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Introduction Female enrollment into medical schools in the United States (13) and Europe (4) has reached more than 50% of the total. Female representation in the field of hematology and [...], BACKGROUND: While female representation in the National Comprehensive Cancer Network (NCCN] and European Society of Medical Oncology (ESMO] clinical practice guidelines (CPGs] has been studied to a limited degree, the change in gender disparity over a decade, among all NCCN and ESMO CPG panelists has not been studied. Our study evaluated gender disparities for all NCCN and ESMO CPG panels (CPGPs] as of 2020 in comparison with 2010. METHODS: The 2010 and 2020 NCCN and ESMO CPGPs were examined, utilizing their websites and archives. We catalogued the number of females vs male panelists for each CPG by reviewing their names, Google search results, and panelists' picture on affiliated websites. We defined greater than 50% representation of either sex in a CPG as 'predominant' representation. RESULTS: Sixty NCCN/2020, 51 NCCN/2010, 78 ESMO/2020, and 55 ESMO/2010 CPGPs were reviewed. NCCN 2010 CPGPs had 27.1% female representation. CPGPs for solid tumors and hematological malignancies were male predominant. CPGPs for breast cancer screening, palliative care, and older adult oncology were female predominant. ESMO 2010 CPGPs had 23.2% female representation. Solid tumors (35 CPGPs] and hematological malignancies (9 CPGPs] were male predominant. CPGPs for cancers specific to women were female predominant. NCCN 2020 CPGPs had 55.5% female representation. For solid tumors, 24 CPGPs had male predominance, and hematological malignancies, with 14 CPGPs, had female predominance. CPGPs for cancers specific to women had more female panelists. ESMO 2020 CPGPs had 27.8% female representation. CPGPs for solid tumors (37 panels] and hematological malignancies (17 panels] were male predominant. Breast and ovarian cancer CPGPs were female predominant. CONCLUSIONS: Over the past decade, female representation in NCCN CPGs has doubled, with more than 50% representation among its 60 CPGPs in 2020. In ESMO, although there has been an increase in women participating in CPGPs for hematological malignancies, overall female representation remains low ( KEYWORDS: Female representation, oncology leadership, clinical practice guidelines, women in oncology

Introduction Evidence-based medicine (EBM) is an interdisciplinary approach that integrates clinical experience and patient values with the best available research information to make clinical decisions for individual patients. Health care [...], BACKGROUND: The level of scientific evidence in National Comprehensive Cancer Network (NCCN) guidelines for malignant hematological conditions haven't been recently investigated. We describe the distribution of categories of evidence and consensus (EC) among the 10 most common hematologic malignancies with regard to recommendations for staging, initial and salvage therapy, and surveillance. METHODS: We reviewed the level of evidence for the 10 most common hematological malignancies by incidence in the United States as of 2020. The NCCN definitions for EC are: category 1, high level of evidence, such as randomized controlled trials, with uniform consensus; category 2A, lower level of evidence with uniform consensus; category 2B, lower level of evidence without a uniform consensus but with no major disagreement; and category 3, any level of evidence but with major disagreement. We compared our results with previously published results from 2011. RESULTS: Of 1353 recommendations, 5%, 91%, 4%, and 1% fell into EC categories 1, 2A, 2B, and 3, respectively, while in 2011 the comparable percentages were 3%, 93%, 4%, and 0%, respectively. Recommendations with category 1 EC were found in all guidelines, except for Burkitt lymphoma. Of all therapeutic recommendations, 6.3% were category 1 EC, with the majority of these (56.4%) pertaining to initial therapy. Guidelines with highest proportions of therapeutic recommendations with category 1 EC were multiple myeloma (12.4%), chronic lymphocytic leukemia/small lymphocytic lymphoma (6.9%), and acute myeloid leukemia (5.6%). CONCLUSIONS: Recommendations in the 2020 NCCN guidelines are largely developed from lower levels of evidence but with uniform expert opinion, underscoring the urgent need and available opportunities to expand the current evidence base in malignant hematological disorders.

To explore patterns in Medicare reimbursement for wasted oncologic and hematologic infusion drugs from 2017 to 2020 and estimate the savings that implementation of the Infrastructure Investment and Jobs Act (IIJA) would have had.

Cause of death (COD) in POEMS (polyneuropathy, organomegaly, endocrinopathies, monoclonal protein and skin changes) syndrome is not well described. We investigated COD in patients with POEMS syndrome treated at Mayo Clinic between 2000 and 2022. Of the 89 deaths, 49 patients had known COD and were the subject of this study. Seventeen patients died of unrelated causes, while 32 patients (65%) died from causes related to POEMS syndrome including secondary malignancies like myelodysplastic syndrome and acute leukemia (n= 5) and complications from active therapy (n= 5). Notably, 19 patients died with a stereotypic syndrome we termed capillary leak phenotype (CLP), which was characterized by refractory ascites, effusions and/or anasarca that ultimately resulted in hypotension, renal failure and cardiopulmonary arrest. Alternate causes for these symptoms, such as cardiac and hepatic etiologies, were excluded. CLP as a COD was an earlier event with a median time from diagnosis to death of 2.5 years compared to 12.0 years for all other deceased patients (p= <0.0001). By definition, treatment of terminal CLP was unsuccessful with median survival of only 4 months after CLP onset. The driver of CLP is unknown, but recognition as an entity should allow for systematic study.

•In CM-TMA, variants in specific genes/regions are associated with high risk of relapse after eculizumab is discontinued.•In CM-TMA, eculizumab discontinuation is appropriate in patients with a low risk of relapse.

•Adults with LCH have a higher risk of mortality from non-LCH causes such as chronic obstructive pulmonary disease and second primary malignancies.•Most LCH-related deaths occurred within 5 years of diagnosis, with other causes predominating beyond that period.

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•RFS shortens with successive rituximab-treated episodes in a subgroup of relapsing patients with iTTP.•Progressively shortened time to relapse is most pronounced in Black patients with iTTP, who require closer monitoring and retreatment.

IMPORTANCE: Rosai-Dorfman disease (RDD) is a rare histiocytic neoplasm with recent studies showing alterations in the MAPK pathway, most commonly in the KRAS and MEK genes in about 40% of patients. Reports on the use of MEK-inhibitor therapy in RDD have been limited to small case studies. There are no approved treatments for this neoplasm, and therefore patients with RDD need efficacious treatments. OBJECTIVE: To study the outcomes after treatment with cobimetinib based on MAPK pathway alterations in patients with RDD. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study conducted at 2 tertiary care centers included patients with RDD who underwent treatment with cobimetinib between January 1, 2013, and December 1, 2021. Cobimetinib was administered at a dosage of 20 to 60 mg orally once daily as a single agent for 21 days in a 28-day cycle. Pathology was centrally reviewed. Response assessment was centrally conducted and was based on the established positron emission radiography response criteria used for clinical trials of targeted therapies in histiocytosis. MAIN OUTCOMES AND MEASURES: Main outcomes were overall response rate (ORR), progression-free survival (PFS), adverse events (AEs) of cobimetinib in the entire cohort, and ORRs and PFS based on MAPK pathway alterations in patients with RDD. RESULTS: A total of 16 patients (median [range] age at cobimetinib initiation, 57 [31-74] years; 11 [69%] women) were included in the study. The median follow-up duration was 19.0 months (95% CI, 8.4-27.8 months). The ORR was 63% (n = 10), including 5 complete responses and 5 partial responses. Somatic alterations in the KRAS or MEK genes were detected in 8 (50%) patients. Patients with KRAS or MEK alterations had significantly higher ORR (88% vs 38%; P = .03), deeper responses (complete responses among responders: 71% vs 0%; P = .002), and better PFS (at 1 year, 100% vs 29% were free from progression or death, respectively; P &lt; .001) compared with those without such alterations. Grade 2 or higher AEs occurred in 12 (75%) patients, and 9 (56%) required dose reduction or temporary/permanent treatment discontinuation due to AEs. CONCLUSIONS AND RELEVANCE: In this cohort study, treatment with cobimetinib was associated with positive outcomes in KRAS- or MEK-variant RDD. However, AEs requiring dose modifications were common.

•Upfront autologous stem cell transplantation more than doubled the rate of minimal residual disease (MRD) negativity in patients with newly diagnosed multiple myeloma.•Patients with MRD-positive complete response (CR) were the most likely to achieve MRD-negative CR.•MRD negativity predicted improved overall survival and time to progression (TTP), especially when MASS-FIX was positive.•MRD negativity did not affect TTP when MASS-FIX was negative (ie, MF- CR).

Bortezomib, a proteasome inhibitor (PI), has shown efficacy in the treatment of newly diagnosed and relapsed light chain (AL) amyloidosis, and is often used in combination with cyclophosphamide and dexamethasone. Ixazomib is the first oral PI to be approved in routine practice but has not yet been evaluated in the upfront treatment setting. Newly diagnosed AL amyloidosis patients with measurable disease and adequate organ function were enrolled. The primary objective was to determine the hematologic response rate of ixazomib in combination with cyclophosphamide and dexamethasone. Treatment was given for 12 cycles, followed by ixazomib maintenance until progression. Thirty-five patients were included; their median age was 67 years, and 69% were male. Major organ involvement included heart (66%) and kidneys (54%). A median of 4 induction cycles (range, 1-12) were administered. The overall hematologic response to induction was 63% and included complete response in 11.4% and very good partial response in 37.1% of patients. One patient was upstaged to complete response during maintenance. The most common reason for going off study was the institution of alternate therapy (61%). With a median follow-up of 29.7 months for the living patients, the 2-year progression-free survival and overall survival were 74% and 78%, respectively. The median time to alternate therapy was 7.5 months. Grade ≥3 hematologic and nonhematologic adverse events occurred in 23% and 49% of patients. Given ixazomib's favorable toxicity profile, which is an important advantage for the typically frail AL population, further evaluation of ixazomib in other combinations in the upfront setting is warranted. This trial was registered at www.clinicaltrials.govas #NCT01864018.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by recurring episodes of thrombotic microangiopathy, causing ischemic organ impairment. Black patients are overrepresented in iTTP cohorts in the United States, but racial disparities in iTTP outcome and response to therapy have not been studied. Using the United States Thrombotic Microangiopathies Consortium iTTP Registry, we evaluated the impact of race on mortality and relapse-free survival (RFS) in confirmed iTTP in the United States from 1995 to 2020. We separately examined the impact of rituximab therapy and presentation with newly diagnosed (de novo) or relapsed iTTP on RFS by race. A total of 645 participants with 1308 iTTP episodes were available for analysis. Acute iTTP mortality did not differ by race. When all episodes of iTTP were included, Black race was associated with shorter RFS (hazard ratio [HR], 1.60; 95% CI, 1.16-2.21); the addition of rituximab to corticosteroids improved RFS in White (HR, 0.37; 95% CI, 0.18-0.73) but not Black patients (HR, 0.96; 95% CI, 0.71-1.31). In de novo iTTP, rituximab delayed relapse, but Black patients had shorter RFS than White patients, regardless of treatment. In relapsed iTTP, rituximab significantly improved RFS in White but not Black patients. Race affects overall relapse risk and response to rituximab in iTTP. Black patients may require closer monitoring, earlier retreatment, and alternative immunosuppression after rituximab treatment. How race, racism, and social determinants of health contribute to the disparity in relapse risk in iTTP deserves further study.

Clinical success with intravenous (IV) oncolytic virotherapy (OV) has to-date been anecdotal. We conducted a phase 1 clinical trial of systemic OV and investigated the mechanisms of action in responding patients. A single IV dose of vesicular stomatitis virus (VSV) interferon-β (IFN-β) with sodium iodide symporter (NIS) was administered to patients with relapsed/refractory hematologic malignancies to determine safety and efficacy across 4 dose levels (DLs). Correlative studies were undertaken to evaluate viremia, virus shedding, virus replication, and immune responses. Fifteen patients received VSV-IFNβ-NIS. Three patients were treated at DL1 through DL3 (0.05, 0.17, and 0.5 × 1011 TCID50), and 6 were treated at DL4 (1.7 × 1011 TCID50) with no dose-limiting toxicities. Three of 7 patients with T-cell lymphoma (TCL) had responses: a 3-month partial response (PR) at DL2, a 6-month PR, and a complete response (CR) ongoing at 20 months at DL4. Viremia peaked at the end of infusion, g was detected. Plasma IFN-β, a biomarker of VSV-IFNβ-NIS replication, peaked between 4 hours and 48 hours after infusion. The patient with CR had robust viral replication with increased plasma cell-free DNA, high peak IFN-β of 18 213 pg/mL, a strong anti-VSV neutralizing antibody response, and increased numbers of tumor reactive T-cells. VSV-IFNβ-NIS as a single agent was effective in patients with TCL, resulting in durable disease remissions in heavily pretreated patients. Correlative analyses suggest that responses may be due to a combination of direct oncolytic tumor destruction and immune-mediated tumor control. This trial is registered at www.clinicaltrials.gov as #NCT03017820.

Langerhans cell histiocytosis (LCH) can affect children and adults with a wide variety of clinical manifestations, including unifocal, single-system multifocal, single-system pulmonary (smoking-associated), or multisystem disease. The existing paradigms in the management of LCH in adults are mostly derived from the pediatric literature. Over the last decade, the discovery of clonality and MAPK-ERK pathway mutations in most cases led to the recognition of LCH as a hematopoietic neoplasm, opening the doors for treatment with targeted therapies. These advances have necessitated an update of the existing recommendations for the diagnosis and treatment of LCH in adults. This document presents consensus recommendations that resulted from the discussions at the annual Histiocyte Society meeting in 2019, encompassing clinical features, classification, diagnostic criteria, treatment algorithm, and response assessment for adults with LCH. The recommendations favor the use of 18F-Fluorodeoxyglucose positron emission tomography-based imaging for staging and response assessment in the majority of cases. Most adults with unifocal disease may be cured by local therapies, while the first-line treatment for single-system pulmonary LCH remains smoking cessation. Among patients not amenable or unresponsive to these treatments and/or have multifocal and multisystem disease, systemic treatments are recommended. Preferred systemic treatments in adults with LCH include cladribine or cytarabine, with the emerging role of targeted (BRAF and MEK inhibitor) therapies. Despite documented responses to treatments, many patients struggle with a high symptom burden from pain, fatigue, and mood disorders that should be acknowledged and managed appropriately.

The causes of hemolytic anemia are numerous and a systematic approach is critical for proper identification and classification. The direct antiglobulin test can establish the diagnosis and subclassify the majority of autoimmune hemolytic anemias. Further testing to identify the driver of AIHA can have significant implications in overall management. Advanced testing for rare nonimmune acquired hemolytic anemias or hereditary hemolytic anemias may be necessary if DAT testing is negative.

Multiple myeloma (MM) is a heterogeneous disease that may be evaluated by a broad array of imaging and laboratory techniques to measure disease activity and predict prognosis. Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scanning has been shown to be predictive of patient outcomes throughout the disease course. We sought to corroborate these findings by examining the prognostic impact of PET/CT scanning in the posttransplant setting. We retrospectively analyzed PET/CT scans in 229 MM patients receiving an autologous stem cell transplant (ASCT) near day 100, and correlated these findings with time to progression(TTP) and overall survival (OS) to assess the impact of day 100 PET/CT scan findings as an independent prognostic factor. The median OS for the entire cohort was 61.5 months (95% confidence interval [CI], 49-75) and the median TTP was 18.5 months (95% CI, 15.4-21.8). Among patients with abnormal day 100 PET findings (PET+), median TTP was 12.4 months vs 24 months among those with normal PET findings (PET−) (P< .0001). The median OS in the PET+group was 46 months compared with 99 months in the PET−group (P< .0001). We conclude that an abnormal PET/CT scan near day 100 post-ASCT is predictive of shorter TTP and OS, with prognostic significance retained after adjusting for disease response and other prognostic variables in MM.

•Second autologous stem cell transplantation (ASCT) for AL amyloidosis is rarely performed but increasingly being used.•Best outcome to second ASCT is seen after durable remission to ASCT1.•Second ASCT, if chosen, should be used early in the relapse course.•Treatment related mortality can be high, making its choice particularly difficult

Immunoglobulin light chain (AL) amyloidosis is a clonal plasma cell disorder leading to progressive and life-threatening organ failure. The heart and the kidneys are the most commonly involved organs, but almost any organ can be involved. Because of the nonspecific presentation, diagnosis delay is common, and many patients are diagnosed with advanced organ failure. In the era of effective therapies and improved outcomes for patients with AL amyloidosis, the importance of early recognition is further enhanced as the ability to reverse organ dysfunction is limited in those with a profound organ failure. As AL amyloidosis is an uncommon disorder and given patients’ frailty and high early death rate, management of this complex condition is challenging. The treatment of AL amyloidosis is based on various anti–plasma cell therapies. These therapies are borrowed and customized from the treatment of multiple myeloma, a more common disorder. However, a growing number of phase 2/3 studies dedicated to the AL amyloidosis population are being performed, making treatment decisions more evidence-based. Supportive care is an integral part of management of AL amyloidosis because of the inherent organ dysfunction, limiting the delivery of effective therapy. This extensive review brings an updated summary on the management of AL amyloidosis, sectioned into the 3 pillars for survival improvement: early disease recognition, anti–plasma cell therapy, and supportive care.

The utility of systemic light chain (AL) amyloidosis staging systems has been validated for newly diagnosed patients, but their role in restaging after treatment has not been explored. We designed this study to evaluate whether the currently used systems are of prognostic value at 3 and 6 months of starting first-line treatment, and whether stage migration from diagnosis impacts survival. This is a retrospective study including Mayo Clinic patients with AL amyloidosis diagnosed between 1 January 2006 and 30 June 2019; 536 and 204 patients had restaging data for at least 1 system at 3 and 6 months, respectively. Using modified Mayo 2004 staging at 3 months, median overall survival (OSs) were 11.8, 10.8, 4.6, and 1.1 years for stage I, II, IIIa, and IIIb, respectively. Using Mayo 2012, median OSs were 11.8, 9.0, 5.2, and 0.8 years for stage I, II, III, and IV, respectively. Using modified Mayo 2004 staging at 6 months, median OSs were not reached (NR), NR, 5.4, and 0.9 years for stage I, II, IIIa, and IIIb, respectively. Using Mayo 2012, OSs were NR, NR, 4.6, and 0.9 years for stage I, II, III, and IV, respectively. Worsening stage at 3 or 6 months was associated with worse survival than retaining baseline stage. In conclusion, the current staging systems can be used for restaging at 3 and 6 months from treatment initiation. Migration to higher stage predicts poor prognosis.

To assess the prevalence of coagulation abnormalities in patients with systemic light chain (AL) amyloidosis and their association with disease-related characteristics, disease progression, and survival.

Rosai-Dorfman disease (RDD) is a rare histiocytosis with heterogenous clinical features. In this study, we characterized the histologic and phenotypic features in 33 RDD patients to better define the pathologic diagnosis. Cases included 24 patients with extracutaneous disease (“R” group), and 9 patients with lesions limited to the skin or subcutaneous tissue (“C” group). We identified OCT2 as a novel marker for the monocyte-macrophage phenotype of RDD, expressed in 97% of RDD cases. In contrast, OCT2 expression was seen in 0% of Erdheim-Chester disease cases and 6.7% of Langerhans cell histiocytosis cases. Other markers useful in the diagnosis of RDD included S100 (100%), CD163 (88%), and cyclin D1 (97%). In a subset of cases, RDD showed moderate to strong expression of factor 13a (30%), p16 (64%), and phosphorylated extracellular signal-regulated kinase (45%); RDD was uniformly negative for ZBTB46, CD1a, and langerin. Within the “R group” of RDD, increased expression of factor 13a or phosphorylated extracellular signal-regulated kinase showed a statistically significant association with multifocal disease (P<0.05). Identification of the unique monocyte-macrophage phenotype of RDD with OCT2 expression furthers our understanding of this complex disease and allows for more uniform classification.

A gain in chromosome 1q (+1q) is among the most common cytogenetic abnormalities in multiple myeloma (MM). It is unclear whether +1q is independently associated with decreased overall survival (OS). The objective of this study was to evaluate the impact of +1q on clinical characteristics, treatment response, and survival outcomes. We included 1376 Mayo Clinic patients diagnosed with MM from 2005 to 2018 who underwent fluorescence in situ hybridization testing at diagnosis with a panel including the +1q probe. A gain in 1q was found in 391 patients (28%) and was associated with anemia, hypercalcemia, high tumor burden, International Staging System (ISS) stage 3, high-risk (HR) translocations, and chromosome 13 abnormalities. There was no difference in overall response or deeper responses to proteasome inhibitor (PI)–, immunomodulatory drug (iMiD)–, or PI plus IMiD–based induction. Time to next treatment was shorter in patients with +1q compared with those without +1q (19.9 vs 27.7 months; P < .001). On univariate analysis, +1q was associated with increased risk of death (risk ratio [RR], 1.9; P < .001), and decreased OS was seen in all treatment groups. +1q was independently associated with decreased OS on multivariate analysis when other HR cytogenetic abnormalities, ISS stage 3, and age ≥70 years were included (RR, 1.5; P < .001). Gain of >1 copy of 1q was not associated with worse OS compared with gain of 1 copy (4.9 vs 4.3 years; P = .21). +1q was associated with high tumor burden, advanced disease stage, and HR translocations. It is independently associated with decreased OS, even in the setting of novel therapy and transplant.

In the presence of effective treatment options for systemic light chain (AL) amyloidosis, autologous stem cell transplantation (ASCT) is sometimes deferred after stem cell collection. We designed this retrospective study to compare overall survival (OS) between patients who proceed directly to ASCT after stem cell collection and those who defer ASCT. We included patients with AL amyloidosis who had stem cell collection at Mayo Clinic, Minnesota, from 2004 to 2018. ASCT was considered “early” if performed within 90 days of collection, and “deferred” if performed after 90 days, or not done by last follow up. We included 651 patients; 527 underwent early ASCT and 124 deferred ASCT. There was no difference in OS with early vs. deferred ASCT (median OS: 13.0 vs. 11.4 years, respectively, P= 0.28). There was no difference in OS between the 2 groups among patients with early or advanced Mayo Stage. Among patients who achieved ≥very good partial response at the time of collection, OS in the early and deferred groups was 14.2 and 13.4 years, respectively (P= 0.06). Survival outcomes are similar with early and deferred ASCT. Further studies are needed to identify patients who would benefit from each approach.

Erdheim-Chester disease (ECD) is a rare histiocytosis that was recently recognized as a neoplastic disorder owing to the discovery of recurrent activating MAPK (RAS-RAF-MEK-ERK) pathway mutations. Typical findings of ECD include central diabetes insipidus, restrictive pericarditis, perinephric fibrosis, and sclerotic bone lesions. The histopathologic diagnosis of ECD is often challenging due to nonspecific inflammatory and fibrotic findings on histopathologic review of tissue specimens. Additionally, the association of ECD with unusual tissue tropism and an insidious onset often results in diagnostic errors and delays. Most patients with ECD require treatment, except for a minority of patients with minimally symptomatic single-organ disease. The first ECD consensus guidelines were published in 2014 on behalf of the physicians and researchers within the Erdheim-Chester Disease Global Alliance. With the recent molecular discoveries and the approval of the first targeted therapy (vemurafenib) for BRAF-V600–mutant ECD, there is a need for updated clinical practice guidelines to optimize the diagnosis and treatment of this disease. This document presents consensus recommendations that resulted from the International Medical Symposia on ECD in 2017 and 2019. Herein, we include the guidelines for the clinical, laboratory, histologic, and radiographic evaluation of ECD patients along with treatment recommendations based on our clinical experience and review of literature in the molecular era.

Metaphase cytogenetic abnormalities, plasma cell proliferation index (PCPro), and gain 1q by fluorescence in situ hybridization (FISH) are associated with inferior survival in newly diagnosed multiple myeloma (MM) treated with novel agents; however, their role in risk stratification is unclear in the era of the revised International Staging System (R-ISS). The objective of this study was to determine if these predictors improve risk stratification in newly diagnosed MM when accounting for R-ISS and age. We studied a retrospective cohort of 483 patients with newly diagnosed MM treated with proteasome inhibitors and/or immunomodulators. On multivariable analysis, R-ISS, age, metaphase cytogenetic abnormalities (both in aggregate and for specific abnormalities), PCPro, and FISH gain 1q were associated with inferior progression-free (PFS) and overall survival (OS). We devised a risk scoring system based on hazard ratios from multivariable analyses and assigned patients to low-, intermediate-, and high-risk groups based on their cumulative scores. The addition of metaphase cytogenetic abnormalities, PCPro, and FISH gain 1q to a risk scoring system accounting for R-ISS and age did not improve risk discrimination of Kaplan-Meier estimates for PFS or OS. Moreover, they did not improve prognostic performance when evaluated by Uno’s censoring-adjusted C-statistic. Lastly, we performed a paired analysis of metaphase cytogenetic and interphase FISH abnormalities, which revealed the former to be insensitive for the detection of prognostic chromosomal abnormalities. Ultimately, metaphase cytogenetics lack sensitivity for important chromosomal aberrations and, along with PCPro and FISH gain 1q, do not improve risk stratification in MM when accounting for R-ISS and age.

To determine the indications for prediagnostic testing, subsequent diagnoses found, and follow-up practices in patients who were incidentally diagnosed with monoclonal gammopathy of undetermined significance (MGUS).

We explored the association between bone marrow plasma cells (BMPCs) and disease presentation and outcome among 1574 AL patients. Three BMPC groups were formulated: <5% (n= 231, 15% of study population), 5–19% (n= 1045, 66%), and ≥20% (n= 298, 19%). Heart and renal involvement were more and less prevalent, respectively, with increasing BMPCs. Patients with ≥20% BMPCs had higher likelihood for classic myeloma phenotype with less skewed lambda restriction, a higher rate of intact immunoglobulin secretion, a lower hemoglobin and higher rates of hypercalcemia and bone lytic lesions. High-risk cytogenetic abnormalities were more common in ≥20% BMPCs. Complete hematological response was less frequent with rising BMPCs. The median survival was inversely associated with the BMPC groups (81, 33, 12 months for <5%, 5–19%, and ≥20% BMPCs, respectively; P< 0.001). Survival discrimination was maintained at 1-year landmark and in those who achieved a complete response. Multivariate analysis accounting for known prognostic markers yielded an independent prognostic role for ≥20% BMPCs, but not for the other BMPC groups. AL patients with 20% or greater BMPCs have poorer outcome independent of their cardiac risk category and stem cell transplant eligibility. Distinct interventions in these patients should be explored to improve outcome.

Histiocytic neoplasms, a rare and heterogeneous group of disorders, primarily include Erdheim-Chester disease, Langerhans cell histiocytosis, and Rosai-Dorfman disease. Due to their diverse clinical manifestations, the greatest challenge posed by these neoplasms is the establishment of a diagnosis, which often leads to a delay in institution of appropriate therapy. Recent insights into their genomic architecture demonstrating mitogen-activated protein kinase/extracellular signal–regulated kinase pathway mutations have now enabled potential treatment with targeted therapies in most patients. This consensus statement represents a joint document from a multidisciplinary group of physicians at Mayo Clinic who specialize in the management of adult histiocytic neoplasms. It consists of evidence- and consensus-based recommendations on when to suspect these neoplasms and what tests to order for the diagnosis and initial evaluation. In addition, it also describes the histopathologic and individual organ manifestations of these neoplasms to help the clinicians in identifying their key features. With uniform guidelines that aid in identifying these neoplasms, we hope to improve the awareness that may lead to their timely and correct diagnosis.

To study the changes in overall outcome of patients with myelodysplastic syndromes (MDSs) after approval of several treatments.

To describe the multifactorial etiologies of extreme thrombocytosis (EXT) in different care settings and the frequency of finding an occult malignancy.

The high-risk abnormality del(17p) can be detected by fluorescence in situ hybridization on malignant plasma cells (PCs) and has an adverse prognostic impact in patients with multiple myeloma (MM). Patients with del(17p) have reduced overall survival (OS). Patients who acquire del(17p) later during the disease course are not well described. The disease characteristics at diagnosis predicting for acquired del(17p) and its overall impact on patient survival is not known. We compared 76 patients with MM who were negative for del(17p) at diagnosis and acquired it later with 152 control MM patients who did not acquire del(17p) at a comparable time point. Patients acquired del(17p) at a median of 35.6 months (range, 4.6-116.1 months) from diagnosis of MM after a median of 2 lines of therapy (range, 1-10 lines of therapy). When compared with controls, patients with acquired del(17p) had shorter median progression-free survival (PFS) (30.1 vs 23.0 months; P = .032) and OS (106.1 vs 68.2 months; P < .001) from diagnosis. After the detection of del(17p), the median PFS was 5.4 months and the median OS was 18.1 months. High lactate dehydrogenase level (odds ratio [OR], 3.69; 95% confidence interval [CI], 1.11-12.24) and presence of t(4;14) (OR, 2.66; 95% CI, 1.09-6.48) or any high-risk translocation (OR, 2.23; 95% CI, 1.00-4.95) at diagnosis predicted acquisition of del(17p). High PC proliferative rate predicted shorter OS from detection of del(17p) (hazard ratio, 2.28; 95% CI, 1.31-3.96; P = .004). Our study shows that acquisition of del(17p) is an important molecular event associated with reduction in OS in MM. Certain baseline factors may predict acquisition of del(17p). This needs validation in prospective data sets.

It is well known that staging of patients with AL amyloidosis at diagnosis predicts for survival, but there is a paucity of literature delineating the prognostic value of these systems at relapse. We evaluated the prognostic value of AL staging among 413 patients initiated with second-line therapy between 2000 and 2015. Both the Revised Mayo 2012 and the European revision of Mayo 2004 staging systems were used. The median time from initial treatment to second-line therapy was 11.7 months. The first-line therapy was autologous stem cell transplant (ASCT) in 179 (43%) patients and non-ASCT therapies in 234 patients. Median survival from the institution of second-line therapy was 61 months. Both the Mayo 2004 and 2012 staging systems were of prognostic benefit at second-line therapy with respective risk ratios of 2.78 (95% CI: 2.15, 3.58) and 3.03 (95% CI: 2.33, 3.93) for patients with > stage 2 disease. On multivariate analysis, the predictive value of staging at second-line therapy was independent of stage at diagnosis and prior ASCT as first-line therapy. This study indicates that the Mayo staging systems work well at second-line therapy. Consequently, it is suitable for the stratification of patients in trials for relapsed, refractory AL amyloidosis.

Multiple myeloma (MM) is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma (SMM), or solitary plasmacytoma (SPC). There is a lack of data regarding impact of these pre-existing monoclonal gammopathies (MGs) on MM outcomes. Patients with prior diagnosis of MGUS, SMM, or PC from 1973 to 2015 (cases) were identified from our institution’s database and compared to those without a known MG (controls). The primary outcome of interest was overall survival (OS). Multivariate analysis was performed to ascertain factors impacting all-cause mortality. We identified 774 patients with a prior diagnosis of MGUS, SMM or SPC (cases) and a control population (1:2) matched for the year of diagnosis (n= 1548). After a median follow-up of 81 months, the cases showed a longer median OS than the controls (71 months vs. 56 months). The improved OS was limited to those with a known prior diagnosis of SMM (80 months) and SPC (95 months), compared to MGUS (60 months). Multivariable analysis revealed that MM patients with known prior MG had less overall mortality than those without, and this was limited to prior SMM/SPC group (HR 0.68, 95% CI: 0.50–0.93), as compared to the MGUS group (HR 0.83, 95% CI: 0.66–1.05).

We retrospectively reviewed the utility of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and transthoracic echocardiogram (TTE) in diagnosing cardiac involvement in patients with biopsy-proven systemic immunoglobulin light chain amyloidosis seen at the Mayo Clinic between 1 January 2006 and 30 December 2015. We analyzed 2 cohorts: patients undergoing endomyocardial biopsy for suspicion of cardiac involvement (cohort 1) and patients who had serum NT-proBNP and comprehensive echocardiographic evaluation at diagnosis (cohort 2). Of 179 patients undergoing endomyocardial biopsy (cohort 1), 173 (97%) had evidence of amyloid deposition, with 159 having NT-proBNP performed at the time of the procedure. The NT-proBNP was elevated (>300 pg/mL) in all 159 patients (sensitivity, 100%; median NT-proBNP, 4917 pg/mL; range, 355-69 541). The left ventricular ejection fraction, interventricular septal thickness, and strain rate were abnormal in 89/168 (53%), 102/64 (61%) and 92/95 (97%), respectively. Among cohort 2 (n = 342), 259 (76%) had an elevated NT-proBNP, of whom 237 (92%) had an abnormality detected on TTE. Of 83 patients with normal NT-proBNP <300 pg/mL, 27 (33%) had an abnormality on TTE (all with borderline strain rate −18% to −15%). Only 5/27 patients were considered to have possible early cardiac involvement and none had any other diagnostic or classical features of amyloidosis on TTE. The combination of NT-proBNP and comprehensive echocardiographic evaluation can diagnose cardiac amyloidosis negating the need for endomyocardial biopsy. A negative NT-proBNP rules out clinically meaningful cardiac involvement and may obviate the routine use of TTE in patients with a low clinical suspicion of cardiac amyloidosis.

We evaluated the impact of achieving a rapid response in 840 newly diagnosed multiple myeloma patients from 2004 to 2015. Rates of very good partial response (VGPR) or better were 29% (240/840) after 2 cycles of treatment, 42% (350/840) after 4 cycles of treatment, and 66% (552/840) as best response. Early responders after 2 cycles of treatment had higher rates of light chain disease, anemia, renal failure, International Staging System (ISS) stage III disease, and high-risk cytogenetics, especially t(4;14), and were more likely to have received triplet therapy and undergo transplant. Median progression-free survival (PFS) and overall survival (OS) were not different among patients with ≥VGPR and

Achieving a complete response (CR) is associated with improved overall survival (OS) in multiple myeloma (MM), but data on duration of CR (DurCR) are limited. We evaluated 351 patients (2004–2016), achieving CR with first-line therapy. Patients with sustained DurCR ≥ 24 months (n= 177) had better OS; 150 vs. 81 months, p< 0.001. DurCR ≥ 24 months remained a significant predictor for OS (HR: 0.3, 95% CI: 0.2–0.5, p< 0.001) after adjusting for age, revised ISS stage, transplant and maintenance therapy. Landmark analysis at 24 months demonstrated similar results, OS: 150 vs. 83 months, p< 0.001. Survival benefit persisted even after loss of CR, with median OS being 89 vs. 56 months (p= 0.005), respectively. Patterns of loss of CR were heterogeneous, with biochemical relapse in 59 (25%); symptomatic relapse in 58 (24%); positive immunofixation/monoclonal protein rise not meeting relapse/progression criteria in 88 (37%) and abnormal free light chain ratio in LC MM in 34 (14%) patients. OS from start of first-line therapy was superior in patients starting second-line treatment for biochemical vs. symptomatic relapse (125 vs. 81 months, p= 0.001). This is likely attributable to underlying disease biology and prevention of end-organ damage by early treatment initiation, as benefit was independent of R-ISS stage.