Diagnosis and treatment of coagulopathy using thromboelastography with platelet mapping is associated with decreased risk of pulmonary failure in COVID-19 patients.

INTRODUCTION: Treatment of coronavirus disease 2019 (COVID-19) patients may require antithrombotic and/or anti-inflammatory medications. We hypothesized that individualized anticoagulant (AC) management, based on diagnosis of coagulopathy using thromboelastography with platelet mapping (TEG-PM), would decrease the frequency of pulmonary failure (PF) requiring mechanical ventilation (MV), mitigate thrombotic and hemorrhagic events, and, in-turn, reduce mortality. METHODS: Hospital-admitted COVID-19 patients, age 18 or older, with escalating oxygen requirements were included. Prospective and supplemental retrospective chart reviews were conducted during a 2-month period. Patients were stratified into two groups based on clinician-administered AC treatment: TEG-PM guided vs. non-TEG guided. RESULTS: Highly-elevated inflammatory markers (D-dimer, C-reactive protein, ferritin) were associated with poor prognosis but did not distinguish coagulopathic from noncoagulopathic patients. TEG-guided AC treatment was used in 145 patients vs. 227 treated without TEG-PM guidance. When managed by TEG-PM, patients had decreased frequency of PF requiring MV (45/145 [31%] vs. 152/227 [66.9%], P  < 0.0001), fewer thrombotic events (2[1.4%] vs. 39[17.2%], P  = 0.0019) and fewer hemorrhagic events (6[4.1%] vs. 24[10.7%], P  = 0.0240), and had markedly reduced mortality (43[29.7%] vs. 142[62.6%], P  < 0.0001). Platelet hyperactivity, indicating the need for antiplatelet medications, was identified in 75% of TEG-PM patients. When adjusted for confounders, empiric, indiscriminate AC treatment (not guided by TEG-PM) was shown to be an associated risk factor for PF requiring MV, while TEG-PM guided management was associated with a protective effect (odds ratio = 0.18, 95% confidence interval 0.08-0.4). CONCLUSIONS: Following COVID-19 diagnosis, AC therapies based on diagnosis of coagulopathy using TEG-PM were associated with significantly less respiratory decompensation, fewer thrombotic and hemorrhagic complications, and improved likelihood of survival.

Integral Use of Thromboelastography With Platelet Mapping to Guide Appropriate Treatment, Avoid Complications, and Improve Survival of Patients With Coronavirus Disease 2019-Related Coagulopathy.

OBJECTIVES: Coagulopathy of coronavirus disease 2019 is largely described as hypercoagulability, yet both thrombotic and hemorrhagic complications occur. Although therapeutic and prophylactic anticoagulant interventions have been recommended, empiric use of antifactor medications (heparin/enoxaparin) may result in hemorrhagic complications, including death. Furthermore, traditional (antifactor) anticoagulation does not address the impact of overactive platelets in coronavirus disease 2019. The primary aim was to evaluate if algorithm-guided thromboelastography with platelet mapping could better characterize an individual's coronavirus disease 2019-relatedcoagulopathic state and, secondarily, improve outcomes. DESIGN SETTING AND PATIENTS: Coronavirus disease 2019 patients (n = 100), receiving thromboelastography with platelet mapping assay upon admission to an 800-bed tertiary-care hospital, were followed prospectively by a hospital-based thromboelastography team. Treating clinicians were provided with the option of using a pre-established algorithm for anticoagulation, including follow-up thromboelastography with platelet mapping assays. Two groups evolved: 1) patients managed by thromboelastography with platelet mapping algorithm (algorithm-guided-thromboelastography); 2) those treated without thromboelastography with platelet mapping protocols (non-algorithm-guided). Outcomes included thrombotic/hemorrhagic complications, pulmonary failure, need for mechanical ventilation, acute kidney injury, dialysis requirement, and nonsurvival. INTERVENTIONS: Standard-of-care therapy with or without algorithm-guided-thromboelastography support. MEASUREMENTS AND MAIN RESULTS: Although d-dimer, C-reactive protein, and ferritin were elevated significantly in critically ill (nonsurvivors, acute kidney injury, pulmonary failure), they did not distinguish between coagulopathic and noncoagulopathic patients. Platelet hyperactivity (maximum amplitude-arachidonic acid/adenosine diphosphate > 50 min), with or without thrombocytosis, was associated with thrombotic/ischemic complications, whereas severe thrombocytopenia (platelet count < 100,000/µL) was uniformly fatal. Hemorrhagic complications were observed with decreased factor activity (reaction time > 8 min). Non-algorithm-guided patients had increased risk for subsequent mechanical ventilation (relative risk = 10.9; p < 0.0001), acute kidney injury (relative risk = 2.3; p = 0.0017), dialysis (relative risk = 7.8; p < 0.0001), and death (relative risk = 7.7; p < 0.0001), with 17 of 28 non-algorithm-guided patients (60.7%) dying versus four algorithm-guided-thromboelastography patients (5.6%) (p < 0.0001). Thromboelastography with platelet mapping-guided antiplatelet treatment decreased mortality 82% (p = 0.0002), whereas non-algorithm-guided (compared with algorithm-guided-thromboelastography) use of antifactor therapy (heparin/enoxaparin) resulted in 10.3-fold increased mortality risk (p = 0.0001). CONCLUSIONS: Thromboelastography with platelet mapping better characterizes the spectrum of coronavirus disease 2019 coagulation-related abnormalities and may guide more tailored, patient-specific therapies in those infected with coronavirus disease 2019.

Big data analysis of treatment patterns and outcomes among elderly acute myeloid leukemia patients in the United States.

Over half of patients diagnosed with acute myeloid leukemia (AML) are 65 years or older. We examined patient characteristics, treatment patterns, and survival among elderly patients in routine clinical practice. We utilized a retrospective cohort analysis of first primary AML patients in the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Patients were diagnosed between January 1, 2000 and December 31, 2009, >66 years, and continuously enrolled in Medicare Part A and B in the year prior to diagnosis. Kaplan-Meier curves and Cox proportional hazards regression assessed overall survival by treatment. There were 3327 (40 %) patients who received chemotherapy within 3 months of diagnosis. Treated patients were more likely younger, male, and married, and less likely to have secondary AML and poor performance indicators and comorbidity score compared to untreated patients. In multivariate survival analysis, treated patients exhibited a significant 33 % lower risk of death compared to untreated patients. Significant survival benefits were noted with receipt of intensive and hypomethylating agent (HMA) therapies compared to no therapy. A survival benefit with allogeneic hematopoietic stem cell transplantation was seen in younger Medicare patients. This real-world study showed that about 60 % of elderly AML patients remain untreated following diagnosis. Use of anti-leukemic therapy was associated with a significant survival benefit in this elderly cohort.

A phase 2 study of the BH3 mimetic BCL2 inhibitor navitoclax (ABT-263) with or without rituximab, in previously untreated B-cell chronic lymphocytic leukemia.

We evaluated the safety and biologic activity of the BH3 mimetic protein, navitoclax, combined with rituximab, in comparison to rituximab alone. One hundred and eighteen patients with chronic lymphocytic leukemia (CLL) were randomized to receive eight weekly doses of rituximab (arm A), eight weekly doses of rituximab plus daily navitoclax for 12 weeks (arm B) or eight weekly doses of rituximab plus daily navitoclax until disease progression or unacceptable toxicity (arm C). Investigator-assessed overall response rates (complete [CR] and partial [PR]) were 35% (arm A), 55% (arm B, p = 0.19 vs. A) and 70% (arm C, p = 0.0034 vs. A). Patients with del(17p) or high levels of BCL2 had significantly better clinical responses when treated with navitoclax. Navitoclax in combination with rituximab was well tolerated as initial therapy for patients with CLL, yielded higher response rates than rituximab alone and resulted in prolonged progression-free survival with treatment beyond 12 weeks.

Phase III safety study of rituximab administered as a 90-minute infusion in patients with previously untreated diffuse large B-cell and follicular lymphoma.

This phase III, multicenter, single-arm trial investigated the impact of 90 min rituximab infusions on infusion-related reactions (IRRs) in patients with untreated diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). Patients received six or eight cycles of rituximab plus cyclophosphamide, vincristine, doxorubicin and prednisone for DLBCL or plus cyclophosphamide, vincristine and prednisolone for FL. A total of 425 patients received the first rituximab infusion per standard guidelines; median duration 240 min. Patients who did not experience grade ≥ 3 IRRs received subsequent infusions over 90 min (363 patients). A total of 303 patients received ≥ 6 cycles of rituximab. Fifty-three patients withdrew after cycle 1; 10 for grade 3 or 4 IRRs and one for a grade 3 adverse event. During cycle 2, 139 patients had IRRs, including four grade 3 IRRs. A 90 min rituximab infusion is well tolerated and feasible for patients with DLBCL or FL who tolerate the first standard rate infusion.

A phase 2 study of rituximab in combination with recombinant interleukin-2 for rituximab-refractory indolent non-Hodgkin's lymphoma.

PURPOSE: The incidence of non-Hodgkin's lymphoma (NHL), the fifth most common malignancy in the United States, has increased over 70% in the last 30 years. Fifty percent to 75% of patients with low-grade or follicular NHL respond to rituximab therapy. However, responses are generally of limited duration, and complete responses are rare. Preclinical work suggests that human recombinant interleukin-2 (rIL-2; aldesleukin, Proleukin) enhances rituximab efficacy. Antibody-dependent cellular cytotoxicity (ADCC) is an important mechanism of action of rituximab. rIL-2 induces expansion and activation of Fc receptor (FcR)-bearing cells, thereby enhancing ADCC. Therefore, a large, multicenter phase 2 trial to assess the effects of rIL-2 on rituximab therapy in patients with rituxumab-refractory low-grade NHL was conducted. EXPERIMENTAL DESIGN: The combination of rituximab and rIL-2 was studied in 57 patients with rituximab-refractory low-grade NHL (i.e., patients must have received a single-agent course of rituximab and showed no tumor response, or had a response lasting <6 months). I.V. rituximab was given at 375 mg/m(2) (weeks 1-4). S.C. rIL-2 was given thrice a week at 14 MIU (weeks 2-5) and at 10 MIU (weeks 6-9). RESULTS: Rituximab plus rIL-2 combination therapy was safe and generally well tolerated, but responses were low. Fifty-seven patients were enrolled with 54 evaluable for response; however, only five responses (one complete and four partial) were observed. Correlative data indicate that rIL-2 expanded FcR-bearing cells and enhanced ADCC. However, other factors, such as FcgammaR polymorphisms in patients refractory to single-agent rituxumab and heterogeneous tumor biology, may have influenced the lack of clinical efficacy seen with this combination therapy. CONCLUSIONS: rIL-2 expands FcR-bearing cellular subsets in vivo and enhances in vitro ADCC of rituxumab. However, these findings do not directly translate into meaningful clinical benefit for patients with rituxumab-refractory NHL.

Phase I studies of interleukin (IL)-2 and rituximab in B-cell non-hodgkin's lymphoma: IL-2 mediated natural killer cell expansion correlations with clinical response.

PURPOSE: Expansion and activation of natural killer (NK) cells with interleukin-2 (IL-2) may enhance antibody-dependent cellular cytotoxicity (ADCC), an important mechanism of rituximab activity. Two parallel Phase I studies evaluated combination therapy with rituximab and IL-2 in relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL). EXPERIMENTAL DESIGN: Thirty-four patients with advanced NHL received rituximab (375 mg/m(2) i.v. weekly, weeks 1-4) and escalating doses of s.c. IL-2 [2-7.5 MIU daily (n = 19) or 4.5-14 million international units three times weekly (n = 15), weeks 2-5]. Safety, tolerability, clinical responses, NK cell counts, and ADCC activity were evaluated. RESULTS: Maximally tolerated doses (MTD) of IL-2 were 6 MIU daily and 14 million international units thrice weekly. The most common adverse events were fever, chills, and injection site reactions. Dose-limiting toxicities were fatigue and reversible liver enzyme test elevations. Of the 9 patients enrolled at the daily schedule MTD, 5 showed clinical response. On the thrice-weekly schedule at the MTD, 4 of 5 patients responded. Responders showed median time to progression of 14.9 and 16.1 months, respectively, for the two studies. For the same total weekly dose, thrice-weekly IL-2 administration induced greater increases in NK cell counts than daily dosing, and NK cells correlated with clinical response on the thrice-weekly regimen. ADCC activity was increased and maintained after IL-2 therapy in responding and stable disease patients. CONCLUSIONS: Addition of IL-2 to rituximab therapy is safe and, using thrice-weekly IL-2 dosing, results in NK cell expansion that correlates with response. This combination treatment regimen merits additional evaluation in a randomized clinical trial.

Phase 1 trial of FVIII gene transfer for severe hemophilia A using a retroviral construct administered by peripheral intravenous infusion.

In a phase 1 dose escalation study, 13 subjects with hemophilia A received by peripheral intravenous infusion a retroviral vector carrying a B-domain-deleted human factor VIII (hFVIII) gene. Infusions were well tolerated. Tests for replication competent retrovirus have been negative. Polymerase chain reaction (PCR) analyses demonstrate the persistence of vector gene sequences in peripheral blood mononuclear cells in 3 of 3 subjects tested. Factor VIII was measured in serial samples using both a one-stage clotting assay and a chromogenic assay. While no subject had sustained FVIII increases, 9 subjects had FVIII higher than 1% on at least 2 occasions 5 or more days after infusion of exogenous FVIII, with isolated levels that ranged from 2.3% to 19%. Pharmacokinetic parameters of exogenous FVIII infused into subjects 13 weeks after vector infusion showed an increased half-life (T1/2; P <.02) and area under the curve (AUC, P <.04) compared with prestudy values. Bleeding frequency decreased in 5 subjects compared with historical rates. These results demonstrate that this retroviral vector (hFVIII(V)) is safe and, in some subjects, persists more than a year in peripheral blood mononuclear cells, with measurable factor VIII levels and with increased available FVIII activity (increased T1/2 and AUC) after infusion of exogenous FVIII concentrate.