Go, Ronald S.

Importance Anemia is a common complication of surgery and acute illness that is associated with adverse clinical outcomes. The role of anemia prevention and treatment strategies in this setting remains unclear. Objective To evaluate the effect of a multifaceted anemia management bundle vs standard care on posthospitalization hemoglobin recovery and multidimensional functional outcomes in survivors of acute illness. Design, Setting, and Participants This parallel group randomized clinical trial, known as the Practical Anemia Bundle for Sustained Blood Recovery, was conducted at postsurgical and medical intensive care units at a large US medical center. Critically ill patients (aged ≥18 years) with moderate to severe anemia (hemoglobin concentration <10 g/dL) were enrolled between March 2022 and November 2023. Participants were randomly assigned 1:1 to the intervention or standard care group. Intention-to-treat analyses were performed between July 2024 and January 2025. Intervention The intervention bundle was delivered throughout the duration of hospitalization and included optimized phlebotomy practices, clinical decision support, and pharmacological anemia treatment with intravenous iron. Main Outcomes and Measures The primary outcome was the mean difference in hemoglobin concentration at 1 month after hospital discharge. Results A total of 100 patients (median [IQR] age, 68 [61-72] years; 57 men [57.0%]; 65 [65.0%] with postsurgical admission to the intensive care unit) were enrolled during acute illness. Forty-nine patients (49.0%) were assigned to receive the intervention, and 51 (51.0%) were assigned to receive standard care. Hemoglobin concentration at 1 month after discharge was greater in patients receiving the intervention vs standard care (median [IQR], 12.2 [11.8-13.0] g/dL vs 11.5 [10.2-12.6] g/dL; adjusted mean difference, 0.69 [95% CI, 0.13-1.20] g/dL; P = .02). Conclusions and Relevance This randomized clinical trial found that a multifaceted anemia prevention and treatment bundle was feasible, was well tolerated, and improved posthospitalization hemoglobin concentrations up to 3 months in critically ill adults. These findings can inform the design of future trials. Trial Registration ClinicalTrials.gov Identifier: NCT05167734

Erdheim–Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterised by multiorgan pathological histiocytic infiltration. Cardiac involvement occurs in 40–75% of patients and increases mortality. A 55-year-old woman with chest pain and dyspnoea was found to have an interatrial septal mass and aortitis suspicious for ECD without other organ involvement. After two inadequate transcatheter interatrial biopsies were obtained using ultrasound guidance alone, diagnostic samples were successfully obtained using intraprocedural frozen section examination. The patient started genotype-targeted treatment with good response. Biopsy confirmation of ECD is required to guide treatment; however, cardiac biopsies are uncommonly performed when other organs are affected. Our unique case of isolated cardiovascular involvement highlights how frozen sectioning with multimodal intraprocedural imaging guidance can improve diagnostic yield of endomyocardial biopsies. It also highlights how diagnosis of rare conditions requires careful multidisciplinary evaluation of affected organs, procedural risk and diagnostic yield. The use of frozen sectioning can improve diagnostic yield of endomyocardial biopsies.

ABSTRACTTransplant‐associated thrombotic microangiopathy (TA‐TMA) is an endothelial dysfunction syndrome observed after allogeneic hematopoietic cell transplant (alloHCT). Our aim was to externally validate the impact of high‐risk features on the clinical outcomes of adult patients meeting the updated TA‐TMA harmonizing criteria. Between 2005 and 2022, 99 patients were diagnosed with TA‐TMA at Mayo Clinic Rochester (incidence 6.2%) after a median of 137 days post alloHCT (IQR: 34–283 days). The development of TA‐TMA was associated with an inferior overall survival posttransplant (HR: 3.8, 95% CI: 2.97–4.72). High‐risk features, including concomitant infection, acute graft‐versus‐host disease (GVHD), and organ dysfunction, were associated with poor survival, while LDH elevation was not associated with inferior outcomes. The most common treatment strategy for TA‐TMA was discontinuation of calcineurin or mTOR inhibitors in 80 (81%) patients. Thirty (37.5%) patients experienced worsening of GVHD with this strategy, of which 26 (86.7%) patients had died at last follow‐up. The most common cause of death among these patients was worsening GVHD (69%; n = 18), followed by infection (11%; n = 3), disease relapse (8%; n = 2), other/unknown causes (8%; n = 2), or TA‐TMA (4%; n = 1). Objective response rate (ORR) to initial treatment for the cohort was 56.6%. Eculizumab was used in 11 patients with an observed ORR of 70%, including 5 complete responses. In conclusion, TA‐TMA remains a significant contributor to non‐relapse mortality and is associated with worse survival following alloHCT. Not all high‐risk features, particularly LDH elevation, have consistently demonstrated a negative impact in adult cohorts. Patients with TA‐TMA may benefit from immune suppression dose adjustment, rather than a discontinuation, and the addition of complement‐directed therapy, particularly among high‐risk patients.

Abstract Among 64 patients with Erdheim-Chester disease treated with a BRAF inhibitor (median follow-up 4 years), we found high response rates (85%) but frequent discontinuations (61%), primarily because of adverse events. Additionally, patients experienced poor health-related quality of life and high symptom burden.

BACKGROUND: Preoperative anemia is common and associated with adverse outcomes in surgical patients. There is limited information to guide the design and implementation of preoperative anemia clinics (PAC), which represents a critical barrier to entry for many practices. METHODS: This is a descriptive observational study highlighting the design and implementation of a multidisciplinary PAC, including key steps in planning, stakeholder engagement, organizational structure, identification of target populations, establishing anemia treatments, information technology and electronic health record integration, provider training, and data infrastructure. Demographic and clinical characteristics, laboratory results, and anemia treatments for individuals evaluated in the PAC from November 4, 2019 through September 15, 2023 are enumerated. Patient-reported outcomes (PROs) assessing changes in anemia symptoms and well-being after surgery are evaluated for 2 subsets of patients (one before PAC implementation [pre-PAC], another after PAC implementation [post-PAC]), without formal statistical comparison given limited sample sizes. RESULTS: The PAC was initiated as a multidisciplinary effort under support from a Mayo Clinic Practice Transformation Award in 2019, including broad representation from anesthesiology, surgery, and medical practices, along with institutional project management support (eg, project manager, information technologists, systems engineers). While initially limited to cardiac surgery patients, the PAC underwent planned incremental expansion to include other surgical services. Over the study period, 1188 PAC consultations across 1159 unique patients met eligibility criteria, with a median age of 66 (57–73) years and 58.1% women. The most common etiology of anemia was iron deficiency (69.1%) followed by anemia related to cancer (17.3%). Anemia-directed therapies were recommended in 1038 (87.4%) encounters, with 730 (70.3%) of those receiving recommended treatment preoperatively. Seven hundred nine (97.1%) treatments included intravenous iron and 146 (20.0%) included erythropoiesis-stimulating agents. Fifteen pre-PAC and 38 post-PAC implementation patients completed PROs. PAC implementation was accompanied by earlier resolution of anemia symptoms and less pronounced declines in postoperative well-being scores. CONCLUSIONS: This report highlights the key steps for successful PAC implementation. Treatment is possible for most patients and may be accompanied by improvements in patient-important outcomes.

Abstract Endocrinopathies are frequently the initial presentation of histiocytic neoplasms, which are rare hematologic disorders affecting multiple organ systems. Langerhans cell histiocytosis and Erdheim–Chester disease are 2 such disorders known to infiltrate the hypothalamus and/or pituitary gland, leading to arginine vasopressin deficiency (AVP-D) and anterior pituitary dysfunction (APD) in 20% to 30% of cases, often as the first manifestation. Conversely, histiocytic disorders account for a notable proportion (10-15%) of all pituitary stalk lesions. The diagnosis of histiocytoses is often delayed in such cases due to the nonspecific presentation of endocrinopathies and pituitary involvement. Consequently, endocrinologists are at the frontline and uniquely positioned to achieve early diagnosis by recognizing the varied nonendocrine features of these disorders. This article provides an overview of the endocrine manifestations of histiocytic disorders and presents a simplified algorithm to guide the diagnostic workup in cases presenting with “idiopathic” AVP-D or APD. Such cases should be evaluated for histiocytic neoplasms with additional imaging studies and biopsies of suspected disease sites. If no disease site beyond the pituitary is identified, the risks and benefits of a pituitary stalk lesion biopsy must be carefully considered. While treatments of histiocytic neoplasms are highly efficacious, endocrinopathies are considered permanent and require long-term hormone replacement. It remains unclear whether early diagnosis and novel targeted therapies can reverse these endocrine disorders. Therefore, the role of the endocrinologist role is critical in the diagnosis and management of these rare diseases.

Introduction Malignant histiocytoses (MH), encompassing histiocytic sarcoma (HS), interdigitating dendritic cell sarcoma (IDCS), and Langerhans cell sarcoma (LCS), are a group of rare, hematologic neoplasms with diverse clinical presentations and poor outcomes. There are no established or effective treatments for patients with MH. The discovery of MAPK/ERK pathway mutations in non-malignant histiocytoses have revolutionized the treatment paradigm, but it is unknown whether novel treatments are efficacious for MH. This study aimed to assess the efficacy of targeted agents (TA) and immune checkpoint inhibitors (ICI) in MH. Methods We conducted a retrospective chart review of MH patients seen at our two institutions. Only patients treated with TA and/or ICI were included. We captured the mutational status by next generation sequencing and PD-L1 expression level by immunohistochemistry, where available. We also conducted a systematic literature review using PubMed to identify additional cases of MH patients treated with TA and/or ICI. Responses were reported as complete (CR), partial (PR), or none (NR) using previously published criteria for histiocytic disorders. Results From our institutions, we identified 12 MH patients (7 HS; 4 LCS; 1 IDCS) who received 14 instances of these treatments including TA (n=9) and/or ICI (n=5). The median age at diagnosis was 55 years (range, 33-70) and 50% were males. TAs included BRAF inhibitor (vemurafenib [1]), MEK inhibitors (binimetinib [1], cobimetinib [2], trametinib [2]) and others (dasatinib [1], pazopanib [1], pexidartinib [1]), while ICIs were exclusively pembrolizumab (5). The median number of prior treatments for those who received TAs and ICIs were 4 and 2, respectively. Responses were observed in 44.4% (1 CR, 3 PRs, 5 NR) and 40% (2 CRs, 3 NRs) of patients who received TA and ICI, respectively. Only 1 patient (20%) treated with MEK inhibitor responded [DOCK8-BRAF; PR 5+ mos]. Other responders received dasatinib [PDFGRA-V608I; PR 2 mos], pexidartinib [PTPN11-A72T; PR 5 mos], and vemurafenib [BRAF-V600E; CR 10+ mos]. Two patients (40%) who received pembrolizumab responded (both CRs 12+ [10% PD-L1] and 44+ mos [40% PD-L1]). We identified 29 MH patients in the literature (27 HS; 2 LCS) treated with TAs (22) and/or ICIs (10). TAs included BRAF inhibitor only (vemurafenib [3], dabrafenib [3]), MEK inhibitor only (trametinib [5]), BRAF + MEK inhibitors (2), and others (apatinib, anlotimib, bevacizumab, daratumumab, dasatinib, imatinib, pazopanib, sorafenib, or combinations [9]), while ICIs included pembrolizumab (4), nivolumab (4), tislelizumab (1), and sintilimab (1). Responses were observed in 77% (7 CRs, 10 PRs, 5 NRs) and 100% (2 CRs, 8 PRs) of patients who received targeted agents and ICI, respectively. Most patients carrying BRAF (7/8; V600E, G596R, D594G, TRIM::BRAF) or MAP2K1 (3/3; C121S, F53I) mutations responded to treatments, irrespective of the number of mutations present. The median durations of response for ICI and targeted agents were 10.5 months (range: 1-36+) and 12+ months (range: 3-44+), respectively. After combining the datasets from our institutions and literature review, we analyzed the association between the extent of PD-L1 expression and response to ICI. Those who responded to ICI had higher PDL-1 expression (median 75% [range, 10-75] vs 25% [range, 1-30]; P=0.0097). Conclusion TAs and ICIs can be considered in the management of MH. The responses to ICI therapy may be associated with the degree of PDL1 expression

INTRODUCTION Primary plasma cell leukemia (pPCL) is a rare and aggressive form of multiple myeloma (MM) with poor survival outcomes. Fluorescence in situ hybridization (FISH) evaluation is essential for the initial risk stratification in MM, and the presence of multiple high-risk (HR) cytogenetic abnormalities by FISH portends a worse prognosis in MM. We have previously observed that the presence of HR cytogenetic abnormalities by FISH at diagnosis is known to confer a poor overall survival (OS) in patients with pPCL. However, less is known about the cumulative effect of multiple HR cytogenetics abnormalities compared to a single HR cytogenetic abnormality on the OS outcomes of patients with pPCL. AIM To evaluate the prognostic implications of additive HR cytogenetics abnormalities by FISH in patients with pPCL treated with novel agents. METHODS We evaluated patients with newly diagnosed pPCL at the Mayo Clinic Comprehensive Cancer Center from 2014 - 2023 that received induction with novel agent combinations. pPCL was defined as patients meeting the diagnostic criteria for MM with 5% or more circulating plasma cells (cPCs) present on morphologic evaluation of their peripheral blood smear. HR cytogenetics abnormalities by FISH was defined by the presence of any one of the following: 1q gain/amplification, t(4;14), t(14;16), t(14;20), and del(17p). Time to next treatment (TTNT) and OS analysis were performed using the Kaplan-Meier method, and differences were assessed using the log-rank test. Statistical analyses were performed using the SAS biostatistical software JMP 17.0.1 (SAS Institute Inc). RESULTS We included 89 patients with newly diagnosed pPCL who received novel agents as first-line therapy between 2014 to 2023. The median follow-up was 45 months (95% CI: 35 - 65). At diagnosis, the median bone marrow plasma cell content was 80% (Range: 10 - 100), and the median cPC% on the peripheral smear was 21% (range: 5 - 85). There were 51 patients (59%) who had 20% or more cPCs on their peripheral smear. There was a preponderance of pPCL patients who had t(11; 14) as their primary cytogenetic abnormality (43%). The median lines of therapy received were 2 (Range: 1 - 9). There were 12 (13%) patients who received intensive induction therapy containing continuous infusional chemotherapy regimens at the onset of their diagnosis. Of the remaining patients, 35 (45%) were treated with a quadruplet (anti-CD38 antibody, proteasome inhibitor and immunomodulator), 24 (31%) with a triplet (proteasome inhibitor and immunomodulator) and 18 (23%) with a doublet (proteasome inhibitor only). The median OS for all pPCL patients in this cohort was 47 months (95% CI: 37 - 100). However, when stratified by cytogenetic risk, the median OS was 101 months (95% CI: 57 - NR) for those patients without any HR cytogenetic abnormalities (N = 24, 27%) vs. 37 months (95% CI: 22 - 63) for those with one or more HR cytogenetic abnormalities (N = 65, 73%) (P = 0.006). Of the patients with any HR cytogenetic abnormalities, 33 (36%) had one HR cytogenetic abnormalities and 32 (34%) had two or more HR cytogenetic abnormalities. The median OS for patients with one compared to two or more HR cytogenetic abnormalities were 47 (95% CI: 38 - 111), and 22 (95% CI: 17 - 37) months, respectively (P = 0.031). The median TTNT was 22 months (95% CI: 16 - 58) for those patients without any HR cytogenetic abnormalities vs. 16 months (95% CI: 9 - 21) for those with one or more HR cytogenetic abnormalities (P = 0.09). The median TTNT from the time of diagnosis for pPCL patients with one compared to two or more HR cytogenetic abnormalities were 18 (95% CI: 6 - 41) and 16 (95% CI: 10 - 19) months, respectively (p = 0.247). CONCLUSION Patients with pPCL with more than one HR cytogenetic abnormality had an inferior OS compared to those with only one HR cytogenetic abnormality, implicating the additive adverse effects of multiple HR cytogenetics abnormalities. In contrast, patients with pPCL without any HR cytogenetic abnormalities had a relatively long median OS (over 100 months).

Introduction. Erdheim-Chester disease (ECD), Langerhans cell histiocytosis (LCH) and Rosai-Dorfman disease (RDD) belong to a group of histiocytic neoplasms often driven by mutations in the mitogen activated protein kinase (MAPK) pathway, most commonly in BRAF, MAP2K1 and K/NRAS. Currently, there are 2 drugs approved by the US Food and Drug Administration for the treatment of histiocytic neoplasms, cobimetinib and vemurafenib, both small molecule kinase inhibitors (SMKI) targeting mitogen-activated extracellular signal-regulated kinase (MEK) and BRAF, respectively. BRAF mutations are functionally classified as RAS-independent - either monomers (class I) or dimers (class II) - and RAS-dependent (class III). MAP2K1 mutations are functionally classified as RAF-independent, RAF-regulated, or RAF-dependent. Preclinical studies suggest class I, but not classes II-III, BRAF mutations are sensitive to RAF monomer inhibitors (dabrafenib, encorafenib, vemurafenib) while classes I-II, but not class III, BRAF mutations are sensitive to MEK inhibitors (Yaeger R, Cancer Discovery 2019). In contrast, RAF-regulated MAP2K1 mutants have variable sensitivities to allosteric MEK inhibitors (binimetinib, cobimetinib, selumetinib, trametinib) while RAF-dependent and RAF-independent MAP2K1 mutations are resistant. KRAS mutations are generally resistant to MEK inhibitors (Johnson C, Cancer Discovery 2022). Our study described the clinical efficacy of commercially available SMKIs in patients with histiocytic neoplasms harboring non-BRAFV600E mutations and compared the findings with preclinical data. Methods. We conducted a retrospective chart review of patients with histiocytic neoplasms who were treated with SMKI at Mayo Clinic. Only those who had adequate genomic testing and non-BRAFV600E mutations were included. Responses were categorized as complete (CR), partial (PR), or none (NR) based on established criteria. Results. We identified 31 non-BRAFV600E patients treated with SMKI (2 LCH; 20 ECD; 9 RDD). The median age at diagnosis was 61 years (range: 16-76) and 52% were females. The distribution of BRAF mutations was: class I (V600delinsRE [1]), class II (V495A [1], V471F [1], N486_P490del [2], GAB2-BRAF [1], UBR2-BRAF [1], RNF11-BRAF [1], UBTD2-BRAF [1]), and class III (G466E [1], D594A [1]). The only patient with class I mutation received cobimetinib and had PR. Among those with BRAF class II mutations, 2 received vemurafenib and had NR, while 9 received MEK inhibitors (binimetinib, cobimetinib, trametinib) and most responded (3 CRs, 5 PRs). The patient who had NR required dose reductions due to side effects. Both patients with class III mutation did not respond to cobimetinib. The median duration of responses was 19 months (range: 3+ to 45+) and 3 patients progressed subsequently. The distribution of MAP2K1 mutations was: RAF-independent (E102_103del [2]), RAF-regulated (I103N [1], K57T [1], Q56P [3], F53L [1], K57N [1]) and RAF-dependent (Y130C [1], D67N [1]). Both patients with RAF-independent mutations treated with cobimetinib had PRs. All patients with RAF-regulated mutations treated with allosteric MEK inhibitors responded (3 CRs, 5 PRs). Both patients with RAF-dependent mutations treated with cobimetinib responded (1 CR, 1 PR). The median duration of responses was 15 months (2 to 29+) with 3 patients progressing after treatment cessation due to intolerance. The distribution of RAS mutations was: NRAS (Q16R [1]) and KRAS (K117N [3], A146T [1], T581 [1], G13C [1], G12D [1]). Most patients treated with allosteric MEK inhibitors responded (3 CR, 4 PR, 1 NR). The median duration of response was 15 months (5 to 41) and 2 patients subsequently progressed, one of them after treatment cessation. Conclusions. Among patients with histiocytic neoplasms with non-BRAFV600E mutations receiving SMKI, our study found mixed patterns of concordance between pre-clinical predictions and clinical responses. There was concordance of efficacy in the setting of BRAF classes I-III and MAP2K1 RAF-regulated mutations. However, we found discordant findings in patients harboring RAF-dependent and RAF-independent MAP2K1 mutations as well as KRAS mutations as most responded to allosteric MEK inhibitors.

Background: There is an increased risk of second primary malignancies including second hematological malignancies (SHM) in multiple myeloma (MM) patients undergoing autologous stem cell transplant (auto-SCT) followed by lenalidomide maintenance. We analyzed the characteristics and outcomes of patients who developed SHM after an auto- SCT for MM. Methods: A retrospective study of all MM patients who underwent auto- SCT at Mayo Clinic, Rochester between January 1, 1990, and 31 August 2023 and later developed SHM. Demographic, clinical and pathologic data were collected retrospectively. Overall survival (OS) was calculated from the date of auto-SCT to the date of last follow up. Statistical analyses were performed using GraphPad prism 9.0. Chi-square test was used to calculate the difference between categorical variables. Kaplan Meier method and log rank test were used to estimate OS. Results: Among 3513 patients who underwent at least 1 auto-SCT, 104 (2.9%) developed a SHM at a median follow up of 59 (range, 0.2-265) months. Patients who developed SHM, more frequently received pretransplant alkylating agents (37.5 vs 24.2 %, odds ratio [OR], 1.87; P=0.003) and topoisomerase II inhibitors (anthracyclines/etoposide) (17.3% vs 10.4%, OR [1.79]; P=0.03) compared to a control group of MM patients without SHM. Further, exposure to lenalidomide (77.8% vs 57.6%, OR[2.59]; P <0.0001) and radiation therapy (32.6% vs 23.1%, [1.54]; P=0.04) were more often seen in the SHM cohort compared to control group. Among the 381 patients who underwent > 1 auto- SCT, 3.1% developed SHM. Therapy related myeloid neoplasms (t-MN) accounted for 90.3% of cases [n=94; t-myelodysplastic syndrome (t-MDS=64), t-acute myeloid leukemia (t-AML=12), t-MDS transformed to AML(n=16), chronic myeloid leukemia (n=1), MDS/myeloproliferative neoplasm overlap syndrome (n=1)]. Eight patients (7.6%) developed therapy related B- cell acute lymphoblastic leukemia (t-ALL); Philadelphia (Ph) negative ALL (n=7) and Ph- like ALL (n=1). One patient each developed mixed phenotype acute leukemia and acute leukemia, not otherwise specified. Sixty patients (57.6%) were males and the median age at diagnosis of SHM was 70 (range, 43-84) years. The median time from auto-SCT to diagnosis of SHM was 58.5 (range, 7-236) months. In a multivariate analysis, receiving an alkylating agent (hazard ratio [95% confidence interval]: 2.51 [1.54 to 4.01]; P = 0.0002) and/or topoisomerase II inhibitor as induction for MM (3.12 [1.59 to 5.88]; P = 0.0006), exposure to lenalidomide (7.08 [3.92 to 13.50]; P = <0.0001) and radiation therapy (1.60 [1.02 to 2.44]; P = 0.03) were independent predictors of developing SHM. At diagnosis, 57% (n=37) of t-MDS and 71% (n=20) with t-AML had high risk disease per R-IPSS and 2022 European Leukemia Net respectively. Clonal abnormality in chromosome 5 and/or 7 was present in 45% (n=42) of patients. Complex and monosomal karyotype was seen in 32% (n=30) with t-MN. The most frequently mutated genes based on next generation sequencing data included TP53 (n=33), DNMT3A (n=9), RUNX1 (n=5), TET2 (n=4) and CEBPA (n=4). In the t-MDS/AML cohort, 3 patients (3.1%) underwent second auto-SCT and 9 (9.5%) received allogenic SCT (allo-SCT) for SHM. After a median follow-up of 27.2 months, the median OS from t-MDS/AML diagnosis was 8.04 months (95%CI, 6.1-11.0 months) and there was no difference in median OS for allo-SCT recipients versus nonrecipients (9.1 vs 6.8 months, P =0.19). In the t-ALL (n=8) cohort, all of them received lenalidomide based induction and five received lenalidomide maintenance. Most of the t-ALL patients had adverse risk cytogenetics [IKZF1 deletion (n=2), complex karyotype (n=2), TP53 mutation (n=1) and P2RY8-CRLF2 fusion (n=1)]. Three patients with t-ALL underwent allo-SCT and the median OS for allo-SCT recipients versus non recipients were 8.3 vs 7.9 months respectively, P=0.50. Among patients with SHM, 92.3% (n = 96) have died with SHM (72%) being the most common cause of death. MM patients who developed SHM had an inferior OS when compared to those without SHM (median OS, 75 vs 90 months, P =0.006). Conclusion: SHM following auto-SCT tends to have aggressive disease biology with poor outcomes. Short term follow up underestimates the risk of SHM and the higher incidence noted in our study may be due to longer follow up. As the OS in MM patients continues to improve, SHM remains an important challenge in improving long term outcomes.