PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.

BACKGROUND: Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade. METHODS: We conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti-programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair-deficient colorectal cancers, patients with mismatch repair-proficient colorectal cancers, and patients with mismatch repair-deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate. RESULTS: The immune-related objective response rate and immune-related progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair-deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair-proficient colorectal cancers. The median progression-free survival and overall survival were not reached in the cohort with mismatch repair-deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with mismatch repair-proficient colorectal cancer (hazard ratio for disease progression or death, 0.10 [P<0.001], and hazard ratio for death, 0.22 [P=0.05]). Patients with mismatch repair-deficient noncolorectal cancer had responses similar to those of patients with mismatch repair-deficient colorectal cancer (immune-related objective response rate, 71% [5 of 7 patients]; immune-related progression-free survival rate, 67% [4 of 6 patients]). Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor in mismatch repair-deficient tumors, as compared with 73 in mismatch repair-proficient tumors (P=0.007), and high somatic mutation loads were associated with prolonged progression-free survival (P=0.02). CONCLUSIONS: This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab. (Funded by Johns Hopkins University and others; ClinicalTrials.gov number, NCT01876511.).

Platelet transfusions and bleeding complications associated with plasma exchange catheter placement in patients with presumed thrombotic thrombocytopenic purpura.

INTRODUCTION: Bleeding risk because of thrombocytopenia in patients with thrombotic thrombocytopenic purpura (TTP) often causes concern during placement of the central venous catheter for plasma exchange. This perceived risk of bleeding often triggers prophylactic platelet transfusion; however, the risk of platelet transfusion is unknown. METHODS: Single institution review of bleeding episodes after catheter insertion in patients with suspected TTP. RESULTS: Fifty-five thrombocytopenic patients with presumed TTP underwent a total of 57 catheter insertion attempts. There were no major bleeding complications and no bleeding that required invasive intervention. Fourteen patients with a median platelet count of 12,000/µL were transfused with platelets prior to catheter placement. Five (35%) of the transfused patients had minor bleeding complications that did not require intervention. In the nontransfused group, 12 (28%) patients had minor bleeding that did not require invasive intervention and three patients experienced bleeding episodes that resolved after applying direct pressure. Eight (15%) patients died during admission. Mortality in the transfused group was 43% versus 5% in the nontransfused group. In general, patients receiving platelet transfusion prior to catheter insertion were more acutely ill. CONCLUSION: There were no major bleeding complications associated with plasma exchange catheter insertion in thrombocytopenic patients with presumed TTP. In light of the uncertain risk of platelet transfusion in patients with TTP, it may be reasonable to forgo prophylactic platelet transfusion prior to catheter placement.