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.)

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.

1162 Introduction: Since the advent of plasma exchange, mortality from thrombotic thrombocytopenic purpura (TTP) has gone from approximately 90% to less than 20%. However, due to thrombocytopenia, placement of a central venous catheter for plasma exchange can cause concern on the part of the proceduralist. Traditional teaching has been that platelet transfusion is contraindicated in TTP unless there is severe bleeding. However, a more recent review shows that the evidence for harm from platelet transfusion is uncertain. Due to the risk of bleeding, proceduralists often ask for platelet transfusion before catheter insertion. We conducted a review in our institution of bleeding episodes after cathether insertion in patients with suspected TTP. Methods: A single institution retrospective review was performed at SUNY Upstate Medical University on patients with presumed TTP from January 1999 until July of 2011. Patients were identified using both pheresis records and diagnosis codes of admitted patients in order to ensure that patients with catastrophic bleeding episodes prior to plasma exchange were not omitted. Each event was defined as placement of a pheresis catheter in a patient who presented with presumed TTP. Data was collected on patient age, platelet count prior to line insertion, the service performing the insertion, use of image guidance, bleeding complications, and survival. Results: There were 55 patients with a total of 57 catheter insertion attempts in thrombocytopenic patients with presumed TTP. One patient had an unsuccessful insertion attempt and another had catheter malfunction; both required a second insertion attempt while thrombocytopenic. Overall there were no major bleeding complications and no bleeding that required invasive intervention or removal of the catheter. There were 3 episodes of bleeding that resolved with pressure. Otherwise, there was minor bleeding that did not require any intervention documented in 14 cases. These included oozing, saturation of dressing, and 6 hematomas which did not require treatment. There was a single unsuccessful attempt at blind catheter placement which resulted in a hematoma. The median platelet count on catheter insertion was 26K with a range from 3K to 128K. Platelet transfusion was given prior to catheter placement in 14 of the episodes. The median platelet count in this population was 12K before transfusion. 5 of these 14 patients had minor bleeding complications (35%). In the 43 attempts in patients who did not receive platelet transfusion prior to line insertion, the median platelet count was 25K. 12 of these patients had minor bleeding (28%). All 3 patients with minor bleeding which required noninvasive intervention were in this group. Of the 57 attempts at line insertion, 32 were in the femoral vein, 23 in the internal jugular vein and 2 in the subclavian vein. Image guidance was used in 25 of the 57 attempts. Of the bleeding episodes that required noninvasive intervention, 2 occurred after blind placement of the catheter and 1 was after image guidance was used. Of the 55 patients treated for presumed TTP, 8 died during admission (15%). Mortality in the group of patients receiving platelet transfusion prior to catheter placement was 43% versus 5% in the patients without platelet transfusion beforehand. When adjusted for 4 patients with other causes for their thrombotic microangiopathy, the mortality in the transfused group was 40%. In general, patients receiving platelet transfusion prior to catheter insertion seemed more acutely ill, including 1 patient with HIV and pancreatitis, 1 patient with HIV, and 1 patient with pancreatitis alone. Conclusion: In this single institution retrospective review 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 is reasonable to forgo prophylactic platelet transfusion prior to catheter placement. Disclosures: No relevant conflicts of interest to declare.

Introduction Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening condition, characterized by thrombotic microangiopathy (TMA) that results in microangiopathic hemolytic anemia (MAHA), thrombocytopenia and clinical symptoms including altered mental status, renal impairment and fever. Diagnosing TTP in acute setting continues to be a challenge, since the clinical pentad is not consistently present in TTP, making it difficult to differentiate from other conditions with TMA. The initial clinical decision for plasma exchange (PEX) is supported if there are MAHA and thrombocytopenia without a clear alternative cause. Acquired autoimmune deficiency of ADAMTS13 is known to cause idiopathic TTP and forms a basis for success of PEX in many patients by replenishing ADAMTS13 in addition to immunosuppressive therapy. However, low levels of ADAMTS13 alone are known to be neither sufficiently sensitive nor specific for diagnosis of TTP in acute setting. The aims of this retrospective study were to evaluate: (i) the utilization of ADAMTS13 testing in suspected TTP; (ii) the utilization of PEX in patients with TTP diagnosis; (iii) the association of low ADAMTS13 activity with early mortality in TTP; and (iv) the incidence of ADAMTS13 deficiency in non-TTP diagnoses. Methods After IRB approval, we identified 49 adult patients at a single tertiary medical center, who had ADAMTS13 testing between 2005 and June 2013 for suspected TTP. We searched the final diagnosis, either TTP or non-TTP. The results of ADAMTS13 testing and use of PEX were reviewed in the TTP and non-TTP patients. We identified the final diagnosis of the non-TTP patients. We assessed association of severely low ADAMTS13 activity (<10%) with early mortality defined as death within 3 months of diagnosis in patients with TTP diagnosis. Results Of the 49 patients who had ADAMTS13 testing 18 (37%) were male. The median age was 51years (range 20-81). All patients with TTP had PEX except one who could not initiate PEX due to early death. Twenty-five of the 30 patients (83%) with TTP had low ADAMTS13 activity and 17 of the 30 patients (57%) had severe deficiency (<10%). Five of the 30 patients with TTP suffered early mortality. The relative risk of death among TTP patients with severely low ADAMTS13 activity (<10%) was 1.15 (95% CI 0.22-5.90) compared to TTP patients with low to normal ADAMTS13 activity. Nineteen of the 49 patients who had ADAMTS13 testing subsequently had non-TTP diagnosis. Eight of these 19 patients with non-TTP diagnoses were found to have low ADAMTS13 activity: two patients with DIC secondary to sepsis; two patients with thrombocytopenia associated with primary presentation of hemophagocytic lymphohistiocytosis (HLH); one patient each with malignancy associated with TMA, vasculitis due to autoimmune disease, hematopoietic stem cell transplantation associated TMA and sepsis with renal failure; None of the eight patients with non-TTP diagnosis had severe deficiency. Four patients with non-TTP diagnosis underwent PEX and all had normal ADAMTS13 activity. Three of the 4 patients were subsequently diagnosed with drug induced TMA after oral opioid injection and one with hemolytic uremic syndrome. Conclusions Patients with a strong suspicion of TTP should be treated with PEX. ADAMTS13 activity is found to be relatively specific for TTP, being supportive of the clinical diagnosis in majority of cases. There was no statistically significant correlation between death and severely low ADAMTS13 activity in the cohort of TTP patients studied. ADAMTS13 activity can be low in a variety of non-TTP conditions. Its utility in diagnosis and prognosis of non-TTP conditions, especially HLH, needs further evaluation. Disclosures: No relevant conflicts of interest to declare.

6572 Background: Optimal treatment of older adults with AML remains challenging. While AML tends to be a disease of older adults, this population experiences greater treatment-related toxicity and worse overall survival than younger patients. Only fit older adults enter clinical trials and thus the results may not apply to the entire population. Methods: We conducted a retrospective analysis of patients > 60 years with AML (APL excluded) diagnosed prior to 2008 with IRB approval. The association of clinical factors (age, sex, comorbidities, prior chemotherapy), leukemia (prior myelodysplastic syndrome or myeloproliferative neoplasm, cytogenetics, WBC count), and therapy (induction chemotherapy, palliative chemotherapy, and best supportive care) as they relate to overall survival was evaluated using bivariate and multivariate regression analyses. Results: Of 87 patients (median age 73), 45% were male, 58% had high risk cytogenetics, 38% had prior MDS/MPD, 92% were chemotherapy naive, and 21% were in the high/very high Charlson risk class. The majority (67%) received standard dose induction chemotherapy (IC), 9% received (palliative intent) low-dose chemotherapy (LDC), and 24% received best supportive care (BSC). The median overall survival (OS) of the entire cohort was 2.5 months. On bivariate analysis high WBC (>50,000 at presentation) was negatively associated (1.0 vs 2.7 months p <0.01) with survival. OS for IC, LDC, and BSC were 3.1, 2.8, and 0.7 months, respectively (p=0.001). On multivariable analysis, IC conferred longer survival when compared to LDC and BSC combined (OR 0.33 CI 0.2-0.6, p<0.001). High WBC was associated with a decreased survival time (OR 2.96 CI 1.6-5.5, p=0.02). Mortality during induction or consolidation chemotherapy was 38%. At 5-year follow-up, only 4 patients were alive. Conclusions: In a non-clinical trial setting, OS of older adults with AML remains dismal. While IC offers a chance of longer survival, mortality with IC is unacceptably high. Further studies are required to identify and validate tools for risk stratification in older adults with AML as well as to utilize therapies with an improved toxicity profile.