Long-term follow-up of methotrexate and cytarabine in adult patients with Langerhans cell histiocytosis.

The optimal treatment strategy for adult Langerhans cell histiocytosis (LCH) remains unclear. Our previous study demonstrated the remarkable efficacy of combined methotrexate and cytarabine (Ara-C) [MA] therapy in patients newly diagnosed with LCH, with a median follow-up of 2 years. The present article reports long-term follow-up data spanning a median of 78 months (6.5 years) from a single-arm, single-centre, prospective phase 2 clinical trial (NCT02389400) conducted between January 2014 and December 2020. Ninety-five adults with newly diagnosed LCH exhibiting multisystem disease or multifocal single-system involvement underwent MA therapy every 35 days for six cycles. Methotrexate (1 g/m2) was administered by 24 h infusion on day 1 and AraC (0.1 g/m2) by 24 h infusion for 5 days. The primary end-point was event-free survival (EFS). The median patient age was 32 years (range 18-65 years). The overall response rate was 89.5%. Seven patients in this cohort died, and 38 experienced disease reactivation. No degenerative central nervous system diseases were observed. The estimated 6-year overall survival (OS) and EFS rates were 93.2% and 55.2% respectively. Multivariate analysis revealed that risk organ (RO) involvement at baseline (hazard ratio [HR] 6.135 [95% confidence interval (CI) 1.185-32.259]; p = 0.031) and age >40 years at diagnosis (HR 7.299 [95% CI 1.056-21.277]; p = 0.042) were associated with inferior OS. RO (HR 2.604 [95% CI 1.418-4.762]; p = 0.002) and skin (HR 2.232 [95% CI 1.171-4.255]; p = 0.015) involvement at baseline were poor prognostic factors for EFS. Regarding adverse events, four patients developed a second primary malignancy. In conclusion, the MA regimen was a valid and safe therapeutic approach for adult patients newly diagnosed with LCH.

Liver involvement with Langerhans cell histiocytosis in adults.

BACKGROUND AND AIMS: Liver involvement portends poor prognosis in adults. We aimed to characterize the clinical features, liver function tests, radiologic findings, molecular profiles, therapeutic approaches and outcomes of adults patients with Langerhans cell histiocytosis (LCH) with liver involvement. METHODS: We conducted a retrospective analysis of all adults with LCH (≥ 18 years) seen at Peking Union Medical College Hospital (Beijing, China) between January 2001 and December 2022. RESULTS: Among the 445 newly diagnosed adults with LCH, 90 patients had liver involvement at diagnosis and 22 patients at relapse. The median age was 32 years (range, 18-66 years). Of 112 evaluable patients, 108 had full liver function testing, including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), and total bilirubin and albumin. Elevated ALP was seen in 63.0% and GGT in 86.1%; 14.8% had elevated bilirubin. Next-generation sequencing of 54 patients revealed frequent BRAFN486_P490 (29.6%), BRAFV600E (18.5%), and MAP2K1 (14.8%). OUTCOMES: After a median 40 months' follow-up (range 1-168 months), 3-year progression-free survival (PFS) and overall survival were 49.7% and 86.6% respectively. In multivariable analyses, ≥3 abnormal liver function tests (HR 3.384, 95% CI 1.550-7.388, P = .002) associated with inferior PFS; immunomodulatory drug therapy (HR 0.073, 95% CI, 0.010-0.541, P = .010) correlated with superior PFS versus chemotherapy. CONCLUSIONS: In summary, elevated GGT and ALP were common in adults with LCH liver involvement. Greater than equal to 3 abnormal liver function tests predicted poor outcomes. Immunomodulatory drug therapy was associated with favorable progression-free survival compared to chemotherapy.

International expert consensus recommendations for the diagnosis and treatment of Langerhans cell histiocytosis in adults.

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.

Co-occurrence of Erdheim-Chester disease and clonally evolving acute myeloid leukemia with FLT3-ITD and PTPN11 mutations.

Erdheim-Chester disease (ECD) is a rare histiocytosis that tends to co-exist with other myeloid malignancies. Here, we use genetic and transcriptomic sequencing to delineate a case of co-occurring BRAFV600E-mutated ECD and acute myeloid leukemia (AML), followed by AML remission and relapse. The AML relapse involved the extinction of clones with KMT2A-AFDN and FLT3-ITD, and the predominance of PTPN11-mutated subclones with distinct transcriptomic features. This case report has highlighted the screening for other myeloid malignancies at the diagnosis of ECD and the clinical significance of PTPN11-mutated AML subclones that require meticulous monitoring.

Serum CXCL13 level is related to treatment response and predicts disease prognosis in Waldenström macroglobulinemia.

Waldenström macroglobulinemia (WM) is a type of B-cell lymphoma that produces IgM. Our study aimed to investigate the role of CXCL13, a chemokine essential for B lymphocytes, in the evaluation of treatment response and prognosis in WM. We collected serum samples and clinical data from 72 WM patients, with 69 patients receiving systemic therapy and 3 patients opting not to receive treatment. Serum CXCL13 levels at baseline and after six months of treatments were measured by enzyme-linked immunosorbent assay. The median serum level of CXCL13 was 1 539.2 pg/ml (range 10.0-21 389.9) at baseline and significantly decreased to 123.1 pg/ml (range 0.0-6 741.5) after 6 months of treatments. At baseline, higher CXCL13 levels were associated with lower hemoglobin levels (p = 0.001), higher ß2-microglobulin levels (p = 0.001), lower albumin levels (p = 0.046), and higher IPSS-WM scores (p = 0.013). After 6 months of treatment, patients who achieved PR/VGPR had significantly lower CXCL13 levels compared to those with SD (70.2 pg/ml vs 798.6 pg/ml, p = 0.002). The median follow-up period was 40 months (range 4.2-188). Eight patients died during the follow-up period. Overall survival differed based on CXCL13 levels. When grouped by baseline CXCL13 levels, the median OS was 60.0 months in patients with serum CXCL13 > 2 000 pg/ml, while it was not reached in patients with low CXCL13 levels (p < 0.001). Based on CXCL13 levels after the treatments, the median OS was 74.0 months in patients with serum CXCL13 > 200 pg/ml, while it was not reached in patients with CXCL13 ≤ 200 pg/ml. In a subgroup of 28 patients with a series of serum samples, the increase of serum CXCL13 level was associated with disease progression or the start of next-line therapy (p < 0.001). Our study concludes that serum CXCL13 levels decrease in WM patients treated with various regimens and correlate with treatment response. Detecting serum CXCL13 at baseline or after treatment help in predicting prognosis.

Manifestations and outcomes of digestive tract involvement in adult Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is a heterogeneous histiocytosis characterized by proliferation of Langerhans cells. While less common, manifestations of digestive tract involvement in LCH remain largely unrevealed. We conducted a retrospective analysis of demographics, clinical, endoscopic, genetic and follow-up data from 13 adult patients with pathologically confirmed gastrointestinal involvement of LCH (LCH-GI), in a single-center cohort of 465 patients. Digestive tract involvement was observed in 2.80% of LCH patients. At LCH-GI diagnosis, 7 patients (53.8%) had unifocal lesions, and 6 patients (46.2%) had multisystem disease. 6 patients (46.2%) experienced no gastrointestinal symptoms at LCH-GI onset, while others were symptomatic. Stomach was most commonly affected (61.5%), followed by esophagus (23.1%), colon (7.7%) and anus (7.7%). Endoscopic findings varied among 12 patients, including submucosal bulge (8 patients, 66.7%) and non-bulging lesions (4 patients, 33.3%) such as erosions, coarse granular mucosa, and regional abnormal coloration. Among 8 patients with genetic analysis, BRAFV600E mutation was detected in 5 patients (62.5%). The estimated 1-year overall survival rate was 91.7%. Progression-free survival of patients with submucosal bulges under endoscopy was significantly better than those with non-bulging lesions. This study presents 13 cases of LCH with digestive tract involvement. We emphasize the importance of endoscopy and biopsy for pathological examination of lesions such as submucosal bulges and erosions under endoscopy to assist in early detection of LCH. Comprehensive systemic assessment and regular endoscopic monitoring are essential in patient management. Treatment should be individualized with dynamic adjustments during follow-up.

Doxycycline Combined With Bortezomib-Cyclophosphamide-Dexamethasone Chemotherapy for Newly Diagnosed Cardiac Light-Chain Amyloidosis: A Multicenter Randomized Controlled Trial.

BACKGROUND: Doxycycline was demonstrated in a retrospective study to be associated with greater survival in patients with light chain amyloidosis. Therefore, we prospectively compared the efficacy of bortezomib-cyclophosphamide-dexamethasone (CyBorD) and CyBorD combined with doxycycline for cardiac light chain amyloidosis. METHODS: This was a multicenter, open-label, randomized controlled trial. Patients with Mayo 2004 stage II to III light chain amyloidosis were included. Patients were randomized to doxycycline 100 mg twice daily along with 9 cycles of CyBorD (doxycycline group) or to 9 cycles of CyBorD alone (control group). The primary outcome was 2-year progression-free survival (PFS). PFS was defined as the time from randomization to death, hematologic progression, or organ progression (heart, kidney or liver). Hematologic progression was defined on the basis of a substantial increase in free light chain. An increase in either NT-proBNP (N-terminal pro B-type natriuretic peptide) or cardiac troponin was the main criterion for defining cardiac progression. Cardiac PFS, defined as the time from randomization to cardiac progression or death, was compared between groups in an exploratory analysis. The corresponding treatment hazard ratio was estimated with a Cox regression model. RESULTS: One hundred forty patients underwent randomization, with 70 in each group. The median age was 61 years (range, 33-78 years) with a male:female ratio of 1.75:1. Stage II disease was present in 34 (48.6%) and 33 (47.1%) patients in the doxycycline and control groups, respectively. After a median follow-up duration of 24.4 months, 32 of 70 (45.7%) patients in the doxycycline group and 30 of 70 (42.9%) patients in the control group experienced progression. PFS was not significantly different between groups (hazard ratio, 0.97 [95% CI, 0.59-1.60]; P=0.91). Cardiac progression occurred in 29 of 70 (41.4%) patients in the doxycycline group and 26 of 70 (37.1%) patients in the control group. The death rates for both groups by the end of follow-up was the same, 25 of 70 (35.7%). No significant differences were observed for either cardiac PFS (hazard ratio, 0.91 [95% CI, 0.54-1.55]; P=0.74) or overall survival (hazard ratio, 1.04 [95% CI, 0.60-1.81]; P=0.89). CONCLUSIONS: Our trial demonstrated that doxycycline combined with CyBorD failed to prolong PFS or cardiac PFS compared with CyBorD alone in cardiac light chain amyloidosis. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03401372.

The clinical spectrum and prognostic factors of Erdheim-Chester disease and mixed Langerhans cell histiocytosis and Erdheim-Chester disease.

Erdheim-Chester disease (ECD) is a rare and probably fatal multisystemic non-Langerhans cell histiocytosis (LCH). To comprehensively investigate the clinical features, genomic analysis, treatments, and prognostic factors of ECD, we retrospectively analyzed the clinical data of 75 ECD patients and 10 mixed LCH and ECD patients in our center. The median age at diagnosis was 46 years (range, 5-70). ECD patients were older at diagnosis (p = 0.006) and had more cardiac involvement (p = 0.011) as well as vascular (p = 0.031) involvement compared to mixed LCH and ECD patients. 64.8% of ECD patients and 87.5% of mixed LCH and ECD patients carried BRAFV600E mutation. The BRAFV600E mutation correlated with a greater number of affected organs (p = 0.030) and was associated with lung involvement (p = 0.033) as well as pleural involvement (p = 0.002). The median follow-up time was 38 months (range, 1-174). The estimated 5-year progression-free survival (PFS) and overall survival (OS) were 48.9% and 84.7%, respectively. In a multivariate analysis, right atrial pseudotumor (p = 0.013) and pancreatic involvement (p = 0.005) predicted worse OS, while pleural (p = 0.042) and central nervous system (CNS) involvement (p = 0.043) predicted worse PFS. Our study described the clinical spectrum of ECD and mixed LCH and ECD, while also revealed the prognostic value of right atrial pseudotumor and pancreatic, pleural, and CNS involvement for worse survival.

Erdheim-Chester disease: consensus recommendations for evaluation, diagnosis, and treatment in the molecular era.

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.

Adult Langerhans cell histiocytosis with thyroid gland involvement: clinical presentation, genomic analysis, and outcome.

The present study aims to evaluate the characteristics and treatment outcomes of adult Langerhans cell histiocytosis (LCH) patients with thyroid involvement. We retrospectively described the clinical, biological, and genomic characteristics of a series of 36 LCH patients with thyroid involvement in our center between January 2001 and December 2021. At the time of diagnosis, only one patient was classified as having single-system LCH, and 35 patients were classified as having multisystem (MS) LCH. Three patients had coexisting papillary thyroid carcinoma. Patients with thyroid gland involvement had higher frequencies of pituitary (88.6% vs. 53.4%, P < 0.001), liver (45.7% vs. 20.7%, P = 0.003), and lymph node (54.3% vs. 31.6%, P = 0.012) involvement and a lower frequency of bone (45.7% vs. 72.0%, P = 0.003) involvement than patients without thyroid gland involvement. Sixteen patients had abnormal thyroid function, including nine patients with primary hypothyroidism, one patient with central hypothyroidism, and six patients with subclinical hypothyroidism. BRAFV600E, BRAF N486_P490, and MAP2K1 mutations were detected in 14.3%, 57.1%, and 7.1% of patients, respectively. After a 43-month median follow-up, none of the patients died, and 15 patients experienced reactivation. The median event-free survival was 37.5 months. Two of 6 patients with subclinical hypothyroidism had normal thyroid function, and 12 patients still had hypothyroidism after treatment. As the largest adult LCH cohort with thyroid gland involvement to date, we found that patients with thyroid gland involvement had different clinical characteristics, genetic profiles, and outcomes than patients without thyroid gland involvement.

Benefit of high-dose idarubicin as induction therapy in acute myeloid leukemia: a prospective phase 2 study.

Idarubicin 12 mg/m2 has been recommended as a standard induction therapy for acute myeloid leukemia (AML). It is unknown whether a higher dose of idarubicin can improve the remission rate. This phase 2 prospective single-arm study enrolled 45 adults with newly diagnosed AML between September 2019 and May 2021 (NCT 04,069,208). Induction therapy included administration of idarubicin 14 mg/m2 for 3 days and cytarabine 100 mg/m2 every 12 h subcutaneously for 7 days. The primary endpoint was the composite complete response rate (complete response (CR) plus complete response with incomplete blood count recovery (CRi)). The median age was 45 years (range 14-60 years). Forty (88.9%) patients had CR or CRi, including 39 patients with CR and 1 patient with CRi after one course of induction therapy. The median times to recovery of absolute neutrophil and platelet counts were 21 days. Only 1 patient died of intracranial hemorrhage during induction therapy. After a median follow-up of 14 months (range 3.5-24 months), the estimated 18-month overall survival and disease-free survival (DFS) were 66.9% and 57.5%, respectively. In conclusion, idarubicin 14 mg/m2 plus cytarabine was a safe and efficient intensive regimen for younger and fit patients with newly diagnosed AML.

Signaling pathways, microenvironment, and targeted treatments in Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid malignancy in the "L-group" histiocytosis. Mitogen-activated protein kinase (MAPK) pathway activating mutations are detectable in nearly all LCH lesions. However, the pathogenic roles of MAPK pathway activation in the development of histiocytosis are still elusive. This review will summarize research concerning the landscape and pathogenic roles of MAPK pathway mutations and related treatment opportunities in Langerhans cell histiocytosis. Video abstract.

Treatment outcomes and prognostic factors of patients with adult Langerhans cell histiocytosis.

Adult Langerhans cell histiocytosis (LCH) remains poorly defined. We retrospectively studied 266 newly diagnosed LCH patients to understand the clinical presentation, treatment, and prognosis of adult LCH. The median age at diagnosis was 32 years (range, 18-79 years). At the time of diagnosis, 40 patients had single lesions within a single system, 18 patients had single pulmonary LCH, 26 patients had multiple lesions within a single system (SS-m), and 182 patients had multisystem disease (MS). The most common organ involved in MS patients was the bone (69.8%), followed by the pituitary (61.5%) and lung (61.0%). BRAFV600E , BRAF deletion, and MAP2K1 mutation were detected in 38.8%, 25.4%, and 19.4% patients, respectively. BRAF deletion was found more common in patients with MS LCH compared to single-system LCH (38.5% vs 7.1%, p = .004), also in patients with liver involvement (69.2% vs 14.3%, p < .001). The estimated 3-year overall survival (OS) and event-free survival (EFS) rates were 94.4% and 54.7%, respectively, in SS-m and MS LCH. Multivariate Cox regression showed that involvement of the liver or spleen at baseline predicted poor EFS and receiving cytarabine-based therapy as a first-line treatment and age older than 30 years at diagnosis predicted favorable EFS. The involvement of risk organs and age older than 50 years predicted poor OS, and receiving cytarabine-based therapy predicted favorable OS. Therefore, BRAF deletion was correlated with MS LCH, particularly those with liver involvement. Liver or spleen involvement at baseline indicates a poor prognosis, and a cytarabine-based regimen could be considered as first-line treatment for adult LCH patients.

Pancreatic involvement in Erdheim-Chester disease: a case report and review of the literature.

BACKGROUND: Erdheim-Chester disease (ECD) is a rare form of non-Langerhans cell histiocytosis characterized by infiltration of lipid-laden foamy macrophages within different tissues. Clinical manifestations of ECD are highly heterogeneous. Bone lesions are found in 80%-95% of patients, while extraosseous lesions usually involve the cardiovascular system, retroperitoneum, central nervous system (CNS), and skin. Pancreatic involvement in ECD has barely been reported. CASE PRESENTATION: A 29-year-old female initially presented with menoxenia, diabetes insipidus and diabetes mellitus. 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT) revealed hypermetabolic foci in the bilateral frontal lobe, saddle area, and pancreas. A 99mTc-MDP bone scrintigraphy scan revealed symmetrical increased uptake in distal femoral and proximal tibial metaphysis, which was confirmed to be osteosclerosis by high-resolution peripheral quantitative computed tomography. The patient underwent incomplete resection of the sellar mass. Histological examination of biopsies showed histiocytic aggregates, which were positive for S100 and negative for CD1a and CD207 on immunohistochemistry. Enhanced abdominal CT scan showed hypointense nodules within the body and tail of the pancreas. Endoscopic ultrasonography guided fine-needle aspiration (EUS-FNA) found no evidence of malignancy. She was diagnosed with ECD and treated with high-dose IFN-α. Repeated examinations at three-and eight-months post treatment revealed markedly reduction of both intracranial and pancreatic lesions. CONCLUSIONS: ECD is a rare histiocytic neoplasm that can involve almost every organ, whereas pancreatic involvement has barely been reported to date. Here, we present the rare case of pancreatic lesions in ECD that responded well to interferon-α. We further reviewed reports of pancreatic involvement in histiocytic disorders and concluded the characteristics of such lesions to help diagnosis and treatment, in which these lesions mimicked pancreatic adenocarcinoma and caused unnecessary invasive surgeries.

Revealing serum lipidomic characteristics and potential lipid biomarkers in patients with POEMS syndrome.

POEMS syndrome is a rare plasma cell dyscrasia with distinct lipid metabolism abnormalities at disease onset. However, the serum lipidomic characteristics in patients with POEMS syndrome were not investigated. The study performed an untargeted lipidome screening by liquid chromatography-tandem mass spectrometry (LS-MS/MS) in the pre- and post-treatment serum of 24 patients with POEMS syndrome, together with the serum of 24 paired healthy controls. Patients with POEMS syndrome had a distinct serum lipid composition compared with healthy controls, and a 3-lipid model had a predictive accuracy of 93.5% in distinguishing patients and healthy controls consisting of fatty acyl 17-oxo-20Z-hexacosenoic acid, phosphatidylcholine(16:0/18:1(9Z)) and sterol lipid 5b-pregnanediol. Four lipids including 17-oxo-20Z-hexacosenoic acid (r = 0.423, P = .040) were correlated with risk stratification, and 2 lipids including Cer(d18:0/13:0) were inversely related to serum vascular endothelial growth factor level (r=-0.465, P = .022). Eleven lipids were related to disease activity, including arachidonic acid which was inversely related and lysoPC(20:4) which was positively related. The study indicated a distinct lipid characteristic profile of patients with POEMS syndrome different from healthy controls and identified several lipids that may serve as potential diagnostic markers and monitors of therapeutic efficacy, as well as indicating potential metabolism pathways involved in the pathological process.

Pulmonary manifestations of Erdheim-Chester disease: clinical characteristics, outcomes and comparison with Langerhans cell histiocytosis.

Erdheim-Chester disease (ECD) is a rare form of non-Langerhans cell histiocytosis that typically affects many organs, including the lung and pleura. However, there are few studies concerning pulmonary involvement in ECD patients, as well as the difference of pulmonary involvement between ECD and Langerhans cell histiocytosis (LCH). We performed a retrospective study of 54 ECD patients, and compared the pulmonary manifestations with those of adult LCH patients in our centre. The median age of diagnosis of the 54 ECD patients was 48 years (range 9-66 years). Chest computed tomography (CT) scans revealed lung involvement in 49 (91%) patients and pleural involvement in 34 (63%). Thirty-three (61%) patients had interstitial lung disease (ILD) with varying degrees of interlobular septal thickening, micronodules, and ground-glass opacities. ECD and LCH patients with pulmonary involvement showed significant differences in smoking status (P < 0·001), respiratory symptoms (P = 0·001) such as cough and pneumothorax (P < 0·001), and radiological findings, including cysts (P < 0·001), opacities (P < 0·001), and pleural thickening (P < 0·001). With a median follow-up duration of 24 months (range, 1-84 months), the estimated three-year overall survival (OS) of this entire ECD cohort was 90·2%. Patients with ILD tended to have worse progression-free survival (PFS) than those with no ILD (P = 0·29).

Phase 2 study using oral thalidomide-cyclophosphamide-prednisone for idiopathic multicentric Castleman disease.

Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder. The anti-interleukin 6 (IL-6) therapy siltuximab is not available everywhere, and is not effective for over one-half of patients. Alternative treatment approaches are urgently needed. In the first iMCD clinical trial directed against a target other than IL-6 signaling, we investigated a thalidomide-cyclophosphamide-prednisone (TCP) regimen in newly diagnosed iMCD patients. This single-center, single-arm, phase 2 study enrolled 25 newly diagnosed iMCD patients between June 2015 and June 2018. The TCP regimen (thalidomide 100 mg daily for 2 years; oral cyclophosphamide 300 mg/m2 weekly for 1 year; prednisone 1 mg/kg twice a week for 1 year) was administered for 2 years or until treatment failure. The primary end point was durable tumor and symptomatic response for at least 24 weeks. Twelve patients (48%) achieved the primary end point with no relapse, 3 patients (12%) demonstrated stable disease, and 10 patients (40%) were evaluated as treatment failure. Even when considering all patients, there were significant (P < .05) improvements in median symptom score, IL-6 level, hemoglobin, erythrocyte sedimentation rate, albumin, and immunoglobulin G. Among responders, the median levels of all evaluated parameters significantly improved, to the normal range, after treatment. The regimen was well tolerated. One patient died of pulmonary infection and 1 patient had a grade 3 adverse event (rash); 2 patients died following disease progression. Estimated 1-year progression-free survival and overall survival were 60% and 88%, respectively. The TCP regimen is an effective and safe treatment of newly diagnosed iMCD patients, particularly when siltuximab is unavailable. This trial was registered at www.clinicaltrials.gov as #NCT03043105.

Impact of Physicians' Personalities and Behavioral Traits on Treatment-Related Decision-making for Elderly Acute Myeloid Leukemia.

BACKGROUND: Elderly patients with acute myeloid leukemia (AML) can be treated with intensive therapy, low-intensity therapy, or best supportive care. Medical decision-making might be affected by physicians' occupational and non-occupational factors. OBJECTIVE: To explore the impact of physicians' personalities and behavioral traits on treatment-related decision-making for elderly AML patients. DESIGN: A nationwide cross-sectional survey. PARTICIPANTS: Hematologists in mainland China (N = 529; response rate 64.5%). MAIN MEASURES: The medical decision-making for elderly AML patients was evaluated using 6 clinical vignettes. Hematologists' attitudes toward risk and uncertainty, Big Five personality traits, and decision-making styles were assessed using binary lottery choices and well-recognized self-report inventories. KEY RESULTS: The resulting binary regression model in predicting treatment intensity contained professional title group (OR = 0.012, 95% CI 0.001 to 0.136, P < 0.001), conscientiousness (OR = 0.336, 95% CI 0.121 to 0.932, P = 0.036), extraversion (OR = 0.403, 95% CI 0.166 to 0.974, P = 0.044), conscientiousness by title group (OR = 2.009, 95% CI 1.100 to 3.667, P = 0.023), and extraversion by title group (OR = 1.627, 95% CI 0.965 to 2.743, P = 0.068) as predictors of therapy intensity preference. Junior physicians with a higher level of extraversion (mean difference = 0.27; 95% CI 0.07 to 0.45; P = 0.009) or conscientiousness (mean difference = 0.19; 95% CI 0.01 to 0.36; P = 0.028) tended to prescribe more intensive therapy. Meanwhile, no significant correlation was found between physicians' personalities or behavioral traits and treatment-related decision-making in senior physicians. CONCLUSIONS: Physicians' personalities contribute to treatment-related decision-making for elderly AML patients, depending on the professional titles. More extravert or conscientious attending physicians tended to prescribe more intensive therapy. Meanwhile, the decisions made by chief and associate chief physicians were not impacted by their personal traits. Junior physicians should be aware of such potential influence when making medical decisions.

Cereblon expression is a prognostic marker in newly diagnosed POEMS syndrome treated with lenalidomide plus dexamethasone.

POEMS syndrome is a rare plasma cell disorder. Lenalidomide has recently emerged as a therapeutic option for POEMS syndrome. Cereblon has been identified as the direct target of lenalidomide, and high cereblon expression is associated with better response and outcome to lenalidomide therapy in multiple myeloma patients. Here, we analyzed the predictive value of cereblon, IKZF1, and IKZF3 in CD138+ selected plasma cells from forty-one newly diagnosed POEMS syndrome patients treated with lenalidomide in combination with dexamethasone at both gene and protein levels. We found that patients with high cereblon expression tended to achieve better hematologic response compared to those with low expression (p = 0.024 for gene expression; p = 0.01 for protein expression). Multivariate Cox regression analysis revealed high cereblon mRNA expression as an independent prognostic marker for longer progression-free survival (hazard ratio 0.542; 95% CI 0.337-0.871; p = 0.011). In conclusion, our results emphasized the role of cereblon mRNA expression as a unique biomarker for predicting the clinical response and outcome of lenalidomide-based therapy in newly diagnosed POEMS syndrome patients.

Bortezomib plus dexamethasone as first-line therapy for patients with POEMS syndrome.

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome is a rare plasma cell dyscrasia without standard front-line treatment. Merely, few studies have reported the responses and outcomes of bortezomib plus dexamethasone (BDex) in POEMS syndrome. In this study, a total of 69 patients (40 males) treated with front-line BDex were included. The median age at diagnosis was 50 years (range, 30-78 years). After a median of 9 cycles BDex (range 1-9), fifty-two (88.1%), thirty-two (46.4%), and forty-seven (71.2%) patients achieved the best neurologic response, hematological complete response, and serum vascular endothelial growth factor (VEGF) response, respectively. The extravascular overload, pulmonary hypertension, and renal impairment also substantially improved. No treatment-related death occurred. Two patients developed grade-1 bortezomib-induced peripheral neuropathy and were reversible after drug withdrawal. After a median follow-up of 22.5 months, the estimated 2-year overall survival and time to next treatment were 95.7% and 65.6%, respectively. In conclusion, the combination of bortezomib and dexamethasone is effective, with a high response rate and safety profile for patients with newly diagnosed POEMS syndrome.