Similar Risks for Chronic Kidney Disease in Long-Term Survivors of Myeloablative and Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation

AbstractChronic kidney disease (CKD) in recipients of myeloablative (MA) allogeneic hematopoietic cell transplantation (HCT) has been well characterized. However, the risk of CKD after HCT using reduced-intensity conditioning (RIC) is not well known. We compared the incidence of CKD by conditioning regimen in 221 allogeneic HCT recipients (MA = 117, RIC = 104) who had survived for ≥1 year post-HCT and had no history of CKD pretransplant. CKD was defined as glomerular filtration rate (GFR) <60 mL/min/1.73 m2 for ≥3 months anytime after 180 days post-HCT. The median follow-up was 28 months (range: 12-75) for MA and 25 months (range: 12-67) for the RIC group. The 3-year cumulative incidence rate of CKD was 28% (95% confidence intervals [CI], 19%-36%) in MA and 29% (95% CI, 20%-38%) in the RIC group (P = .44). In multivariate analysis, conditioning regimen intensity had no impact on the risk of developing CKD (relative risk [RR] for MA 1.50 [95% CI, 0.78-2.89] versus the RIC regimen). Factors independently associated with an increased risk of CKD were older age at transplant, acute graft-versus-host disease, cyclosporine use for >6 months, and acute kidney injury in the early posttransplant period. CKD is frequent in long-term adult allogeneic HCT survivors, but RIC is associated with similar risks as MA conditioning. Continuous monitoring of renal function is necessary in allogeneic HCT survivors, and studies exploring prevention strategies are needed

A Randomized, Double-Blinded, Phase II Trial of Gemcitabine and Nab-Paclitaxel Plus Apatorsen or Placebo in Patients with Metastatic Pancreatic Cancer: The RAINIER Trial.

Lessons learnedThe addition of the heat shock protein 27 (Hsp27)-targeting antisense oligonucleotide, apatorsen, to a standard first-line chemotherapy regimen did not result in improved survival in unselected patients with metastatic pancreatic cancer.Findings from this trial hint at the possible prognostic and predictive value of serum Hsp27 that may warrant further investigation.BackgroundThis randomized, double-blinded, phase II trial evaluated the efficacy of gemcitabine/nab-paclitaxel plus either apatorsen, an antisense oligonucleotide targeting heat shock protein 27 (Hsp27) mRNA, or placebo in patients with metastatic pancreatic cancer.MethodsPatients were randomized 1:1 to Arm A (gemcitabine/nab-paclitaxel plus apatorsen) or Arm B (gemcitabine/nab-paclitaxel plus placebo). Treatment was administered in 28-day cycles, with restaging every 2 cycles, until progression or intolerable toxicity. Serum Hsp27 levels were analyzed at baseline and on treatment. The primary endpoint was overall survival (OS).ResultsOne hundred thirty-two patients were enrolled, 66 per arm. Cytopenias and fatigue were the most frequent grade 3/4 treatment-related adverse events for both arms. Median progression-free survival (PFS) and OS were 2.7 and 5.3 months, respectively, for arm A, and 3.8 and 6.9 months, respectively, for arm B. Objective response rate was 18% for both arms. Patients with high serum level of Hsp27 represented a poor-prognosis subgroup who may have derived modest benefit from addition of apatorsen.ConclusionAddition of apatorsen to chemotherapy does not improve outcomes in unselected patients with metastatic pancreatic cancer in the first-line setting, although a trend toward prolonged PFS and OS in patients with high baseline serum Hsp27 suggests this therapy may warrant further evaluation in this subgroup

Does the Hematopoietic Cell Transplantation Specific Comorbidity Index Predict Transplant Outcomes? A Validation Study in a Large Cohort of Umbilical Cord Blood and Matched Related Donor Transplants

AbstractThe hematopoietic cell transplantation specific comorbidity index (HCT-CI) has been recently proposed to predict the probability of nonrelapse mortality (NRM) and overall survival (OS) in allogeneic HCT recipients while taking into account any pretransplant comorbidity. We tested the validity of the HCT-CI in a cohort of 373 adult HCT recipients (184 matched-related donor and 189 unrelated umbilical cord blood) who received a myeloablative (N = 150) or nonmyeloablative (N = 223) conditioning regimen. HCT-CI scores of 0, 1, 2, and ≥3 were present in 58 (16%), 56 (15%), 64 (17%), and 195 (52%) patients, respectively. Pulmonary conditions were the most common comorbidity. Cumulative incidence of NRM at 2 years was 10%, 20%, 24%, and 28% for HCT-CI scores of 0, 1, 2, and ≥3, respectively (P = .01). The corresponding probability of OS at 2 years was 72%, 67%, 51%, and 48%, respectively (P < .01). On multivariate analyses adjusted for recipient age, disease risk, donor source, and conditioning regimen intensity, the relative risks for NRM for HCT-CI scores of 1, 2, and ≥3 (compared to a score of 0) were 2.0 (95% confidence intervals, 0.8–5.3), 2.6 (1.0–6.7), and 3.2 (1.4-7.4), respectively. The risks for overall mortality were 1.2 (0.6-2.1), 2.0 (1.1-3.4), and 2.1 (1.3-3.3), respectively. In subgroup analyses, the HCT-CI score did not consistently predict NRM and OS among different donor sources and conditioning regimens. The HCT-CI, although a useful tool for capturing pretransplant comorbidity and risk-assessment, needs to be further validated prior to adopting it for routine clinical use

The Relationship between Weekend Admissions and Outcome in Older Adults with Acute Myelogenous Leukemia (AML)

Abstract Patients with serious medical conditions admitted to the hospital on the weekend have higher in-hospital mortality rates compared to those admitted on weekdays (Bell et al, NEJM2001;345:663–668). It is a common perception that patients with AML are hospitalized on Friday or on the weekend. It is unknown whether weekend vs. weekday admission for AML correlates with outcome, as delay in treatment or delay in obtainment of procedures (such as central venous line (CVL) placement) requisite for anthracycline delivery may occur for weekend admissions. We retrospectively studied 118 older adults (age ≥55 years) diagnosed with AML and treated with anthracycline-based remission induction therapy from 1994 to 2002 at the Cleveland Clinic Foundation. Patients’ demographics, baseline hematologic parameters, cytogenetic risk groups (based on CALGB 8461), response to chemotherapy, and survival information were recorded. Weekends were defined as admission to the hospital on Friday, Saturday, or Sunday. Survival and in-hospital mortality were compared between weekend and weekday groups, controlling for known adverse prognostic factors, using Cox proportional hazards analysis for overall survival. Patient characteristics were typical of other studies in older adults with AML: the median age was 69 years (range 55–81); 54.2% were male, and 37 patients (31.6%) had secondary AML. The median baseline white blood cell count was 10.2 x 103/uL. Cytogenetics were available for 104 patients (88.1%): 4 (3.8%) had favorable, 63 (60.6%) had intermediate, and 37 (35.6%) had unfavorable cytogenetics. Baseline values of these known prognostic factors were similar for weekend and weekday admission groups, reflecting similar disease severity. A total of 88 patients (74.6%) were admitted on weekdays, 30 (25.4%) on weekends. Fifty-nine patients (50.4%) achieved a complete remission and 22 patients (18.6%) died during their hospitalization. Only 16.9% of patients were admitted on Friday, while another 8.4% were admitted on Saturday or Sunday. While weekend admission did predict for a delay in CVL placement of 1 day and delay in chemotherapy start of 1 day, this was not associated with increased in-hospital mortality or with a difference in overall survival (Hazard ratio for weekend vs. weekday admission, 0.97, P=0.90 and 1.10, P=0.72, respectively). Results were similar in univariate and multivariable analyses. Weekday Admits Weekend Admits P-Value N=88 N=30 Days to CVL [Median (Range)] 2 (0–11) 3 (0–17) 0.008 Days to Chemotherapy [Median (Range)] 2 (0–32) 3 (0–18) 0.20 In-hospital Mortality [N(%)] 18 (20.4) 4 (13.3) 0.39 In conclusion, in-hospital mortality rates and overall survival are similar for older AML patients receiving remission induction chemotherapy who are admitted on weekends and weekdays, and patients do not appear to be preferentially admitted on Fridays or the weekend, contrary to common beliefs. This similarity in outcome likely reflects staff awareness in tertiary referral centers of the urgency of treatment in AML, thus ameliorating the technical difficulties that may arise when patients are admitted over the weekend

A Randomized, Double-Blinded, Phase II Trial of Gemcitabine and Nab-Paclitaxel Plus Apatorsen or Placebo in Patients with Metastatic Pancreatic Cancer: The RAINIER Trial.

Lessons learnedThe addition of the heat shock protein 27 (Hsp27)-targeting antisense oligonucleotide, apatorsen, to a standard first-line chemotherapy regimen did not result in improved survival in unselected patients with metastatic pancreatic cancer.Findings from this trial hint at the possible prognostic and predictive value of serum Hsp27 that may warrant further investigation.BackgroundThis randomized, double-blinded, phase II trial evaluated the efficacy of gemcitabine/nab-paclitaxel plus either apatorsen, an antisense oligonucleotide targeting heat shock protein 27 (Hsp27) mRNA, or placebo in patients with metastatic pancreatic cancer.MethodsPatients were randomized 1:1 to Arm A (gemcitabine/nab-paclitaxel plus apatorsen) or Arm B (gemcitabine/nab-paclitaxel plus placebo). Treatment was administered in 28-day cycles, with restaging every 2 cycles, until progression or intolerable toxicity. Serum Hsp27 levels were analyzed at baseline and on treatment. The primary endpoint was overall survival (OS).ResultsOne hundred thirty-two patients were enrolled, 66 per arm. Cytopenias and fatigue were the most frequent grade 3/4 treatment-related adverse events for both arms. Median progression-free survival (PFS) and OS were 2.7 and 5.3 months, respectively, for arm A, and 3.8 and 6.9 months, respectively, for arm B. Objective response rate was 18% for both arms. Patients with high serum level of Hsp27 represented a poor-prognosis subgroup who may have derived modest benefit from addition of apatorsen.ConclusionAddition of apatorsen to chemotherapy does not improve outcomes in unselected patients with metastatic pancreatic cancer in the first-line setting, although a trend toward prolonged PFS and OS in patients with high baseline serum Hsp27 suggests this therapy may warrant further evaluation in this subgroup