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Overall survival following reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) using alemtuzumab, fludarabine, and melphalan is favorable in patients transplanted for inborn errors of immunity (IEI), but RIC is associated with high rates of mixed chimerism (MC) and secondary graft failure (GF). We hypothesized that peri-transplant alemtuzumab levels or specific patterns of inflammation would predict these risks. We assessed samples from BMT CTN 1204 (NCT01998633) to study the impact of alemtuzumab levels and cytokine patterns on MC and impending or established secondary GF (defined as donor chimerism 0.32μg/mL (p=0.008). Impending or established secondary GF was only observed in patients with day 0 alemtuzumab levels >0.32µg/mL (p=0.08). Unexpectedly, patients with impending or established secondary GF had lower CXCL9 levels. The cumulative incidence of impending or established secondary GF in patients with a day +14 CXCL9 level ≤2394pg/mL (day +14 median) was 73.6% versus 0% in patients >2394pg/mL (p=0.002). CXCL9 levels inversely correlated with alemtuzumab levels. These findings support a relationship between alemtuzumab levels, CXCL9 levels, and sustained engraftment. These data suggest a model in which higher levels of alemtuzumab at day 0 deplete donor T-cells, inhibit the graft-versus-marrow reaction (thereby suppressing CXCL9 levels), and adversely impact sustained engraftment in the non-myeloablative HCT setting. Clinical Trial # NCT01998633.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that may complicate hematologic malignancies. HLH and malignancies have common clinical features, and HLH diagnostic criteria (HLH-2004/Hscore) were not validated in this specific population. We describe a case of a 72-year-old patient with a history of chronic lymphocytic leukemia stable for over 10 years who presented with fever and cytopenia. After excluding infectious etiologies and the progression of her disease, HLH was diagnosed. The patient was treated with etoposide, dexamethasone, intravenous immunoglobulin, and rituximab. Despite initial clinical improvement, the patient deteriorated and developed pulmonary aspergillosis and CNS involvement that reflected uncontrolled HLH. The patient died 45 days after her presentation. An unusual feature of this case was that HLH was not triggered by infection, disease transformation, or treatment. This case emphasizes the challenges of differentiating the development of overwhelming HLH from other complications associated with hematologic malignancy.

Hemophagocytic lymphohistiocytosis (HLH) is a fatal disorder of immune hyperactivation that has been described as a cytokine storm. Sepsis due to known or suspected infection has also been viewed as a cytokine storm. Although clinical similarities between these syndromes suggest similar immunopathology and may create diagnostic uncertainty, distinguishing them is critical as treatments are widely divergent. We examined T-cell profiles from children with either HLH or sepsis and found that HLH is characterized by acute T-cell activation, in clear contrast to sepsis. Activated T cells in patients with HLH were characterized as CD38high/HLA-DR+ effector cells, with activation of CD8+ T cells being most pronounced. Activated T cells were type 1 polarized, proliferative, and displayed evidence of recent and persistent activation. Circulating activated T cells appeared to be broadly characteristic of HLH, as they were seen in children with and without genetic lesions or identifiable infections and resolved with conventional treatment of HLH. Furthermore, we observed even greater activation and type 1 polarization in tissue-infiltrating T cells, described here for the first time in a series of patients with HLH. Finally, we observed that a threshold of >7% CD38high/HLA-DR+ cells among CD8+ T cells had strong positive and negative predictive value for distinguishing HLH from early sepsis or healthy controls. We conclude that the cytokine storm of HLH is marked by distinctive T-cell activation whereas early sepsis is not, and that these 2 syndromes can be readily distinguished by T-cell phenotypes.

Outcomes for patients with hemophagocytic lymphohistiocytosis (HLH) have improved significantly in recent decades. This is a direct outcome of an improved diagnostic process, the development of eff...

Haemophagocytic lymphohistiocytosis (HLH) is an inflammatory syndrome that can occur with cancer (malignancy-associated HLH) or with immune-activating therapies for cancer. Patients with lymphoma appear to be at particularly high risk for malignancy-associated HLH. The familial form of HLH is characterised by uncontrolled activation of macrophages and cytotoxic T cells, which can be identified by genetics or specific immune markers. However, the pathophysiology of malignancy-associated HLH is not well understood, and distinguishing pathological immune activation from the laboratory and clinical abnormalities seen in cancer and cancer treatment is challenging. Emerging diagnostic tools, such as serum cytokine or chemokine concentrations, flow cytometry, and other functional measures, are discussed. Mortality remains high with current approaches. Targeted therapy, including blockade of specific cytokines such as IL-1, IL-6, and IFNγ, and inhibition of the JAK-STAT pathways might improve outcomes for some patients. Finally, we discuss a framework for thinking of malignancy-associated HLH within a larger umbrella concept of cytokine storm syndrome.

Hemophagocytic lymphohistiocytosis (HLH) is a rare hyperinflammatory syndrome, which can manifest either secondary to a variety of underlying causes, or due to a primary genetic defect. Malignancy is the most common underlying disease in adults with HLH, with lymphomas being the most common malignancy. Lymphoma-associated hemophagocytic syndrome (LAHS) typically follows a rapidly progressive clinical course and is associated with poor prognosis. We herein present four patients with HLH associated with aggressive lymphoma. At initial presentation, the underlying etiology of the HLH was unclear. Two patients were eventually diagnosed with anaplastic large cell lymphoma, while the other two had diffuse large B cell lymphoma. Two of the patients experienced rapid clinical deterioration, one at diagnosis and the other at relapse, and both died prior to diagnosis of lymphoma despite HLH-directed therapy. These cases highlight the need for intensive management in adults with HLH without a clear etiology, especially in cases when lymphoma-associated HLH is suspected. We describe the current pitfalls in diagnosis and treatment of LAHS and discuss possible ways to improve patient management.

7570 Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome that may complicate hematologic malignancies (HM). We recently developed a simplified diagnostic and prognostic index termed the ‘optimized HLH inflammatory’ (OHI) index comprising the combined elevation of sCD25 ( > 3,900 U/mL) and serum ferritin ( > 1,000 ng/mL), which in HM patients both identifies HLH and predicts mortality more accurately than conventional criteria for HLH. In this study, we examined whether mortality in our cohort is directly related to progressive malignancy vs. HLH-associated causes in OHI+ and OHI- patients. Methods: We performed a multicenter, retrospective study of patients with newly diagnosed lymphoma from Israel, the USA, and Japan for whom sCD25 and ferritin levels were measured either as routine surveillance or during investigation for HLH and classified patients by their OHI status. The International Prognostic Index, International Prognostic Score, and Follicular Lymphoma International Prognostic Index were used to estimate the predicted prognosis of T/B cell non-Hodgkin’s lymphoma (NHL), Hodgkin’s lymphoma, and follicular lymphoma, respectively. Predicted five-year overall survival was calculated based on the relevant prognostic index and was compared between OHI+ and OHI- patients using the unpaired t-test. The actual survival at five years/last follow-up was recorded, as was the cause of death. The odds ratios (ORs) for observed vs. predicted mortality, and for HLH- vs. malignancy-related death were calculated using the Chi-square test. Results: 100 lymphoma patients were studied: 65% with B cell NHL, 18% with natural killer/ T cell lymphoma, 17% with Hodgkin’s lymphoma; 37 were OHI+, and 63 were OHI-. The disease-relevant international prognostic index-predicted five-year survival did not differ between OHI + and OHI- patients (a mean of 58% n OHI+ and 57% in OHI- p = 0.62). However, the observed five-year survival in OHI+ patients was lower (12%) than predicted, reflecting a mortality incidence that was four times higher than predicted by the relevant prognostic score (OR 3.9; CI 1.3-12.1). By contrast, OHI- patients had better survival (79%) than predicted by their prognostic scores (OR 0.15; CI 0.07-0.34). More than half of the OHI+ patients died from non-malignant causes (39% multi-organ dysfunction or HLH, 18% infection), while most OHI- patients (92%) died from progressive malignancy. The likelihood of dying from multi-organ dysfunction or HLH was 26 times higher in OHI+ vs. OHI- patients (OR 26.2; CI 4.1-286.7). Conclusions: OHI index status strongly correlated with mortality in patients with lymphoma within our cohort, and death in OHI+ patients was largely due to causes other than progressive malignancy. The OHI index appears to identify a harmful inflammatory state and deserves further prospective study.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome that may complicate hematologic malignancies (HMs). The appropriateness of current criteria for diagnosing HLH in the context of HMs is unknown because they were developed for children with familial HLH (HLH-2004) or derived from adult patient cohorts in which HMs were underrepresented (HScore). Moreover, many features of these criteria may directly reflect the underlying HM rather than an abnormal inflammatory state. To improve and potentially simplify HLH diagnosis in patients with HMs, we studied an international cohort of 225 adult patients with various HMs both with and without HLH and for whom HLH-2004 criteria were available. Classification and regression tree and receiver-operating curve analyses were used to identify the most useful diagnostic and prognostic parameters and to optimize laboratory cutoff values. Combined elevation of soluble CD25 (>3900 U/mL) and ferritin (>1000 ng/mL) best identified HLH-2004–defining features (sensitivity, 84%; specificity, 81%). Moreover, this combination, which we term the optimized HLH inflammatory (OHI) index, was highly predictive of mortality (hazard ratio, 4.3; 95% confidence interval, 3.0-6.2) across diverse HMs. Furthermore, the OHI index identified a large group of patients with high mortality risk who were not defined as having HLH according to HLH-2004/HScore. Finally, the OHI index shows diagnostic and prognostic value when used for routine surveillance of patients with newly diagnosed HMs as well as those with clinically suspected HLH. Thus, we conclude that the OHI index identifies patients with HM and an inflammatory state associated with a high mortality risk and warrants further prospective validation.

Background Iodinated contrast media (ICM) allergy may entail severe adverse events in patients who undergo percutaneous coronary intervention (PCI). Premedication protocols and low-osmolality contrast media have been thought to improve the outcomes of these individuals. Objective The objective of this study was to assess the prevalence and severity of allergic reactions during PCI in patients admitted for investigation of chest pain. Methods This is a retrospective analysis of 13,652 patients who were hospitalized with chest pain during the years 2010-2016, at the Department of Internal Medicine, Meir Medical Center. Patient records were screened for diagnosis of prior ICM allergy. Primary outcomes were: (1) records of previous allergy to ICM, (2) administration of antiallergic premedication, and (3) allergic reactions to the ICM during the procedure. Results Nine hundred thirty-one individuals without prior ICM allergy were referred for PCI, of whom 2 had minor allergic reactions. Previously diagnosed ICM allergy was recorded for 216 subjects (mean age 65.5 ± 10 years, 42% males). Of these, 32 were referred to in-hospital PCI. Premedication was administered in 10 cases only with no documented rationale for not treating the other 22. Only one of the pretreated patients experienced a reaction attributed to allergy, showing no statistical advantage for premedication. No mortality was documented in the 30 days after PCI among the patients with known ICM allergy. Conclusions PCI did not induce substantial allergic reactions to ICM in patients with a previously diagnosed allergy. This study did not demonstrate an advantage for premedication.

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyper-inflammatory syndrome which may occur in adults with hematologic malignancies (HM). The diagnosis of HLH in this context (HM-HLH) is hindered by a number of factors. First, the currently used HLH 2004 diagnostic criteria are derived from pediatric patients commonly with HLH-associated genetic lesions, a very different population than adults with cancer. Second, most parameters used for diagnosis of HLH are directly impacted by the underlying HM and may reflect the presence of the malignant clone itself rather than an inflammatory process. Finally, appropriate diagnostic cutoff values for laboratory abnormalities in HM-HLH have not been defined. In this study we determine the diagnostic value of the laboratory components of the HLH 2004 diagnostic criteria and establish optimal cutoffs for the diagnosis of HM-HLH in HM patients. Methods: This is a multicenter, retrospective study of adult patients with a hematologic malignancy in whom sCD25 was measured because of clinically suspected HM-HLH or as part of routine screening of patients with a newly diagnosed hematologic malignancy, between January 2012 and March 2020. We considered patients fulfilling the five of eight of the HLH 2004 diagnostic criteria to have HM-HLH. Patients fulfilling fewer than five criteria were assigned to the HM group. These cohorts were well balanced in terms of disease distribution. We established the optimal cutoffs for laboratory parameters used for the diagnosis of HM-HLH using receiver operating curves (ROC) in a discovery cohort and tested their performance in a validation cohort. In order to improve the results obtained using the individual ROC, we then created a combined ROC using parameters demonstrating the highest individual performance (highest area under the curve (AUC)), in order to develop a diagnostic index. Finally, we examined the performance of each parameter in each cohort by using a contingency table and Chi-square and Fisher's exact test to determine the positive predictive value (PPV), negative predictive value (NPV), sensitivity, specificity and likelihood ratio (LR) of disease for each parameter. Results: 212 adults with HM with or without HLH in whom testing for HLH was performed were included in the study. HMs were: B cell lymphoma (41%), T cell lymphoma (26%), Hodgkin lymphoma (9%), acute myeloid leukemia (8%), myelodysplastic syndrome (8%), myeloproliferative neoplasms (5%) and chronic lymphocytic leukemia (4%). 99 (47%) patients had HM-HLH. Despite considerable overlap in laboratory values between the patient groups, all parameters apart from fibrinogen were able to distinguish HM-HLH from HM alone, with ferritin and sCD25 having the greatest discriminatory power. ROC analysis revealed an optimal cutoff value of >5,600 U/mL for sCD25 (sensitivity/specificity 76%/78%, AUC=0.83) and >1,300 ng/ml for ferritin (sensitivity/specificity 76%/76%, AUC=0.83). Combining the two markers to create a novel inflammatory index (HM-INFL) yielded superior diagnostic ability (AUC =0.86). Using HLH 2004 cutoff levels the HM-INFL index had a sensitivity of 94% and NPV of 94% and when using the optimal cutoff levels, it had a specificity of 92% and PPV of 90% (Table 1). Conclusions: HM-INFL is an index comprising only ferritin and sCD25. Using the original HLH 2004 cutoffs the index is an effective screening tool. Using our newly defined cutoff levels obtained by ROC analysis it is highly specific and can be used as a confirmatory test for the diagnosis of HLH in HM patients. These findings also support the hypothesis that HLH in the context of HM is an inflammatory condition associated with immune dysregulation. Disclosures Miller: Foundation Medicines, Inc.: Consultancy. Daver:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jordan:Sobi: Consultancy.

7563 Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome that may accompany hematologic malignancies (HM). The diagnosis of HLH in patients with HM (HM-HLH) is confounded by a number of factors: the most commonly used HLH-2004 diagnostic criteria are derived from studies in infants while the Hscore used in adults is not specific for HMs; moreover, most parameters in these scoring systems may reflect features of the underlying HM rather than HLH associated inflammation; and finally specific diagnostic cutoff values for laboratory abnormalities in HM-HLH have not been defined. We therefore conducted a study to optimize the HLH-2004 laboratory thresholds for the diagnosis of HM-HLH. Methods: A multi-center retrospective study in adult patients with HM in whom testing for HLH was performed. HM-HLH was defined as fulfillment of 5/8 HLH-2004 diagnostic criteria. We established the optimal diagnostic cutoff levels for HLH-2004 laboratory parameters using receiver operating curves (ROC) and combined the best performing parameters into a combined index, using binary logistic regression. We then created a clinical decision tree using a Classification and Regression Tree (CART) analysis with all available parameters, using cross validation. We also determined the prognostic value of our combined diagnostic tool. Results: 225 adults were analyzed (112 with HM-HLH per HLH-2004 and 113 with HM only). 35% of patients were evaluated for HLH routinely upon HM diagnosis. Soluble CD25 (sCD25) and ferritin best discriminated HM-HLH from HM, with an area under the curve (AUC) of 0.83 for each. ROC analysis demonstrated an optimal cutoff of > 4190 U/mL for sCD25 (sensitivity/specificity 91%/69%) and an optimal cutoff of > 2636 ng/ml for ferritin (sensitivity/specificity 64%/86%) for HM-HLH. We term the combination of elevated sCD25 and ferritin using optimized cutoff levels the ‘optimized HLH inflammatory’ (OHI) index. This OHI index was highly specific for the diagnosis of HM-HLH (specificity of 92%, sensitivity 79%). CART analysis demonstrated that OHI index positivity was sufficient to diagnose HM-HLH. In patients without a positive OHI index an Hscore > 168 and either splenomegaly or triglycerides > 279 ng/dL can still diagnose HM-HLH. By following this decision pathway, approximately 92% of patients were accurately classified based on HLH-2004. Furthermore, the OHI was better (odds ratio (OR) 7.9; 95% confidence interval (CI) 4.2-14.6) than Hscore >169 (OR 5.5; CI 3.9-9.6) and > 5/8 HLH-2004 (OR 5.3; CI 3-9.3) at predicting mortality at 1 year. Conclusions: The OHI index derived here is a simple tool that can accurately diagnose HLH and predict mortality in patients with hematologic malignancies. Some patients may not need full HLH workup before intervening with therapy that is HLH directed and not only malignancy directed.