen therapy to berotralstat prophylaxis in under 60 days, irrespective of duration of prior androgen therapy or timing of transition (N = 39). Similarly, meaningful patient-reported improvements from both Angioedema Quality of Life Questionnaire and Treatment Satisfaction Questionnaire for Medication scores were achieved, with a sustained benefit shown over the berotralstat treatment period. Conclusions: Berotralstat treatment led to sustained HAE symptom control irrespective of duration of prior androgen therapy or timing of transition. Most patients safely transitioned from long-term androgens to berotralstat. Although occurring in a small group of patients, liver-related adverse events following berotralstat treatment may be associated with a shorter androgen washout period, but further research is required to confirm this. Clinical trial registration: NCT03472040. Retrospectively registered March 21, 2018.

A Randomized, Double-Blind, Placebo-Controlled, Phase III Noninferiority Study of the Long-Term Safety and Efficacy of Darbepoetin Alfa for Chemotherapy-Induced Anemia in Patients With Advanced NSCLC.

INTRODUCTION: This study evaluated noninferiority of darbepoetin alfa versus placebo for overall survival (OS) and progression-free survival (PFS) in anemic patients with NSCLC treated to a 12.0-g/dL hemoglobin (Hb) ceiling. METHODS: Adults with stage IV NSCLC expected to receive two or more cycles of myelosuppressive chemotherapy and Hb less than or equal to 11.0 g/dL were randomized 2:1 to blinded 500 µg darbepoetin alfa or placebo every 3 weeks. The primary endpoint was OS; a stratified Cox proportional hazards model was used to evaluate noninferiority (upper confidence limit for hazard ratio [HR] < 1.15). Secondary endpoints were PFS and incidence of transfusions or Hb less than or equal to 8.0 g/dL from week 5 to end of the efficacy treatment period. RESULTS: The primary analysis set included 2516 patients: 1680 were randomized to darbepoetin alfa; 836 to placebo. The study was stopped early per independent Data Monitoring Committee recommendation after the primary endpoint was met with no new safety concerns. Darbepoetin alfa was noninferior to placebo for OS (stratified HR = 0.92; 95% confidence interval [CI]: 0.83‒1.01) and PFS (stratified HR = 0.95; 95% CI: 0.87‒1.04). Darbepoetin alfa was superior to placebo for transfusion or Hb less than or equal to 8.0 g/dL from week 5 to end of the efficacy treatment period (stratified odds ratio = 0.70; 95% CI: 0.57‒0.86; p < 0.001). Objective tumor response was similar between the groups (darbepoetin alfa, 36.4%; placebo, 32.6%). Incidence of serious adverse events was 31.1% in both groups. No unexpected adverse events were observed. CONCLUSIONS: Darbepoetin alfa dosed to a 12.0-g/dL Hb ceiling was noninferior to placebo for OS and PFS and significantly reduced odds of transfusion or Hb less than or equal to 8.0 g/dL in anemic patients with NSCLC receiving myelosuppressive chemotherapy.

Changes in the use of erythropoiesis-stimulating agents (ESAs) and red blood cell transfusion in patients with cancer amidst regulatory and reimbursement changes.

PURPOSE: Evaluate changes in use of erythropoiesis-stimulating agents (ESAs) and red blood cell transfusion in cancer patients receiving myelosuppressive chemotherapy following regulatory and reimbursement actions. METHODS: Calendar year patient cohorts (2005-2013) with breast, colorectal, lung, multiple myeloma, non-Hodgkin lymphoma, ovarian, or prostate cancer and receiving myelosuppressive chemotherapy were identified within the Marketscan database. Incidence of ESA treatment and transfusion were estimated in each year, as was median number of ESA administrations. Clinical characteristics associated with ESA administration and transfusions were evaluated by using multivariable logistic regression. Additionally, annual new ESA user cohorts within the Oncology Services Comprehensive Electronic Records database (2011-2014) were examined to assess hemoglobin levels at ESA initiation. RESULTS: Across all tumor types, ESA use decreased substantially (breast cancer: 53.7 to 3.2%; lung cancer: 66.0 to 13.3%, non-Hodgkin lymphoma: 39.8 to 3.8%), transfusion use increased (2 to 5.5%, 5.5 to 18.2%, and 4.5 to 9.1%, respectively), and median number of ESA administrations declined. Across all tumor types, proportion of patients initiating an ESA with hemoglobin >10 g/dL was <10% from 2011 onward. In recent years, cancer patients who are older, female, and have chronic kidney disease or moderate or severe liver disease were most likely to receive ESAs. CONCLUSION: Subsequent to important regulatory and reimbursement ESA-related actions, total ESA exposure among cancer patients receiving myelosuppressive chemotherapy declined substantially. Today, fewer patients receive ESA therapy, and among those treated, more are initiated at hemoglobin levels <10 g/dL and are exposed for a shorter duration, consistent with current product labeling.

Erythropoiesis stimulating agents and reno-protection: a meta-analysis.

BACKGROUND: Erythropoiesis stimulating agents (ESAs) were proposed to enhance survival of renal tissues through direct effects via activation of EPO receptors on renal cells resulting in reduced cell apoptosis, or indirect effects via increased oxygen delivery due to increased numbers of Hb containing red blood cells. Thus through several mechanisms there may be benefit of ESA administration on kidney disease progression and kidney function in renal patients. However conflicting ESA reno-protection outcomes have been reported in both pre-clinical animal studies and human clinical trials. To better understand the potential beneficial effects of ESAs on renal-patients, meta-analyses of clinical trials is needed. METHODS: Literature searches and manual searches of references lists from published studies were performed. Controlled trials that included ESA treatment on renal patients with relevant renal endpoints were selected. RESULTS: Thirty two ESA controlled trials in 3 categories of intervention were identified. These included 7 trials with patients who had a high likelihood of AKI, 7 trials with kidney transplant patients and 18 anemia correction trials with chronic kidney disease (predialysis) patients. There was a trend toward improvement in renal outcomes in the ESA treated arm of AKI and transplant trials, but none reached statistical significance. In 12 of the anemia correction trials, meta-analyses showed no difference in renal outcomes with the anemia correction but both arms received some ESA treatment making it difficult to assess effects of ESA treatment alone. However, in 6 trials the low Hb arm received no ESAs and meta-analysis also showed no difference in renal outcomes, consistent with no benefit of ESA/ Hb increase. CONCLUSIONS: Most ESA trials were small with modest event rates. While trends tended to favor the ESA treatment arm, these meta-analyses showed no reduction of incidence of AKI, no reduction in DGF or improvement in 1-year graft survival after renal transplantation and no significant delay in progression of CKD. These results do not support significant clinical reno-protection by ESAs.

Efficacy and safety of darbepoetin alpha in patients with myelodysplastic syndromes: a systematic review and meta-analysis.

We conducted a systematic review and meta-analysis to estimate the efficacy of darbepoetin alpha (DA) for treatment of myelodysplastic syndrome (MDS)-related anaemia. Eligible studies were prospective, interventional, and reported World Health Organization, French-American-British, or International Prognostic Scoring System (IPSS) criteria. Outcomes included erythroid response rate (primary); haemoglobin response; change in haemoglobin, transfusion status, and quality-of-life (QoL); and safety. Ten studies (N = 647) were analysed. Erythroid response rate range was 38-72%; median response duration range was 12-51+ months. Patients with erythropoietin (EPO) <100 iu/l had 35% [95% confidence interval (CI): 22-48%; P < 0·001) better response than patients with EPO >100 iu/l. Erythropoesis-stimulating agent (ESA)-naïve patients had 17% (95% CI: 3-32%; P = 0·022) greater response rate than those previously treated with ESA. Nonetheless, previously treated patients had response rates of 25-75%. Higher baseline haemoglobin levels, higher dose, transfusion-independence and low-risk IPSS status were reported by several studies to be associated with better response. QoL, transfusion rates and haemoglobin levels improved with treatment. Hypertension, thromboembolism and progression to acute myeloid leukaemia were reported in 2%, 1% and 1% of patients, respectively. This meta-analysis suggests that DA treatment can be useful for improving erythroid response in MDS patients with anaemia, even among patients previously treated with ESA.

Changing patterns of chemotherapy relative dose intensity and supportive care for aggressive B-cell non-Hodgkin lymphoma.

Maintaining high relative dose intensity (RDI) is associated with improved outcomes, especially in patients with aggressive B-cell non-Hodgkin lymphoma (NHL). To evaluate changes in practice, we examined RDI, chemotherapy treatment patterns, dose delays and reductions, neutropenia and related consequences, and supportive care in 500 patients with aggressive B-cell NHL treated between 2006-2009. We then compared the results to a previous study of patients treated between 1993-2001. Relative to the previous study, rituximab was a common addition to CHOP-21 (91% vs. 3%), more patients received an RDI ≥ 85% (68% vs. 52%), and fewer patients experienced dose reductions (21% vs. 35%), though incidences of dose delays were similar (26% vs. 23%). Incidences of febrile neutropenia (FN; 12% vs. 21%) and FN-related hospitalizations (10% vs. 16%) were lower. Finally, more patients received primary prophylaxis with colony-stimulating factors (75% vs. 12%). Together, these results illustrate evolving practice patterns for patients with aggressive B-cell NHL.

A retrospective evaluation of chemotherapy dose intensity and supportive care for early-stage breast cancer in a curative setting.

Early-stage breast cancer (ESBC) is commonly treated with myelosuppressive chemotherapy, and maintaining full-dose chemotherapy on the planned schedule is associated with improved patient outcome. Retrospective analysis of patients with ESBC treated from 1997 to 2000 showed that 56 % of patients received a relative dose intensity (RDI) <85 % (Lyman et al., J Clin Oncol 21(24):4524-4531, 2003). To determine current practice, we evaluated treatment patterns at 24 US community- and hospital-based oncology practices, 79 % of which participated in the previous study. Data were abstracted from medical records of 532 patients with surgically resected ESBC (stage I-IIIa) treated from 2007 to 2009, who were ≥18 years old and had completed ≥1 cycle of one of the following regimens: docetaxel + cyclophosphamide (TC); doxorubicin + cyclophosphamide (AC); AC followed by paclitaxel (AC-T); docetaxel + carboplatin + trastuzumab (TCH); or docetaxel + doxorubicin + cyclophosphamide (TAC). Endpoints included RDI, dose delays, dose reductions, grade 3/4 neutropenia, febrile neutropenia (FN), FN-related hospitalization, granulocyte colony-stimulating factor (G-CSF) use, and antimicrobial use. In this study, TC was the most common chemotherapy regimen (42 %), and taxane-based chemotherapy regimens were more common relative to the previously published results (89 vs <4 %). Overall, 83.8 % of patients received an RDI ≥85 %, an improvement over the previous study where 44.5 % received an RDI ≥85 %. Other changes seen between this and the previous study included a lower incidence of dose delays (16 vs 25 %) and dose reductions (21 vs 37 %) and increased use of primary prophylactic G-CSF (76 vs ~3 %). Here, 40 % of patients had grade 3/4 neutropenia, 3 % had FN, 2 % had an FN-related hospitalization, and 30 % received antimicrobial therapy; these measures were not available in the previously published results. Though RDI was higher here than in the previous study, 16.2 % of patients still received an RDI <85 %. Understanding factors that contribute to reduced RDI may further improve chemotherapy delivery, and ultimately, patient outcomes.

Effects of erythropoiesis-stimulating agents on survival and other outcomes in patients with lymphoproliferative malignancies: a study-level meta-analysis.

Erythropoiesis-stimulating agents (ESAs) are approved to treat anemia in patients with non-myeloid malignancies receiving myelosuppressive chemotherapy. ESAs reduce transfusion rates, but some clinical studies suggest that ESAs may reduce survival or increase disease progression. This study-level meta-analysis examined the effects of darbepoetin alfa, epoetin alfa or epoetin beta on mortality, disease progression and transfusion incidence in patients with lymphoproliferative malignancies, using randomized, controlled trials of patients receiving chemotherapy and ESAs or standard of care. The odds ratio (OR) for mortality was 1.04 (95% confidence interval [CI], 0.81-1.34, random-effects model, 10 studies); the risk difference was - 0.01 (95% CI, - 0.03-0.02). The OR for disease progression was 1.02 (95% CI 0.81-1.30, random-effects model, five studies). A lower proportion of ESA-treated patients than controls received transfusions (seven studies). In this meta-analysis, ESAs reduced transfusions with no clear effect on mortality or disease progression in patients with lymphoproliferative malignancies receiving chemotherapy.

Benefits and risks of using erythropoiesis-stimulating agents (ESAs) in lung cancer patients: study-level and patient-level meta-analyses.

In anemic patients receiving myelosuppressive chemotherapy, erythropoiesis-stimulating agents (ESAs) raise hemoglobin levels and reduce transfusion requirements, but ESA-related safety concerns exist. To evaluate ESA benefits and risks in lung cancer, we conducted meta-analyses of data from controlled ESA trials conducted in lung cancer patients. Study-level analyses included controlled ESA trials reporting lung cancer mortality, identified from the 2006 Cochrane ESA report and from a systematic search for studies published through December 2010. Patient-level analyses included data from lung cancer patients receiving chemotherapy in Amgen studies evaluating darbepoetin alfa (DA) vs placebo. Study-level and patient-level analyses examined deaths, progression, and transfusion incidence. Patient-level analyses also examined adverse events (AEs) and fatigue. In a study-level meta-analysis of nine ESA studies of 2342 patients receiving chemotherapy, the ESA odds ratio (OR) was 0.87 (95% confidence interval [CI] 0.69-1.09) for mortality; the overall random-effects risk difference (95% CI) for mortality was -0.02 (-0.06, 0.02). The ESA OR (95% CI) for disease progression in five chemotherapy studies reporting progression was 0.84 (0.65-1.09). The ESA odds ratio (95% CI) was 0.34 (0.28-0.41) for transfusion incidence. In a patient-level meta-analysis of four studies evaluating 1009 patients through follow-up, the median survival time was 41 weeks with DA and 38 weeks with placebo. During the combined study and follow-up periods, 80% of placebo-group patients and 74% of DA patients died (mortality hazard ratio [HR] 0.90 [95% CI, 0.78-1.03] for DA); results were similar for small cell lung cancer and non-small cell lung cancer. Overall, 87% of placebo patients and 84% of DA patients progressed or died. Fewer DA patients had transfusions (week 5 through end-of-study, DA 19%, placebo 43%). AEs included thrombotic/embolic events (DA 10.5%, placebo 7.2%), cerebrovascular disorders (DA 3.7%, placebo 4.2%), pulmonary edema (DA 0.4%, placebo 1.0%) and pulmonary embolism (DA 1.8%, placebo 0.6%). These meta-analyses suggest that ESAs reduce transfusions without increasing mortality or disease progression in lung cancer patients undergoing chemotherapy.

Assessing the effect of darbepoetin alfa on patient-reported fatigue in chemotherapy-induced anemia in four randomized, placebo-controlled clinical trials.

PURPOSE: This analysis examined the effects of darbepoetin alfa on hemoglobin and fatigue outcomes in patients with cancer using latent growth curve modeling (LGM). METHODS: Data from 4 clinical trials of darbepoetin alfa in lung cancer (2 studies; n = 547; n = 288), lymphoproliferative malignancies (n = 339), and non-myeloid malignancies (n = 320) were analyzed separately. Fatigue was assessed using the FACT-Fatigue (FACT-F) scale. Effects of darbepoetin alfa on changes in hemoglobin and FACT-F scores were evaluated using LGM, controlling for age, gender, Eastern Cooperative Oncology Group performance status, health status, and total transfusions. RESULTS: Patients receiving darbepoetin alfa had higher rates of change in hemoglobin (standardized regression coefficient [[Formula: see text]] = 0.30 to 0.53, all P < 0.05) than placebo. Patients with greater rates of change in hemoglobin reported improvements in fatigue outcomes ([Formula: see text] = 0.28 to 0.59, all P < 0.05). The total standardized effect of darbepoetin alfa on fatigue outcomes corresponded to a mean change of 0.9 to 3.5 points in FACT-F scores, with one trial demonstrating changes exceeding the minimal important difference of 3 points. CONCLUSIONS: Darbepoetin alfa improved hemoglobin which was associated with improved fatigue across the 4 trials. Clinically, meaningful improvement in fatigue was seen in 2 trials. More complex statistical analysis models of treatment may assist in understanding the effects of erythropoiesis-stimulating agents on patient-reported outcomes.

Randomized, double-blind, placebo-controlled trial of every-3-week darbepoetin alfa 300 micrograms for treatment of chemotherapy-induced anemia.

OBJECTIVE: Darbepoetin alfa is effective in treating chemotherapy-induced anemia (CIA). Administration of subcutaneous darbepoetin alfa every 3 weeks (Q3W) could simplify treatment through synchronization with common Q3W chemotherapy regimens. We report results from a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial evaluating the efficacy and safety of fixed-dose Q3W darbepoetin alfa in patients with a wide variety of tumor types who experienced CIA. RESEARCH DESIGN AND METHODS: Patients aged > or = 18 years with anemia (hemoglobin <11 g/dL) being treated for nonmyeloid malignancy were randomized 1:1 to receive darbepoetin alfa 300 microg (n = 193) or placebo (n = 193) subcutaneously Q3W from weeks 1 to 13 in this 16-week study. Doses could be adjusted per prespecified rules. MAIN OUTCOME MEASURES: The primary endpoint was the proportion of patients who received > or =1 red blood cell (RBC) transfusion between week 5 and the end of the treatment period (EOTP). The study also analyzed the proportions of patients achieving a hemoglobin concentration > or =11 g/dL and subsequently maintaining hemoglobin levels above 11 g/dL, and the change in hemoglobin concentration over time. RESULTS: The proportion of patients requiring RBC transfusions between week 5 and EOTP was significantly lower in the darbepoetin alfa-treated group than in the placebo-treated group (24 vs. 41% of patients, a 16.3% difference, p < 0.001). There were no differences between the two treatment arms in quality-of-life measures. Cardiovascular/thromboembolic adverse events were uncommon and were not associated with increases in hemoglobin levels. Study limitations suggest caution in the interpretation of these results: transfusions, the primary endpoint, were recommended but not required if hemoglobin concentrations were < or =8.0 g/dL, and protocol deviations (primarily dosing errors) occurred in approximately one-half of the patients in both treatment groups. CONCLUSIONS: In this study, fixed-dose Q3W darbepoetin alfa appeared to be well-tolerated and effective for the treatment of CIA. TRIAL REGISTRATION: Study 20030232; ClinicalTrials.Gov Identifier: NCT00110955.

Treating anemia of cancer with every-4-week darbepoetin alfa: final efficacy and safety results from a phase II, randomized, double-blind, placebo-controlled study.

Darbepoetin alfa is an erythropoiesis-stimulating agent (ESA) approved for treating chemotherapy-induced anemia. This phase II, double-blind, placebo-controlled study examined the efficacy of darbepoetin alfa for treating anemia of cancer (AoC) in patients not receiving chemotherapy or radiotherapy. Patients were randomized 3:1 to receive darbepoetin alfa (6.75 microg/kg) or placebo every 4 weeks; the end of the study was at week 17. The primary endpoint was the percentage of patients with a hematopoietic response. Secondary endpoints included transfusion incidence and safety parameters. Efficacy analyses were performed on 162 patients in the darbepoetin alfa group and 56 patients in the placebo group. The Kaplan-Meier percentages of patients who achieved a hematopoietic response (darbepoetin alfa, 69%; placebo, 24%) or achieved the target hemoglobin (darbepoetin alfa, 85%; placebo, 50%) differed significantly between treatment groups. The transfusion incidence did not differ between treatment groups probably because of the low baseline transfusion rates in AoC patients. The incidence of adverse events (including on-study deaths) was similar in both groups. In conclusion, darbepoetin alfa appeared to be well tolerated and significantly increased hemoglobin levels in these AoC study patients.

Phase 2, single-arm trial to evaluate the effectiveness of darbepoetin alfa for correcting anaemia in patients with myelodysplastic syndromes.

Patients with myelodysplastic syndromes (MDS) often develop anaemia resulting in frequent transfusions and fatigue. Darbepoetin alfa is an erythropoiesis-stimulating agent (ESA) approved for treating chemotherapy-induced anaemia. This single-arm, phase 2 study examined the efficacy of darbepoetin alfa 500 microg every 3 weeks (Q3W) for treating anaemia in low-risk MDS patients (after 6 weeks, poor responders received darbepoetin alfa 500 microg every 2 weeks). The primary end-point was the incidence of erythroid responses (International Working Group criteria) after 13 weeks of therapy. Secondary end-points included the incidence of erythroid responses at weeks 28 and 55, [or weeks 27 and 53 for dose escalations to every two weeks (Q2W)], and safety parameters. Analyses were stratified by the patient's previous ESA therapy status [ESA-naïve (n = 144) vs. prior ESA-treated (n = 62)]. After 13 weeks of therapy, 49% of ESA-naïve patients and 26% of prior ESA-treated patients achieved a major erythroid response. After 53/55 weeks, 59% of ESA-naïve patients and 34% of prior ESA-treated patients achieved a major erythroid response; 82% of ESA-naïve patients and 55% of prior ESA-treated patients achieved target haemoglobin of 110 g/l. Thromboembolic or related adverse events occurred in 2% of patients; no pulmonary embolisms were reported. In conclusion, darbepoetin alfa, 500 microg Q3W appeared well tolerated and increased haemoglobin levels in low-risk MDS patients.

A randomized, open-label, multicenter trial of immediate versus delayed intervention with darbepoetin alfa for chemotherapy-induced anemia.

The optimal hemoglobin concentration at which to initiate erythropoietic therapy for chemotherapy-induced anemia (CIA) is not well defined. This randomized, open-label, multicenter study evaluated the ability of darbepoetin alfa (300 microg every 3 weeks) to maintain hemoglobin levels > or =10 g/dl in patients with CIA (hemoglobin > or =10.5 g/dl and < or =12.0 g/dl) randomized 1:1 to an immediate-intervention group (received darbepoetin alfa immediately) or observation group (received darbepoetin alfa if hemoglobin fell to <10 g/dl). In 201 evaluable patients, there was a significant difference between the two groups in the Kaplan-Meier proportion of patients with a hemoglobin decrease to <10 g/dl during weeks 1-13 (test period) (primary endpoint): 29% for immediate-intervention patients versus 65% for observation patients. Sixty-four patients in the observation group received darbepoetin alfa (delayed-intervention subgroup). The Kaplan-Meier proportion of patients who received transfusions was lower in the immediate-intervention group than in the delayed-intervention subgroup (14% versus 31% for the test period; 17% versus 36% over the whole study). The target hemoglobin level (> or =11 g/dl) was achieved by a higher percentage of patients (crude percentage) in less time in the immediate-intervention group (94% in 2 weeks) than in the delayed-intervention subgroup (73% in 6 weeks); hemoglobin endpoints for the delayed-intervention subgroup were calculated from recalibrated study week 1 (the date patients first received darbepoetin alfa). For both groups, a higher mean change in hemoglobin from baseline led to a greater improvement in Functional Assessment of Cancer Therapy-Fatigue scores. In conclusion, immediate intervention resulted in a significantly lower proportion of patients who experienced a decline in hemoglobin, lower requirement for transfusions, and greater proportion of patients achieving and maintaining the target hemoglobin level.

Assessing symptom burden using the M. D. Anderson symptom inventory in patients with chemotherapy-induced anemia: results of a multicenter, open-label study (SURPASS) of patients treated with darbepoetin-alpha at a dose of 200 microg every 2 weeks.

BACKGROUND: Patients with cancer who are receiving chemotherapy often experience chemotherapy-induced anemia (CIA), which is associated with symptoms that reduce quality of life. The M. D. Anderson Symptom Inventory (MDASI) is a brief, self-rating assessment scale that measures the severity of core symptoms and symptom interference with function. The current study used the MDASI to prospectively assess the correlation between hemoglobin and self-perceived cancer-related symptoms in a large patient population with CIA who were receiving darbepoetin-alpha at a dose of 200 mug every 2 weeks. METHODS: Eligible patients enrolled in this multicenter, open-label study were age > or =18 years, had a nonmyeloid malignancy, were receiving multicycle chemotherapy, and were anemic (hemoglobin < or = 11 g/dL). Hemoglobin was measured every 2 weeks; the MDASI was administered weekly. For hemoglobin-based endpoints, patients were stratified by baseline hemoglobin (< 10 g/dL or > or =10 g/dL). RESULTS: Of 2422 enrolled patients, 2401 received > or =1 dose of darbepoetin-alpha. Eighty percent of patients (95% confidence limit, 78-82 patients) achieved target hemoglobin levels (> or =11 g/dL) during the study. Patients with a baseline hemoglobin < 10 g/dL had a greater increase in hemoglobin, took longer to achieve the target hemoglobin, and received more red blood cell transfusions than patients with a baseline hemoglobin > or =10 g/dL. The percentage of patients with moderate to severe MDASI scores (> or =5 points) for fatigue, distress, loss of appetite, disturbed sleep, and interference with function was reduced during the study. Improvement in symptom burden was associated with an increase in hemoglobin concentration. CONCLUSIONS: Treatment with darbepoetin-alpha at a dose of 200 mug every 2 weeks is associated with improvement in symptom burden as measured by the MDASI, a simple tool that may improve symptom management for cancer patients with CIA.

Efficacy and safety of every-2-week darbepoetin alfa in patients with anemia of cancer: a controlled, randomized, open-label phase II trial.

This randomized, controlled trial evaluated the effect of darbepoetin alfa on hospitalization days, transfusion requirements, hemoglobin levels, and fatigue in patients with anemia of cancer (AOC). Eligible patients were anemic (hemoglobin or=18 years old, and had not received chemotherapy or radiotherapy within 4 weeks of study screening. Patients were randomized 4:1 to receive darbepoetin alfa, 3.0 microg/kg every 2 weeks (Q2W) (n = 226), or observation only for 12 weeks (n = 59), followed by an optional 9 weeks of darbepoetin alfa, 3.0 microg/kg Q2W. Endpoints were compared between the two treatment arms at week 13. A planned interim analysis indicated that assumptions regarding hospitalization in the study design were incorrect, so the study was terminated early. Therefore, results for the primary endpoint should be interpreted cautiously. The hospitalization rate was similar (0.5 days) for both the darbepoetin alfa and observation groups (p = .73). Transfusion incidence (weeks 5-12) was significantly lower for darbepoetin alfa patients (8%) than for observation patients (22%) (p = .0092). By week 13, hemoglobin increased by 2.1 g/dl in patients receiving darbepoetin alfa, compared with 0.1 g/dl in the observation group p < .0001. Hemoglobin improvements were paralleled by an increase in Functional Assessment of Cancer Therapy-Fatigue score (mean change in score at week 13: darbepoetin alfa, 6.0; observation, 2.2; p < .05). Darbepoetin alfa Q2W can significantly improve hemoglobin levels and reduce transfusion requirements in patients with AOC, resulting in significant improvements in health-related quality of life.