Systemic toxicities of trastuzumab-emtansine predict tumor response in HER2+ metastatic breast cancer.

The mechanism by which trastuzumab-emtansine (T-DM1) causes systemic toxicities apart from trastuzumab alone is currently unknown. We hypothesized that the systemic toxicities from T-DM1 may have been caused by the free and active maytansine released from the lysed HER2+ tumor cells, and if so, they may correlate with the response to treatment and eventually disease-free survival or patient outcome. In a retrospective, observational study, we evaluated 73 patients from three centers in the United States and Canada with advanced HER2+ breast cancer that received at least one dose of T-DM1. Toxicity grades were summed to create a corresponding toxicity sum score (TSS), and its association with clinical outcomes was analyzed. A higher TSS was significantly associated with longer progression-free survival with an HR = 0.66 [95% confidence interval [CI]: 0.47-0.92], P = .014, for each 1-point increase in the TSS score. Adjusted for baseline platelet count, aspartate transaminase and alanine transaminase, higher TSS remains significantly associated with longer progression-free survival with adjusted HR = 0.67 [95% CI: 0.47-0.93], P = .020. The analysis suggests that the systemic toxicities of T-DM1 were significantly correlated with its clinical efficacy. This is the first report to correlate the systemic toxicities of T-DM1 with clinical outcome. Further, this suggests that systemic toxicities of antibody-drug conjugates (ADCs) may serve as a predictive biomarker, particularly if noncleavable linkers are used. If confirmed in larger prospective studies, the present finding is significant because most ADCs do not have a biomarker predictive of clinical outcome other than the presence or absence of the antibody target.

Epidemiology, Staging, and Management of Multiple Myeloma.

Multiple myeloma (MM) is a plasma cell disorder that is on the rise throughout the world, especially in the US, Australia, and Western Europe. In the US, MM accounts for almost 2% of cancer diagnoses and over 2% of cancer deaths (more than double the global proportion). Incidence has risen by 126% globally and over 40% in the US since 1990, while global mortality has risen by 94% and US mortality has fallen by 18%. The 5 year survival in the US has more than doubled over the past decades with the introduction of new targeted therapies and transplant techniques. Risk factors for MM include age (average age of diagnosis is 69), race (African Americans are over double as likely to be diagnosed), sex (men are at a 1.5× risk), and family history. Diagnosis includes serum or urine electrophoresis and free light-chain assay but requires bone marrow biopsy. It is distinguished from smoldering myeloma and monoclonal gammopathy of undetermined significance by a high (>3 g/dL) level of M-protein (monoclonal light chains) and the presence of CRAB (Hypercalcemia, Renal failure, Anemia, Bone pain) symptoms, which include hypercalcemia, renal failure, anemia, and bone pain, suggesting an end-organ damage. International staging system staging involves beta 2 microglobulin and albumin levels, while the revised system considers prognostic factors such as lactate dehydrogenase levels and chromosomal abnormalities. Front-line management includes induction regimen, maintenance therapy and hematopoietic cell transplantation for eligible patients and bisphosphonates or bone-stimulating agents for the prevention of skeletal events. Treatment for relapsed disease includes newly approved monoclonal antibodies like the CD38-targeting daratumumab, proteasome inhibitors, immunomodulating agents, and investigational therapies such as B cell maturation antigen Chimeric antigen receptor T cells.

Premedications for Cancer Therapies: A Primer for the Hematology/Oncology Provider.

Chemotherapeutic agents and radiation therapy are associated with numerous potential adverse events (AEs). Many of these common AEs, namely chemotherapy- or radiation-induced nausea and vomiting, hypersensitivity reactions, and edema, can lead to deleterious outcomes (such as treatment nonadherence or cessation, or poor clinical outcomes) if not prevented appropriately. The occurrence and severity of these AEs can be prevented with the correct prescribing of prophylactic medications, often called "premedications." The advanced practitioner in hematology/oncology should have a good understanding of which chemotherapeutic agents are known to place patients at risk for these adverse events as well as be able to determine appropriate prophylactic medications to employ in the prevention of these adverse events. While several guidelines and literature exist regarding best practices for prophylaxis strategies, differences among guidelines and quality of data should be explored in order to accurately implement patient-specific recommendations. Herein, we review the existing literature for prophylaxis and summarize best practices.

DIAPH1 Mutation as a Novel Cause of Autosomal Dominant Macrothrombocytopenia and Hearing Loss.

Macrothrombocytopenia (MTP) is a group of rare disorders characterized by giant platelets, thrombocytopenia, and variable association with abnormal bleeding. Inherited MTP are frequently misdiagnosed as immune thrombocytopenia. Associated second-organ manifestation can help narrow down syndromic MTPs. We describe a case of autosomal dominant sensorineural hearing loss and MTP caused by a gain of function mutation in DIAPH1. This mutation causes altered megarkaryopoiesis and platelet cytoskeletal deregulation. Although hearing loss and MTP were likely progressive, clinically significant bleeding was not observed. DIAPH1-related MTP can be distinguished clinically from MYH9 mutation by the absence of cataracts and glomerular disease.

Lenalidomide-Associated Immune Thrombocytopenia: A Case Report and Review of the Literature.

Lenalidomide is indicated in the front-line management of multiple myeloma. More recently, it has been introduced for use in treating other hematologic malignancies. Although the drug is known to cause myelosuppression, there have been rare reports of lenalidomide-associated immune thrombocytopenia (ITP). Here, we review the literature on lenalidomide-associated ITP and report upon a 59-year-old man who was administered lenalidomide due to concern of progressive multiple myeloma more than a year following his having undergone an autologous hematopoietic stem cell transplant. His platelet count precipitously declined and lead to his hospitalization. Despite our withholding of the drug, he did not respond to platelet transfusions or administration of corticosteroids. He was successfully managed with intermittent immune globulin for several months before definitive treatment with splenectomy, which resulted in the complete resolution of his thrombocytopenia. A literature search identified a total of six additional cases of lenalidomide-associated ITP. Similarly, many of the reported cases were associated with persistent thrombocytopenia after discontinuation of the drug. Furthermore, these patients were generally managed successfully with standard ITP therapies, such as corticosteroids or intravenous immune globulin.

Mortality trends in sickle cell patients.

BACKGROUND: Sickle cell disease affects a significant portion of US patients with African descent. It continues to be one of the leading causes of frequent hospitalizations and high in-hospital morality risk. Until the approval of disease-modifying therapies in last two years, medical therapy has relied mostly on management of pain episodes and the use of hydroxyurea. We discuss the nationwide analysis of trends in in-hospital mortality in patients with Sickle Cell Disease from 2000 to 2014. METHODS: Trends of in-hospital mortality in sickle cell patients were analyzed from a database provided by the Agency of Healthcare Research and Quality. From the data hospitalization rates and in-hospital mortality in categories by region in the US, hospital size, health insurance status, comorbidities and gender were examined. Patterns of in-hospital mortality were analyzed by logistic regression. RESULTS: Ratio for hospitalization and mortality among the four regions described Northeast, Midwest, South, West with respective values of 0.63%, 0.65%, 0.76% and 0.89% with P = 0.008 and OR = 1.07. Odds ratio for sickle cell patients that died during hospitalization and health insurance status was OR = 0.08. Comorbidities considered in sickle cell patients; diabetes mellitus (DM), hypertension (HTN), hyperlipidemia (HLD), chronic kidney disease (CKD), smoking status. The odds ratio for comorbidities show A-fib with a value of OR = 4.47, followed by hypertension OR = 1.92, diabetes mellitus OR = 1.44 and chronic kidney disease OR = 1.29, smoking status OR = 0.60. Mortality-hospitalization ratio by gender was: males 0.77% and females 0.69% with OR = 0.87. CONCLUSIONS: In-hospital mortality by US regions, as well as health insurance status are important measurable elements that show the impact of the disease from a public health perspective. Further and more specific data of regions by states, comorbidities by states and sex, as well as health insurance status by states will provide further insight in local mortality trends.

Outcomes of hospitalized patients with myocardial infarction and immune thrombocytopenic purpura: a cross sectional study over 15 years.

BACKGROUND: Immune Thrombocytopenic Purpura (ITP) is an autoimmune disorder characterized by low platelet counts and mucocutaneous bleeding. The outcomes of hospitalized patients with ITP and myocardial infarction (MI) have not been extensively studied and may help identify risk factors associated with adverse outcomes in this unique patient population. METHODS: Patients with ITP who were admitted with MI using the National Inpatient Database for the years 2000 to 2014. Patient demographics, hospital characteristics and medical comorbidities were studied. Chi square test was used to determine associations with statistical significance and logistic regression was used to determine independent predictors of mortality. RESULTS: A total of 753732 hospitalized patients with ITP were identified over the time period of 2000 to 2014, of which 37695 patients had both ITP and acute MI. There were more females with ITP in general (60% females vs. 40 males), but more males with ITP and acute MI (55.8% males vs. 44.2% females; P=0.0000). Caucasians were affected the most (5.5%) amongst all races and the age group of 65-79 years had the highest percentage of patients with ITP and MI (7.3%). The classical risk factors of hypertension, hyperlipidemia, and diabetes were also noted to be highly prevalent in patients with ITP and MI. 10.05% of patients with ITP and acute MI died during hospitalization, while 4% of all patients with ITP died during hospitalization (P<0.05). Multiple regression showed that stent placement, female gender, blood transfusions, platelet transfusion, 80+ age group and higher Charlson's score were independent predictors of mortality in patients with ITP which have MI. CONCLUSIONS: MI is associated with an increased rate of in-hospital death in patients with ITP. Both blood transfusions and platelet transfusions adversely affect outcomes in the management of AMI in ITP patients.

Analysis of outcomes in hospitalized pregnant patients with acute myeloid leukemia.

BACKGROUND: There have been significant advances in the management of acute myeloid leukemia (AML) in the past decade. However, management of AML in the pregnant patient has been challenging as most interventions are contraindicated in pregnancy. Medical termination of pregnancy is advocated over chemotherapy in the first trimester as delaying chemotherapy could often be fatal. Chemotherapy during second and third trimesters may be provided with close surveillance of fetal abnormalities. The outcomes in these patients have not been systematically studied and have been limited to case reports and case series in medical literature. METHODS: Patients hospitalized with a diagnosis of AML were identified using the International Classification of Disease (ICD-9) codes in the National Inpatient Sample database. This database is maintained by the Agency of Healthcare Research Quality under the United States Department of Health and Human Services. It represents 20% of all hospitalizations occurring in the United States every year. Amongst these AML patients, all patients who were pregnant were identified and their demographic information was extracted. Other details related to their hospitalization, hospital size, location, region and teaching status were also determined. The association of outcomes with common medical comorbidities was studied. Pregnancy related outcomes, mode of delivery and mortality rates were calculated for the 15 year time period. RESULTS: During the time period of 2000 to 2014, 678942 hospitalizations involved AML patients of which 5076 were noted to be from pregnant women. The hospitalization trend gradually increased over these years and was noted to be the highest in the age group of 18-34 years. The highest hospitalization rates were noted in African American and Native American patient populations. Hypertension, hyperlipidemia, chronic kidney disease and smoking were noted to be more prevalent in pregnant women with AML. A majority of these patients had a Charlson's comorbidity index of 1-3. 3.5% of patients underwent medical termination of pregnancy, 16.25% suffered from pregnancy related complications, 0.6% suffered from puerperal infection, 4% of patients had normal vaginal delivery, 2.8% of patients had caesarian section and 5.7% of patient died. The rate of mortality was the highest in Native Americans followed by Caucasians. Multiple regression showed that odds of mortality have decreased from 2000 to 2015 and that a higher Charlson's comorbidity score was an independent predictor of mortality. CONCLUSIONS: This is the first nationwide study to document the outcomes of pregnancy in hospitalized AML patients. AML in pregnancy is rare and this study shows that the mortality has been improving over the past 15 years. Notably, vaginal delivery has been more common than caesarian section in pregnant AML patients. Native Americans have high prevalence and high mortality rates, a likely result of healthcare disparity. Pregnant AML patients with high Charlson's comorbidity score may benefit from aggressive management of their comorbidities. Further studies are required to better characterize outcomes in pregnant women with AML.

A nationwide analysis of outcomes of stroke in hospitalized patients with essential thrombocythemia: 2006 to 2014.

BACKGROUND: Essential thrombocythemia (ET) is a subtype of myeloproliferative neoplasm associated with an increased risk of thrombohemorrhagic complications such as stroke. However, studies of prevalence and outcomes of stroke in hospitalized patients with ET have been limited to case series. METHODS: Data from the National Inpatient Sample was utilized to identify outcomes in hospitalized patient with ET who were admitted for stroke. Utilizing the current procedural terminology code (CPT) for ET, outcomes of patients with ET who were hospitalized with stroke were studied for the years 2006 to 2014. Patient demographics of age, gender and race were collected and hospital characteristics of location and size were correlated to outcomes. Chi square test was used to determine odds ratios and multiple logistic regression was used to determine independent predictors of mortality. RESULTS: Between the years of 2006 to 2014, a total of 552422 hospitalizations involved patients with a diagnosis of ET, 20650 of which were due to stroke. The percentage of stroke in these hospitalizations varied between 3.64 to 4.29 over 9 years and mortality in these patients did not significantly change during this time period. The prevalence of stroke was highest amongst Asians and Caucasians (4.7% and 3.86%) with a statistically significant difference (P=0.0000). A majority of ET patients with stroke were discharged to skilled nursing facilities. Multiple regression showed that female gender, atrial fibrillation, stroke, higher Charlson's comorbidity score and 80+ age were independent predictors of mortality (OR: 0.75, 1.35, 1.8, 2 to 5.7, 13.9 respectively). CONCLUSIONS: This study demonstrated that Female gender, atrial fibrillation, stroke, higher Charlson's comorbidity score and 80+ age group were found to be statistically significant independent predictors of mortality (OR: 0.75, 1.35, 1.8, 2 to 5.7, 13.9 respectively) in patients with ET and stroke. Inclusion of these factors in the risk stratification of patients with ET may decrease the morbidity and mortality associated with the disease.

Regulation of iron homeostasis through the erythroferrone-hepcidin axis in sickle cell disease.

Sickle cell disease (SCD) has a distinct pattern of transfusional iron overload (IO) when compared to transfusion-dependent ß-thalassaemia major (TDT). We conducted a single institution prospective study to evaluate plasma biomarkers of iron regulation and inflammation in patients with SCD with IO (SCD IO cases, n = 22) and without IO (SCD non-IO cases, n = 11), and non-SCD controls (n = 13). Hepcidin was found to be inappropriately low, as evidenced by a significantly higher median hepcidin/ferritin ratio in non-SCD controls compared to SCD IO cases (0·3 vs. 0·02, P < 0·0001) and SCD non-IO cases (0·3 vs. 0·02, P < 0·0001), suggesting that certain inhibitory mechanism (s) work to suppress hepcidin in SCD. As opposed to the SCD non-IO state, where hepcidin shows a strong significant positive correlation with ferritin (Spearman ρ = 0·7, P = 0·02), this correlation was lost when IO occurs (Spearman ρ = -0·2, P = 0·4). Although a direct non-linear correlation between erythroferrone (ERFE) and hepcidin did not reach statistical significance both in the IO (Spearman ρ = -0·4, P = 0·08) and non-IO state (Spearman ρ = -0·6, P = 0·07), patients with highest ERFE had low hepcidin levels, suggesting that ERFE contributes to hepcidin regulation in some patients. Our results suggest a multifactorial mechanism of hepcidin regulation in SCD.