Molecular determinants of outcomes in relapsed or refractory mantle cell lymphoma treated with ibrutinib or temsirolimus in the MCL3001 (RAY) trial.

Mantle cell lymphoma (MCL) is a rare, incurable lymphoma subtype characterized by heterogeneous outcomes. To better understand the clinical behavior and response to treatment, predictive biomarkers are needed. Using residual archived material from patients enrolled in the MCL3001 (RAY) study, we performed detailed analyses of gene expression and targeted genetic sequencing. This phase III clinical trial randomized patients with relapsed or refractory MCL to treatment with either ibrutinib or temsirolimus. We confirmed the prognostic capability of the gene expression proliferation assay MCL35 in this cohort treated with novel agents; it outperformed the simplified MCL International Prognostic Index in discriminating patients with different outcomes. Regardless of treatment arm, our data demonstrated that this assay captures the risk conferred by known biological factors, including increased MYC expression, blastoid morphology, aberrations of TP53, and truncated CCND1 3' untranslated region. We showed the negative impact of BIRC3 mutations/deletions on outcomes in this cohort and identified that deletion of chromosome 8p23.3 also negatively impacts survival. Restricted to patients with deletions/alterations in TP53, ibrutinib appeared to abrogate the deleterious impact on outcome. These data illustrate the potential to perform a molecular analysis of predictive biomarkers on routine patient samples that can meaningfully inform clinical practice.

Health-related quality of life data from a phase 3, international, randomized, open-label, multicenter study in patients with previously treated mantle cell lymphoma treated with ibrutinib versus temsirolimus.

Mantle cell lymphoma (MCL) is a rare, aggressive, incurable B-cell malignancy. Ibrutinib has been shown to be highly active for patients with relapsed/refractory (R/R) MCL. The RAY trial (MCL3001) was a phase 3, randomized, open-label, multicenter study that compared ibrutinib with temsirolimus in patients with R/R MCL. Active disease is frequently associated with impaired functional status and reduced well-being. Therefore, the current study employed two patient-reported outcome instruments, the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and the EQ-5D-5L, to assess symptoms, well-being, health status, and health-related quality of life of patients on treatment within the RAY trial. We found that patients on ibrutinib had substantial improvement in FACT-Lym subscale and total scores, and had improvement in EQ-5D-5L utility and VAS scores compared with temsirolimus patients, indicating a superior well-being. These improvements in well-being correlated with clinical response, indicating that better health-related quality of life was associated with decreased disease burden.

Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study.

BACKGROUND: Mantle-cell lymphoma is an aggressive B-cell lymphoma with a poor prognosis. Both ibrutinib and temsirolimus have shown single-agent activity in patients with relapsed or refractory mantle-cell lymphoma. We undertook a phase 3 study to assess the efficacy and safety of ibrutinib versus temsirolimus in relapsed or refractory mantle-cell lymphoma. METHODS: This randomised, open-label, multicentre, phase 3 clinical trial enrolled patients with relapsed or refractory mantle-cell lymphoma confirmed by central pathology in 21 countries who had received one or more rituximab-containing treatments. Patients were stratified by previous therapy and simplified mantle-cell lymphoma international prognostic index score, and were randomly assigned with a computer-generated randomisation schedule to receive daily oral ibrutinib 560 mg or intravenous temsirolimus (175 mg on days 1, 8, and 15 of cycle 1; 75 mg on days 1, 8, and 15 of subsequent 21-day cycles). Randomisation was balanced by using randomly permuted blocks. The primary efficacy endpoint was progression-free survival assessed by a masked independent review committee with the primary hypothesis that ibrutinib compared with temsirolimus significantly improves progression-free survival. The analysis followed the intention-to-treat principle. The trial is ongoing and is registered with ClinicalTrials.gov (number NCT01646021) and with the EU Clinical Trials Register, EudraCT (number 2012-000601-74). FINDINGS: Between Dec 10, 2012, and Nov 26, 2013, 280 patients were randomised to ibrutinib (n=139) or temsirolimus (n=141). Primary efficacy analysis showed significant improvement in progression-free survival (p<0·0001) for patients treated with ibrutinib versus temsirolimus (hazard ratio 0·43 [95% CI 0·32-0·58]; median progression-free survival 14·6 months [95% CI 10·4-not estimable] vs 6·2 months [4·2-7·9], respectively). Ibrutinib was better tolerated than temsirolimus, with grade 3 or higher treatment-emergent adverse events reported for 94 (68%) versus 121 (87%) patients, and fewer discontinuations of study medication due to adverse events for ibrutinib versus temsirolimus (9 [6%] vs 36 [26%]). INTERPRETATION: Ibrutinib treatment resulted in significant improvement in progression-free survival and better tolerability versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma. These data lend further support to the positive benefit-risk ratio for ibrutinib in relapsed or refractory mantle-cell lymphoma. FUNDING: Janssen Research & Development, LLC.

Frontline rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib (VR-CAP) or vincristine (R-CHOP) for non-GCB DLBCL.

This phase 2 study evaluated whether substituting bortezomib for vincristine in frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy could improve efficacy in non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB DLBCL), centrally confirmed by immunohistochemistry (Hans method). In total, 164 patients were randomized 1:1 to receive six 21-day cycles of rituximab 375 mg/m(2), cyclophosphamide 750 mg/m(2), and doxorubicin 50 mg/m(2), all IV day 1, prednisone 100 mg/m(2) orally days 1-5, plus either bortezomib 1.3 mg/m(2) IV days 1, 4, 8, 11 (rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib [VR-CAP]; n = 84) or vincristine 1.4 mg/m(2) (maximum 2 mg) IV day 1 (R-CHOP; n = 80). There were no significant differences between VR-CAP and R-CHOP in complete response rate (64.5%, 66.2%; odds ratio [OR], 0.91; P = .80), overall response rate (93.4%, 98.6%; OR, 0.21; P = .11), progression-free survival (hazard ratio [HR], 1.12; P = .76), or overall survival (HR, 0.89; P = .75). Rates of grade ≥3 adverse events (AEs; 88%, 89%), serious AEs (38%, 34%), discontinuations due to AEs (7%, 3%), and deaths due to AEs (2%, 5%) were similar with VR-CAP and R-CHOP. Grade ≥3 peripheral neuropathy rates were 6% and 3%, respectively. VR-CAP did not improve efficacy vs R-CHOP in non-GCB DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT01040871.

Bortezomib, thalidomide and dexamethasone, with or without cyclophosphamide, for patients with previously untreated multiple myeloma: 5-year follow-up.

This follow-up extension of a randomised phase II study assessed differences in long-term outcomes between bortezomib-thalidomide-dexamethasone (VTD) and VTD-cyclophosphamide (VTDC) induction therapy in multiple myeloma. Newly diagnosed patients (n = 98) were randomised 1:1 to intravenous bortezomib (1·3 mg/m(2); days 1, 4, 8, 11), thalidomide (100 mg; days 1-21), and dexamethasone (40 mg; days 1-4, 9-12), with/without cyclophosphamide (400 mg/m(2); days 1, 8), for four 21-day cycles before stem-cell mobilisation/transplantation. After a median follow-up of 64·8 months, median time-to-next therapy was 51·8 and 47·9 months with VTD and VTDC, respectively. Type of subsequent therapy was similar in both arms. After adjusting for asymmetric censoring, median time to progression was not significantly different between VTD and VTDC [35·7 vs. 34·5 months; Hazard ratio (HR) 1·26, 95% confidence interval: 0·76-2·09; P = 0·370]. Five-year survival was 69·1% and 65·3% with VTD and VTDC, respectively. When analysed by minimal residual disease (MRD) status, overall survival was longer in MRD-negative versus MRD-positive patients with bone marrow-confirmed complete response (HR 3·66, P = 0·0318). VTD induction followed by transplantation provides long-term disease control and, consistent with the primary analysis, there is no additional benefit from adding cyclophosphamide. This study was registered at ClinicalTrials.gov (NCT00531453).

Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis.

CAN2007 was a phase 1/2 study of once- and twice-weekly single-agent bortezomib in relapsed primary systemic amyloid light chain amyloidosis (AL) amyloidosis. Seventy patients were treated, including 18 and 34 patients at the maximum planned doses on the once- and twice-weekly schedules. This prespecified final analysis provides mature response and long-term outcomes data after 3-year additional follow-up since the last report. In the once-weekly 1.6 mg/m(2) and twice-weekly 1.3 mg/m(2) bortezomib groups, final hematologic response rates were 68.8% and 66.7%; 80% of patients in each group sustained their response for ≥1 year. One-year progression-free rates were 72.2% and 76.8%. Median overall survival (OS) was 62.1 months and not reached; 4-year OS rates were 75.0% and 63.0%. Low baseline difference in κ/λ free light-chain level was associated with higher hematologic complete response rates and longer OS. At data cutoff, 40 (57%) patients had received subsequent therapy, including 19 (27%) retreated with bortezomib, 11 (58%) of whom achieved complete or partial hematologic responses. Four patients received prolonged bortezomib for between 3.5 and 5.6 years, with no new safety concerns, highlighting the feasibility of long-term therapy. Single-agent bortezomib produced durable hematologic responses and promising long-term OS in relapsed AL amyloidosis. This trial was registered at www.clinicaltrials.gov as #NCT00298766.

Randomized phase II study of bortezomib, thalidomide, and dexamethasone with or without cyclophosphamide as induction therapy in previously untreated multiple myeloma.

PURPOSE: Bortezomib-thalidomide-dexamethasone (VTD) is an effective induction therapy in multiple myeloma (MM). This phase II, noncomparative study sought to determine whether addition of cyclophosphamide to this regimen (VTDC) could further increase efficacy without compromising safety. PATIENTS AND METHODS: Patients age 18 to 70 years with previously untreated, measurable MM, who were eligible for high-dose chemotherapy-autologous stem-cell transplantation (HDCT-ASCT), were randomly assigned to bortezomib 1.3 mg/m(2), thalidomide 100 mg, and dexamethasone 40 mg, with (n = 49) or without (n = 49) cyclophosphamide 400 mg/m(2) for four 21-day cycles, followed by HDCT-ASCT. The primary end point was postinduction combined rate of near-complete response (nCR) or better (including complete response [CR] with normalized serum κ:λ free light chain ratio, CR, and nCR). RESULTS: Postinduction, 51% (VTD) and 44% (VTDC) of patients achieved combined CR/nCR, with bone marrow-confirmed CR in 29% and 31%, overall response rates of 100% and 96%, respectively, and very good partial response or better rates of 69% per arm. Post-HDCT-ASCT, combined CR/nCR rates were 85% (VTD) and 77% (VTDC). In all, 35% (VTD) and 27% (VTDC) of patients were negative for minimal residual disease (MRD) during induction and postinduction. Three-year overall survival was 80% (both arms). Grade 3 to 4 adverse events (AEs) and serious AEs were observed in 47% and 22% (VTD) and 57% and 41% (VTDC) of patients, respectively. The primary health-related quality of life end point (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 [EORTC QLQ-C30] Global Health score) steadily increased with VTD during induction and reached a clinically relevant difference post-transplantation versus baseline. CONCLUSION: Both VTD and VTDC are highly active induction regimens producing high combined CR/nCR and MRD-negative rates; however, VTDC was associated with increased toxicity and suggestion of transient decreases in Global Health score, without an increase in activity.

Bortezomib plus rituximab versus rituximab in patients with high-risk, relapsed, rituximab-naïve or rituximab-sensitive follicular lymphoma: subgroup analysis of a randomized phase 3 trial.

BACKGROUND: The randomized phase 3 LYM3001 trial in relapsed follicular lymphoma (FL) demonstrated higher overall (ORR) and complete response (CR) rates and prolonged progression-free survival (PFS) with bortezomib-rituximab versus rituximab. We report findings in high-risk patients (FL International Prognostic Index [FLIPI] score ≥3, and high tumor burden by modified Groupe d'Etude des Lymphomas Folliculaires [GELF] criteria). METHODS: Patients aged ≥18 years with grade 1/2 FL, ≥1 measurable lesion, and documented relapse or progression following prior therapy, rituximab-naïve or rituximab-sensitive, were enrolled at 164 centers in 29 countries across Europe, the Americas, and Asia-Pacific. Patients were randomized (1:1) to five 5-week cycles of bortezomib-rituximab (bortezomib 1.6 mg/m2, days 1, 8, 15, and 22, all cycles; rituximab 375 mg/m2, days 1, 8, 15, and 22, cycle 1, and day 1, cycles 2-5; N=336) or rituximab alone (N=340). Randomization was stratified by FLIPI score, prior rituximab, time since last dose of anti-lymphoma therapy, and geographical region. The primary endpoint of the study was PFS. RESULTS: 103 bortezomib-rituximab and 98 rituximab patients had high-risk FL. The ORR was 59% versus 37% (p=0.002), the CR/CRu rate was 13% versus 6% (p=0.145), and the durable response rate was 45% versus 26% (p=0.008) with bortezomib-rituximab versus rituximab. Median PFS was 9.5 versus 6.7 months (hazard ratio [HR] 0.667, p=0.012) with bortezomib-rituximab versus rituximab; median time to progression was 10.9 versus 6.8 months (HR 0.656, p=0.009); median time to next anti-lymphoma treatment was 14.8 versus 9.1 months (HR 0.762, p=0.103); and the 1-year Overall Survival rate was 83.1% versus 76.6%. Overall, 51% of bortezomib-rituximab and 32% of rituximab patients reported grade ≥3 adverse events, including neutropenia (18%, 6%), anemia (4%, 5%), diarrhea (8%, 0%), thrombocytopenia (5%, 2%), and sensory neuropathy (1%, 0%). CONCLUSIONS: High-risk FL patients treated with bortezomib-rituximab had significantly higher ORR and longer PFS than patients receiving rituximab alone, with greater clinical benefit than in the overall study population; additional toxicity was acceptable and did not affect treatment feasibility. TRIAL REGISTRATION: The phase 3 LYM3001 trial is registered with ClinicalTrials.gov, with the identifier NCT00312845.

Bortezomib plus rituximab versus rituximab alone in patients with relapsed, rituximab-naive or rituximab-sensitive, follicular lymphoma: a randomised phase 3 trial.

BACKGROUND: Bortezomib and rituximab have shown additive activity in preclinical models of lymphoma, and have been shown to be active and generally well tolerated in a randomised phase 2 study in patients with follicular and marginal zone lymphoma. We compared the efficacy and safety of rituximab alone or combined with bortezomib in patients with relapsed or refractory follicular lymphoma in a phase 3 setting. METHODS: In this multicentre phase 3 trial, rituximab-naive or rituximab-sensitive patients aged 18 years or older with relapsed grade 1 or 2 follicular lymphoma were randomly assigned (1:1) to receive five 35-day cycles consisting of intravenous infusions of rituximab 375 mg/m(2) on days 1, 8, 15, and 22 of cycle 1, and on day 1 of cycles 2-5, either alone or with bortezomib 1·6 mg/m(2), administered by intravenous injection on days 1, 8, 15, and 22 of all cycles. Randomisation was stratified by FLIPI score, previous use of rituximab, time since last therapy, and region. Treatment assignment was based on a computer-generated randomisation schedule prepared by the sponsor. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00312845. FINDINGS: Between April 10, 2006, and Aug 12, 2008, 676 patients were randomised to receive rituximab (n=340) or bortezomib plus rituximab (n=336). After a median follow-up of 33·9 months (IQR 26·4-39·7), median progression-free survival was 11·0 months (95% CI 9·1-12·0) in the rituximab group and 12·8 months (11·5-15·0) in the bortezomib plus rituximab group (hazard ratio 0·82, 95% CI 0·68-0·99; p=0·039). The magnitude of clinical benefit was not as large as the anticipated prespecified improvement of 33% in progression-free survival. Patients in both groups received a median of five treatment cycles (range 1-5); 245 of 339 (72%) and 237 of 334 (71%) patients in the rituximab and bortezomib plus rituximab groups, respectively, completed five cycles. Of patients who did not complete five cycles, most discontinued early because of disease progression (77 [23%] patients in the rituximab group, and 56 [17%] patients in the bortezomib plus rituximab group). Rates of adverse events of grade 3 or higher (70 [21%] of 339 rituximab-treated patients vs 152 [46%] of 334 bortezomib plus rituximab treated patients), and serious adverse events (37 [11%] patients vs 59 [18%] patients) were lower in the rituximab group than in the combination group. The most common adverse events of grade 3 or higher were neutropenia (15 [4%] patients in the rituximab group and 37 [11%] patients in the bortezomib plus rituximab group), infection (15 [4%] patients and 36 [11%] patients, respectively), diarrhoea (no patients and 25 [7%] patients, respectively), herpes zoster (one [<1%] patient and 12 [4%] patients, respectively), nausea or vomiting (two [<1%] patients and 10 [3%] patients, respectively) and thrombocytopenia (two [<1%] patients and 10 [3%] patients, respectively). No individual serious adverse event was reported by more than three patients in the rituximab group; in the bortezomib plus rituximab group, only pneumonia (seven patients [2%]) and pyrexia (six patients [2%]) were reported in more than five patients. In the bortezomib plus rituximab group 57 (17%) of 334 patients had peripheral neuropathy (including sensory, motor, and sensorimotor neuropathy), including nine (3%) with grade 3 or higher, compared with three (1%) of 339 patients in the rituximab group (no events of grade ≥3). No patients in the rituximab group but three (1%) patients in the bortezomib plus rituximab group died of adverse events considered at least possibly related to treatment. INTERPRETATION: Although a regimen of bortezomib plus rituximab is feasible, the improvement in progression-free survival provided by this regimen versus rituximab alone was not as great as expected. The regimen might represent a useful addition to the armamentarium, particularly for some subgroups of patients. FUNDING: Johnson & Johnson Pharmaceutical Research & Development and Millennium Pharmaceuticals, Inc.

Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study.

This first prospective phase 2 study of single-agent bortezomib in relapsed primary systemic AL amyloidosis evaluated the recommended (maximum planned) doses identified in phase 1 testing (1.6 mg/m² once weekly [days 1, 8, 15, and 22; 35-day cycles]; 1.3 mg/m² twice weekly [days 1, 4, 8, and 11; 21-day cycles]). Among all 70 patients enrolled in the study, 44% had ≥ 3 organs involved, including 73% and 56% with renal and cardiac involvement. In the 1.6 mg/m² once-weekly and 1.3 mg/m² twice-weekly groups, the hematologic response rate was 68.8% and 66.7% (37.5% and 24.2% complete responses, respectively); median time to first/best response was 2.1/3.2 and 0.7/1.2 months, and 78.8% and 75.5% had response durations of ≥ 1 year, respectively. One-year hematologic progression-free rates were 72.2% and 74.6%, and 1-year survival rates were 93.8% and 84.0%, respectively. Outcomes appeared similar in patients with cardiac involvement. Among all 70 patients, organ responses included 29% renal and 13% cardiac responses. Rates of grade ≥ 3 toxicities (79% vs 50%) and discontinuations/dose reductions (38%/53% vs 28%/22%) resulting from toxicities appeared higher with 1.3 mg/m² twice-weekly versus 1.6 mg/m² once-weekly dosing. Both bortezomib dose schedules represent active, well-tolerated regimens in relapsed AL amyloidosis. This study was registered at www.clinicaltrials.gov as #NCT00298766.

An open-label, randomized, parallel-group study of perioperative epoetin alfa versus standard of care for blood conservation in major elective spinal surgery: safety analysis.

STUDY DESIGN: Prospective, open-label, randomized, parallel-group study at 80 centers. OBJECTIVE: To demonstrate there is no clinically important additional risk for deep vein thrombosis with perioperative use of epoetin alfa versus standard of care in spine surgery without prophylactic anticoagulation. SUMMARY OF BACKGROUND DATA: Trials of epoetin alfa in orthopedic surgery that demonstrated no additional risk of thrombovascular events included perioperative pharmacologic anticoagulation. METHODS: Subjects received epoetin alfa 600 U/kg subcutaneously once weekly starting 3 weeks before spinal surgery plus standard of care for blood conservation, or standard of care alone. Perioperative anticoagulation therapy was not permitted; mechanical deep vein thrombosis prophylaxis was allowed. Doppler imaging for deep vein thrombosis was done on postoperative day 4 (or day of discharge), or for suspected deep vein thrombosis. Deep vein thrombosis was diagnosed by Doppler result or adverse event report. The criterion for no additional risk of deep vein thrombosis was a 1-sided 97.5% upper confidence limit < or =4% between groups. RESULTS: Of the 680 subjects analyzed (340 in each treatment group), 16 (4.7%) in the epoetin alfa group and 7 (2.1%) in the standard of care group had a diagnosis of deep vein thrombosis either by Doppler or by adverse event report with normal Doppler. The between-group difference was 2.6% (97.5% upper confidence limit, 5.4%). Deep vein thrombosis confirmed by Doppler (4.1% vs. 2.1%), other clinically relevant thrombovascular events (1.5% vs. 0.9%), and all adverse events combined (76.5% vs. 73.2%) occurred with similar frequency in the 2 treatment groups. CONCLUSION: This study documented a higher incidence of deep vein thrombosis and similar rates of other clinically relevant thrombovascular events with epoetin alfa versus standard of care for blood conservation in subjects who did not receive prophylactic anticoagulation before spinal surgery. Antithrombotic prophylaxis should be considered when erythropoietin is used in the surgical setting.

Improved survival of critically ill trauma patients treated with recombinant human erythropoietin.

BACKGROUND: A randomized, double-blind, placebo-controlled, multicenter trial (EPO-2, N = 1,302) in anemic critically ill patients demonstrated a 29-day survival benefit in the trauma subgroup receiving epoetin alfa (mortality 8.9% vs. 4.1%). A second similarly designed trial (EPO-3, N = 1,460) confirmed this survival benefit in the epoetin alfa-treated trauma cohort (mortality 6.7% vs. 3.5%). This analysis presents trauma cohort data from both trials for evaluation of the impact of baseline factors including trauma-specific variables on outcomes. METHODS: Patients received 40,000 U epoetin alfa or placebo weekly, for a total of 4 (EPO-2) or 3 (EPO-3) doses, starting on ICU day 3. Kaplan-Meier survival curves for the two groups were compared using the log-rank test. Univariate and multivariate Cox proportional hazard regression methods were used to evaluate relationship between baseline factors and mortality. RESULTS: Demographic and trauma variables at baseline were comparable. Mortality was consistently reduced by approximately 50% in both studies (EPO-2--day 29 unadjusted HR: 0.46, 95% CI: 0.24-0.89; EPO-3--day 29 unadjusted HR: 0.51, 95% CI: 0.27-0.98.). Adjusting for baseline and trauma variables had minimal effect on hazard ratios for mortality at day 29 (EPO-2--day 29 adjusted HR: 0.50, 95% CI: 0.26-0.97; EPO-3--day 29 adjusted HR: 0.38, 95% CI: 0.19-0.74) and day 140 (EPO-3--adjusted HR: 0.39, 95% CI: 0.21-0.72). In EPO-3, there appeared to be an increase in clinically relevant thrombovascular events in the epoetin alfa treated group (16.4% vs. 12.5%, RR: 1.3, 95% CI: 0.93-1.85) but not in EPO-2 (11.1% vs. 13.3%, RR: 0.84, 95% CI: 0.56-1.28). CONCLUSION: Epoetin alfa demonstrated a survival advantage in both of the critically ill trauma patient cohorts of two prospective, randomized clinical trials, which was not affected by baseline factors including trauma-specific variables. A definitive study in trauma subjects is warranted.

Relationship between hemoglobin level and quality of life in anemic patients with chronic kidney disease receiving epoetin alfa.

OBJECTIVES: To evaluate the relationship between hemoglobin (Hb) level and quality of life (QOL) in anemic patients with non-dialysis chronic kidney disease receiving epoetin alfa. PATIENTS AND METHODS: A post-hoc analysis using data from a multicenter, open-label, prospective study of epoetin alfa for anemia in patients with chronic kidney disease not on dialysis was conducted. The relationship between Hb and QOL was analyzed using correlation and longitudinal analyses, the latter adjusting for sample selection bias. The Linear Analog Scale Assessment (LASA) and the Kidney Disease Questionnaire (KDQ) subscales were used to measure QOL. The impact of an incremental 1 g/dL increase in Hb level on LASA and KDQ scores was determined using an incremental analysis. RESULTS: A total of 1183 and 1044 patients formed the study populations for the LASA and KDQ analyses, respectively. There was a positive and significant relationship between Hb levels and QOL (p < 0.05). Using non-linear regression analysis, we characterized the sigmoid-shape of the relationship between Hb levels and QOL scores. Hemoglobin change was a statistically significant determinant of QOL improvement for both LASA and KDQ scales (p < 0.05). The model predicted that, based on a 2 unit change in Hb, the greatest incremental QOL improvement per unit of Hb increase occurred when Hb was in the range of 11 to 12 g/dL. CONCLUSIONS: This study demonstrates that, beyond the well-known relationship between Hb increases and QOL improvements, the maximal incremental gain in QOL occurred when Hb reached 11 to 12 g/dL. This suggests that treating anemic patients with non-dialysis chronic kidney disease until their Hb level reaches 12 g/dL will result in the greatest QOL improvement per Hb unit increase. The analyses were conducted based on an open-label study of epoetin alfa and could be further validated using a randomized, controlled trial, comparing incremental gains in QOL associated with treatment initiation at varying levels of Hb across arms.

Efficacy of recombinant human erythropoietin in critically ill patients admitted to a long-term acute care facility: a randomized, double-blind, placebo-controlled trial.

CONTEXT: Anemia is common in the critically ill and results in a large number of red blood cell transfusions. Recent data have shown that red blood cell transfusions in critically ill patients can be decreased with recombinant human erythropoietin (rHuEPO) therapy during their intensive care unit stay. OBJECTIVE: To assess the efficacy of rHuEPO therapy in decreasing the occurrence of red blood cell transfusions in patients admitted to a long-term acute care facility (LTAC). DESIGN: A prospective, randomized, double-blind, placebo-controlled, multiple-center trial. SETTING: Two long-term acute care facilities. PATIENTS: A total of 86 patients who met eligibility criteria were enrolled in the study with 42 randomized to rHuEPO and 44 to placebo. INTERVENTIONS: Study drug (rHuEPO 40,000 units) or a placebo was administered by subcutaneous injection before day 7 of long-term acute care facility admission and continued weekly for up to 12 doses. MAIN OUTCOME MEASURES: The primary efficacy end point was cumulative red blood cell units transfused. Secondary efficacy end points were the percent of patients receiving any red blood cell transfusion; the percent of patients alive and transfusion independent; cumulative mortality; and change in hematologic variables from baseline. Logistic regression was used to adjust the odds ratio for red blood cell transfusion. All end points were assessed at both study day 42 and study day 84. RESULTS: The baseline hemoglobin level was higher in the rHuEPO group (9.9 +/- 1.15 g/dL vs. 9.3 +/- 1.41 g/dL, p = .02) as was the pretransfusion hemoglobin level (8.0 +/- 0.5 g/dL vs. 7.5 +/- 0.8 g/dL, p = .04). At day 84, patients receiving rHuEPO received fewer red blood cell transfusions (median units per patient 0 vs. 2, p = .05), and the ratio of red blood cell transfusion rates per day alive was 0.61 with 95% confidence interval of 0.2, 1.01, indicating a 39% relative reduction in transfusion burden for the rHuEPO group compared with placebo. There was also a trend at day 84 toward a reduction in the total units of red blood cells transfused in the rHuEPO group (113 units of placebo vs. 73 units of rHuEPO). Patients receiving rHuEPO were also less likely to be transfused (64% placebo vs. 41% rHuEPO, p = .05; adjusted odds ratio 0.47, 95% confidence interval 0.19, 1.16). Most of the transfusion benefit of rHuEPO occurred by study day 42. Increase in hemoglobin from baseline to final was greater in the rHuEPO group (1.0 +/- 2 g/dL vs. 0.4 +/- 1.7 g/dL, p < .001). Mortality rate (19% rHuEPO, 29.5% placebo, p = .17; relative risk, 0.55, 95% confidence interval 0.21-1.43) and serious adverse clinical events (38 % rHuEPO, 32% placebo, p = .65) were not significantly different between the two groups. CONCLUSIONS: In patients admitted to a long-term acute care facility, administration of weekly rHuEPO results in a significant reduction in exposure to allogeneic red blood cell transfusion during the initial 42 days of rHuEPO therapy, with little additional benefit achieved with therapy to 84 days. Despite receiving fewer red blood cell transfusions, patients treated with rHuEPO achieve a higher hemoglobin level.