Efficacy of diclofenac in the prevention of post-ERCP pancreatitis in predominantly high-risk patients: a randomized double-blind prospective trial

Abstract Introduction The order of alternative donor selection for hematopoietic stem cell transplantation (HSCT) for patients with hematologic malignancies has not been addressed. We performed the first prospective trial to compare the effect of HSCT from matched sibling donors (MSDs), unrelated donors (URDs) and haploidentical- related donors (HRDs) in a contemporary protocol. Methods From 2008 to 2012, 234 patients with hematologic malignancies were enrolled. The treatment schedule was as follows: if a fully MSD was available, patients were assigned treatment with MSD-HSCT. If an MSD was unavailable, a suitably matched URD was used as the alternative, where a suitable match involved matching more than 8 of 10 HLA-A, -B, -C, -DRB1and DQ allele loci ( ¡Ý 8/10) and at least 5 of 6 matching HLA-A, -B, and -DRB1 antigen loci. If only URDs with > 2 mismatching allele loci were available, patients were allowed treatment with HRD-HSCT. Results (1) Sixty-eight patients underwent MSD-HSCT, 98 patients underwent URD-HSCT, and 68 patients underwent HRD-HSCT (Table 1). (2) Grades II¨CIV and severe aGVHD were all significantly more frequent in patients undergoing HRD-HSCT compared with those undergoing MSD-HSCT (II¨CIV: 42.6% vs 19.1%, P = 0.0015; severe aGVHD: 17.65% vs 5.88%, P = 0.03). However, the incidences of II¨CIV and severe aGVHD were comparable in patients receiving transplants from HRDs to those from URDs (II¨CIV: 42.6% vs 40.8%, P = 0.89; severe aGVHD: 17.65% vs 13.27%, P = 0.48). The incidence of cGVHD was not significantly affected by donor types. (3) The 4-year incidence of relapse was not significantly affected by donor types according to all patients (24.2% in the MSD cohort, 22.8% in the URD cohort, 11.9% in the HRD cohort, P > 0.05). However, after controlling for high-risk patients, a superior graft-versus-leukemia (GVL) effect was observed in patients undergoing HRD-HSCT compared to MSD-HSCT or URD-HSCT. In high-risk patients receiving MSD, 36.8% experienced relapse, as did 33.6% in the URD cohort, but the incidence decreased to11.1% in the HRD cohort (MSD vs HRD, P = 0.015; URD vs HRD, P = 0 .028). (4) HRD-HSCT yielded comparable rates of 4-year overall survival (OS) and disease-free survival (DFS) to MSD-HSCT ( OS: 66.4% vs 79.5%, P = 0.071; DFS: 66.4% vs 78.2 %, P = 0.109) or URD-HSCT (OS: 66.4% vs 59%, P = 0.952; DFS: 66.4% vs 58.1%, P = 0.864) (Figure 1). Conclusion Our data provide convincing clinical evidence to support the use of HRDs, as well as URDs, can be selected as first-line alternative donors, especially for high-risk patients. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

ARISER: A randomized double blind phase III study to evaluate adjuvant cG250 treatment versus placebo in patients with high-risk ccRCC—Results and implications for adjuvant clinical trials.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.4507 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 4507-4507 ◽

Cited By ~ 26

Author(s):

Arie S. Belldegrun ◽

Karim Chamie ◽

Pia Kloepfer ◽

Barbara Fall ◽

Paul Bevan ◽

...

Keyword(s):

High Risk ◽

Antigen Expression ◽

Phase Iii ◽

Double Blind ◽

Significant Treatment ◽

High Risk Patients ◽

Phase Ii Studies ◽

Caix Expression ◽

Risk Patients ◽

Phase Iii Study

4507^ Background: cG250 (Rencarex) is a chimeric monoclonal antibody that binds to the CAIX cell-surface antigen present on 95% of ccRCC. Its safety and activity in phase II studies provided the rationale to investigate its use as an adjuvant monotherapy in subjects with clinically localized high-risk ccRCC—50% of whom progress to metastatic disease. Methods: We performed an international, prospective, multicenter, phase III trial of the efficacy and safety of adjuvant cG250 vs placebo (randomized 1:1) by assessing disease-free (DFS) and overall survival (OS) in 864 RCC patients after nephrectomy. Inclusion criteria were: 1) T3/T4 N0/M0; 2) any T stage and N+/M0; or 3) T1b/T2 N0/M0 high-grade ccRCC. Treatment consisted of a 50 mg loading dose followed by 23-weekly infusions of 20 mg. DFS and CAIX antigen expression were quantified by an independent radiological review and a central pathologist. CAIX score was derived by multiplying the intensity of staining (1–3) by the fraction of positive of cells (0–1), yielding a range of 0.0–3.0. Results: Baseline demographics were well balanced across groups. Treatment demonstrated an excellent safety profile. There were 360 confirmed recurrences and 181 deaths during follow up. When compared with the placebo group, cG250-treated subjects did not enjoy a statistically significant DFS (HR=0.99, p=0.74) or OS advantage (HR=1.01, p=0.94). Median DFS and OS were over 6 years and never reached irrespective of treatment, respectively. However, on subset analysis, subjects with high CAIX expression (>2.0) who received cG250 experienced a statistically significant treatment effect with improved DFS (HR=0.55; p=0.01). Conclusions: While cG250 appears not to have clinical benefit in the adjuvant treatment for all high-risk patients, cG250-treated patients with a high CAIX score appeared to have a significantly improved DFS. The CAIX score may help in stratifying patients who may benefit from cG250 adjuvant therapy. Notwithstanding this benefit, the surprising median DFS of over 6 years and outstanding OS in high-risk patients represent a significant challenge to adjuvant ccRCC drug development. Clinical trial information: NCT00087022.

Download Full-text