Proteomic profiling for biomarker discovery in heparin-induced thrombocytopenia.

New analytical techniques can assess hundreds of proteins simultaneously with high sensitivity, facilitating the observation of their complex interplay and role in disease mechanisms. We hypothesized that proteomic profiling targeting proteins involved in thrombus formation, inflammation, and the immune response would identify potentially new biomarkers for heparin-induced thrombocytopenia (HIT). Four existing panels of the Olink proximity extension assay covering 356 proteins involved in thrombus formation, inflammation, and immune response were applied to randomly selected patients with suspected HIT (confirmed HIT, n=32; HIT ruled-out, n=38; positive heparin/PF4 [H/PF4] antibodies, n=28). The relative difference in protein concentration was analyzed using a linear regression model adjusted for sex and age. To confirm the test results, soluble P-selectin was determined using ELISA in above mentioned patients and an additional second dataset (n=49). HIT was defined as a positive heparin-induced platelet aggregation test (HIPA; washed platelet assay). Among 98 patients of the primary dataset, the median 4Ts score was 5 in patients with HIT, 4 in patients with positive heparin/PF4 antibodies, and 3 in patients without HIT. The median OD of a polyspecific heparin/PF4 ELISA was 3.0, 0.9, and 0.3, respectively. Soluble P-selectin remained statistically significant after multiple test adjustments. The area under the receiver-operating-characteristics-curve was 0.81 for Olink and 0.8 for ELISA. Future studies shall assess the diagnostic and prognostic value of soluble P-selectin in the management of HIT.

Accuracy of Diagnosing Heparin-Induced Thrombocytopenia.

Importance: Heparin-induced thrombocytopenia (HIT) is a life-threatening condition that requires urgent diagnostic clarification. However, knowledge of the diagnostic utility of the recommended diagnostic tests is limited in clinical practice. Objective: To evaluate the current diagnostic practice for managing the suspicion of HIT. Design, Setting, and Participants: This prospective diagnostic study was conducted from January 2018 to May 2021 among consecutive patients with suspected HIT from 11 study centers in Switzerland, Germany, and the United States. Detailed clinical data and laboratory information were recorded. Platelet factor 4/heparin antibodies were quantified using an automated chemiluminescent immunoassay (CLIA). A washed-platelet heparin-induced platelet activation (HIPA) test was used as a reference standard to define HIT. Exposures: Suspicion of HIT. Main Outcomes and Measures: The primary outcome was the diagnostic accuracy of the 4Ts score, the CLIA, and the recommended algorithm serially combining both tests. Results: Of 1448 patients included between 2018 and 2021, 1318 were available for the current analysis (median [IQR] age, 67 [57-75] years; 849 [64.6%] male). HIPA was positive in 111 patients (prevalence, 8.4%). The most frequent setting was intensive care unit (487 [37.0%]) or cardiovascular surgery (434 [33.0%]). The 4Ts score was low risk in 625 patients (46.8%). By 2 × 2 table, the numbers of patients with false-negative results were 10 (9.0%; 4Ts score), 5 (4.5%; CLIA), and 15 (13.5%; recommended diagnostic algorithm). The numbers of patients with false-positive results were 592 (49.0%; 4Ts score), 73 (6.0%; CLIA), and 50 (4.1%; recommended diagnostic algorithm), respectively. Conclusions and Relevance: In this diagnostic study of patients suspected of having HIT, when the recommended diagnostic algorithm was used in clinical practice, antibody testing was required in half the patients. A substantial number of patients were, however, still misclassified, which could lead to delayed diagnosis or overtreatment. Development of improved diagnostic algorithms for HIT diagnosis should be pursued.

Limited concordance of heparin/platelet factor 4 antibody assays for the diagnosis of heparin-induced thrombocytopenia: an analysis of the TORADI-HIT study.

BACKGROUND: Anecdotal reports suggest that the correlation between heparin/platelet factor 4 (PF4) antibody assays for the diagnosis of heparin-induced thrombocytopenia (HIT) is limited. OBJECTIVES: To investigate the correlation between widely used assays and examine possible factors contributing to variability. METHODS: This is a large, prospective cohort study with 10 participating tertiary care hospitals including 1393 patients with suspected HIT in clinical practice. HIT was defined by a positive heparin-induced platelet activation (HIPA) assay (washed platelet reference standard test). Three different immunoassays were used to measure heparin/PF4 antibodies: chemiluminescent immunoassay, enzyme-linked immunosorbent assay, and particle gel immunoassay. Various factors that could influence the assays were examined: sex (male or female), age (<65 years or ≥65 years), unfractionated heparin exposure, presence of thrombosis, cardiovascular surgery, and intensive care unit. Spearman's correlation coefficients were calculated. Z-scores and diagnostic odds ratios were determined in the aforementioned subgroups of patients. RESULTS: Among 1393 patients, 119 were classified as HIT-positive (prevalence, 8.5%). The median 4Ts score was 5 (IQR, 4-6) in patients with HIT compared with 3 (IQR, 2-4) in patients without HIT. Correlations (rs) between immunoassays were weak (0.53-0.65). Inconsistencies between immunoassays could not be explained by further analyses of z-scored test results and diagnostic odds ratios in subgroups of patients. CONCLUSION: The correlation between widely used heparin/PF4 antibody assays was weak, and key factors could not explain this variability. Standardization of immunoassays is requested to improve comparability.

A machine-learning model for reducing misdiagnosis in heparin-induced thrombocytopenia: A prospective, multicenter, observational study.

Background: Diagnosing heparin-induced thrombocytopenia (HIT) at the bedside remains challenging, exposing a significant number of patients at risk of delayed diagnosis or overtreatment. We hypothesized that machine-learning algorithms could be utilized to develop a more accurate and user-friendly diagnostic tool that integrates diverse clinical and laboratory information and accounts for complex interactions. Methods: We conducted a prospective cohort study including 1393 patients with suspected HIT between 2018 and 2021 from 10 study centers. Detailed clinical information and laboratory data were collected, and various immunoassays were conducted. The washed platelet heparin-induced platelet activation assay (HIPA) served as the reference standard. Findings: HIPA diagnosed HIT in 119 patients (prevalence 8.5%). The feature selection process in the training dataset (75% of patients) yielded the following predictor variables: (1) immunoassay test result, (2) platelet nadir, (3) unfractionated heparin use, (4) CRP, (5) timing of thrombocytopenia, and (6) other causes of thrombocytopenia. The best performing models were a support vector machine in case of the chemiluminescent immunoassay (CLIA) and the ELISA, as well as a gradient boosting machine in particle-gel immunoassay (PaGIA). In the validation dataset (25% of patients), the AUROC of all models was 0.99 (95% CI: 0.97, 1.00). Compared to the currently recommended diagnostic algorithm (4Ts score, immunoassay), the numbers of false-negative patients were reduced from 12 to 6 (-50.0%; ELISA), 9 to 3 (-66.7%, PaGIA) and 14 to 5 (-64.3%; CLIA). The numbers of false-positive individuals were reduced from 87 to 61 (-29.8%; ELISA), 200 to 63 (-68.5%; PaGIA) and increased from 50 to 63 (+29.0%) for the CLIA. Interpretation: Our user-friendly machine-learning algorithm for the diagnosis of HIT (https://toradi-hit.org) was substantially more accurate than the currently recommended diagnostic algorithm. It has the potential to reduce delayed diagnosis and overtreatment in clinical practice. Future studies shall validate this model in wider settings. Funding: Swiss National Science Foundation (SNSF), and International Society on Thrombosis and Haemostasis (ISTH).

COVID-19 vaccination associated severe immune thrombocytopenia.

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 has emerged as a deadliest global pandemic after its identification in December 2019 in Wuhan, China resulting in more than three million deaths worldwide. Recently FDA issued emergency authorization for three vaccines for prevention of COVID-19. Here in, we report three cases of severe immune thrombocytopenia (ITP) following COVID-19 vaccination and their clinical course. CASE PRESENTATIONS: Case #1: 53 year old male with past medical history of Crohn's disease was admitted for myalgias and diffuse petechial rash 8 days after receiving second dose of Pfizer-BioNTech COVID-19 vaccine. A complete blood test showed a platelet count of 2 × 109/L. Patient did not have a prior history of thrombocytopenia and other causes of thrombocytopenia were ruled out by history and pertinent lab data. He received two doses of intravenous immunoglobulin and oral dexamethasone for 4 days resulting in normalization of platelet counts. Case #2: 67 year male with past medical history of chronic ITP in remission was admitted for melena 2 days after receiving his first dose of Pfizer-BioNTech COVID-19 vaccine. A complete blood test showed a platelet count of 2 × 109/L. Physical exam showed generalized petechiae. There was no history of recent flares of ITP and patient had normal platelet counts following his splenectomy 4 years ago. He received two doses of IVIG and oral dexamethasone for 4 days with gradual improvement in platelet counts. Case #3: 59 year old female with past medical history of chronic ITP secondary to SLE was admitted for bloody diarrhea 2 days after receiving her first dose of Johnson and Johnson COVID-19 vaccine. Physical exam was unremarkable. A complete blood test showed platelet count of 64 × 109/L which dropped to 27 × 109/L during hospital course. She received oral dexamethasone for 4 days with improvement in platelet counts. CONCLUSION: COVID-19 vaccination induced ITP has been recently acknowledged. However, given very few cases and limited data, currently there are no guidelines for management of ITP caused by COVID-19 vaccine as well as vaccination of people with predisposing conditions.

International survey on Helicobacter pylori testing in patients with immune thrombocytopenia: Communication of the platelet immunology scientific and standardization committee.

Essentials When to test and treat H pylori among patients with ITP is controversial. We report the results of an international survey administered to physicians with experience treating ITP across 39 countries. The decision to test for H pylori was influenced by country, country of origin, and concomitant gastrointestinal symptoms. Testing and treating for H pylori among patients with ITP varied across geographic regions. ABSTRACT: Background Investigations for patients suspected of immune thrombocytopenia (ITP) lack standardization. A controversial issue is whether such patients should be tested for Helicobacter pylori, a known cause of secondary ITP. Objectives This Scientific and Standardization Committee Communication reports the results of an international survey to describe patterns of practice with respect to screening and treatment of H pylori among patients with ITP. Patients/Methods A 17-item scenario-based questionnaire was delivered to hematologists in countries across the world. The questionnaire was pilot tested before use. We used snowball sampling and a contact list of physicians from the Platelet Disorders Support Association to identify survey respondents. Data were analyzed descriptively. Results A total of 186 respondents from 39 countries completed the survey. Response rate from the snowball sample was 53.6%. Twenty-nine percent (n = 55) of respondents always tested ITP patients for H pylori, and 53% (n = 98) sometimes tested. Of the 37 respondents from Asia and the Middle East, 51.4% (n = 19) always tested for H pylori for the stated reasons of high local prevalence and perceived benefit of treatment on platelet count levels. Respondents were more likely to test patients who were from Asia (145/177, 80%) and who had concomitant gastrointestinal symptoms (133/183, 72%). For eradication therapy, 71 of 118 (60.2%) respondents used the combination of a proton pump inhibitor, clarithromycin, and amoxicillin for 14 days. Conclusions This international survey showed that testing for H pylori was most common in Asia and in patients from Asia. Testing and treating practices varied across geographic regions.

Perioperative oral eltrombopag versus intravenous immunoglobulin in patients with immune thrombocytopenia: a non-inferiority, multicentre, randomised trial.

BACKGROUND: Patients with immune thrombocytopenia are at risk of bleeding during surgery, and intravenous immunoglobulin is commonly used to increase the platelet count. We aimed to establish whether perioperative eltrombopag was non-inferior to intravenous immunoglobulin. METHODS: We did a randomised, open-label trial in eight academic hospitals in Canada. Patients were aged at least 18 years, with primary or secondary immune thrombocytopenia and platelet counts less than 100 × 109 cells per L before major surgery or less than 50 × 109 cells per L before minor surgery. Previous intravenous immunoglobulin within 2 weeks or thrombopoietin receptor agonists within 4 weeks before randomisation were not permitted. Patients were randomly assigned to receive oral daily eltrombopag 50 mg from 21 days preoperatively to postoperative day 7 or intravenous immunoglobulin 1 g/kg or 2 g/kg 7 days before surgery. Eltrombopag dose adjustments were allowed weekly based on platelet counts. The randomisation sequence was generated by a computerised random number generator, concealed and stratified by centre and surgery type (major or minor). The central study statistician was masked to treatment allocation. The primary outcome was achievement of perioperative platelet count targets (90 × 109 cells per L before major surgery or 45 × 109 cells per L before minor surgery) without rescue treatment. We did intention-to-treat and per-protocol analyses using an absolute non-inferiority margin of -10%. This trial is registered with ClinicalTrials.gov, NCT01621204. FINDINGS: Between June 5, 2013, and March 7, 2019, 92 patients with immune thrombocytopenia were screened, of whom 74 (80%) were randomly assigned: 38 to eltrombopag and 36 to intravenous immunoglobulin. Median follow-up was 50 days (IQR 49-55). By intention-to-treat analysis, perioperative platelet targets were achieved for 30 (79%) of 38 patients assigned to eltrombopag and 22 (61%) of 36 patients assigned to intravenous immunoglobulin (absolute risk difference 17·8%, one-sided lower limit of the 95% CI 0·4%; pnon-inferiority=0·005). In the per-protocol analysis, perioperative platelet targets were achieved for 29 (78%) of 37 patients in the eltrombopag group and 20 (63%) of 32 in the intravenous immunoglobulin group (absolute risk difference 15·9%, one-sided lower limit of the 95% CI -2·1%; pnon-inferiority=0·009). Two serious adverse events occurred in the eltrombopag group: one treatment-related pulmonary embolism and one vertigo. Five serious adverse events occurred in the intravenous immunoglobulin group (atrial fibrillation, pancreatitis, vulvar pain, chest tube malfunction and conversion to open splenectomy); all were related to complications of surgery. No treatment-related deaths occurred. INTERPRETATION: Eltrombopag is an effective alternative to intravenous immunoglobulin for perioperative treatment of immune thrombocytopenia. However, treatment with eltrombopag might increase risk of thrombosis. The decision to choose one treatment over the other will depend on patient preference, resource limitations, cost, and individual risk profiles. FUNDING: GlaxoSmithKline and Novartis.

Timeliness of Initial Therapy in Multiple Myeloma: Trends and Factors Affecting Patient Care.

Multiple myeloma (MM) treatment has advanced significantly over the last 2 decades. In most patients, the disease course has been altered from early fatality to chronic morbidity with multiple lines of treatment. The MM treatment paradigm has shifted toward treating patients before end-organ damage occurs. Thus, timeliness of treatment initiation in this era might improve patient outcomes. This is the first report to our knowledge analyzing disparities and trends in treatment timeliness of patients with MM using the National Cancer Database. Multiple factors affected the timing of treatment initiation in MM and disparities were found. We noted that initiation of treatment was delayed in women (odds ratio [OR], 1.15; 95% CI, 1.1 to 1.2) and blacks (OR, 1.21; 95% CI, 1.14 to 1.28; reference, whites) and in patients diagnosed in more recent years (2012-2015; OR, 1.15; 95% CI, 1.1 to 1.22; reference, 2004-2007). Patients were likely to start treatment earlier if they were age ≥ 80 years (OR, 0.83; 95% CI, 0.76 to 0.9; reference, age < 60 years), were uninsured (OR, 0.81; 95% CI, 0.72 to 0.91; reference, private insurance), had Medicaid (OR, 0.87; 95% CI, 0.79 to 0.95; reference, private insurance), were treated in a comprehensive community cancer program (OR, 0.7; 95% CI, 0.65 to 0.77; reference, community cancer program), lived in a location other than the US Northeast, or had a higher Charlson comorbidity score. Patient education and income levels did not affect time to treatment initiation. Particular aspects of these disparities could be explained by our current health care system and insurance rules, whereas others need to be investigated more deeply.

Elevated Neutrophil-Lymphocyte Ratio is Predictive of Poor Outcomes Following Aneurysmal Subarachnoid Hemorrhage.

Background Recent studies of patients with intracerebral hemorrhage suggest an association between peripheral blood neutrophil-lymphocyte ratio and neurologic deterioration. We aimed to study the prognostic utility of neutrophil-lymphocyte ratio in predicting inpatient mortality in aneurysmal subarachnoid hemorrhage. Methods We conducted a retrospective electronic medical record review of the clinical, laboratory, and radiographic data of patients with aneurysmal subarachnoid hemorrhage 18 years of age or older presenting to the neuroscience intensive care unit from January 1, 2011, to December 31, 2017. Patients with aneurysmal subarachnoid hemorrhage were divided into 2 groups (group 1, alive at discharge; group 2, deceased prior to discharge), and neutrophil-lymphocyte ratio laboratory mean values were recorded for each patient. Our primary outcome measure was inpatient mortality, and our secondary measure was incidence of pneumonia with hospitalization. Results We identified 403 patients with aneurysmal subarachnoid hemorrhage for the study. After exclusion criteria, 44 eligible patients were divided into the 2 groups (group 1, n = 32; group 2, n = 12). Mean neutrophil-lymphocyte ratio for group 1 was 11.53, and for group 2, 17.85 (P < .01). The mean neutrophil-lymphocyte ratio of those who developed pneumonia compared to those who did not was 15.28 versus 12.81, respectively (P = .39). A Kaplan-Meier plot demonstrated increased mortality among patients with a neutrophil-lymphocyte ratio equal to or greater than 12.5 compared to those with a neutrophil-lymphocyte ratio less than 12.5. Conclusions These preliminary data demonstrate that a neutrophil-lymphocyte ratio equal to or greater than 12.5 at admission predict higher inpatient mortality in patients with aneurysmal subarachnoid hemorrhage.

Incidence of Skin and Respiratory Immune-Related Adverse Events Correlates With Specific Tumor Types in Patients Treated With Checkpoint Inhibitors.

Checkpoint inhibitors (CPIs) increase antitumor activity by unblocking regulators of the immune response. This action can provoke a wide range of immunologic and inflammatory side effects, some of which can be fatal. Recent studies suggest that CPI-induced immune-related adverse events (irAEs) may predict survival and response. However, little is known about the mechanisms of this association. This study was undertaken to evaluate the influence of tumor diagnosis and preexisting clinical factors on the types of irAEs experienced by cancer patients treated with CPIs. The correlation between irAEs and overall survival (OS) was also assessed. All cancer patients treated with atezolizumab (ATEZO), ipilimumab (IPI), nivolumab (NIVO), or pembrolizumab (PEMBRO) at Virginia Mason Medical Center between 2011 and 2019 were evaluated. irAEs were graded according to the Common Terminology Criteria for Adverse Events (Version 5) and verified independently. Statistical analyses were performed to assess associations between irAEs, pre-treatment factors, and OS. Of the 288 patients evaluated, 59% developed irAEs of any grade, and 19% developed irAEs of grade 3 or 4. A time-dependent survival analysis demonstrated a clear association between the occurrence of irAEs and OS (P < 0.001). A 6-week landmark analysis adjusted for body mass index confirmed an association between irAEs and OS in non-Small Cell Lung Cancer (NSCLC) (P < 0.03). An association between melanoma and skin irAEs (P < 0.01) and between NSCLC and respiratory irAEs (P = 0.03) was observed, independent of CPI administered. Patients with preexisting autoimmune disease experienced a higher incidence of severe irAEs (P = 0.01), but not a higher overall incidence of irAEs (P = 0.6). A significant association between irAEs and OS was observed in this diverse patient population. No correlation was observed between preexisting comorbid conditions and the type of irAE observed. However, a correlation between skin-related irAEs and melanoma and between respiratory irAEs and NSCLC was observed, suggesting that many irAEs are driven by a specific response to the primary tumor. In patients with NSCLC, the respiratory irAEs were associated with a survival benefit.

Cost Analysis of R-CHOP Versus Dose-Adjusted R-EPOCH in Treatment of Diffuse Large B-Cell Lymphoma with High-Risk Features.

Dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (DA.R-EPOCH) is used for upfront treatment of high-risk diffuse large B cell lymphoma (DLBCL). In this study, we compared the outcomes in patients with high-risk DLBCL who received frontline rituximab, cycophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) or DA.R-EPOCH immunochemotherapy. Outcomes and treatment-related cost were analyzed. DLBCL with one of the following features were included in the study: MYC ± BCL2 or BCL6 rearrangement by FISH or MYC overexpression by immunohistochemistry, Ki67 index ≥ 80% or nongerminal center immunophenotype, tumor measuring ≥5 cm and NCCN- IPI score ≥4. A total of 80 patients were treated with R-CHOP (n = 52, 65%) or DA.R-EPOCH (n = 28, 35%), with a median follow-up of 11.2 months (range: 0.7-151.3 months). The hazard ratios (HRs) for progression-free survival and overall survival were 0.79 [95% confidence interval (CI) 0.28%-2.29%, p = 0.67] and 0.86 (95% CI 0.26%-2.78%, p = 0.80), respectively for DA.R-EPOCH compared to R-CHOP. The total mean cost was USD106,940 ± USD39,351 and USD58,509 ± 24,588 for DA.R-EPOCH and R-CHOP respectively (p < 0.001). In our analysis, DA.R-EPOCH resulted comparable clinical outcomes and increased treatment-related expenses compared to R-CHOP in high-risk DLBCL.

Apixaban and dalteparin in active malignancy-associated venous thromboembolism: The ADAM VTE trial.

BACKGROUND: Low-molecular-weight heparin is the guideline-endorsed treatment for cancer-associated venous thromboembolism (VTE). While apixaban is approved for the treatment of acute VTE, limited data support its use in cancer patients. OBJECTIVES: The primary outcome was major bleeding. Secondary outcomes included VTE recurrence and a composite of major plus clinically relevant non-major bleeding (CRNMB). PATIENTS/METHODS: Patients with cancer-associated VTE were randomly assigned to receive either apixaban 10 mg twice daily for seven days followed by 5 mg twice daily for six months or subcutaneous dalteparin (200 IU/kg for one month followed by 150 IU/kg once daily). RESULTS: Of 300 patients randomized, 287 were included in the primary analysis. Metastatic disease was present in 66% of subjects; 74% were receiving concurrent chemotherapy. Major bleeding occurred in 0% of 145 patients receiving apixaban, compared with 1.4% of 142 patients receiving dalteparin [P = .138; hazard ratio (HR) not estimable because of 0 bleeding event in apixaban group]. Recurrent VTE occurred in 0.7% of apixaban, compared to 6.3% of dalteparin patients [HR 0.099, 95% confidence interval [CI], 0.013-0.780, P = .0281). Major bleeding or CRNMB rates were 6% for both groups. CONCLUSIONS: Oral apixaban was associated with low major bleeding and VTE recurrence rates for the treatment of VTE in cancer patients.

Sequence of Splenectomy and Rituximab for the Treatment of Steroid-Refractory Immune Thrombocytopenia: Does It Matter?

OBJECTIVE: To evaluate the impact of the sequence of treatment with rituximab and/or splenectomy on time to relapse for patients with steroid-refractory immune thrombocytopenia (ITP). PATIENTS AND METHODS: Patients 18 years or older with steroid-refractory immune thrombocytopenia who underwent treatment with splenectomy or rituximab from January 1, 2002, through December 31, 2015, at Mayo Clinic. Evaluation included freedom from relapse (FFR) and response rates after treatment with rituximab or splenectomy as single or sequential interventions. RESULTS: A total of 218 eligible patients with ITP who were treated according to standard of care were included in this analysis. Patients failing steroids treated with splenectomy had a higher 5-year FFR than did those treated with rituximab (67.4% vs 19.2%; P<.001, propensity-score matched). Patients who failed splenectomy and were then treated with rituximab had a 2-year FFR similar to that of patients who failed rituximab and were then treated with splenectomy (73.4% vs 59.9%; P=.52). Patients treated with rituximab after splenectomy had a longer 2-year FFR than did patients treated with rituximab as a second-line treatment (73.4% vs 29.0%; P<.001). CONCLUSION: For patients with ITP that relapse after treatment with steroids, splenectomy provides longer FFR than rituximab as a second-line therapy. Among patients who fail second-line treatment with splenectomy or rituximab, those who end up receiving sequential splenectomy-rituximab or rituximab-splenectomy therapy seem to derive similar benefit in the long term. Patients who received rituximab after splenectomy seem to derive superior benefit than do those who are treated with rituximab with an intact spleen.

B-cell acute lymphoblastic leukemia in an elderly man with plasma cell myeloma and long-term exposure to thalidomide and lenalidomide: a case report and literature review.

BACKGROUND: The advent of the immunomodulatory imide drugs (IMiDs) lenalidomide and thalidomide for the treatment of patients with plasma cell myeloma (PCM), has contributed to more than a doubling of the overall survival of these individuals. As a result, PCM patients join survivors of other malignancies such as breast and prostate cancer with a relatively new clinical problem - second primary malignancies (SPMs) - many of which are a result of the treatment of the initial cancer. PCM patients have a statistically significant increased risk for acute myeloid leukemia (AML) and Kaposi sarcoma. IMiD treatment has also been associated with an increased risk of myelodysplastic syndrome (MDS), AML, and squamous cell carcinoma of the skin. However, within these overlapping groups, acute lymphoblastic leukemia (ALL) is much less common. CASE PRESENTATION: Herein, we describe an elderly man with PCM and a 14-year cumulative history of IMiD therapy who developed persistent pancytopenia and was diagnosed with B-cell acute lymphoblastic leukemia (B-ALL). He joins a group of 17 other patients documented in the literature who have followed a similar sequence of events starting with worsening cytopenias while on IMiD maintenance for PCM. These PCM patients were diagnosed with B-ALL after a median time of 36 months after starting IMiD therapy and at a median age of 61.5 years old. CONCLUSIONS: PCM patients with subsequent B-ALL have a poorer prognosis than their de novo B-ALL counterparts, however, the very low prevalence rate of subsequent B-ALL and high efficacy of IMiD maintenance therapy in PCM should not alter physicians' current practice. Instead, there should be a low threshold for bone marrow biopsy for unexplained cytopenias.

Trends in the risk of second primary malignancies among survivors of chronic lymphocytic leukemia.

With improving survivorship in chronic lymphocytic leukemia (CLL), the risk of second primary malignancies (SPMs) has not been systematically addressed. Differences in risk for SPMs among CLL survivors from the Surveillance, Epidemiology, and End Results (SEER) database (1973-2015) were compared to risk of individual malignancies expected in the general population. In ~270,000 person-year follow-up, 6487 new SPMs were diagnosed with a standardized incidence ratio (SIR) of 1.2 (95% CI:1.17-1.23). The higher risk was for both solid (SIR 1.15; 95% CI:1.12-1.18) and hematological malignancies (SIR 1.61; 95% CI:1.5-1.73). The highest risk for SPMs was noted between 2 and 5 months after CLL diagnosis (SIR 1.57; 95% CI:1.41-1.74) and for CLL patients between 50- and 79-years-old. There was a significant increase in SPMs in years 2003-2015 (SIR 1.36; 95% CI:1.3-1.42) as compared to 1973-1982 (SIR 1.19; 95% CI:1.12-1.26). The risk of SPMs was higher in CLL patients who had received prior chemotherapy (SIR 1.38 95% CI:1.31-1.44) as compared to those untreated/treatment status unknown (SIR 1.16, 95% CI:1.13-1.19, p < 0.001). In a multivariate analysis, the hazard of developing SPMs was higher among men, post-chemotherapy, recent years of diagnosis, advanced age, and non-Whites. Active survivorship plans and long-term surveillance for SPMs is crucial for improved outcomes of patients with a history of CLL.

Etiologies of Extreme Thrombocytosis: A Contemporary Series.

OBJECTIVE: To describe the multifactorial etiologies of extreme thrombocytosis (EXT) in different care settings and the frequency of finding an occult malignancy. PATIENTS AND METHODS: We conducted a retrospective chart review at Mayo Clinic from January 1, 2011, through December 31, 2016. Adult patients who had at least 2 readings of platelet counts greater than 1000×109/L within 30 days of each other were included. We determined the causes of EXT on the basis of preset definitions of precipitating factors and identified the dominant causes on the basis of the trend of platelet counts. RESULTS: A total of 44,490 patients had thrombocytosis, and 305 patients (0.7%) had EXT. In 242 patients (79.3%), EXT was multifactorial. Surgical complications (54.1%) and hematologic malignancies (27.9%) were the 2 most dominant causes. Thirty-eight patients (12.5%) had new diagnoses of malignancies, mostly myeloproliferative neoplasms. In inpatients, surgical complications (71.9%), concurrent/previous splenectomy (50.5%), and infections (44.9%) were the most common causes, whereas hematologic malignancies (56.9%), iron deficiency (36.7%), and previous splenectomy (28.4%) were the most common causes in outpatients. Hematologic malignancy was 3.4 times more likely to be the cause of EXT in outpatients than in inpatients (56.9% vs 16.8%), and a new diagnosis of hematologic malignancy was 1.9 times more likely to be made in outpatients (15.6% vs 8.2%). Eighty-four percent of patients had resolution of EXT within 30 days. One patient died during the period of EXT. Nonsurgical patients with hematologic malignancies had the most prolonged period of EXT. CONCLUSION: Extreme thrombocytosis is a multifactorial hematologic condition, and its etiology differs substantially between inpatients and outpatients. Occult hematologic malignancies are uncommon in EXT when other major causes are present.

Hepatic iron overload identified by magnetic resonance imaging-based T2* is a predictor of non-diagnostic elastography.

BACKGROUND: Magnetic resonance elastography (MRE) is a non-invasive test used to assess liver stiffness and fibrosis in chronic liver disease, which includes systemic iron overload. However, iron deposition by itself is associated with technical failure of MRE of the liver which necessitates the use of invasive liver biopsy as an alternative monitoring method for these patients. T2*-weighted magnetic resonance imaging (T2*) is a reliable modality to asses for hepatic as well as total body iron overload. Therefore, we aimed to determine a cutoff value on the T2* reading at which MRE would no longer provide accurate stiffness measurements in patients with iron overload. METHODS: Ninety-five patients with iron overload who underwent MRE at our institution, between 2010 and 2017 were reviewed retrospectively. We compared T2* values between patients with adequate elastography (N=63) versus those with non-diagnostic elastography (N=32). We additionally examined the ability of T2* to predict the likelihood of non-diagnostic elastography by estimating area under the ROC curve (AUC). RESULTS: T2* was significantly different between patients with and without an adequate elastography (P<0.0001) and predicted occurrence of non-diagnostic elastography with an AUC of 0.95. All patients with a non-diagnostic elastography had a T2* value below 20 milliseconds (ms), and correspondingly 55% of the patients with a T2* value below 20 ms had a non-diagnostic elastography. The subgroups of patients with a T2* value ≤10, ≤8, and ≤6 ms, had a higher likelihood of non-diagnostic elastography (87%, 92%, and 95%, respectively). CONCLUSIONS: T2* can be used to accurately predict which patients are most likely to have a non-diagnostic elastography reading. T2* of 20 ms or lower reflects a higher likelihood of non-diagnostic elastography.

Survival Trends in Young Patients With Multiple Myeloma: A Focus on Racial-Ethnic Minorities.

INTRODUCTION: Outcomes in multiple myeloma (MM) have improved significantly over time. This is true overall for all patients as well as patient subgroups based on age and race/ethnicity. Despite this, disparities are noted in outcomes when looking at racial subgroups. MATERIALS AND METHODS: We performed an analysis from the population-based Surveillance, Epidemiology, and End Results (SEER) database to evaluate improvement in relative survival rates (RSRs) for young (≤ 40 years at the time of MM diagnosis) and older (> 40 years at the time of MM diagnosis) over time by race/ethnicity, specifically focusing on Hispanic patients with MM. Expected survival was estimated using the age- and gender-specific death rates from the United States population. RSR was provided as the ratio of the observed to expected survival at individual time points. Five-year and 10-year RSRs were calculated for patients based on treatments modalities available in various time periods. RESULTS: We identified a total of 89,451 patients with MM in SEER, of which 1460 patients formed the young patients with MM (≤ 40 years) cohort. Five- and 10-year RSR improved significantly over time for all patients and older patients (> 40 years) by race (all P < .001). Evaluating the younger patients, RSR improved significantly for non-Hispanic whites and non-Hispanic blacks, but not for Hispanics. This was true for the 5-year (P = .08) and 10-year (P = .13) RSRs. CONCLUSION: We report a lack of significant benefit in long-term outcomes for younger Hispanic patients with MM over time. This could be owing to multifactorial causes that need to be addressed to mitigate outcome disparities.

Hypereosinophilia in a patient with metastatic non-small-cell lung cancer treated with antiprogrammed cell death 1 (anti-PD-1) therapy.

Immune checkpoint inhibitors have changed the treatment paradigm for patients with cancer. Though a majority of patients tolerate treatment, some develop hematologic toxicities, including eosinophilia. Eosinophilia has been associated with better responses in some patients with melanoma, but this has not been investigated in non-small-cell lung cancer. We present a case of a woman with metastatic lung adenocarcinoma who developed asymptomatic hypereosinophilia after initiation of nivolumab. Her eosinophil count temporarily decreased after transiently stopping the medication, but increased again after re-initiation. She had a favorable tumor response to therapy. This exemplifies the potential role of eosinophilia as a peripheral, readily available biomarker of favorable response to immunotherapy in patients with lung cancer. Awareness of this manifestation is important.