Tissue factor activates the coagulation cascade in mouse models of acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is associated with a high risk of bleeding and thrombosis. APL patients have an activated coagulation system, hyperfibrinolysis, and thrombocytopenia. APL cells express tissue factor (TF), a receptor and cofactor for factor VII/VIIa. This study had 2 goals. Firstly, we measured biomarkers of coagulation and fibrinolysis activation as well as platelet counts and bleeding in both mouse xenograft and allograft models of APL. Secondly, we determined the effect of inhibiting TF on the activation of coagulation in these models. We observed increased levels of plasma thrombin-antithrombin complexes (TAT), D-dimer, and plasmin-antiplasmin complexes, reduced platelet counts, and increased tail bleeding in both mouse models of APL. Fibrinogen levels decreased in the xenograft model but not in the allograft model. In contrast, the red blood cell count decreased in the allograft model but not in the xenograft model. Inhibition of APL-derived human TF with an anti-human TF monoclonal antibody reduced the level of TAT, increased platelet count, and normalized tail bleeding in a xenograft model. Inhibition of all sources of TF (APL cells and host cells) in the allograft model with a rat anti-mouse TF monoclonal antibody decreased the levels of TAT but did not affect the platelet count. Our study demonstrates that TF plays a central role in the activation of coagulation in both the xenograft and allograft mouse models of APL. These APL mouse models can be used to investigate the mechanisms of coagulopathy and thrombocytopenia in APL.

JAK2 V617F allele burden in polycythemia vera: burden of proof.

Polycythemia vera (PV) is a hematopoietic stem cell neoplasm defined by activating somatic mutations in the JAK2 gene and characterized clinically by overproduction of red blood cells, platelets, and neutrophils; a significant burden of disease-specific symptoms; high rates of vascular events; and evolution to a myelofibrosis phase or acute leukemia. The JAK2V617F variant allele frequency (VAF) is a key determinant of outcomes in PV, including thrombosis and myelofibrotic progression. Here, we critically review the dynamic role of JAK2V617F mutation burden in the pathogenesis and natural history of PV, the suitability of JAK2V617F VAF as a diagnostic and prognostic biomarker, and the utility of JAK2V617F VAF reduction in PV treatment.

Phase I study of opaganib, an oral sphingosine kinase 2-specific inhibitor, in relapsed and/or refractory multiple myeloma.

Multiple myeloma (MM) remains an incurable disease and there is an unmet medical need for novel therapeutic drugs that do not share similar mechanisms of action with currently available agents. Sphingosine kinase 2 (SK2) is an innovative molecular target for anticancer therapy. We previously reported that treatment with SK2 inhibitor opaganib inhibited myeloma tumor growth in vitro and in vivo in a mouse xenograft model. In the current study, we performed a phase I study of opaganib in patients with relapsed/refractory multiple myeloma (RRMM). Thirteen patients with RRMM previously treated with immunomodulatory agents and proteasome inhibitors were enrolled and treated with single-agent opaganib at three oral dosing regimens (250 mg BID, 500 mg BID, or 750 mg BID, 28 days as a cycle). Safety and maximal tolerated dose (MTD) were determined. Pharmacokinetics, pharmacodynamics, and correlative studies were also performed. Opaganib was well tolerated up to a dose of 750 mg BID. The most common possibly related adverse event (AE) was decreased neutrophil counts. There were no serious AEs considered to be related to opaganib. MTD was determined as at least 750 mg BID. On an intent-to-treat basis, one patient (7.7%) in the 500 mg BID dose cohort showed a very good partial response, and one other patient (7.7%) achieved stable disease for 3 months. SK2 is an innovative molecular target for antimyeloma therapy. The first-in-class SK2 inhibitor opaganib is generally safe for administration to RRMM patients, and has potential therapeutic activity in these patients. Clinicaltrials.gov: NCT02757326.

Prophylactic tranexamic acid in patients with hematologic malignancy: a placebo-controlled, randomized clinical trial.

Evidence of the effectiveness of prophylactic use of tranexamic acid (TXA) in thrombocytopenia is lacking. To determine whether TXA safely reduces bleeding incidence in patients undergoing treatment for hematologic malignancies, a randomized, double-blind clinical trial was conducted from June 2016 through June 2020. Of 3120 screened adults, 356 patients were eligible and enrolled, and 337 patients (mean age, 53.9; 141 [41.8%] women), randomized to 1300 mg TXA orally or 1000 mg TXA through IV (n = 168) vs placebo (n = 169) thrice daily for maximum 30 days. Three hundred thirty patients were activated when their platelet counts fell below 30 000 per µL; 279 (83%) had complete outcome ascertainment. World Health Organization (WHO) grade ≥2 bleeding was observed in the 30 days following activation in 50.3% (73/145) and 54.2% (78/144) of patients in the TXA and placebo groups, with an adjusted odds ratio of 0.83 (95% confidence interval [CI], 0.50-1.34; P = .44). There was no statistically significant difference in the mean number of platelet transfusions (mean difference, 0.1; 95% CI, -1.9 to 2.0), mean days alive without grade ≥2 bleeding (mean difference, 0.8; 95% CI, -0.4 to 2.0), thrombotic events (6/163 [3.7%] TXA, 9/163 [5.5%] placebo), or deaths due to serious bleeding. Most common adverse events were: diarrhea (116/164 [70.7%] TXA and 114/163 [69.9%] placebo); febrile neutropenia (111/164 [67.7%] TXA, 105/163 [64.4%] placebo); fatigue (106/164 [64.6%] TXA, 109/163 [66.9%] placebo); and nausea (104/164 [63.4%] TXA, 97/163 [59.5%] placebo). Among patients with hematologic malignancy undergoing chemotherapy or hematopoietic stem cell transplantation, prophylactic treatment with TXA compared with placebo did not significantly reduce the risk of WHO grade ≥2 bleeding.

Thrombosis in myeloproliferative neoplasms: update in pathophysiology.

PURPOSE OF REVIEW: This review summarizes high-impact research in myeloproliferative neoplasms (MPN) from the last 18 months, with a particular focus on basic science findings. RECENT FINDINGS: A pseudo-hypoxia state with stabilization of hypoxia-inducible factor (HIFα exists that is central to cell growth, cell renewal, inflammation, and thrombotic potential in MPN hematopoietic cells. SUMMARY: HIFα and inflammatory pathways are new therapeutic targets in MPN, with the potential to ameliorate thrombotic risk and perhaps eradicate mutant progenitor cells.

Novel Pathophysiological Mechanisms of Thrombosis in Myeloproliferative Neoplasms.

PURPOSE OF REVIEW: Thrombosis remains a leading cause of morbidity and mortality in BCR/ABL negative myeloproliferative neoplasms (MPN). Circulating blood cells are both increased in quantity and qualitatively abnormal in MPN, resulting in an increased thrombotic risk. Herein, we review recently elucidated mechanisms of MPN thrombosis and discuss implications of drugs currently under investigation for MPN. RECENT FINDINGS: Recent studies highlight that in JAK2V617F granulocytes and platelets, thrombo-inflammatory genes are upregulated. Furthermore, in JAK2V617F granulocytes, protein expression of integrin CD11b, tissue factor, and leukocyte alkaline phosphatase are all increased. Overall, myeloid cells, namely neutrophils, may contribute in several ways, such as through increased adhesion via ß1 integrin binding to VCAM1, increased infiltration, and enhanced inducibility to extrude neutrophil extracellular traps. Non-myeloid inflammatory cells may also contribute via secretion of cytokines. With regard to red blood cells, number, rigidity, adhesion, and generation of microvesicles may lead to increased vascular resistance as well as increased cell-cell interactions that promote rolling and adhesion. Platelets may also contribute in a similar fashion. Lastly, the vasculature is also increasingly appreciated, as several studies have demonstrated increased endothelial expression of pro-coagulant and pro-adhesive proteins, such as von Willebrand factor or P-selectin in JAK2V617F endothelial cells. With the advent of molecular diagnostics, MPN therapeutics are advancing beyond cytoreduction. Our increased understanding of pro-inflammatory and thrombotic pathophysiology in MPN provides a rational basis for evaluation of in-development MPN therapeutics to reduce thrombosis.

Cancer Therapy-Associated Thrombosis.

[Figure: see text].

Thrombotic, inflammatory, and HIF-regulated genes and thrombosis risk in polycythemia vera and essential thrombocythemia.

Thrombosis is a major cause of morbidity and mortality in polycythemia vera (PV) and essential thrombocythemia (ET). The pathophysiology of thrombosis in these disorders remains unclear, and we hypothesized that upregulation of thrombotic, inflammatory, and hypoxia-inducible factor (HIF)-regulated genes may play a role in it. We performed unbiased RNA sequencing in granulocytes and platelets of PV patients and found differential expression of several thrombotic, inflammatory, and HIF-regulated genes. The expression of many of these genes positively correlated with JAK2 expression and JAK2V617F allelic burden. We then validated these findings by quantitative polymerase chain reaction analyses of selected gene transcripts in a larger number of PV and ET granulocytes and platelets (58 patients) and in 28 controls, and we compared these findings in patients with and without thrombosis. The study included 29 females and 29 males; of these, 28 had a history of thrombosis. We found that transcripts of several selected genes were upregulated in patients with PV or ET compared with controls. In granulocytes, the expression levels of F3, SELP, VEGFA, and SLC2A1 were significantly higher in patients with a history of thrombosis compared with those who did not have thrombosis. Patients with a history of thrombosis have significantly higher expression of IL1RAP (P < .05) in platelets compared with those without thrombosis. Our study confirms the presence of a thrombo-inflammatory state and augmented HIF activity in PV and ET and its role in thrombosis. These data may provide the background for targeted therapies in PV and ET.

Neutrophils: back in the thrombosis spotlight.

Reactive and clonal neutrophil expansion has been associated with thrombosis, suggesting that neutrophils play a role in this process. However, although there is no doubt that activated monocytes trigger coagulation in a tissue factor-dependent manner, it remains uncertain whether stimulated neutrophils can also directly activate coagulation. After more than a decade of debate, it is now largely accepted that normal human neutrophils do not synthetize tissue factor, the initiator of the extrinsic pathway of coagulation. However, neutrophils may passively acquire tissue factor from monocytes. Recently, the contact system, which initiates coagulation via the intrinsic pathway, has been implicated in the pathogenesis of thrombosis. After the recent description of neutrophil extracellular trap (NET) release by activated neutrophils, some animal models of thrombosis have demonstrated that coagulation may be enhanced by direct NET-dependent activation of the contact system. However, there is currently no consensus on how to assess or quantify NETosis in vivo, and other experimental animal models have failed to demonstrate a role for neutrophils in thrombogenesis. Nevertheless, it is likely that NETs can serve to localize other circulating coagulation components and can also promote vessel occlusion independent of fibrin formation. This article provides a critical appraisal of the possible roles of neutrophils in thrombosis and highlights some existing knowledge gaps regarding the procoagulant activities of neutrophil-derived extracellular chromatin and its molecular components. A better understanding of these mechanisms could guide future approaches to prevent and/or treat thrombosis.

A comparison of response in the presence or absence of a delay in induction therapy with bortezomib, lenalidomide, and dexamethasone.

PURPOSE: Lenalidomide, bortezomib, and dexamethasone (RVd) has emerged as a preferred induction therapy in multiple myeloma (MM) in the United States. Due to lenalidomide's teratogenic risk, patients and prescribers must comply with a risk evaluation and mitigation strategy (REMS) program. The REMS program limits dispensing to certain third-party specialty pharmacies, whose average prescription fill times are longer than in-house specialty pharmacies. In practice, a delay in procurement of lenalidomide may mean that patients start therapy with only bortezomib and dexamethasone, delaying the start of more effective triplet therapy. The primary objective of this study is to determine if a delay from start of bortezomib and dexamethasone to start of triplet therapy with lenalidomide impacts rate of achievement of very good partial response (VGPR) after four cycles of RVd. METHODS: This was a single-center retrospective review of adults with newly diagnosed MM who received RVd induction therapy at University of North Carolina Medical Center between April 2014 and June 2017. Patients who started lenalidomide ≥10 days after bortezomib comprised the "Delay" group, while those who started lenalidomide concurrently with bortezomib or within 1-9 days after bortezomib comprised the "No Delay" group. The primary outcome was VGPR or better response rate after four cycles of RVd. RESULTS: Thirty-eight patients met inclusion criteria. Nine patients (23.7%) experienced any delay in initiation of lenalidomide, with a mean delay of 7.8 days (range 1-18). Four patients (10.5%) experienced a delay ≥10 days. No patients in the Delay group were of reproductive potential, compared to 8.8% in the No Delay group (p = 0.54). VGPR or better response rate did not differ between the Delay and No Delay groups (66.7% vs. 58.8%, p = 0.79). The mean number of lenalidomide prescriptions generated per RVd cycle was 1.35 (range 1-5, SD 0.74). CONCLUSIONS: This study did not demonstrate an effect on clinical response after delays ≥10 days between bortezomib and lenalidomide initiation. No patients in the delay group were females of reproductive potential, which is the primary target for increased safety behind the REMS program.

Acquired hemophilia in malignancy.

Acquired hemophilia is a rare but potentially morbid complication in patients with cancer. It may be seen in patients with hematologic neoplasms (usually lymphoproliferative disorders) or with solid tumors. Although the presence of an underlying malignancy portends a worse outcome, the literature suggests that the usual principles of treatment, including immunosuppression, apply to these patients. However, appropriate consideration should be given to the choice of agents, depending on individual risk factors for complications such as thrombosis and infection.

Further data supporting that paclitaxel-associated acute pain syndrome is associated with development of peripheral neuropathy: North Central Cancer Treatment Group trial N08C1.

BACKGROUND: Paclitaxel causes an acute pain syndrome (P-APS), occurring within days after each dose and usually abating within days. Paclitaxel also causes a more classic peripheral neuropathy, which steadily increases in severity with increasing paclitaxel total doses. Little detail is available regarding the natural history of these 2 syndromes, or any relationship between them, although a recent publication does provide natural history data about weekly paclitaxel, supporting an association between the severity of P-APS and eventual peripheral neuropathy symptoms. METHODS: Patients entering this study were about to receive paclitaxel and carboplatin every 3 weeks. Daily questionnaires were completed for the first week after every chemotherapy dose, and European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire, Chemotherapy-Induced Peripheral Neuropathy 20-item instruments were completed weekly. RESULTS: The P-APS severity peaked on day 4 after the initial chemotherapy dose, with 12%, 29%, 23%, and 36% of patients having maximal pain scores of 0, 1 to 4, 5 or 6, or 7 to 10 during the first week after the first dose of therapy, respectively. Patients with P-APS scores of 0 to 4 with the first dose of chemotherapy had less eventual sensory neuropathy than did patients with P-APS scores of 5 to 10 (P = 0.001). With regard to the more peripheral neuropathy, sensory neuropathy was more problematic than was either motor or autonomic neuropathy. Numbness and tingling were more common components of the sensory neuropathy than was pain. CONCLUSIONS: Patients with worse P-APS severities appear to have more eventual chemotherapy-induced peripheral neuropathy. This provides support for the concept that P-APS is a form of nerve pathology.

Natural history of paclitaxel-associated acute pain syndrome: prospective cohort study NCCTG N08C1.

PURPOSE: The characteristics and natural history of the paclitaxel-acute pain syndrome (P-APS) and paclitaxel's more chronic neuropathy have not been well delineated. METHODS: Patients receiving weekly paclitaxel (70 to 90 mg/m(2)) completed daily questionnaires and weekly European Organisation for Research and Treatment of Cancer (EORTC) Chemotherapy-Induced Peripheral Neuropathy (CIPN) -20 instruments during the entire course of therapy. RESULTS: P-APS symptoms peaked 3 days after chemotherapy. Twenty percent of patients had pain scores of 5 to 10 of 10 with the first dose of paclitaxel. Sensory neuropathy symptoms were more prominent than were motor or autonomic neuropathy symptoms. Of the sensory neuropathy symptoms, numbness and tingling were more prominent than was shooting or burning pain. Patients with higher P-APS pain scores with the first dose of paclitaxel appeared to have more chronic neuropathy. CONCLUSION: These data support that the P-APS is related to nerve pathology as opposed to being arthralgias and/or myalgias. Numbness and tingling are more prominent chronic neuropathic symptoms than is shooting or burning pain.