Clinical experience with three-factor prothrombin complex concentrate to reverse warfarin anticoagulation in intracranial hemorrhage.

BACKGROUND AND PURPOSE: The effectiveness of prothrombin complex concentrate (PCC) products available in the United States that contain low levels of factor VII (3-factor PCC) has not been tested. The purpose of this study was to review our experience with 3-factor PCC (Profilnine) in the setting of warfarin-associated intracranial hemorrhage (wICH). METHODS: In November 2007, we implemented a protocol for reversal of anticoagulation in wICH using Profilnine. Additional treatment with fresh-frozen plasma was at the discretion of the treating physician. Medical records of all patients receiving PCC for wICH between November 1, 2007, and December 7, 2011 were reviewed. Correction of the international normalized rate (INR) was defined as an INR <1.4. RESULTS: Seventy wICH patients were treated with Profilnine, including 46 (66%) with intraparenchymal hemorrhage, 22 (31%) with subdural hemorrhage, and 2 (3%) with subarachnoid hemorrhage. Mean INR was reduced from 3.36 to 1.96, and in 44 (62.9%) patients the INR corrected to <1.4. Baseline INR ≥3.0 decreased the likelihood of INR correction. Concomitant administration of fresh-frozen plasma (mean, 2.6 U) did not increase the likelihood of INR correction. Seven (10%) patients had serious adverse events during their hospital course, including 2 sudden deaths from suspected pulmonary embolism. CONCLUSIONS: Reversal of coagulopathy in wICH with Profilnine was incomplete and associated with serious adverse events. In the absence of available 4-factor PCC, options for urgent reversal of anticoagulation in wICH remain limited.

Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells.

The mutant JAK2V617F tyrosine kinase (TK) is present in the majority of patients with BCR-ABL-negative myeloproliferative neoplasms (MPNs). JAK2V617F activates downstream signaling through the signal transducers and activators of transcription (STAT), RAS/mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3 (PI3)/AKT pathways, conferring proliferative and survival advantages in the MPN hematopoietic progenitor cells (HPCs). Treatment with the pan-histone deacetylase (HDAC) inhibitor panobinostat (PS) is known to inhibit the chaperone function of heat shock protein 90, as well as induce growth arrest and apoptosis of transformed HPCs. Here, we demonstrate that PS treatment depletes the autophosphorylation, expression, and downstream signaling of JAK2V617F. Treatment with PS also disrupted the chaperone association of JAK2V617F with hsp90, promoting proteasomal degradation of JAK2V617F. PS also induced apoptosis of the cultured JAK2V617F-expressing human erythroleukemia HEL92.1.7 and Ba/F3-JAK2V617F cells. Treatment with the JAK2 TK inhibitor TG101209 attenuated JAK2V617F autophosphorylation and induced apoptosis of HEL92.1.7 and Ba/F3-JAK2V617F cells. Cotreatment with PS and TG101209 further depleted JAK/STAT signaling and synergistically induced apoptosis of HEL92.1.7 and Ba/F3-JAK2V617F cells. Cotreatment with TG101209 and PS exerted greater cytotoxicity against primary CD34(+) MPN cells than normal CD34(+) HPCs. These in vitro findings suggest combination therapy with HDAC and JAK2V617F inhibitors is of potential value for the treatment of JAK2V617F-positive MPN.

Acute splenic complications and implications of splenectomy in hemoglobin SC disease.

Splenectomy indications and outcome were evaluated in 124 adults with hemoglobin SC disease (Hb SC). Twelve patients (9.6%) required splenectomy. There was a significant difference between the splenectomy group and the non-splenectomy group, respectively, regarding Hb levels (median 7.2 g/dL vs. 12.5 g/dL, P < 0.0001), platelet counts (median 146 x 10(6)/L vs. 275 x 10(6)/L, P = 0.031), palpable spleen rate (66% vs. 16%, P = 0.0003%), acute chest syndrome frequency (75% vs. 12%P = 0.0004) and cholecystectomy rate (66% vs. 13%, P = 0.0004). No significant morbidity or mortality occurred postsplenectomy. There is a subgroup of Hb SC patients requiring splenectomy, in which splenectomy is effective. Although it appears to be safe regarding short-term complications of surgery, long-term adverse effects such as infections have to be evaluated cautiously.

Cotreatment with BCL-2 antagonist sensitizes cutaneous T-cell lymphoma to lethal action of HDAC7-Nur77-based mechanism.

Pan-histone deacetylase inhibitors, for example, vorinostat and panobinostat (LBH589; Novartis Pharmaceuticals, East Hanover, NJ), have shown clinical efficacy against advanced cutaneous T-cell lymphoma (CTCL). However, the molecular basis of this activity remains unclear. HDAC7, a class IIA histone deacetylase (HDAC), is overexpressed in thymocytes, where it represses expression of the proapoptotic nuclear orphan receptor Nur77. Here, we demonstrate that treatment with panobinostat rapidly inhibits the in vitro and intracellular activity, as well as the mRNA and protein levels of HDAC7, and induces expression and translocation of Nur77 to the mitochondria. There, Nur77 converts death resistance protein Bcl-2 into a killer protein, promoting cell death of cultured and patient-derived human CTCL cells. Treatment with panobinostat improved survival of athymic nude mice implanted with human CTCL cells. Ectopic expression of Nur77 induced apoptosis and sensitized HH cells to panobinostat, whereas combined knockdown of Nur77 and its family member Nor1 was necessary to inhibit panobinostat-induced apoptosis of CTCL cells. Cotreatment with the Bcl-2/Bcl-x(L) antagonist ABT-737 decreased resistance and synergistically induced apoptosis of human CTCL cells. These findings mechanistically implicate HDAC7 and Nur77 in sensitizing human CTCL cells to panobinostat as well as suggest that cotreatment with an anti-Bcl-2 agent would augment the anti-CTCL activity of panobinostat.

Nilotinib: a second-generation tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia.

BACKGROUND: Nilotinib, a second-generation tyrosine kinase inhibitor (TKI) formerly known as AMN107, was approved by the US Food and Drug Administration (FDA) on October 29, 2007, for the treatment of adult patients with chronic-phase (CP) and accelerated-phase (AP) Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) resistant to or intolerant of prior treatment that included imatinib. OBJECTIVE: The purpose of this review was to evaluate the pharmacology, pharmacokinetic properties, and pharmacodynamic properties of nilotinib; results of clinical trials in patients with CML, Ph+ acute lymphoblastic leukemia (ALL), and gastrointestinal stromal tumors (GISTs); and potential drug interactions. METHODS: Literature was identified and reviewed using searches of MEDLINE (1966-April 1, 2008), the American Society of Hematology and American Society of Clinical Oncology abstracts databases (2002-2008 annual meetings/symposia), the European Hematology Association abstracts database (2006-2007 annual meetings), and the American Association for Cancer Research symposia (2000-2007). Search terms included, but were not limited to, nilotinib, AMN107, chronic myelogenous leukemia, acute lymphoblastic leukemia, bcr-abl, imatinib resistance, adverse events, pharmacology, and clinical trials. RESULTS: Nilotinib is an orally bioavailable derivative of imatinib with improved specificity toward the breakpoint cluster region-Abelson murine leukemia (bcr-abl) viral protooncogene. In preclinical studies, nilotinib was found to have activity against 32 of 33 imatinib-resistant bcr-abl mutations, but not against the T3151 mutation. On pharmacokinetic analysis, T(max) was 3 hours. The calculated t((1/2)) following multiple daily dosing was approximately 17 hours. The main metabolic pathways identified were oxidation and hydroxylation. The parent compound is the circulating component found in serum; the metabolites were not found to contribute to pharmacologic activity. Nilotinib is a competitive inhibitor of cytochrome P450 (CYP) 3A4, CYP2C8, CYP2C9, and CYP2D6. In 2 Phase II, open-label, single-arm clinical studies, nilotinib was found to be beneficial in patients with CML that was imatinib resistant or intolerant. Overall, 58% of patients with CML-CP achieved a major cytogenetic response; 42%, a complete cytogenetic response; and 77%, a complete hematologic response (CHR). At 18 months, the estimated overall survival rate was 91%. Of patients whose disease had progressed to AP, nilotinib was associated with major cytogenetic response in 32%; complete cytogenetic response in 19%; and CHR in 30%. At 12 months, an estimated 56% of patients lacked progression of disease, and the estimated overall survival rate was 82%. Concurrent use of CYP3A4 inhibitors should be avoided. The most common toxicities attributable to nilotinib include rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, and vomiting. Grade 3/4 toxicities (> or = 10%) have included thrombocytopenia, neutropenia, elevated lipase, hyperglycemia, and hypophosphatemia. Nilotinib has been associated with a prolonged QT interval, and sudden death has been reported. The FDA-approved regimen of nilotinib is 400 mg PO BID on an empty stomach. CONCLUSIONS: Nilotinib is an oral second-generation bcr-abl TKI indicated for the treatment of imatinib resistant or -intolerant Ph+ CML-CP and -AP in adults. Positive clinical activity and tolerability have been reported in clinical trials. Clinical data on off-label indications and in patients with Ph+ ALL and GIST continue to emerge.