Surrogates of Endothelial Injury Predict Survival After Post-transplant Cyclophosphamide.

Post-transplant cyclophosphamide (PT-Cy) is becoming the standard of care for preventing graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplant (alloHCT). Cyclophosphamide is associated with endothelial injury. We hypothesized that the endothelial activation and stress index (EASIX) score, being a marker of endothelial dysfunction, will predict non-relapse mortality (NRM) in alloHCT patients receiving PT-Cy for GVHD prophylaxis. We evaluate the prognostic ability of the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and EASIX scores, and report other factors influencing survival, in patients with hematologic malignancies undergoing alloHCT and receiving PT-Cy-based GVHD prophylaxis. Adult patients with hematologic malignancies who underwent alloHCT and received PT-Cy for GVHD prophylaxis at the three Mayo Clinic locations were included in this study. We retrospectively reviewed the Mayo Clinic database and the available electronic medical records to determine the patient, disease, and transplant characteristics. An HCT-CI score of ≥3 was considered high. The EASIX score was calculated from labs available between day -28 (of alloHCT) to the day of starting conditioning and analyzed on log2 transformed values. A log2-EASIX score ≥2.32 was considered high. The cumulative incidence of NRM was determined using competing risk analysis, with relapse considered as competing risk. Overall survival (OS) from transplant was determined using Kaplan-Meier and log-rank methods. Cox-proportional hazard method was used to evaluate factors impacting survival. A total of 199 patients were evaluated. Patients with a high log2-EASIX score had a significantly higher cumulative incidence of NRM at 1 year after alloHCT (34.5% versus 12.3%, P = .003). Competing risk analysis showed that a high log2-EASIX score (HR 2.92, 95% CI 1.38 to 6.17, P = .005) and pre-alloHCT hypertension (HR 2.15, 95% CI 1.06 to 4.36, P = .034) were independently predictive of 1 year-NRM. Accordingly, we combined the two factors to develop a composite risk model stratifying patients in low, intermediate, and high-risk groups: 111 (55.8%) patients were considered low-risk, 76 (38.2%) were intermediate and 12 (6%) were high-risk. Compared to patients in the low-risk group, the intermediate (HR 2.38, 95% CI 1.31 to 4.33, P = .005) and high-risk (HR 5.77, 95% CI 2.31 to 14.39, P < .001) groups were associated with a significantly inferior 1-year OS. Multiorgan failure (MOF) was among the common causes of NRM (14/32, 43.8%) particularly among patients with prior pulmonary comorbidities [7 (50%) patients]. Our study shows that EASIX score is predictive of survival after PT-Cy. The novel EASIX-HTN composite risk model may stratify patients prior to transplant. MOF is a common cause of NRM in patients receiving PT-Cy, particularly among patients with pulmonary comorbidities.

FLT3 inhibitors potentially improve response rates in acute myeloid leukemia harboring t(6;9)(DEK::NUP214): The Mayo Clinic experience.

Not available.

IDH-mutant myeloid neoplasms are associated with seronegative rheumatoid arthritis and innate immune activation.

ABSTRACT: High prevalence of IDH mutations in seronegative rheumatoid arthritis (RA) with myeloid neoplasm, elevated 2-hydroxyglutarate, dysregulated innate immunity, and proinflammatory microenvironment suggests causative association between IDH mutations and seronegative RA. Our findings merit investigation of IDH inhibitors as therapeutics for seronegative IDH-mutated RA.

Genetic landscape and clinical outcomes of patients with BCOR mutated myeloid neoplasms.

The BCL6-corepressor (BCOR) is a tumor-suppressor gene located on the short arm of chromosome X. Data are limited regarding factors predicting survival in BCOR-mutated (mBCOR) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We evaluated 138 patients with mBCOR myeloid disorders, of which 36 (26.1%) had AML and 63 (45.6%) had MDS. Sixty-six (47.8%) patients had a normal karyotype while 18 (13%) patients had complex karyotype. BCOR-mutated MDS/AML were highly associated with RUNX1 and U2AF1 co-mutations. In contrast, TP53 mutation was infrequently seen with mBCOR MDS. Patients with an isolated BCOR mutation had similar survival compared to those with high-risk co-mutations by European LeukemiaNet (ELN) 2022 criteria (median OS 1.16 vs. 1.27 years, P=0.46). Complex karyotype adversely impacted survival among mBCOR AML/MDS (HR 4.12, P<0.001), while allogeneic stem cell transplant (alloSCT) improved survival (HR 0.38, P=0.04). However, RUNX1 co-mutation was associated with an increased risk of post-alloSCT relapse (HR 88.0, P=0.02), whereas melphalan-based conditioning was associated with a decreased relapse risk (HR 0.02, P=0.01). We conclude that mBCOR is a high-risk feature across MDS/AML, and that alloSCT improves survival in this population.

Clinical characteristics, molecular aberrations, treatments, and outcomes of malignant histiocytosis.

Malignant histiocytosis (MH) is an extremely rare neoplasm of the macrophage-dendritic cell lineage. We report the clinical characteristics, molecular aberrations, treatments, and outcomes of patients with MH seen at two referral centers from January 2000 to May 2023. We identified 43 patients with MH, of which 26 had histiocytic sarcoma (MH-H), 9 interdigitating dendritic cell sarcoma (MH-IDC), and 8 Langerhans cell sarcoma (MH-LC). The median age at diagnosis was 61 years (range, 3-83). Thirty-three patients (77%) had multifocal disease, while 10 had unifocal involvement. Tumor specimens from 22 patients (51%) underwent targeted next generation sequencing, and 19 of 22 (86%) had at least one pathogenic mutation, including mutations in MAPK pathway genes (73%). The median overall survival (OS) among the entire cohort was 16 months (95% CI: 8-50). The outcomes of those with multifocal disease were significantly shorter than their unifocal counterpart: median OS of 10 months versus 50 months (p = .07). Patients with risk organ involvement (bone marrow, spleen, or liver) had significantly inferior outcomes. Chemotherapy and surgery were the most common first-line treatments for multifocal and unifocal disease, respectively. While the outcome for patients with multifocal disease was poor, there was a subset of patients who had durable responses to treatment. Our study highlights that MH has heterogeneous clinical presentation, frequent oncogenic mutations, and prognosis, which is strongly tied to disease extent and type of organ involvement.

Long-term outcomes among adults with Langerhans cell histiocytosis.

Advances in the treatment of Langerhans cell histiocytosis (LCH) have resulted in a growing survivor population. There is a lack of data on long-term outcomes among adults with LCH. We conducted a retrospective record review of 219 adults (aged ≥18 years) with LCH. Most common presentation was multisystem (34.2%), followed by single-system pulmonary (32%), unifocal (28.3%), and single-system multifocal (5.5%) LCH. Risk organ involvement (the liver, spleen, or bone marrow) was seen in 8.7% of cases, and 40 of 88 (45.5%) tested cases were BRAFV600E. At a median follow-up of 74 months, 5-year progression-free survival (PFS) was 58.3% and estimated median PFS was 83 months. Median overall survival (OS) was not reached; 5- and 10-year OS rates were 88.7% and 74.5%, respectively. Risk organ involvement was associated with worse PFS (hazard ratio [HR], 4.5) and OS (HR, 10.8). BRAFV600E was not associated with risk organ involvement or survival. When compared with matched unaffected US population, individuals with LCH had a significantly higher risk of overall mortality (standardized mortality ratio [SMR], 2.66), specifically among those aged <55 years at diagnosis (SMR, 5.94) and those with multisystem disease (SMR, 4.12). Second cancers occurred in 16.4% cases, including diverse hematologic and solid organ malignancies. LCH-associated deaths constituted 36.1% of deaths and occurred within 5 years of diagnosis. After 5 years, non-LCH causes of death, including second cancers, chronic obstructive pulmonary disease, and cardiovascular diseases, predominated. Our study highlights, to our knowledge, for the first time, that adults with LCH experience early and late mortality from non-LCH causes and the need for development of targeted survivorship programs to improve outcomes.

BRAF V600E is associated with higher incidence of second cancers in adults with Langerhans cell histiocytosis.

In this retrospective study, BRAF mutation status did not correlate with disease extent or (event-free) survival in 156 adults with Langerhans cell histiocytosis. BRAFV600E was associated with an increased incidence of second malignancies, often comprising hematological cancers, which may be clonally related.

The clinical and molecular spectrum of ETV6 mutated myeloid neoplasms.

ETV6 mutations are rare but recurrent somatic events in myeloid neoplasms and are negatively prognostic in myelodysplastic syndrome. We set out to examine the clinical and molecular characteristics of patients undergoing investigation for myeloid neoplasms, found to have deleterious ETV6 mutations. ETV6 mutations occurred in 33 of 5793 (0.6%) cases investigated and predominantly in high-risk disease entities including MDS with increased blasts, primary myelofibrosis and AML, myelodysplasia-related. In three cases, isolated iso (17q) karyotype was concurrently detected, an otherwise rare karyotype in myeloid neoplasms. ETV6 mutations were frequently subclonal and never occurred as an isolated abnormality with ASXL1 (n = 22, 75%), SRSF2 (n = 14, 42%) and SETBP1 (n = 11, 33%) the predominant co-mutations. Restricting to patients with MDS, higher rates of ASXL1, SETBP1, RUNX1 and U2AF1 mutations occurred in ETV6 mutated cases, relative to a consecutive control cohort with wild-type ETV6. The median OS of the cohort was 17.5 months. This report highlights the clinical and molecular associations of somatic ETV6 mutations in myeloid neoplasms, suggests their occurrence as a later event, and proposes further translational research questions for their role in myeloid neoplasia.

Neurological Manifestations of Histiocytic Disorders.

PURPOSE OF REVIEW: Histiocytic disorders, including Erdheim-Chester disease (ECD), Langerhans cell histiocytosis (LCH), and Rosai-Dorfman disease (RDD), are rare neoplasms that may present with a spectrum of neurologic involvement. Diagnostic delay is common due to heterogeneity in presentation and challenging pathology. RECENT FINDINGS: Recent advances in the treatment of these diseases targeted towards mutations in the MAP kinase pathway have led to an improved prognosis in these patients with neurologic involvement. It is critical for clinicians to have a high index of suspicion to allow for early targeted treatment and optimize neurologic outcomes. A systematic approach to diagnosis is presented in this article to allow for accurate diagnosis of these rare diseases.

Comparison of Pretransplantation Prediction Models for Nonrelapse Mortality in Patients with Myelofibrosis Undergoing Allogeneic Stem Cell Transplantation.

Allogeneic stem cell transplantation (alloSCT) is the only known curative treatment for myelofibrosis (MF). Risk assessment remains important for patient counseling and predicting survival outcomes for relapse and nonrelapse mortality (NRM). Outcome-prediction tools can guide decision-making. Their use in MF has relied on their extrapolation from other malignancies. The primary objective of this study was to assess the performance of the Hematopoietic cell Transplantation Comorbidity Index (HCT-CI), the augmented HCT-CI (aHCT-CI), and the Endothelial Activation and Stress Index (EASIX) in predicting NRM in patients with MF undergoing alloSCT. We retrospectively reviewed patients with MF undergoing alloSCT between 2012 and 2020 at the Mayo Clinic. Data were abstracted from the electronic medical record. EASIX score was calculated before starting conditioning therapy and analyzed based on log2- transformed values. We evaluated the log2-EASIX scores by quartiles to assess the effect of increasing values on NRM. NRM was evaluated using competing risk analyses. We used the Kaplan-Meier and log-rank methods to evaluate OS. The Fine-Gray model was used to determine risk factors for NRM. The performance of HCT-CI and aHCT-CI was compared by evaluation of model concordance given the high correlation between HCT-CI and aHCT-CI (r = .75). A total of 87 patients were evaluated. The median duration of follow-up after alloSCT was 5 years (95% confidence interval [CI], 4.4 to 6.31 years). Patients with a high HCT-CI score had significantly increased cumulative incidence of NRM at 3 years (35.5% versus 11.6%; P = .011) after alloSCT. A progressively increasing 3-year NRM was observed with increasing aHCT-CI risk category, and patients with a high or very high aHCT-CI score had significantly higher 3-year NRM compared to those with intermediate-risk or low-risk aHCT-CI scores at 3 years post-alloSCT (31.9% versus 6.52%; P = .004). An increasing log2-EASIX score quartile was not associated with 3-year NRM (19.0% versus 10.1% versus 25% versus 14.3%; P = .59), and the EASIX score was not found to be a predictor of post-transplantation NRM. A high HCT-CI was associated with significantly worse 3-year overall survival (OS) (hazard ratio [HR], 4.41; 95% CI, 1.97 to 9.87; P < .001). A high or very high aHCT-CI was significantly associated with poor 3-year OS (HR, 3.99; 95% CI, 1.56 to 10.22; P = .004). An increasing log2-EASIX score quartile group was not associated with 3-year OS (3-year OS rate, 66.7% versus 80.4% versus 64.6% versus 76.2%; P = .57). The EASIX score should not be used routinely in patients with MF. Both the HCT-CI and the aHCT-CI are accurate in predicting long-term survival outcomes in this patient population. Further studies are important to validate our findings of the role of EASIX in predicting NRM in patients with MF or other myeloproliferative neoplasms undergoing alloSCT. © 2023 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Pericardial Effusion as a Purported Manifestation of Graft-versus-Host Disease following Allogeneic Hematopoietic Cell Transplantation.

Large pericardial effusion (LPE) and tamponade are purported manifestations associated with atypical chronic graft-versus-host disease (cGVHD); however, their temporal association with GVHD, management, and impact on overall outcome are not well established. We report a retrospective analysis of 38 patients who developed LPE from a cohort of 1265 (3.00%) patients age ≥18 years who underwent allogeneic hematopoietic cell transplantation (alloHCT) at Mayo Clinic between March 1993 and August 2020. The median patient age at the time of LPE was 54 years (interquartile range [IQR], 44 to 58 years), and 8 of the 38 patients (21%) had previous cardiomyopathy. The median time from alloHCT to detection of LPE was 197 days (IQR, 40 to 378 days). Overall, the incidence of grade II (15 of 38; 40%) and grade III-IV (9 of 38; 24%) acute GVHD (aGVHD) was higher in patients who developed LPE compared with those who did not develop LPE (P = .005). The incidence rates of moderate (10 of 38; 26%) and severe (15 of 38; 40%) cGVHD according to the 2014 National Institutes of Health cGVHD criteria were also higher in the LPE cohort (P = .03). Twenty-nine patients (76%) presented with cardiac tamponade, 32 patients (84%) underwent urgent pericardiocentesis for symptomatic LPE, and 2 patients had a pericardial window placement. Four patients were medically managed with colchicine, steroids, diuresis, and immunosuppressive therapy (IST). On multivariable analysis, HCT Comorbidity Index (HCT-CI) group (hazard ratio [HR] 3.57; [95% confidence interval (CI), 1.29 to 9.85; P = .014] for HCT-CI 1 to 2; 4.06 [95% CI, 1.50 to 10.99; P = .006] for HCT-CI ≥3) and aGVHD (HR, 2.38 [95% CI, 1.11 to 5.12; P = .026] for grade II and 2.82 [95% CI, 1.07 to 7.44; P = .038] for grade III-IV) were significant risk factors for developing LPE. At a median follow-up of 40 months post-alloHCT, median disease-free survival (DFS) was 34.2 months (95% CI, 25.3 to 45.7 months) in patients who did not develop LPE and 32.2 months (95% CI, 13.2 to undefined upper limit) in those who developed LPE (P = .41). The median overall survival (OS) post-alloHCT was 50.9 months (95% CI, 41.8 to 64.8 months) in patients who did not develop LPE and was 32.9 months (95% CI, 19.5 to undefined upper limit) in patients who developed LPE (P = .003). In summary, LPE and tamponade can present at various time points post-alloHCT, and management includes pericardiocentesis, steroids, and intensification/initiation of IST if associated with serositis. LPE does not appear to result in permanent cardiac damage but results in inferior OS.