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Langerhans 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.

Background: Although the majority of patients with diffuse large B-cell lymphoma (DLBCL) can be cured with intensive chemotherapy and rituximab, 30-40% of patients will be refractory to or relapse after first line treatment. For these patients, the current standard of care is salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT). Prior studies have largely examined clinical risk factors associated with higher risk of relapse after ASCT; however, there is limited data integrating both pathologic and molecular features. Thus, we aimed to identify high-risk features associated with relapse and survival after ASCT using a combination of clinical, molecular, pathologic, and transplant characteristics. Methods: We retrospectively analyzed the medical records of all adult patients with DLBCL who underwent ASCT at our two institutions from 2010 to 2020. Patients with primary CNS lymphoma, primary mediastinal B-cell lymphoma, or Burkitt lymphoma were excluded. We analyzed demographics, clinical characteristics, cell of origin (COO) by immunohistochemistry (IHC), fluorescence in-situ hybridization (FISH) testing, and treatment/transplant characteristics. The primary endpoints were 3-year progression-free survival (PFS) and overall survival (OS) from ASCT. The Kaplan-Meier method was used to estimate survival with univariate and multivariate Cox proportional hazards regression performed to identify factors associating with PFS and OS, summarized using hazard ratios (HR) with 95% confidence intervals (CI). Results: A total of 235 DLBCL patients underwent ASCT from 2010 to 2020. Median age at ASCT was 61 years (range: 25-75) and 63% were male. At DLBCL diagnosis, 80% had advanced stage disease, 74% had extranodal involvement, 13% had poor performance status, and 65% had elevated lactate dehydrogenase (LDH). 71 patients (30%) had a prior or concurrent indolent lymphoma diagnosis indicating transformed disease. Of the patients with available COO and molecular data, 115 (60%) had germinal center B-cell (GCB) phenotype by IHC, 10 (6%) had a single MYC rearrangement by FISH, and 35 (22%) had MYC plus BCL2 and/or BCL6 rearrangements (DHL/THL). After first-line treatment, 12% remained refractory and 62% later relapsed at a median of 13 months (range: 1-240). Patients received a median of 2 (range: 1-5) lines of treatment pre-ASCT. At time of ASCT, 66% were in complete response (CR) and 32% were in partial response (PR) by standard of care imaging and response criteria. With median follow-up of 5.2 years from time of ASCT, 98 patients (42%) relapsed and 78 (33%) died. 3-year PFS and OS were 58% (95% CI 51-64%) and 74% (95% CI 67-79%), respectively. In univariate analysis, factors associated with worse PFS and worse OS included 3 or more lines of treatment pre-ASCT (p60 at ASCT (HR 1.92, 95% CI 1.06-3.47, p=0.03) (Figure 1C). Stratifying by COO and disease status at transplant, 3-year OS was best in the GCB/CR group (84%, 95% CI 73-90%), while worse but similar in the GCB/non-CR and non-GCB/CR groups (68%, 95% CI 51-80% and 71%, 95% CI 56-83%, respectively) (Figure 1D). The non-GCB/non-CR group had the worst 3-year OS (48%, 95% CI 27-67%). No individual factors beyond CR/non-CR at ASCT were associated with worse 3-year PFS. Notably, DHL/THL patients (77% of whom were in CR at time of ASCT) had similar PFS (p=0.08) and OS (p=0.30) to non-DHL/THL patients, suggesting that response to therapy may be more prognostic than high-risk molecular features alone. Conclusions: This analysis indicated that factors associated with OS after ASCT were disease status at time of transplant and COO, with non-GCB patients not in CR having the poorest outcomes. GCB patients not in CR were still able to be cured by ASCT at a high rate. Molecular rearrangements including DHL/THL were not prognostic, although interpretation may be limited by the modest number of DHL/THL patients. These findings may inform which patients should undergo ASCT, while the highest risk group may be better treated with alternatives including novel targeted agents or chimeric antigen receptor cell therapy. Figure 1 Figure 1. Disclosures Bachanova: FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fehniger: Compass Therapeutics: Research Funding; Affimed: Research Funding; ImmunityBio: Research Funding; Wugen: Consultancy, Current equity holder in publicly-traded company, Patents & Royalties: related to memory like NK cells, Research Funding; OrcaBio: Other; Kiadis: Other; HCW Biologics: Research Funding; Indapta: Other. Weisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding.

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 Langerhans cell histiocytosis (LCH) is an uncommon histiocytic disorder which is now categorized as a hematopoietic neoplasm. Most treatment and outcomes data in LCH are derived from pediatric studies, and there is a lack of FDA-approved treatment options for adult LCH. There is some evidence that cladribine may be toxic to monocytes and monocyte-derived dendritic cells. In this study, we report the efficacy of cladribine in adult LCH patients seen at our institution. Methods We retrospectively reviewed the charts of all LCH patients seen at our institution between 1998 and 2018. Where necessary, the radiological images and histopathological slides were reviewed by an expert radiologist and pathologist. Since prospective uniform response assessment was not performed, we utilized the clinical documentation and radiological reports to assess the overall response rate (ORR). All time to event analyses were performed from the time of cladribine initiation. Results We included a total of 37 adult LCH patients in the study. The median age at diagnosis for this cohort was 35 years (range, 21-76), and 51% were males. Although 31 (84%) patients had multi-system disease, all patients had more than one LCH lesion (multifocal). Most commonly involved organs were bone (65%), lung (60%), skin (38%), lymph nodes (30%), and pituitary/hypothalamus (27%). BRAF-mutational analysis was performed in 13 patients, with 7 (54%) demonstrating the presence of BRAF-V600E mutation. Cladribine was administered as first line therapy in 22 (59%) patients and subsequent line treatment in 15 (41%). Of the 15 patients who received cladribine in subsequent line, surgery (n=3), radiation (n=3), steroids (n=3), antibiotic with inhaled steroids (n=1), vinblastine (n=3), topical nitrogen mustard cream (n=1) and vemurafenib (n=1) were the treatments utilized before the initiation of cladribine. Two patients received the drug more than once during the course of their disease. The dosing of cladribine for all patients was based on one of the two intravenous regimens (0.14 mg/kg for days 1-5 every 28 days or 5 mg/m2 for days 1-5 every 28 days). The median follow-up for the entire cohort was 4.5 years (95% CI:2-7) and the treatment outcomes are shown in Table 1. Median number of cycles of cladribine administered was 1.5 (range, 1-9). Clinical/radiographic responses were noted in 29 (78%) patientsORR was 78%, with 24% complete responses and 54% partial responses (PR). Responses were seen in various disease sites: lung nodules/infiltrates (13/29, 45%), bone (12/29, 41%), lymph nodes (8/29, 28%), skin (3/29, 10%), pituitary/hypothalamus (4/29, 14%). Eight (22%) patients did not respond and had progressive disease (PD)- cystic/bullous lung disease (n=2), skin (n=2), abdominal/peritoneal lymph nodes (n=2), and hypothalamus (n=3).The treatment was well tolerated, with grade 3 or above adverse effects seen in three patients: two with lymphopenia requiring dose delays and one with congestive cardiac failure leading to drug discontinuation. After initial disease response, PD was seen in three patients. 89%, 78%, 64% of those who responded initially maintained their responses at years 1, 3, and 5, respectively (Table 1). The 5-year progression free survival (PFS) was 55% for the entire cohort. BRAF-status was evaluated on 13 of 37 patients in the entire cohort (35%): BRAFV600E positive [n=7 (53%)] and WT [n=6 (46%)]. Of the 7 patients who had BRAFV600E mutation, responses were seen in 71%, while 100% of those without BRAFV600E achieved a response (p=0.09). At the time of last follow-up, 9 patients (24%) were dead. Of those, cause of death were available on 5 patients; due to LCH (n=1), stroke (n=1), gastrointestinal hemorrhage (n=1), acute myeloid leukemia (n=2). Conclusion In our study, cladribine monotherapy yielded a high ORR, with the majority of patients achieving a PR. The responses were durable with a small risk of subsequent disease relapse. Responses were seen irrespective of the presence of BRAFV600E mutation. Cladribine was well tolerated overall, and may be considered a potential therapy for adult LCH patients. Disclosures Vassallo: Sun Pharmaceuticals: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding; Sun Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding. OffLabel Disclosure: Cladribine for langerhans cell histiocytosis

7018 Background: Langerhans cell histiocytosis (LCH) is a rare histiocytic neoplasm driven by MAPK-ERK mutations in majority of patients. Contemporary data on treatments and outcomes in adult LCH are lacking. Hence, we undertook this study to analyze a large cohort of adult LCH patients. Methods: This was a retrospective study of adult (≥18 years) LCH patients seen at our institution between 1998 and 2018. Results: We included 186 patients with adult LCH (median age 43; 19-88), and 54% were females. 70% of patients were diagnosed after 2007. Common presenting symptoms were cough/dyspnea (30%), rash (17%), pain/swelling in head (17%), and diabetes insipidus (10%). 70 (38%) patients had multisystem LCH, 62 (33%) had isolated pulmonary LCH, and 35 (19%) had unifocal LCH. Common sites of involvement included lung (59%), bone (37%), skin (21%), and nervous system (16%). 121 (65%) were smokers; 48% of these had lung disease, while 52% had multisystem disease. 18 of 31 tested (58%) patients had BRAF-V600E mutation. Most common first-line treatment was smoking cessation in 24 patients, and led to an overall response rate (ORR) of 83% in pulmonary lesions. Radiation therapy was used in 11 patients, and led to an ORR 82%. Surgical resection of lesion was done in 23 patients, with relapses in 24%. Systemic therapies were used in 78 (42%) patients (Table). Most common first-line systemic therapy was cladribine with ORR of 78%. Vemurafenib was used in 3 patients with BRAF-V600E, leading to an ORR of 67% . After a median follow-up of 23 months (0-261), 21 patients had died. Of these, 10 died of progressive LCH. Median OS was not reached, and mean OS was 196 months. Conclusions: This is the largest contemporary series of adult LCH. It shows that diverse clinical spectrum, ranging from benign course to a progressive multisystem disease. Although smoking cessation was an effective treatment for pulmonary LCH, a large subset required systemic chemotherapy. [Table: see text]

In an effort to determine the usefulness of prodromata for predicting a myocardial infarction, a prospective analysis was made of 211 consecutive patients with chest pain who were admitted to the Stanford University Medical Center Coronary Care Unit. In their subsequent course, 91 patients had a myocardial infarction, 102 had a myocardial infarction ruled-out, and 18 had a noncardiac etiology for their chest pain. Prodromal chest pain in the previous six months had occurred in 65% of patients and unstable angina in 61%. Infarction versus noninfarction patient groups could not be identified on the basis of prodromal ill health, chest pain, unstable angina, typical versus atypical nature of the chest pain, or activity at the onset of pain. Complaints of preceding fatigue and increased perceived stress were common in both groups. Activity at the onset of the admission chest pain was strenuous in 15% of the infarction patients and 12% of the noninfarction patients. We conclude that prodromal symptoms are common in both infarction and noninfarction patients. Although chest pain probably remains the single most frequent identifier of a new cardiac event, it is common in noninfarction patients and cannot be used alone to predict infarction or death.

In order to determine whether prehospitalization characteristics of patients with chest pain are useful in predicting their subsequent course, we analyzed the precoronary care course in 211 consecutive patients admitted because of suspected myocardial infarction. On the basis of serial electrocardiograms and enzymes, 61 patients had a definite myocardial infarction on admission, 30 patients evolved criteria for an infarction during hospitallzation, 102 patients had cardiac pain without infarction, and 18 patients were judged to have noncardiac pain. The mean patient delay from onset of chest pain to arrival at the hospital was 456 ± 703 minutes (median 210 minutes). The decision to seek medical help consumed a mean 307 ± 575 minutes of this delay, whereas transportation to the hospital required only a mean of 17 ± 49 minutes. Known heart disease, known stable angina and progressive unstable angina tended to prolong the patient's decision to seek medical help. Of 140 patients who contacted a physician, 67 (48 per cent) were sent to the emergency room; whereas 71 had an additional mean 180 ± 436 minutes (median 38 minutes) of physician-advised delay consisting of office visits (59 patients), house call (five patients) and other attempted therapy (seven patients). The presence of prodromas or chest pain consistent with unstable angina was not significantly different in any patient group. We conclude that prodromas, although common, are not helpful in differentiating those with infarction from those without infarction among the patients hospitalized because of chest pain. Furthermore, the mean patient delay of over 6 hours and median delay of 3 12 hours indicates that this delay is the most immediate problem to be solved in order to decrease out of hospital mortality.

The results of the first 400 consecutive patients (335 males, 65 females; mean age 52 years) having saphenous vein-coronary artery graft surgery at Stanford between October 1968 and January 1972 were reviewed. Through patient or physician contact, 100% follow-up period was achieved in the 375 patients surviving surgery. The mean follow-up period was 9.9 months, with the range 2 to 40 months. The operative mortality was 6.5%; patients having this surgery electively had a 0.8% mortality. The major cause of operative mortality was myocardial infarction (9 patients) and congestive heart failure and cardiogenic shock (10 patients). Predominant postoperative morbidity was due to pulmonary emboli (17 patients) and intrathoracic hemorrhage requiring thoracotomy (11 patients). The use of anticoagulants in the early postoperative period has reduced the incidence of pulmonary emboli. Angina was completely relieved in 79% (295 patients), 237 of whom had returned to full time employment. However, another 12% either were unchanged from their preoperative symptomatic state or incurred major late complications. This group includes 15 patients (3.9%) who had late deaths from cardiovascular causes. Another 23 patients had late, nonfatal myocardial infarctions. Using as a data base the degree of preoperative congestive heart failure, the extent of electrocardiographic changes and the presence of mitral regurgitation, a prognostic preoperative clinical risk-benefit guideline has been developed for use in any patient undergoing saphenous vein coronary artery graft surgery.

To determine the prognosis after hospitalization of patients hospitalized with acute chest pain in a coronary-care unit, we undertook a prospective study of 211 consecutive admissions to the Stanford Coronary Care Unit. On the basis of predetermined criteria, 16 patients were found to have noncardiac chest pain, and myocardial infarction was ruled out in 89, one of whom died in the hospital. Infarction was documented in 84 others, six of whom died in the hospital. Prospective follow-up after hospitalization was carried out in the 88 patients in whom infarction was ruled out and in the 78 patients who survived infarction. The rate of myocardial infarction or death was 8.0 per cent at six months and 21.6 per cent at a mean of 27.8 months of follow-up for patients who had infarction ruled out, as compared with 7.7 per cent at six months and 21.8 per cent at a mean of 27.8 months of follow-up for those who had a documented infarction during the initial hospitalization. Cardiomegaly, congestive heart failure, and angina after discharge from the hospital tended to increase the risk of morbidity and mortality in both groups. The patient hospitalized with acute ischemic chest pain without evolution of a myocardial infarction has a six to 24-month prognosis similar to that of the patient hospitalized with an acute infarction, and therefore requires similar diagnostic and therapeutic assessment.

The first 81 patients to undergo coronary artery bypass surgery for unstable angina pectoris at Stanford Hospital have been observed for a mean of 40.8 months. Surgical mortality was 8.5%, and perioperative incidence of myocardial infarction was 16%. The mean 18-month follow-up showed two early cardiac deaths and 12 additional myocardial infarctions. Sixty-seven percent of the patients were angina-free, and the condition of none was worse. After a mean of 40.8 months, two late cardiac deaths and two myocardial infarctions had occurred. Complete relief of angina was present in 51%; 22% had unstable or worsening angina. The probability of survival from time of operation to four months after surgery was 88.8%±3.5%, and this remained unchanged until the two late deaths, which decreased survival probability to 83.8%±4.8% at 43 months. The two late cardiac deaths and the 22% incidence of patients with worsening angina may reflect progression of the atherosclerotic process, late graft occlusion, or both. ( JAMA 237:2609-2612, 1977)