Management and Outcomes of Hematological Immune-related Adverse Events: Systematic Review and Meta-analysis.

Data regarding clinical outcomes and management of hematological manifestations of immune checkpoint inhibition (ICI) is limited to case reports, series, and a few retrospective reviews. We aimed to determine the rate of response of hematological immune-related adverse events (irAEs) to immunosuppressive therapy. MEDLINE (OVID), EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched from inception to the present day. Retrospective reports were included without language restrictions. The risk of bias was evaluated with the Cochrane Collaboration's tool. The primary outcome of this study was the rate of response to immunosuppression. Eighty studies (14 case series and 66 individual case reports) were analyzed with a total of 135 patients with ICI-related hematological irAEs. Data analysis showed an average proportional response rate to immunosuppression among hematological irAE entities of 50% (range: 25%-70%). The heterogeneity index (I2) was 0% among reports within each entity. There is a wide spectrum of hematological manifestations to ICI therapy, and to date there is no large randomized-controlled trial data to evaluate the efficacy of treatment strategies for hematological irAEs. We found a variable overall response rate to immunosuppression therapy of around 50%, without statistically significant heterogeneity among different irAE types but significant differences among the different countries of publication. Future studies evaluating the optimal dose and duration of immunosuppressive agents for patients with hematological irAEs should be undertaken.

Risk of pulmonary emboli after removal of an upper extremity central catheter associated with a deep vein thrombosis.

Standard treatment of catheter-associated upper extremity deep vein thrombosis (UE-DVT) is anticoagulation, although catheters are often removed for this indication. The optimal time for catheter removal and whether the act and/or timing of catheter removal is associated with pulmonary embolism (PE) remain unknown. A retrospective cohort study was performed at 8 participating institutions through the Venous thromboEmbolism Network US. Patients with hematologic malignancies and central venous catheter (CVC)-associated UE-DVT were included from 1 January 2010 through 31 December 2016. The primary outcome was objectively confirmed PE within 7 days of UE-DVT diagnosis in anticoagulated patients comparing early (≤48 hours) vs delayed (>48 hours) catheter removal. A total of 626 patients were included, among whom 480 were treated with anticoagulation. Among anticoagulated patients, 255 underwent early CVC removal, while 225 had delayed or no CVC removal; 146 patients received no anticoagulation, among whom 116 underwent CVC removal alone. PE within 7 days occurred in 2 patients (0.78%) with early removal compared with 1 patient (0.44%) with delayed or no CVC removal (P > .9). PE or any cause of death within 7 days occurred in 3 patients in both the early removal (1.18%) and delayed/no removal (1.33%) groups (P > .9). In patients treated with CVC removal only (no anticoagulation), there were no PEs but 3 deaths within 7 days. In patients with hematological malignancy and CVC-associated UE-DVT, early removal of CVCs was not associated with an increased risk of PE compared with delayed or no removal.

Treatment of catheter-related thrombosis in patients with hematologic malignancies: A Venous thromboEmbolism Network U.S. retrospective cohort study.

INTRODUCTION: Optimal treatment of catheter-related thrombosis (CRT) is uncertain in patients with hematologic malignancy. We aimed to evaluate the treatment strategies, outcomes, and predictors of recurrent venous thromboembolism (VTE) associated with catheter-related thrombosis (CRT) in patients with hematologic malignancy. METHODS: We performed a multicenter retrospective cohort study of eight institutions through the Venous thromboEmbolism Network US. Patients with hematologic malignancies with documented CRT were identified using ICD-9 and ICD-10 diagnostic codes. Semi-competing risks proportional hazard regression models were created. RESULTS AND CONCLUSIONS: Of the 663 patients in the cohort, 124 (19%) were treated with anticoagulation alone, 388 (58%) were treated with anticoagulation and catheter removal, 119 (18%) treated with catheter removal only, and 32 (5%) had neither catheter removal nor anticoagulation. 100 (15%) patients experienced a recurrent VTE event. In the 579 patients who had catheter removal, the most common reason for catheter removal was the CRT [392 (68%)]. For subjects who received any anticoagulation (n = 512), total anticoagulation duration was not associated with VTE recurrence [1.000 (0.999-1.002)]. After adjustment patients treated with catheter removal only had an increased risk of VTE recurrence [2.50 (1.24-5.07)] and death [4.96 (2.47-9.97)]. Patients with no treatment had increased risk of death [16.81 (6.22-45.38)] and death after VTE recurrence [27.29 (3.13-238.13)]. In this large, multicenter retrospective cohort, we found significant variability in the treatment of CRT in patients with hematologic malignancy. Treatment without anticoagulation was associated with recurrent VTE.

Clinical and laboratory features of autoimmune hemolytic anemia associated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICPis) are a novel class of immunotherapeutic agents that have revolutionized the treatment of cancer; however, these drugs can also cause a unique spectrum of autoimmune toxicity. Autoimmune hemolytic anemia (AIHA) is a rare, but often severe, complication of ICPis. We identified 14 patients from nine institutions across the United States who developed ICPi-AIHA. The median interval from ICPi initiation to development of AIHA was 55 days (interquartile range [IQR], 22-110 days). Results from the direct antiglobulin test (DAT) were available for 13 of 14 patients: 8 patients (62%) had a positive DAT and 5 (38%) had a negative DAT. The median pretreatment and nadir hemoglobin concentrations were 11.8 g/dL (IQR, 10.2-12.9 g/dL) and 6.3 g/dL (IQR, 6.1-8.0 g/dL), respectively. Four patients (29%) had a preexisting lymphoproliferative disorder, and two (14%) had a positive DAT prior to initiation of ICPi therapy. All patients were treated with glucocorticoids, with three requiring additional immunosuppressive therapy. Complete and partial recoveries of hemoglobin were achieved in 12 (86%) and 2 (14%) patients, respectively. Seven patients (50%) were rechallenged with ICPis, and one (14%) developed recurrent AIHA. Clinical and laboratory features of ICPi-AIHA were similar in DAT positive and negative patients. ICPi-AIHA shares many clinical features with primary AIHA; however, a unique aspect of ICPi-AIHA is a high incidence of DAT negativity. Glucocorticoids are an effective first-line treatment in the majority of patients with ICPi-AIHA, and most patients who are rechallenged with an ICPi do not appear to develop recurrence of AIHA.

Acquired amegakaryocytic thrombocytopenia and red cell aplasia in a patient with thymoma progressing to aplastic anemia successfully treated with allogenic stem cell transplantation.

Association of pure red-cell aplasia with thymoma is well documented. However, acquired amegakaryocytic thrombocytopenia (AAMT) has been rarely associated with thymoma with only five reported cases in literature. We report a patient with thymoma complicated by pure red cell aplasia (PRCA) and AAMT who progressed to develop aplastic anemia (AA). The patient was refractory to 10-months of immunosuppressive therapy with cyclosporine, prednisone, and antithymocyte globulin. She was eventually treated with allogeneic stem cell transplantation (allo-SCT). On Day +323 the patient continues to be transfusion-independent. This case illustrates how in patients with thymoma and AAMT may herald development of AA. This is also the first report of a patient with AAMT progressing to thymoma-associated AA being successfully treated with allo-SCT. The successful outcome suggests allo-SCT as a feasible option similar to other AA patients.

Copper deficiency anemia: review article.

Copper is a crucial micronutrient needed by animals and humans for proper organ function and metabolic processes such as hemoglobin synthesis, as a neurotransmitter, for iron oxidation, cellular respiration, and antioxidant defense peptide amidation, and in the formation of pigments and connective tissue. Multiple factors, either hereditary or acquired, contribute to the increase in copper deficiency seen clinically over the past decades. The uptake of dietary copper into intestinal cells is via the Ctr1 transporter, located at the apical membrane aspect of intestinal cells and in most tissues. Copper is excreted from enterocytes into the blood via the Cu-ATPase, ATP7A, by trafficking the transporter towards the basolateral membrane. Zinc is another important micronutrient in animals and humans. Although zinc absorption may occur by direct interaction with the Ctr1 transporter, its absorption is slightly different. Copper deficiency affects physiologic systems such as bone marrow hematopoiesis, optic nerve function, and the nervous system in general. Detailed pathophysiology and its related diseases are explained in this manuscript. Diagnosis is made by measuring serum copper, serum ceruloplasmin, and 24-h urine copper levels. Copper deficiency anemia is treated with oral or intravenous copper replacement in the form of copper gluconate, copper sulfate, or copper chloride. Hematological manifestations are fully reversible with copper supplementation over a 4- to 12-week period. However, neurological manifestations are only partially reversible with copper supplementation.

Management of Immune-mediated Cytopenias in the Era of Cancer Immunotherapy: A Report of 4 Cases.

Recent advancements in immunotherapy have brought promising drugs to fight cancers; a subset of immunotherapy medications are known as checkpoint inhibitors. Their mechanism of action relies on upregulating antitumor response by reversing T-cell suppression; as a consequence the effect can also result in a spectrum of immune related complications. Reported complications to date include: skin, gastrointestinal mucosa, hypophysis, liver, endocrine system, nervous system, kidney, musculoskeletal system and the hematologic system. The management of immune related complications typically includes the use of steroids and other strategies of immunosuppression. The current recommendations are not organ-specific and little is known about the response and outcomes related to the hematologic system. Hereby we report four cases evaluated at the hematology service at the University of Texas MD Anderson Cancer Center for cytopenias after check point inhibitor therapies. All cases were responsive to conventional interventions for immune-mediated cytopenias.

Estimating chronic hepatitis C prognosis using transient elastography-based liver stiffness: A systematic review and meta-analysis.

Chronic hepatitis C (CHC) is a leading cause of hepatic fibrosis and cirrhosis. The level of fibrosis is traditionally established by histology, and prognosis is estimated using fibrosis progression rates (FPRs; annual probability of progressing across histological stages). However, newer noninvasive alternatives are quickly replacing biopsy. One alternative, transient elastography (TE), quantifies fibrosis by measuring liver stiffness (LSM). Given these developments, the purpose of this study was (i) to estimate prognosis in treatment-naïve CHC patients using TE-based liver stiffness progression rates (LSPR) as an alternative to FPRs and (ii) to compare consistency between LSPRs and FPRs. A systematic literature search was performed using multiple databases (January 1990 to February 2016). LSPRs were calculated using either a direct method (given the difference in serial LSMs and time elapsed) or an indirect method given a single LSM and the estimated duration of infection and pooled using random-effects meta-analyses. For validation purposes, FPRs were also estimated. Heterogeneity was explored by random-effects meta-regression. Twenty-seven studies reporting on 39 groups of patients (N = 5874) were identified with 35 groups allowing for indirect and 8 for direct estimation of LSPR. The majority (~58%) of patients were HIV/HCV-coinfected. The estimated time-to-cirrhosis based on TE vs biopsy was 39 and 38 years, respectively. In univariate meta-regressions, male sex and HIV were positively and age at assessment, negatively associated with LSPRs. Noninvasive prognosis of HCV is consistent with FPRs in predicting time-to-cirrhosis, but more longitudinal studies of liver stiffness are needed to obtain refined estimates.

Frequency of venous thromboembolism events during acute inpatient rehabilitation in a comprehensive cancer centre.

OBJECTIVE: To determine the frequency of venous thromboembolism, possible predictors, and the association between venous thromboembolism and Functional Independence Measure (FIM) scores and length of stay among cancer patients admitted to the inpatient rehabilitation unit at a cancer centre. DESIGN: Retrospective analysis of patients admitted to acute inpatient rehabilitation from September 2011 to June 2013. Subject/patients: Cancer patients in the acute inpatient rehabilitation unit within a tertiary cancer centre. METHODS: International Classification of Diseases (ICD-9) codes identified deep vein thrombosis, pulmonary embolism, and inferior vena cava filter. RESULTS: Venous thromboembolism occurred in 32/611 patients (5.2%): 23/611 (3.8%) during the course of hospitalization before admission to rehabilitation, and 9/611 patients (1.5%) during rehabilitation. Patients with lower extremity oedema at admission (p = 0.0218) had a higher chance of subsequently developing venous thromboembolism. Patients with venous thromboembolism during rehabilitation had a significantly lower FIM transfer score at admission to rehabilitation (p = 0.0247), a longer length of stay in rehabilitation (p = 0.0013) and overall hospitalization (p = 0.0580). CONCLUSION: Cancer patients with low FIM transfer scores and lower extremity oedema are at higher risk of venous thromboembolism. Patients with these clinical findings at admission may require measures for more aggressive surveillance for the presence of venous thromboembolism. Patients with venous thromboembolism had an increased length of stay in rehabilitation, but ultimately did not have significant differences in FIM score changes.

Cost-effectiveness analysis of universal screening for carbapenemase-producing Enterobacteriaceae in hospital inpatients.

The purpose of this study was to assess the cost-effectiveness of screening all hospital inpatients for carbapenemase-producing Enterobacteriaceae (CPE) at the time of hospital admission, compared to not screening, from a US hospital perspective. We used a linked transmission/Markov model to compare outcomes for a typical hospitalized medical patient, from a community with a colonization prevalence of 0.05%. Outcomes were number of colonized patients, CPE-related clinical infections and deaths, expected quality-adjusted life years (QALYs), cost, and the incremental cost-effectiveness ratio (ICER). Sensitivity analyses were performed to assess the effect of parameter uncertainty, using a willingness-to-pay threshold of $100,000 per QALY gained. Screening prevented six CPE colonization cases per 1000 patients (1/1000 colonized with screening, 7/1000 without screening), over half of all symptomatic CPE infections (2/10,000 symptomatic with screening, 5/10,000 symptomatic without screening), and nearly half of all CPE-related deaths (8/100,000 deaths with screening, 15/100,000 deaths without screening). Screening accrued 0.0009 additional QALYs and cost an additional $24.68, compared to not screening, and was cost-effective (ICER $26,283 per QALY gained). Our results were sensitive to uncertainty in prevalence and the number of secondary colonizations per colonized patient. Screening was not cost-effective at a prevalence below 0.015% or if transmission to fewer than 0.9 new patients occurred for each colonized patient. At prevalence levels above 0.3%, screening was cost-saving compared to not screening. Screening inpatients for CPE carriage is likely cost-effective, and may be cost-saving, depending on the local prevalence of carriage.

Retrospective review of lupus nephritis in a New Zealand multi-ethnic cohort.

Increased lupus nephritis has been reported in Pacific Island and Maori populations. Previous studies suggest ethnic variation in response to immunosuppression treatment; however this has not been assessed in Pacific Island and Maori cohorts. This retrospective study reviewed class 3, 4 and 5 lupus nephritis outcomes and response to induction immunosuppression over a 10-year period in a New Zealand multi-ethnic cohort with high Pacific Island representation. This included 49 renal biopsies in 41 patients; by ethnicity Pacific Island 53.7%, Asian 31.7%, Caucasian 12.2%, and New Zealand Maori 2.4%. There were 11 class 3, 24 class 4 and 17 class 5 either alone or in combination with class 3/4. There were no statistically significant differences in renal function or proteinuria between ethnic groups at baseline. Pacific Island class 3/4 showed similar rates of renal remission with intravenous cyclophosphamide (6/8) and mycophenolate (4/7) induction treatment; results were comparable to the overall study group. There were no deaths or permanent dialysis requirements in the first six months of treatment, and no increased risk of adverse outcomes when stratified by ethnicity. Five lupus nephritis relapses occurred during maintenance treatment and there was no apparent ethnicity bias. CONCLUSION: Pacific Island people disproportionately present with increased lupus nephritis; and had comparable renal remission rates with intravenous cyclophosphamide and oral mycophenolate which were similar to the whole study cohort.

Successful treatment of aplastic anemia-paroxysmal nocturnal hemoglobinuria associated with eosinophilic fasciitis with matched unrelated donor allogeneic peripheral blood stem cell transplantation.

We report the first patient case of successful treatment intervention for both eosinophilic fasciitis and aplastic anemia with allogeneic peripheral blood stem cell transplantation from a matched unrelated donor after multiple immunosuppressant failure.

Trends in health care utilization and costs attributable to hepatocellular carcinoma, 2002-2009: a population-based cohort study.

BACKGROUND: The incidence of hepatocellular carcinoma (hcc) and the complexity of its diagnosis and treatment are increasing. We estimated trends in net health care utilization, costs of care attributable to hcc in Ontario, and rate ratios of resource use at various stages of care. METHODS: This population-based retrospective cohort study identified hcc patients and non-cancer control subjects, and health care resource utilization between 2002 and 2009. Generalized estimating equations were then used to estimate net health care utilization (hcc patients vs. the matched control subjects) and net costs of care attributable to hcc. Generalized linear models were used to analyze rate ratios of resource use. RESULTS: We identified 2832 hcc patients and 2808 matched control subjects. In comparison with the control subjects, hcc patients generally used a greater number of health care services. Overall, the mean net cost of care per 30 patient-days (2013 Canadian dollars) attributable to outpatient visits and hospitalizations was highest in the pre-diagnosis (1 year before diagnosis), initial (1st year after diagnosis), and end-of-life (last 6 months before death, short-term survivors) phases. Mean net homecare costs were highest in the end-of-life phase (long-term survivors). In the end-of-life phase (short-term survivors), mean net costs attributable to outpatient visits and total services significantly increased to $14,220 from $1,547 and to $33,121 from $14,450 (2008-2009 and 2002-2003 respectively). CONCLUSIONS: In hcc, our study found increasing resource use and net costs of care, particularly in the end-of-life phase among short-term survivors. Our findings offer a basis for resource allocation decisions in the area of cancer prevention and control.

JAK2 (V617F) Positive Latent Myeloproliferative Neoplasm Presenting with Splanchnic Vein Thrombosis.

Myeloproliferative neoplasms (MPNs) are chronic clonal hematopoietic stem cell disorders characterized by proliferation of one or more of the granulocytic, red cell or platelet lineages in the bone marrow, with fairly normal maturation, resulting in increase in the leukocyte, erythrocytes and platelets in the blood. They also represent a common cause of splanchnic vein thrombosis (SVT). Herein, we describe a case of SVT as a presenting symptom of latent MPN. The patient has had normal complete blood counts since presentation. 3 ½ years later, she was found to have JAK2 (V617F) mutation and bone marrow biopsy was consistent with MPN. Five years later, her platelet count started to rise. In patients with a first episode of SVT, thrombophilia workup including JAK2 (V617F) mutation is warranted. Anticoagulation with heparin and warfarin is the treatment of choice for SVT.

Lower life expectancy among people with an HCV notification: a population-based linkage study.

Among people with hepatitis C virus (HCV) infection, liver disease-related deaths have risen over the last 20 years. Life expectancy has not been estimated in this population. HCV notifications (mandatory notification of anti-HCV-positive serology since 1991) reported to the New South Wales Health Department from 1992 to 2006 were linked to cause of death data. Abridged life tables were constructed from age-specific mortality rates. Life expectancy from ages 18-70 years for non-drug-related mortality causes was estimated using competing risk methods and compared to the general population of Australia. The cohort comprised 81 644 individuals with an HCV notification, with median follow-up of 7.6 years. Median age at notification was 34 years [interquartile range (IQR) 28-42] and 63% were male. Between 1992 and 2006, 4607 deaths occurred. Median age at liver- and drug-related death among males was 51 (IQR 45-66) and 36 (IQR 31-42) years, respectively, and among females was 63 (IQR 49-74) and 36 (IQR 30-41) years, respectively. In each year of follow-up before 2000, 15-21% of deaths were liver- and 30-39% were drug-related. After 2000, liver-related deaths increased to 20-26% of deaths in each year and drug-related deaths decreased to 13-19%. Excluding drug-related causes of death, life expectancy was lowered by an average of 4.2 (SD ± 1.0) and 5.4 (SD ± 0.7) years for males and females, respectively. Among people with an HCV notification, an increasing proportion of deaths are liver-related. Following removal of drug-related mortality, life expectancy in this population remained considerably lower, compared with the general population.

Coadministration of telaprevir and transcatheter arterial chemoembolization in hepatitis C virus-associated hepatocellular carcinoma.

The use of direct-acting antiviral agents (e.g., telaprevir, boceprevir) has improved response rates in patients with hepatitis C virus (HCV) genotype 1 infections. Substantial number of drug-drug interactions are anticipated with the use of telaprevir, a cytochrome P450 3A and P-glycoprotein substrate and inhibitor. Herein we describe a patient with HCV-associated hepatocellular carcinoma treated simultaneously with a telaprevir-containing regimen and localized chemotherapy (transcatheter arterial chemoembolization) with doxorubicin. No clinically relevant interactions or adverse events developed while on antiviral therapy.