Hypercoagulability of COVID-19 and Neurological Complications: A Review.

The SARS-CoV-2 virus, which causes Coronavirus disease 2019 (COVID-19), has resulted in millions of worldwide deaths. When the SARS-CoV-2 virus emerged from Wuhan, China in December 2019, reports of patients with COVID-19 revealed that hospitalized patients had acute changes in mental status, cognition, and encephalopathy. Neurologic complications can be a consequence from overall severity of the systemic infection, direct viral invasion of the SARS-CoV-2 virus in the central nervous system, and possible immune mediated mechanisms. We will examine the landscape regarding this topic in this review in addition to current understandings of COVID-19 and hemostasis, treatment, and prevention, as well as vaccination.

Comparable outcomes of patients eligible vs ineligible for SWOG leukemia studies.

Patients may be deemed ineligible for a clinical trial for reasons that do not directly impact efficacy or safety. We identified reasons for ineligibility and compared outcomes of ineligible with eligible patients treated on Southwest Oncology Group (SWOG) Leukemia Committee protocols. Patients enrolled in SWOG phase 2, 2/3, or 3 protocols open since 2005 were analyzed for eligibility status, reasons for ineligibility, baseline characteristics, Eastern Cooperative Oncology Group (ECOG) performance status (PS), serious adverse events (SAEs), complete remission (CR) status, and overall survival. A total of 2361 patients were enrolled in the 13 included studies. Of these, 247 (10%) were deemed ineligible; 78 were excluded from analyses, and 169 were included. Of the 169 included in analyses, 60% (101/169) were excluded due to missing baseline documentation. Baseline characteristics comparing ineligible to eligible patients were similar, with the exception of ECOG PS for S0325 (P = .02) and S0530 (P = .002). In multivariable analyses, neither the proportion of patients with ECOG PS ≥ 2 (P = .12) nor the rate of grade 5 SAEs (P = .62) differed between groups. There was no difference in survival between eligible and ineligible patients (P = .25), and CR rates were similar, with the exception of S0325 (P < .001) and S0703 (P = .004). The findings of this study suggest that nonessential eligibility criteria can be less restrictive, thus expanding patient enrollment and avoiding protocol deviations. The clinical trials included in this study were registered at www.clincialtrials.gov as #NCT00085709, #NCT00066794, #NCT00070499, #NCT00109837, #NCT00093418, #NCT00492856, #NCT00337168, #NCT00352365, #NCT00658814, #NCT00792948, #NCT00945815, #NCT00840177, and #NCT01522976.

Neurological Complications of the Leukemias Across the Ages.

PURPOSE OF REVIEW: Acute and chronic leukemias are heterogeneous diseases and can affect any part of the body upon initial discovery. Understanding the sequela of systemic involvement is key for proper diagnosis and treatment. RECENT FINDINGS: Over the decades, new research has emerged regarding neurological complications of the myeloid or lymphoid leukemias. Central nervous system involvement usually confers a poor prognosis and requires emergent treatment. Standard of care still involves systemic therapy, intrathecal administration of chemotherapeutic agents, and cranial radiation. Treatment-related side effects can occur and need to be recognized by any practitioner involved with patient care. It is imperative to understand neurologic complications from leukemia to prevent delays and initiate necessary treatment to maintain neurologic and cognitive function.

A phase 2 trial of azacitidine and gemtuzumab ozogamicin therapy in older patients with acute myeloid leukemia.

This trial tested the safety and efficacy of a regimen consisting of hydroxyurea followed by azacitidine, 75 mg/m(2) for 7 days, and gemtuzumab ozogamicin, 3 mg/m(2) on day 8, in older patients with newly diagnosed acute myeloid leukemia. Those achieving a complete remission received 1 consolidation treatment followed by 4 cycles of azacitidine. The patients were stratified into good-risk (age 60-69 years or performance status 0-1) and poor-risk (age ≥70 years and performance status 2 or 3) groups. Specific efficacy and safety goals were defined as being supportive of further study of the regimen. Eighty-three patients were registered in the good-risk cohort and 59 in poor-risk cohort, with median age of 71 and 75 years, respectively. In the good-risk group, 35 patients (44%) achieved a complete remission. Median relapse-free and overall survivals were 8 and 11 months, respectively. Six patients (8%) died within 30 days of registration. In the poor-risk group, 19 (35%) achieved a complete remission. Median relapse-free and overall survivals were 7 and 11 months, respectively. Seven patients (14%) died early. The results of this trial met predefined goals for efficacy and safety for the poor-risk cohort but not the good-risk group. .

Hypercellular bone marrow in aplastic anemia: A case report of two patients.

Aplastic anemia is a disorder of bone marrow failure characterized by a hypocellular bone marrow. We report two cases with an initial hypercellular bone marrow at the time of presentation, suggesting a new phase in the pathogenesis of the disease.

Kidney Transplantation for Erdheim-Chester Disease.

Erdheim-Chester disease is a rare inflammatory disease that infiltrates skeletal and extra-skeletal tissue. Chronic kidney disease (CKD) in Erdheim-Chester disease is usually attributed to retroperitoneal lesions that lead to urologic obstruction and hydronephrosis. In this report, we describe a patient diagnosed with Erdheim-Chester disease who eventually developed end-stage kidney disease (ESKD). After complete remission of Erdheim-Chester disease by vemurafenib therapy and 2 years of hemodialysis, the patient underwent a deceased donor kidney transplantation with basiliximab induction and tacrolimus/mycophenolic acid maintenance. After conversion of mycophenolic acid to azathioprine due to cost, acute cellular rejection had occurred, and he was treated with steroid therapy. The patient remained in complete remission from Erdheim-Chester disease and dialysis-free 16 months after transplant. Kidney transplantation is another treatment option for those patients with Erdheim-Chester disease who suffer from renal failure in the setting of complete remission.

Safety of gemtuzumab ozogamicin as monotherapy or combination therapy in an expanded-access protocol for patients with relapsed or refractory acute myeloid leukemia.

Gemtuzumab ozogamicin (GO) remained available to US clinicians through an open-label expanded-access protocol (NCT02312037) until GO was reapproved. Patients were aged ≥3 months with relapsed/refractory (R/R) acute myeloid leukemia (AML), high-risk myelodysplastic syndrome, or acute promyelocytic leukemia (APL), and had exhausted other treatment options. Three hundred and thirty one patients received GO as monotherapy for R/R AML (n = 139), combination therapy for R/R AML (n = 183), or treatment for R/R APL (n = 9). Corresponding treatment discontinuations occurred in 68, 39, and 33% of patients. All-causality grade 5 AEs occurred in 52, 22, and 22% of patients in the monotherapy, combination, and APL groups, respectively. Corresponding grades 3 and 4 treatment-related AEs were reported in 60, 55 and 78% of patients. Hepatotoxicity occurred in five patients: veno-occlusive disease (n = 4) and drug-induced liver injury (n = 1). GO was generally well tolerated in patients with R/R AML or APL. Most frequent treatment-related grade ≥3 AEs were hematologic AEs.Clinicaltrials.gov identifier: NCT02312037.

Hemophagocytic Lymphohistiocytosis in Adults: Associated Diagnoses and Outcomes, a Ten-Year Experience at a Single Institution.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of excessive systemic inflammation which causes tissue damage due to abnormal immune system activation and has a high fatality rate even with treatment. HLH continues to be a difficult diagnosis to make because of lack of awareness and its overlap with other illnesses. This disorder is well defined in pediatric patients under the age of 18, but there is also a paucity of data in the adult population. The goals of this study were to describe associated disorders, clinical course and outcomes, and to determine if additional clinical criteria can be used to help with the diagnosis of HLH in adult patients. METHODS: Patients' electronic medical records from 2007 to 2017 (who were ≥ 18 years old at the time of the search) were screened by ICD 9 and ICD 10 codes which contain the diagnosis of HLH or hemophagocytic syndrome, infection-associated. We identified 41 adult cases of HLH that were treated at our medical center over the course of 10 years and assessed these patients using both the historical and newly proposed diagnostic criteria. We also identified underlying diagnoses related to the development of HLH and fatality rates. RESULTS: Median age at diagnosis was 55 years old (18 - 87 years old) and 22 were male. Twenty-two had an infection, 16 with malignancy, seven had an autoimmune disorder and one with Sweet syndrome. Fifteen patients were treated with steroids alone, 18 with steroids and chemotherapy, three with steroids and antiviral agents, and two with chemotherapy alone. Sixteen (39%) died and 25 (60%) survived discharge. Seven patients died after discharge. Median survival of all patients was 1,095 days. CONCLUSIONS: Our data show that HLH is primarily associated with infections and malignancies. Newly proposed diagnostic criteria are not as specific, but can be helpful in making the diagnosis of HLH. We also showed that the fatality rate at our institution was lower than currently published rates of adult HLH.

Relative survival following response to 7 + 3 versus azacytidine is similar in acute myeloid leukemia and high-risk myelodysplastic syndromes: an analysis of four SWOG studies.

Here we quantify and compare the absolute and relative overall survival (OS) benefits conveyed by complete remission (CR) in AML and high-risk MDS, and by CR with incomplete count recovery (CRi) in AML and by hematologic improvement (HI) in MDS, following treatment with 7 + 3 versus azacytidine. We compared patients receiving 7 + 3 in SWOG studies S0106 (n = 301) and S1203 (n = 261) enrolling adults ≤ 60 years, with patients receiving azacytidine therapies in S0703 (n = 133 AML patients ≥ 60) and S1117 (n = 277 MDS patients ≥ 18). Absolute survival benefit was evaluated with 1-year, 3-year, and median OS; relative benefit was evaluated with univariate and covariate-adjusted hazard ratios. CR conveyed a relative survival advantage in multivariable analysis, with a similar relative effect of CR across studies. CR also conferred an absolute survival benefit, but with a smaller magnitude of absolute benefit in the azacytidine trials. In AML, OS was similar for CRi and failure to achieve CR/CRi. In MDS, CR conferred a survival advantage versus HI and HI versus failure. The relative survival benefit of CR was similar regardless of initial therapy for AML or high-risk MDS. With both therapies, CR has a beneficial effect on survival compared with CRi or HI.

Inherited thrombophilia and the eye.

Inherited thrombophilic disorders are a well-recognized risk factor for systemic thromboembolism. These disorders include deficiencies of anticoagulant proteins such as protein C, protein S, and antithrombin III, abnormalities of factor V and prothrombin resulting from genetic mutations, and hyperhomocysteinemia. Except for hyperhomocysteinemia, which has been associated with both venous and arterial thrombosis, the other heritable disorders primarily cause venous thromboembolism. We have reviewed the association between heritable thrombophilia and the development of thrombosis in the eye. The available literature consists of case-control studies and case reports. Preliminary data suggest a relationship between thrombotic disorders of the eye and the inherited hypercoagulable states. Some reports show a risk of thrombosis with the presence of factor V Leiden and hyperhomocysteinemia but these associations frequently disappear upon multivariate analysis. It is possible that inherited thrombophilia plays a supportive role to well-established risk factors such as hypertension and diabetes. Larger, well-designed studies will be necessary to clearly define the role of inherited thrombophilia in the development of thrombotic disorders of the eye.

Genetics of Hypercoagulable and Hypocoagulable States.

Hemostasis is the normal process of blood coagulation in vivo to stop pathologic bleeding. Virchow triad includes venous stasis, hypercoagulability, and vascular injury. Natural anticoagulants include protein C, protein S, and antithrombin. Factor V Leiden is the most common inherited thrombophilia, followed by prothrombin gene mutation. All inherited thrombophilias are passed down in an autosomal dominant fashion. Patients harboring the antiphospholipid antibodies have an increased risk for thrombosis. von Willebrand disease is the most common inherited bleeding disorder; the pattern of inheritance is autosomal. Hemophilia A and B are the only hereditary bleeding disorders inherited in a sex-linked recessive pattern.

Sensitizing leukemia stem cells to NF-κB inhibitor treatment in vivo by inactivation of both TNF and IL-1 signaling.

We previously reported that autocrine TNF-α (TNF) is responsible for JNK pathway activation in a subset of acute myeloid leukemia (AML) patient samples, providing a survival/proliferation signaling parallel to NF-κB in AML stem cells (LSCs). In this study, we report that most TNF-expressing AML cells (LCs) also express another pro-inflammatory cytokine, IL1ß, which acts in a parallel manner. TNF was produced primarily by LSCs and leukemic progenitors (LPs), whereas IL1ß was mainly produced by partially differentiated leukemic blasts (LBs). IL1ß also stimulates an NF-κB-independent pro-survival and proliferation signal through activation of the JNK pathway. We determined that co-inhibition of signaling stimulated by both TNF and IL1ß synergizes with NF-κB inhibition in eliminating LSCs both ex vivo and in vivo. Our studies show that such treatments are most effective in M4/5 subtypes of AML.

Thromboembolism in cancer patients: pathogenesis and treatment.

In this review we summarize the causes of cancer related thrombosis as well as modern treatment approaches. Malignancy as a risk factor for thromboembolism is becoming increasingly recognized by clinicians caring for these patients. The probability of thrombosis occurring in an individual patient is dependent on several factors, including accompanying medical problems, the type of cancer, the clinical stage, performance status, and the treatment modalities employed. Thrombophilia with a history of thromboembolism is important as well. The overall risk of thrombosis is sevenfold that of noncancer patients. Though much has been learned about the pathogenesis of cancer-related thrombosis, we are in fact just beginning to understand the cross-talk between cancer cells and their related microenvironment, and such investigations are likely to increase our knowledge of cancer-related thrombosis mechanisms. Research in these areas may also suggest new strategies for cancer prevention, metastasis suppression, and new treatments. Drugs used in cancer therapy are increasingly recognized to directly contribute to the thrombotic tendency. Few studies provide data on the optimal management of cancer patients with thrombosis. It has been learned that retreating with the same drug can be very hazardous. In general the approach to prevention of thrombosis is the same as for noncancer patients, recognizing that specific cancer types and stage can place a patient in a high-risk category. Initial coumadin therapy fails in a significant number of patients with cancer. Recognition of the cancer patients at highest risk for coumadin failure is challenging. Low-molecular-weight heparins appear to be more effective in such situations where coumadin is likely to fail or has failed, but these drugs are thought to be costlier. Newer agents such as Factor Xa inhibitors and TF inhibitors are currently under investigation and may be found useful in the management of cancer-related thrombosis.

γ-δ T-Cell Lymphoma With Disseminated Intravascular Coagulation and Autoimmune Hemolytic Anemia.

This unique presentation may help in further characterizing and understanding this uncommon disease and in developing more effective therapies.

Association between early promoter-specific DNA methylation changes and outcome in older acute myeloid leukemia patients.

Treatment options for older patients with acute myeloid leukemia (AML) range from supportive care alone to full-dose chemotherapy. Identifying factors that predict response to therapy may help increase efficacy and avoid toxicity. The phase II SWOG S0703 study investigated the use of hydroxyurea and azacitidine with gemtuzumab ozogamicin in the elderly AML population and found survival rates similar to those expected with standard AML regimens, with less toxicity. As part of this study, global DNA methylation along with promoter DNA methylation and expression analysis of six candidate genes (CDKN2A, CDKN2B, HIC1, RARB, CDH1 and APAF1) were determined before and during therapy to investigate whether very early changes are prognostic for clinical response. Global DNA methylation was not associated with a clinical response. Samples after 3 or 4 days of treatment with azacitidine showed significantly decreased CDKN2A promoter DNA methylation in patients achieving complete remission (CR) compared to those who did not. Samples from day 7 of treatment showed significantly decreased RARB, CDKN2B and CDH1 promoter DNA methylation in responders compared to nonresponders. Gene-specific DNA methylation analysis of peripheral blood samples may help early identification of those older AML patients most likely to benefit from demethylating agent therapy.