Shah, Meera

Abstract DDX41 mutations (germline and somatic) are associated with late onset myelodysplastic syndromes/acute myeloid leukemia (MDS/AML). Myeloid neoplasms (MN) with germline predisposition was identified as a distinct category in the 2016 WHO classification revision, including MN with germline DDX41 mutation. We retrospectively analyzed the molecular findings and clinical characteristics of thirty-three DDX41-mutated (mDDX41) patients at our institution. We identified 14 distinct pathogenic DDX41 variants in 32 patients and 8 DDX41 variants of unknown significance (VUS) in 9 patients. Five (16%) patients had a second DDX41 somatic mutation p.R525H and 13 (40%) had at least one additional oncogenic co-mutation in other genes. The median age at the time of diagnosis was 66 years, with male predominance (72%) and the majority of patients had normal cytogenetics (91%). Two-year overall survival (OS) was 86% and 6 (21%) MDS/AML patients with relatively preserved hematopoietic function were observed without further intervention. In comparison to AML patients with prognostically more favorable subtypes [t(8;21), n=27 and inv(16), n=40], mDDX41 patients in our cohort showed similarly favorable OS. Our study highlights that mDDX41-MN patients often have an indolent course and mDDX41-AML has comparable OS to favorable-risk AML.

AbstractLangerhans cell histiocytosis (LCH) is a histiocytic neoplasm that can involve the lungs as single system (LCH‐SSL) or multisystem disease (LCH‐MSL). The role of full‐body radiographic staging to determine whether patients have LCH‐SSL or LCH‐MSL is unclear. Long‐term outcomes of LCH‐SSL versus LCH‐MSL and multisystem without lung involvement (LCH‐MSNL) are unknown. A retrospective study of adult LCH patients seen at our center from January 2000 to 2020 was performed. In Part 1, we addressed utility of whole‐body staging imaging among those presenting with isolated pulmonary signs or symptoms. Staging was defined as fluorodeoxyglucose positron emission tomography‐computed tomography (CT) or whole‐body CT obtained within 3 months of diagnosis. In Part 2, we examined the frequency of developing extra‐pulmonary disease over time and mortality in patients with LCH‐SSL. In Part 3, we compared the overall survival of LCH‐SSL, LCH‐MSL, and LCH‐MSNL. Part 1: 240 patients with LCH were identified. A total of 112 (47%) had pulmonary signs or symptoms at presentation. Thirty‐four (30%) underwent radiographic staging and only one showed evidence of extra‐pulmonary disease. Part 2: 108 (45%) were LCH‐SSL. Median follow‐up duration of 4.5 years (95% confidence interval [CI]: 2.9–6.0). None developed extra‐pulmonary disease. Part 3: 5‐year survival: 94% (95% CI: 84%–98%) for LCH‐SSL, 78% (95% CI: 59%–90%) for LCH‐MSL, and 75% (95% CI: 53%–89%) for LCH‐MSNL. LCH patients presenting with isolated pulmonary signs or symptoms rarely have extra‐pulmonary involvement at the time of diagnosis and generally do not develop extra‐pulmonary progression. LCH‐SSL has the best overall survival, while LCH‐MSL and LCH‐MSNL have similar clinical outcomes.

e19003 Background: Acute panmyelosis with myelofibrosis (APMF) is a rare subtype of acute myeloid leukemia characterized by acute panmyeloid proliferation with increased blasts, cytopenias with bone marrow fibrosis, and absence of splenomegaly. There is a paucity of population-based studies of APMF. Methods: We queried the United States Surveillance, Epidemiology, and End Results (SEER) database and National Cancer Database (NCDB) using the ICD-O-3 code 9931/3. The SEER 17 registries (2004-2015) were used to find data on incidence. For NCDB data, comorbid disease burden was calculated using the Charlson-Deyo Score (CDS). Hazard ratios (HR) with confidence intervals (CI) were calculated using a Cox proportional hazards model. Overall survival (OS) was estimated with the Kaplan-Meier method. Variables significant in univariable analysis were included in a multivariable analysis. Results: We identified 260 APMF patients using the SEER database. Incidence was 0.3 cases/million individuals and did not change significantly from 2004-2015. With a median follow up of 6.9 years (95% CI 6.1-7.8), the median OS was 2.3 years (95% CI 1.7-2.8). We identified 530 APMF patients using the NCDB. The median age at diagnosis was 67 years (range 22-90) and 311 (59%) were male. With a median follow up of 5.0 years (95% CI 3.0-7.6), the median OS was 2.3 years (95% CI: 0.8-6.5). OS was 69%, 31%, and 18% at 1-, 5-, and 10- years, respectively. Patients diagnosed in 2012-2015 had a significantly improved OS compared to those diagnosed in 2004-2007 (HR 0.65, 95% CI 0.49-0.85; p=0.002). 271 patients (53%) patients received chemotherapy. The OS for those that received chemotherapy was 70% at 1 year and 30% at 5 years versus 70% and 32% at 1- and 5- years for those who did not ( p=0.99). The median time to chemotherapy from time of diagnosis was 25 days (range 0-532 days). 52 patients (10%) underwent transplantation and the OS of those patients was 90% at 1 year and 45% at 5 years versus 67% and 29% at 1- and 5- years for those who did not (HR: 1.7 (95% CI: 1.2-2.6), p=0.006). In univariable analysis, factors predicting inferior OS were age ≥ 65 years old at diagnosis (HR 1.8, 95% CI 1.5-2.3; p<0.001), male sex (HR 1.5, 95% CI 1.2-1.8; p<0.001), CDS ≥ 1 (HR: 1.5 (95% CI: 1.2-2.0), p<0.001), government insurance (HR 1.8, 95% CI 1.4-2.3; p<0.001), diagnosis at a non-academic facility (HR 1.6, 95% CI 1.2-2.0, p<0.001), and not receiving a hematologic transplant (HR 1.7, 95% CI 1.2-2.6; p=0.006). Multivariable-adjusted analysis is shown in the Table. Conclusions: The overall incidence of APMF has not changed between 2004 and 2015, but OS for 2012-2015 was improved compared to 2004-2007. Age ≥ 65 years old, male sex, CDS ≥ 1, and diagnosis at a nonacademic facility predicted inferior OS. Multivariable-adjusted analysis.[Table: see text]

7554 Background: Chimeric antigen receptor T-cell therapy (CAR-T) are commonly administered inpatient due to concern for early onset cytokine release syndrome (CRS), especially with axicabtagene ciloleucel (axi-cel). We report Mayo Clinic Rochester experience for hospital-based outpatient (HBO) management of patients (pts) receiving axi-cel and identify opportunities for improvement. HBO is closely integrated with inpatient practice and includes the same specialty trained clinical team. It is the first point of contact 24/7 for pts and triage evaluations. Lymphodepletion chemotherapy and CAR-T infusion is given on HBO followed by daily monitoring till day 8 and thereafter, as clinically needed until admission criteria is met. Methods: We retrospectively analyzed database of pts who received axi-cel between 1/2018 and 1/2021. After 06/2020, remote patient monitoring (RPM) tools were implemented to collect patient-reported neurologic symptoms and vital signs via bluetooth-enabled devices 4 times daily through month 1. Adverse data trends are addressed by the HBO team. Results: Among 72 recipients, 89% received their cells outpatient; 8% remained outpatient for the entire month. CRS and neurotoxicity incidence were comparable to those reported from CIBMTR. Median time to first admission was 2 days (Table). Use of bridging therapy, increased CRP and LDH were associated with early admission (≤3 days). Median time to tocilizumab, steroid, oxygen support, vasopressor was 4 days after admission. Half of HBO visits required intervention such as blood transfusions, IV medications through the first month. Nine pts had enrolled in RPM to date; with 8 having evaluable data. With 4 scheduled entries/day, a median of 1 entry/day was skipped and 2 entries/day were answered incompletely. An average of 57 additional unscheduled entries were generated per pt. Among a median of 373 (range 91-522) readings per pt over the first month, 4% (2%-20%) of the readings generated alerts. An average of 4 alerts were seen within 48 hours prior to admission. Data including additional subjects will be presented at ASCO meeting. Conclusions: We report a feasible outpatient care model for management of axi-cel recipients with safe outcomes. Clinical characteristics associated with more aggressive disease are associated with likelihood of early admission. Early RPM experience suggest use of digital tools could improve monitoring compliance and may predict evolution to symptoms requiring escalation of care.[Table: see text]

7050 Background: Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm manifesting as unifocal, multifocal, multisystem (MS) or pulmonary LCH (smoking-related). In pediatric LCH, somatic BRAFV600E prevalence is reported at 55-70%, and associated with increased risk of multisystem disease and early treatment failure. Our aim was to describe the prevalence of BRAFV600E mutation and evaluate its association with clinical manifestations and outcomes in adults with LCH. Methods: A retrospective review of adult patients diagnosed with LCH consecutively seen at Mayo Clinic from 2011 to 2020 was performed.Evaluation of association of BRAFV600E mutational status and clinical factors was conducted by the Chi-square test for independence. Progression-free survival (PFS) and overall survival (OS) were analyzed via the Kaplan Meier method and compared with the log-rank test to assess the effect of BRAFV600E. Results: Of the total LCH cohort ( n= 128), 88 patients with available BRAFV600E results were included in the study. Median age at diagnosis was 41y (range 19 - 88); 52.3% were male. 40 (45.5%) patients had a BRAFV600E mutation. Increasing age was associated with BRAFV600E (10-year increase OR 1.42, 95%CI 1.07-1.89; p= 0.017). No correlation was observed between BRAFV600E status and site of disease, risk organ (RO: liver, spleen, marrow) involvement, or MS disease. Patients with BRAFV600E were 4 times more likely to receive targeted therapy ( BRAF inhibitor) than non- BRAFV600E patients ( p= 0.018). After a median follow up of 46 mo (95% CI 30.8-61.2), PFS was similar between BRAFV600E and non- BRAFV600E patients ( p= 0.167). However, patients with BRAFV600E had a worse 3-year OS compared with non- BRAFV600E patients (84% vs. 97.1%, p= 0.027). Patients who died had a significantly higher age at LCH diagnosis (median 62 vs. 38 years; p= 0.0002). Conclusions: In our cohort of adults with LCH, BRAFV600E was less frequent than reported in pediatric literature and was associated with worse OS. The frequency of BRAFV600E was positively correlated with increasing age. Contrary to reports in pediatric LCH, there were no significant associations between BRAFV600E and high-risk or multisystem disease.[Table: see text]

7049 Background: Langerhans cell histiocytosis (LCH) can manifest as single system (SS) disease, multisystem (MS) disease, or pulmonary LCH (smoking-related). There is a paucity of data on prognostic factors including risk organ (RO) involvement (liver, spleen, and bone marrow) in adult LCH, which we sought to address in this study. Methods: Single-center retrospective study of patients ≥18y diagnosed with LCH from 1998 to 2020. Univariate and multivariate analyses for progression free survival (PFS) and overall survival (OS) were conducted using age, sex, organ involvement, LCH subtype, year of diagnosis, BRAF V600E status, and treatments. Results: We included 219 patients with LCH; median age 43y (range 19-88), females 51%, SS unifocal (23%), SS multifocal (6%), pulmonary (31%) and MS (40%). Commonly involved organs included lung (53%), bone (42%), skin (24%), pituitary (16%), and CNS (12%). BRAF V600E was positive in 40/88 (46%). Median follow-up duration was 6.1y (95% CI, 5.1- 7.1). On univariate analysis, factors associated with worse PFS were bone LCH, RO involvement, multifocal/MS LCH, and radiation therapy alone; those with worse OS included RO involvement, MS disease, BRAF V600E+, and age ≥45y at diagnosis. In multivariate analysis, BRAF V600E and age ≥45y at diagnosis were associated with worse mortality (Table). Median PFS was not reached (NR-NR) for SS unifocal LCH, 5mo (0-12.7) for SS multifocal LCH, 110mo (84.7-135.3) for pulmonary LCH, and 27mo (17.2-36.8) for MS LCH. 5-year OS was 97.4% for SS unifocal LCH, 100% for SS multifocal LCH, 96.1% for pulmonary LCH, and 79.9% for MS LCH. 41 (18.7%) developed a second primary malignancy (SPM), of which 11 were hematologic neoplasms. There was a trend towards a higher prevalence of SPMs in patients with BRAF V600E (28% vs. 17%; p = 0.22). Conclusions: In our large single-center study, PFS for multifocal and MS LCH was worse than SS unifocal or pulmonary LCH. RO involvement was not associated with outcomes in multivariate analysis. Overall prognosis was excellent for all subtypes except MS LCH. BRAF V600E and older age were associated with worse OS. The prevalence of SPMs was very high and needs to be explored further.[Table: see text]

Introduction Orally administered tacrolimus is widely used in hematopoietic cell transplant patients, but multiple clinical situations may arise rendering oral administration infeasible. The undesirable sequelae of intravenous administration, including toxicity, challenges with administration and cost call for innovative solutions to conserve existing supply and optimize safety and efficacy of medication delivery. We sought to demonstrate feasibility of sublingual tacrolimus use and estimate a sublingual-to-oral (SL:PO) conversion ratio in the hematopoietic cell transplant setting. Methods Ten adults undergoing allogeneic hematopoietic cell transplant received tacrolimus 0.04 mg/kg/dose twice daily. Initial doses were given via sublingual route and a steady state trough level was collected after 4 consecutive doses. Participants were then switched to oral tacrolimus, the dose adjusted for a goal trough 8-12ng/mL, and another steady state trough was drawn. Total daily dose was divided by trough concentration for each route to determine the dosing ratio of SL:PO. Results Median trough level following sublingual administration was 11.3 ng/mL. Three of these were within goal, 3 were low (4.7–6.4 ng/mL) and 4 were elevated (15.9–18.6 ng/mL). Median SL:PO ratio was 1.02. In 5 participants the SL:PO ratio was <1 (range 0.57–0.94) and in 5 the ratio was ≥1 (range 1.10–1.92). No significant barriers or intolerance to sublingual tacrolimus use were noted. Conclusions Results demonstrate reliable absorption with sublingual tacrolimus use in patients undergoing hematopoietic cell transplant. Sublingual administration may allow for avoidance of the undesirable complications of IV tacrolimus, such as increased toxicities, required hospitalization for continuous infusion, risk of dose conversion and dilution errors and increased cost. Trial Registry name: Use of Sublingual Tacrolimus in Adult Blood and Marrow Transplant Patients, NCT04041219 https://clinicaltrials.gov/ct2/show/NCT04041219?term=NCT04041219&draw=2&rank=1