Phase II study of idelalisib, a selective inhibitor of PI3Kδ, for relapsed/refractory classical Hodgkin lymphoma.

BACKGROUND: The phosphatidylinositol-3-kinase delta (PI3Kδ) inhibitor idelalisib has been shown to block downstream intracellular signaling, reduce the production of prosurvival chemokines and induce apoptosis in classical Hodgkin lymphoma (HL) cell lines. It has also been shown to inhibit regulatory T cells and myeloid-derived suppressor cells in other tumor models. We hypothesized that inhibiting PI3Kδ would have both direct and indirect antitumor effects by directly targeting the malignant cells as well as modulating the inflammatory microenvironment. We tested this hypothesis in a phase II study. PATIENTS AND METHODS: We enrolled 25 patients with relapsed/refractory HL with a median age of 42 years and who had previously received a median of five therapies including 18 (72%) with failed autologous stem cell transplant, 23 (92%) with failed brentuximab vedotin, and 11 (44%) with prior radiation therapy. Idelalisib was administered at 150 mg two times daily; an increase to 300 mg two times daily was permitted at the time of disease progression. RESULTS: The overall response rate to idelalisib therapy was 20% (95% confidence interval: 6.8%, 40.7%) with a median time to response of 2.0 months. Seventeen patients (68%) experienced reduction in target lesions with one complete remission and four partial remissions. The median duration of response was 8.4 months and median progression-free survival was 2.3 months. The most common grade ≥3 adverse event was elevation of alanine aminotransferase (two patients, 8%). Diarrhea/colitis was seen in three patients and was grade 1-2. There was one adverse event leading to death (hypoxia). CONCLUSIONS: Idelalisib was tolerable and had modest single-agent activity in heavily pretreated patients with HL. Rational combinations with other novel agents may improve response rate and duration of response. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov # NCT01393106.

Maintenance rituximab after autologous stem cell transplantation in patients with mantle cell lymphoma.

BACKGROUND: High-dose therapy and autologous stem cell transplantation (ASCT) improves outcomes for patients with mantle cell lymphoma (MCL), but relapse ultimately occurs in most patients. Recently presented interim results from a phase III prospective trial suggest maintenance rituximab (MR) after ASCT for MCL improves progression-free survival (PFS). The maturation of these data and any benefit of MR on overall survival (OS) remain to be defined. PATIENTS AND METHODS: In this retrospective study, we examined a cohort of consecutive patients with MCL that underwent ASCT for MCL at our center and evaluated their outcomes according to whether they received MR after ASCT (n = 50) or did not (n = 107). MR was treated as a time-dependent covariate to account for variation in timing of its initiation. RESULTS: MR was associated with an improved PFS [hazard ratio (HR) 0.44; confidence interval (CI) (0.24-0.80), P = 0.007] and overall survival (OS; HR 0.46; CI 0.23-0.93, P = 0.03) following a multivariate adjustment for confounding factors with a median follow-up of ∼5 years. Grade 4 neutropenia was increased (34% versus 18%, P = 0.04) in the MR group, but no effect on the rate of mortality unrelated to relapse was observed. CONCLUSIONS: These data support that MR after ASCT for MCL confers a benefit in PFS and additionally suggest it may improve OS. General application of this strategy will require confirmation of benefit in prospective randomized trials.

Increased baseline levels of platelet P-selectin, and platelet-endothelial cell adhesion molecule-1 in patients with acute myocardial infarction as predictors of unsuccessful thrombolysis.

BACKGROUND: Platelets play a pivotal role in the pathogenesis of acute myocardial infarction and their activation can cause thrombolysis to fail. METHODS: Baseline aggregation of platelets and expression of major surface receptors measured by flow cytometry were compared with clinical outcome after thrombolysis for 23 patients enrolled in the GUSTO-III trial. RESULTS: Failure to reperfuse (n = 3) and recurrent ischemia (n = 2) were observed in five patients who subsequently underwent emergency angioplasty. These patients were treated later in their course of disease than were the 18 patients who were successfully reperfused and remained free of recurrent ischemia. Greater than normal expression of platelet P-selectin (33.7 +/- 1.1 versus 28.1 +/- 1.9, P = 0.01) and expression of platelet--endothelial cell adhesion molecule-1 (PECAM-1; (57.1 +/- 2.3 versus 50.2 +/- 2.8, P = 0.02) were observed in members of the group with recurrent ischemia or failed reperfusion. CONCLUSION: Greater than normal baseline expression of P-selectin and PECAM-1 platelet receptors was correlated to delayed and unsuccessful coronary thrombolysis among patients presenting with acute myocardial infarction.

Heterogeneity of platelet aggregation and major surface receptor expression in patients with acute myocardial infarction.

BACKGROUND: Platelets play an important role in the natural history of acute myocardial infarction (AMI). METHODS AND RESULTS: Platelet aggregation and receptor expression were studied in 23 patients with AMI before reperfusion therapy and compared with 10 healthy control subjects. Platelet aggregation was induced with 5 micromol/L adenosine 5'-diphosphate, 10 micromol/L ADP, 1 microg/mL collagen, 1 mg/mL thrombin, and 1.25 mg/mL ristocetin. Receptor expression was measured by flow cytometry with monoclonal antibodies to p24 (CD9), Ib (CD42b), IIb (CD41b), IIIa (CD61), IIb/IIIa (CD41b/CD61), very late antigen-2 (CD49b), P-selectin (CD62p), platelet/endothelial cell adhesion molecule-1 (CD31); and vitronectin (CD51/CD61). The percentage of platelet aggregation was higher in patients with AMI when induced by 5 micromol/L ADP (64.1+/-12.7 vs 52.0+/-6.7; P=.04), by 10 micromol/L ADP (71.7+/-13.0 vs 59.2+/-7.2, P=.003), by thrombin (75.8+/-10.9 vs 60.5+/-6.9, P=.01), and by ristocetin (92.5+/-7.8 vs 71.3+/-7.4, P=.0001). Collagen-induced platelet aggregation did not differ between groups. Expression of P-selectin (log amplification of fluorescence intensity) (31.5+/-5.0 vs 25.1+/-2.6, P=.003) and platelet/endothelial cell adhesion molecule-1 (56.8+/-17.7 vs 44.5+/-3.7, P=.04) were significantly increased in patients with AMI. The expression of IIb (28.4+/-2.5 vs 37.2+/-1.7, P=.0001) and Ib (103.6+/-29.9 vs 133.8+/-8.0, P=.007) were reduced in patients with AMI. CONCLUSIONS: Platelets are not necessarily systemically activated during the prereperfusion phase of AMI. For each agonist used and surface antigen measured, there was a cohort of patients with AMI within the normal or even below normal range of platelet status.

Effects of reteplase and alteplase on platelet aggregation and major receptor expression during the first 24 hours of acute myocardial infarction treatment. GUSTO-III Investigators. Global Use of Strategies to Open Occluded Coronary Arteries.

OBJECTIVES: We sought to compare platelet characteristics after reteplase and alteplase therapy in the setting of the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)-III trial. BACKGROUND: Platelet function may be impaired during thrombolysis in patients with an acute myocardial infarction. The effects of reteplase and alteplase on platelet aggregation and major surface antigen expression during the first 24 h of infarction therapy are unknown. METHODS: Platelet aggregation and receptor expression by flow cytometry were determined in 23 patients before thrombolysis and thereafter at 3, 6, 12 and 24 h. RESULTS: Aggregation was higher after reteplase at 24 h when induced by 5 micromol/liter adenosine diphosphate (ADP) (p = 0.007), 10 micromol/liter ADP (p = 0.02), collagen (p = 0.003) and thrombin (p = 0.009) than after alteplase. Reteplase therapy exhibited greater glycoprotein (GP) IIb/IIIa (p = 0.04), very late antigen-2 (p = 0.04) and platelet/endothelial cell adhesion molecule-I (p = 0.002) expression at 24 h. Trends toward decreased receptor expression early (3 to 6 h), followed by a progressive increase at 12 h and especially at 24 h occurred after both agents. CONCLUSIONS: In this prospective clinical ex vivo platelet study, similar patterns of platelet aggregation and surface receptor expression occurred during the first 24 h of coronary thrombolysis with reteplase and alteplase. However, after reteplase, indicators of platelet activity were higher at 24 h after thrombolysis than after alteplase. These data suggest that GP IIb/IIIa inhibitors or other antiplatelet strategies may be particularly advantageous when used 12 to 24 h after thrombolysis, especially after reteplase therapy. It is at this time point during the first day of coronary thrombolysis that GP IIb/IIIa is markedly expressed and platelets are most active.

Depressed platelet status in an elderly patient with hemorrhagic stroke after thrombolysis for acute myocardial infarction. GUSTO-III Investigators.

BACKGROUND: Impaired platelet function has been reported in acute myocardial infarction (AMI) and stroke. However, prospective data on the changes of platelet status in patients before the occurrence of hemorrhagic stroke after thrombolytic therapy are unavailable. CASE DESCRIPTION: An 86-year-old male patient was among the 23 AMI patients enrolled in the platelet study for the GUSTO-III trial. He received 325 mg of aspirin daily for at least 6 years, suffered an AMI, and was successfully reperfused with alteplase, but after 44 hours developed a large hemorrhagic stroke resulting in paraplegia. Platelet aggregation and receptor expression were measured by flow cytometry and ELISA before thrombolysis and at 3, 6, 12, and 24 hours thereafter. The percentage of platelet aggregation was lower in the stroke patient at every time point when induced by 5 micromol/L of ADP, by 10 micromol/L of ADP, and by thrombin than in the rest of the AMI group. Ristocetin and collagen-induced aggregability were within the group range. Decreased platelet glycoprotein Ib, IIb, IIIa, and IIb/IIIa and vitronectin receptor expression were observed in the stroke patient. No other differences in p24 (CD9), very late antigen-2, P-selectin, and platelet/endothelial cell adhesion molecule-1 expression were determined. CONCLUSIONS: Profound depression of platelet status preceded the occurrence of hemorrhagic stroke in an elderly long-term aspirin user treated with thrombolytic therapy. Initial "exhausted" platelets may be responsible for the increased risk for hemorrhagic stroke after coronary thrombolysis.

Changes in the haemostatic profile during magnesium deficiency in swine.

Epidemiological studies of populations living in areas of low magnesium (Mg) intake have consistently shown a higher cardiovascular morbidity. Several hypotheses have been advanced to explain the cardioprotective properties of magnesium. Few studies, however, have analysed the relation of magnesium to haemostasis. The overall purpose of this project was to assess the association between certain haemostatic variables and magnesium deficiency. This experiment was designed to assess the effect of magnesium deficiency on various haemostatic variables which may relate to cardiovascular morbidity. Twelve female Yorkshire swine were fed for seven weeks on an Mg-sufficient or an Mg-deficient diet. Blood samples were obtained at baseline and after the termination of feeding in order to evaluate platelet aggregability and concentrations of antithrombin-III (AT-III), protein C, total protein S, fibronectin, endothelin-1 (ET-1), as well as the stable metabolites of thromboxane (TxB2) and prostacyclin (6-keto-PGF1 alpha). In animals on an Mg-sufficient diet, there were no significant differences in any of the investigated haemostatic variables. In the Mg-deficient group, a significant decrease in serum magnesium was noted after the feeding period (from 2.0 +/- 0.1 to 1.3 +/- 0.1; P < 0.01). Mg-deficient swine showed significant increases in ADP-induced (33.3 per cent and 59.6 per cent) and collagen-induced (36.6 per cent) platelet aggregation, and decreased plasma antithrombin-III (17.7 per cent) and protein S (14.4 per cent) when compared to baseline. Plasma concentrations of TxB2 (28.7 per cent), protein C (57.2 per cent), and ET-1 (74.9 per cent) were dramatically increased. There were no significant differences in plasma fibronectin and 6-keto-PGF1 alpha levels in the magnesium-depleted animals. We conclude that magnesium deficiency is associated with significant proaggregatory and coagulation alterations. This may contribute to the increased cardiovascular morbidity found in magnesium-deficient populations. The beneficial effects of magnesium supplementation in an expanding array of clinical conditions including cardiovascular disease may, in part, be related to the improved haemostatic profile in such patients.