A consensus review on malignancy‐associated hemophagocytic lymphohistiocytosis in adults

Daver, Naval; McClain, Kenneth L.; Allen, Carl E.; Parikh, Sameer A.; Otrock, Zaher K.; Rojas‐Hernandez, Cristhiam M.; Blechacz, Boris; Wang, Sa; Minkov, Milen; Jordan, Michael B.; Rosée, Paul La; Kantarjian, Hagop M.

doi:10.1002/cncr.30826

Cited by 169 publications

(231 citation statements)

References 72 publications

(162 reference statements)

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“…50 To determine whether a patient has an inherited form of HLH, genetic analyses (ie, next-generation sequencing, gene panels, whole-exome sequencing), along with functional testing (ie, NK cell cytotoxicity and CD107a upregulation), will be needed. 10,[15][16][17]46,51 This is particularly true for patients with a family history of consanguinity and/or HLH, partial albinism, or recurrent disease and for young male adults with Epstein-Barr virus (EBV) infection or lymphoproliferation. Testing should also be considered for HLH patients with unknown trigger.…”

Section: Statementmentioning

confidence: 99%

“…In highly active HLH, or if severe organ damage is imminent, dose-adjusted etoposide (50-100 mg/m 2 ) may be used prior to tumor-specific treatment. 16 Etoposide can be added to CHOP or CHOP-like protocols (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone [CHOEP] or doseadapted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin [DA-EPOCH]). 9 Patients with aggressive lymphomas should be considered for evaluation of involvement of the central nervous system (CNS), with cerebral magnetic resonance imaging and lumbar puncture.…”

Section: Malignancy-triggered Hlhmentioning

confidence: 99%

“…10,14 In adults, particularly with increasing age, malignancies, primarily lymphomas, are another major cause (Table 1). 10,[15][16][17] A variety of malignancies are associated with HLH in adults, including T-cell or natural killer (NK) cell lymphomas (35%), B-cell lymphomas (32%), leukemias (6%), Hodgkin lymphoma (6%), other hematologic neoplasms (14%), solid tumors (3%), and other nonspecified neoplasms (3%). 10,15 The epidemiology of HLH varies substantially as a result of population heterogeneity and variable underlying triggers.…”

Section: Introductionmentioning

confidence: 99%

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Recommendations for the management of hemophagocytic lymphohistiocytosis in adults

Rosée

Horne

Hines

et al. 2019

Blood

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Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome induced by aberrantly activated macrophages and cytotoxic T cells. The primary (genetic) form, caused by mutations affecting lymphocyte cytotoxicity and immune regulation, is most common in children, whereas the secondary (acquired) form is most frequent in adults. Secondary HLH is commonly triggered by infections or malignancies but may also be induced by autoinflammatory/autoimmune disorders, in which case it is called macrophage activation syndrome (MAS; or MAS-HLH). Most information on the diagnosis and treatment of HLH comes from the pediatric literature. Although helpful in some adult cases, this raises several challenges. For example, the HLH-2004 diagnostic criteria developed for children are commonly applied but are not validated for adults. Another challenge in HLH diagnosis is that patients may present with a phenotype indistinguishable from sepsis or multiple organ dysfunction syndrome. Treatment algorithms targeting hyperinflammation are frequently based on pediatric protocols, such as HLH-94 and HLH-2004, which may result in overtreatment and unnecessary toxicity in adults. Therefore, dose reductions, individualized tailoring of treatment duration, and an age-dependent modified diagnostic approach are to be considered. Here, we present expert opinions derived from an interdisciplinary working group on adult HLH, sponsored by the Histiocyte Society, to facilitate knowledge transfer between physicians caring for pediatric and adult patients with HLH, with the aim to improve the outcome for adult patients affected by HLH.

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Section: Statementmentioning

confidence: 99%

Section: Malignancy-triggered Hlhmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Recommendations for the management of hemophagocytic lymphohistiocytosis in adults

Rosée

Horne

Hines

et al. 2019

Blood

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713

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“…In adults, all of the studies examining treatment of secondary HLH have included fewer than 20 patients and have been retrospective in nature 15. Therefore, expert guidelines generally recommend adaptation of the HLH-94 regimen to treat adult patients 19. Our patient’s clinical presentation was felt to be most consistent with secondary HLH, and her treatment plan was therefore designed to approximate the HLH-94 regimen rather than therapies recommended for treatment of CRS.…”

Section: Discussionmentioning

confidence: 99%

Haemophagocytic lymphohistiocytosis complicating pembrolizumab treatment for metastatic breast cancer in a patient with the PRF1A91V gene polymorphism

et al. 2018

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BackgroundImmune checkpoint inhibitor therapy is a modern breakthrough in medical oncology, but it can precipitate inflammatory and autoimmune adverse effects. Among the most serious of these toxicities is haemophagocytic lymphohistiocytosis (HLH), a life-threatening disorder of unbridled immune activation that results in injury to multiple organ systems.ObjectiveDescription of a case of pembrolizumab-associated HLH in a patient with a proposed underlying genetic risk factor for its occurrence.Methods and resultsWe describe a patient with aggressive metastatic breast cancer who developed HLH while undergoing experimental treatment with pembrolizumab, resulting in critical illness and multiorgan system failure. Pembrolizumab discontinuation and high-dose corticosteroids were effective in managing HLH. Subsequent next-generation sequencing of 15 genes associated with HLH revealed a germline polymorphism in perforin-1 (PRF1), PRFA91V, that may have predisposed the patient to develop HLH. The patient has had no evidence of malignancy for 2 years following recovery despite receiving no further cancer-directed treatment.ConclusionsHLH is a rare but serious complication of immune checkpoint blockade. Patients with underlying hypomorphic alleles in PRF1 may be predisposed to develop this toxicity. Further studies are necessary to confirm a possible link between perforin gene mutations and immune checkpoint blockade-associated HLH.

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“…Antithymocyte globulin has also been used in combination with steroids, cyclosporine and intrathecal chemotherapy [11]. A recent consensus review on malignancy-associated HLH suggests tailoring treatment to the underlying trigger, performance status, organ function and additional therapies the patient is receiving [12]. Early consultation with a hematologist and center experienced in the treatment of HLH is critical, both because immunomodulatory therapy for HLH is an area of active investigation, and because bone marrow transplantation is considered the curative therapy for patient with a known or suspected genetic cause of HLH.…”

Section: Hlh Treatment Treatmentmentioning

confidence: 99%

Hemophagocytic Lymphohistiocytosis and Other Culture Negative Sepsis-Like Syndromes in the ICU

Denstaedt

Singer

2020

Evidence-Based Critical Care

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A 57 year old man with history of idiopathic panniculitis on long-term steroid treatment presented to the hospital with a 1 month history of dyspnea, malaise, nausea and vomiting. He was hypotensive and tachycardic with an acute kidney injury. Prior to this presentation, he had been hospitalized for 2 weeks at a nearby hospital with similar symptoms and had been found to have multifocal ground glass opacities on CT of the chest. His condition after admission improved with fluid resuscitation, stress-dose steroids, and treatment for presumed sepsis. Infectious and rheumatologic workups were negative. He was noted to have bilateral pulmonary infiltrates ( Fig. 79.1a, b). One week after discharge, however, he presented again with systemic inflammatory response syndrome (SIRS). A bronchoscopy revealed only acute and chronic organizing pneumonia, with no evidence of infection. A bone marrow biopsy was performed, which demonstrated a hypercellular marrow. Pulse dose steroids were initiated for organizing pneumonia and he improved significantly over the next week with continuation of empiric antimicrobials and tapering of steroids. After 1 week of this regimen, however, he again decompensated with hypoxia and hypotension. Worsening infiltrates were noted on his chest radiograph ( Fig. 79.1c). Ferritin was elevated at 7652 ng/mL, and sIL-2R was elevated at 3432 U/ mL. Trigylcerides were normal and fibrinogen was elevated. Given his unremarkable bone marrow biopsy 7 days before and elevated fibrinogen, the possibility of hemophagocytic lymphohistiocytosis (HLH) was dismissed as his hyperferritinemia and elevated sIL-2R were attributed to history of blood transfusion and occult infection. He continued to improve with empiric antimicrobials and steroids, and was discharged from the hospital 5 days after admission to the ICU to complete a course of levofloxacin on 40 mg of prednisone daily.He presented to the hospital for the third time 2 days after discharge with hypotension and hypoxia requiring endotracheal intubation and vasopressors, and antibiotics and steroids were restarted. He was admitted to the ICU and his pulmonary status rapidly improved. After 3 days, however, he again decompensated with hypotension and an elevated lactate. He received intravenous fluids and intravenous steroids. Given the unclear association between changes in his antimicrobial regimen, steroid dosing, and clinical condition, his steroid dose was decreased from 40 mg prednisone daily by 10 mg each day. A repeat bone marrow biopsy was performed, which showed rare hemophagocytic macrophages but no evidence of malignancy. The next day, in the setting of reducing his steroid dose, he again had an episode of hypoxia and hypotension. Ferritin was measured at that time and was 9148 ng/mL, increased from 4074 ng/mL the day before ( Fig. 79.2). sIL2-R was measured and was elevated at 3494 U/mL. A diagnosis of HLH was made, and he was started on chemotherapy with etoposide and high dose dexamethasone. Eight weeks had elapsed since his initial presentati...

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A consensus review on malignancy‐associated hemophagocytic lymphohistiocytosis in adults

Cited by 169 publications

References 72 publications

Recommendations for the management of hemophagocytic lymphohistiocytosis in adults

Recommendations for the management of hemophagocytic lymphohistiocytosis in adults

Haemophagocytic lymphohistiocytosis complicating pembrolizumab treatment for metastatic breast cancer in a patient with the PRF1A91V gene polymorphism

Hemophagocytic Lymphohistiocytosis and Other Culture Negative Sepsis-Like Syndromes in the ICU

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