Personalized treatment of immune checkpoint inhibitor-related severe hemophagocytic lymphohistiocytosis (HLH).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15079-e15079
Author(s):  
Michel Obeid ◽  
Berna C. Özdemir ◽  
Sofiya Latifyan ◽  
Olivier Michielin
Keyword(s):  
Bone Marrow ◽  
Immune Checkpoint ◽  
Cytokine Profile ◽  
High Dose ◽  
Variable Response ◽  
Centre Hospitalier Universitaire ◽  
Life Threatening ◽  
Melanoma Patients ◽  
Dose Corticosteroid ◽  
Th1 Cytokines

e15079 Background: HLH is a rare but potentially lethal immune related adverse event (irAE) with an incidence of 0.03-0.4 % in cancer patients undergoing immune checkpoint inhibition (ICI). Given the rarity of HLH there are currently no diagnostic or therapeutic guidelines and the majority of the reported cases have been treated with corticosteroids alone with very variable response rates. There is currently no established therapy for corticosteroid resistant HLH occurring in the context of immunotherapies. We investigated the treatment possibility of severe HLH according to the cytokine profile. Methods: We report the clinical presentation, the cytokine profile and the outcome of three melanoma patients with ICI-related HLH not responding to high dose corticosteroid therapy alone who were treated with additional anti-IL-6R at the Centre Hospitalier Universitaire Vaudoise. We collected the following data: treatment setting, ICIs received, duration of each treatment, HLH criteria, bone marrow biopsy, cytokine profile, response to corticosteroid and to anti-IL-6R therapy. Results: We identified a severe HLH in three metastatic melanoma patients treated with ipilimumab and nivolumab for 2 of them and 1 with pembrolizumab. HLH occurred in a median of 10 weeks after initiation of immunotherapy. The patients met at least five of the HLH-2004 criteria including high ferritin levels ( > 100.000 ng/ml). High levels of interferon-gamma (IFNγ), IFNγ-induced chemokines, particularly CXCL9, CXCL10, CXCL13, IL-18 and IL-6 were found in all patients. For 2 of them we identified a highly infiltrated bone marrow by activated CD8+ T and NK cells. Median duration of corticosteroids therapy was 6.5 weeks. The evolution of the three patients was rapidly favorable in a median of 2.5 weeks after the addition of an anti-IL-6R therapy targeting the IFNγ/Th1 axis. Conclusions: HLH is a potentially life-threatening irAE necessitating emergency therapy. CXCL9 and Th1 cytokines are markedly elevated in patients with ICI-related HLH due to the activation of the IFNγ pathway. High CXCL9 and Th1 cytokines levels appear to be potential specific biomarkers for ICI-related HLH diagnosis. Blocking this axis by anti-IL-6 therapy seems a very promising strategy for severe ICI-related HLH allowing rapid resolution of symptoms and normalization of the abnormal laboratory results.

Concurrent Vogt–Koyanagi–Harada disease and impressive response to immune checkpoint blockade in metastatic melanoma

Immunotherapy ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 439-444 ◽  
Author(s):  
T Gambichler ◽  
C Seifert ◽  
M Lehmann ◽  
C Lukas ◽  
C Scheel ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Complete Response ◽  
Immune Checkpoint Blockade ◽  
High Dose ◽  
Ocular Ultrasound ◽  
Melanoma Patients ◽  
Dose Corticosteroid

Background: Vogt–Koyanagi–Harada disease (VKHD)-like symptoms have previously been reported in 11 melanoma patients treated with immune checkpoint inhibitors. Materials & methods: We report a female patient with multilocular metastatic melanoma who was treated with nivolumab. Results: Following the first nivolumab dose, she experienced bilateral blurry vision, hearing loss, vertigo and ataxia. Ocular ultrasound was consistent with the diagnosis of uveitis. Audiography revealed severe bilateral sensorineural hearing loss. A high-dose corticosteroid regimen was initiated under which the patient developed generalized vitiligo. Abdominal and thoracic CT scans showed an almost complete response to nivolumab therapy. This patient fulfilled all criteria of VKHD which is characterized pathogenetically by an antimelanocytic autoimmune process. Conclusion: The present case showed an impressive response to antimelanoma immunotherapy. Based on these data, the occurrence of VKHD in melanoma patients appears to be a strong indicator for immune checkpoint inhibitor efficacy.

scholarly journals Anakinra in the treatment of protracted paradoxical inflammatory reactions in HIV-associated tuberculosis in the United Kingdom: a report of two cases

2020 ◽  
Vol 31 (8) ◽  
pp. 808-812 ◽  
Author(s):  
Alexander J Keeley ◽  
Vivak Parkash ◽  
Anne Tunbridge ◽  
Julia Greig ◽  
Paul Collini ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Therapeutic Option ◽  
Interleukin 1 ◽  
High Dose ◽  
Inflammatory Reactions ◽  
Amyloid A ◽  
The United Kingdom ◽  
First Case ◽  
Life Threatening ◽  
Dose Corticosteroid

Paradoxical reactions, including immune reconstitution inflammatory syndrome (IRIS), are common in patients co-infected with human immunodeficiency virus (HIV) and tuberculosis (TB). Paradoxical reactions may confer substantial morbidity and mortality, especially in cases of central nervous system (CNS) TB, or through protracted usage of corticosteroids. No high-quality evidence is available to guide management in this scenario. Interleukin-1-mediated inflammation has been implicated in the pathophysiology of TB–IRIS. We describe two cases where anakinra (human recombinant interleukin-1 receptor antagonist) was used as steroid-sparing therapy for life-threatening protracted paradoxical inflammation in HIV-associated TB. In the first case of disseminated TB with lymphadenitis, protracted TB–IRIS led to amyloid A amyloidosis and nephrotic syndrome. In the second case of disseminated TB with cerebral tuberculomata, paradoxical inflammation caused unstable tuberculomata leading to profound neuro-disability. In both cases, paradoxical inflammation persisted for over a year. Protracted high-dose corticosteroid use led to adverse events yet failed to control inflammatory pathology. In both patients, anakinra successfully controlled paradoxical inflammation and facilitated withdrawal of corticosteroid therapy. Following anakinra therapy, nephrotic syndrome and neuro-disability resolved, respectively. Anakinra therapy for protracted paradoxical inflammation in HIV-associated TB may be a viable therapeutic option and warrants further research.

scholarly journals Autoimmune-Associated Hemophagocytosis and Myelofibrosis in a Newly Diagnosed Lupus Patient: Case Report and Literature Review

2019 ◽  
Vol 2019 ◽  
pp. 1-7
Author(s):  
Deonne Thaddeus V. Gauiran ◽  
Paula Victoria Catherine Y. Cheng ◽  
Christopher Ryan P. Pagaduan ◽  
Maria Clariza M. Santos
Keyword(s):  
Bone Marrow ◽  
Hemophagocytic Syndrome ◽  
Target Organ Damage ◽  
Organ Damage ◽  
Target Organ ◽  
High Dose ◽  
Newly Diagnosed ◽  
Timely Initiation ◽  
Life Threatening ◽  
Important Site

Bone marrow abnormalities in SLE are now becoming increasingly recognized, suggesting that the bone marrow may also be an important site of target organ damage. In this study, we present a rare case of concurrent autoimmune hemophagocytic syndrome and autoimmune myelofibrosis, potentially life-threatening conditions, in a newly diagnosed SLE patient. We report a case of a 30-year-old Filipino woman who presented with a one-year history of fever, constitutional symptoms, exertional dyspnea, joint pains, and alopecia and physical examination findings of fever, facial flushing, cervical lymphadenopathies, and knee joint effusions. Laboratory workup revealed pancytopenia with leukoerythroblastosis, elevated ESR, increased serum levels of transaminases, elevated CRP and LDH, hyperferritinemia, hypertriglyceridemia, proteinuria, hepatomegaly, and positive antinuclear antibody. Bone marrow aspiration and trephine biopsy revealed hemophagocytosis and moderate myelofibrosis. The patient was diagnosed with SLE with concomitant autoimmune-associated hemophagocytic syndrome and autoimmune myelofibrosis. Treatment with high-dose corticosteroids led to dramatic clinical improvement with normalization of laboratory data and complete resolution of bone marrow hemophagocytosis and myelofibrosis. Hemophagocytosis and myelofibrosis, although uncommon, are possible initial manifestations of SLE and should be included in the differential diagnosis of cytopenias in SLE. Thorough clinical assessment and microscopic bone marrow examination and timely initiation of corticosteroid therapy are essential in the diagnosis and management of these potentially life-threatening conditions. This case emphasizes that the bone marrow is an important site of target organ damage in SLE, and evaluation of cytopenias in SLE should take this into consideration.

Regimen-related toxicity in patients undergoing bone marrow transplantation.

1988 ◽  
Vol 6 (10) ◽  
pp. 1562-1568 ◽  
Author(s):  
S I Bearman ◽  
F R Appelbaum ◽  
C D Buckner ◽  
F B Petersen ◽  
L D Fisher ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Disease Status ◽  
High Dose ◽  
Gvhd Prophylaxis ◽  
Preparative Regimen ◽  
Life Threatening ◽  
Grade Ii ◽  
Total Body

Bone marrow transplantation is associated with significant morbidity and mortality, some of which is due to high-dose chemoradiotherapy. In order to quantitate toxicity that was felt to be due to the preparative regimen (termed regimen-related toxicity [RRT]), a system was developed in which toxicities were graded from 0 (none) to 4 (fatal). One hundred ninety-five patients who underwent marrow transplantation for leukemia were studied retrospectively to determine whether toxicities that were clinically felt to be due to the preparative regimen were influenced by other factors such as disease status, graft-versus-host disease (GVHD) prophylaxis, and allogenicity. All patients developed grade I toxicity in at least one organ, and 30 developed grades III-IV (life-threatening or fatal) RRT. RRT was more common in relapsed patients v remission patients (P = .04), in those receiving 15.75 Gy total body irradiation (TBI) v 12.0 Gy TBI (P = .028), and in those receiving allogeneic marrow v autologous marrow (P = .0029). Autologous marrow recipients did not develop grades III-IV toxicity in this study. A multivariate analysis controlling for autologous marrow grafting showed that the dose of TBI was the only statistically significant predictor of grades III-IV RRT. Those patients who developed grade III RRT were unlikely to survive 100 days from transplant, though not all deaths could be attributed to RRT. Patients who developed grade II toxicity in three or more organs were more likely to die within 100 days than those developing grade II toxicity in two or less organs (P = .0027). This system was generally able to distinguish RRT from other toxicities observed in marrow recipients.

Improved Response With Higher Corticosteroid Dose in Children With Acute Lymphoblastic Leukemia

2001 ◽  
Vol 19 (4) ◽  
pp. 1040-1046 ◽  
Author(s):  
Cindy L. Schwartz ◽  
E. Brad Thompson ◽  
Richard D. Gelber ◽  
Mary L. Young ◽  
David Chilton ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Peripheral Blood ◽  
Standard Dose ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
High Dose Corticosteroid ◽  
Blast Response ◽  
Dose Corticosteroid

PURPOSE: We investigated whether there was a dose-response relationship for the use of corticosteroids in childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Three hundred sixty-nine patients, ages 1 to 18 years with ALL, were randomly assigned to receive one of four different doses of corticosteroid (prednisolone 40 mg/m2/d or dexamethasone 6, 18, or 150 mg/m2/d) administered as a 3-day, single-drug window before initiation of standard, multidrug induction chemotherapy. Corticosteroid drug response was measured by reduction in bone marrow blast counts and absolute peripheral blast counts after 3 days. Glucocorticoid receptor (GCR) number and the effective concentration of dexamethasone resulting in a 50% reduction of leukemic cell viability in vitro (EC-50) were evaluated at days 0 and 3. RESULTS: Increasing dexamethasone doses resulted in greater marrow blast response (P = .007), with a similar trend in peripheral-blood blast response. High-dose corticosteroid regimens (dexamethasone 18 or 150 mg/m2/d) elicited better responses than standard doses of dexamethasone or prednisone (bone marrow, P = .002; peripheral blasts, P = .05). Among patients treated with standard-dose corticosteroids, 38% with resistant (EC-50 > 10-7) peripheral blasts had a good response compared with 92% with sensitive (EC-50 < 10-7) peripheral blasts (P = .01). In contrast, there was no differential response according to EC-50 group after high-dose corticosteroids. Similarly, an association between response and GCR on peripheral-blood blasts was noted after standard-dose corticosteroid regimens but not after high-dose corticosteroid regimens. CONCLUSION: Response of ALL to glucocorticoid therapy increased with dose. Higher-dose corticosteroid treatment abrogated the effect of relative drug insensitivity and of low GCR on peripheral blasts.

Rare case of life-threatening thrombocytopenia occurring after radiotherapy in a patient treated with immune checkpoint inhibitor

2020 ◽  
Vol 13 (6) ◽  
pp. e235249 ◽  
Author(s):  
Aurore Hendrix ◽  
Anne-Emmanuella Yeo ◽  
Sarah Lejeune ◽  
Emmanuel Seront
Keyword(s):  
Renal Cancer ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Potential Interaction ◽  
High Dose ◽  
Severe Thrombocytopenia ◽  
Metastatic Renal Cancer ◽  
Advanced Renal Cancer ◽  
Endocrine Organs ◽  
Life Threatening

Immune checkpoint inhibitors (ICIs) improve significantly outcome of patients with advanced renal cancer. Although immune-related adverse events involve frequently skin, digestive tract, lung, liver and endocrine organs, haematological toxicities are rare. We describe the case of a patient with metastatic renal cancer who was treated with nivolumab. Eight courses of nivolumab were administered without any toxicity; brain metastases were then diagnosed and treated with stereotactic radiotherapy. As the extra-cranial disease was stable, the ninth course of nivolumab was administered 5 days after the end of radiotherapy. One week later, he presented with rectal and nasal bleeding in a context of severe thrombocytopenia (1000/mm3). High dose of steroids and intravenous immunoglobulin reversed slowly the thrombocytopenia. This case highlights the possibility of life-threatening thrombocytopenia with ICIs. Interestingly, the close time relation with radiotherapy highlights a potential interaction, warranting a close follow-up of patients in this situation.

scholarly journals Laryngeal Myofibroblastic Tumor: A New Therapeutic Approach. A Case Report

2020 ◽  
pp. 014556132091874
Author(s):  
Javier Gómez-Hervás ◽  
Manuel Moreno-Romera ◽  
Fabio Hugo Escobar Arias ◽  
Esteban Merino Gálvez
Keyword(s):  
Corticosteroid Therapy ◽  
Therapeutic Approach ◽  
English Literature ◽  
Mass Effect ◽  
The Body ◽  
High Dose ◽  
High Tendency ◽  
Laryngeal Tumors ◽  
Life Threatening ◽  
Dose Corticosteroid

Myofibroblastic tumors are rare lesions which can affect any part of the body. Although benign, their mass effect causes symptoms that can become life-threatening. Supraglottic laryngeal involvement is extremely rare, with only 4 cases described in the English literature. Because the pathophysiology is unknown and the incidence is so low, there is no standardized therapeutic management, although for laryngeal tumors surgery has traditionally been the preferred initial option. Another less common option is intravenous and oral corticosteroid therapy, but this is usually reserved for myofibroblastic tumors in other head and neck sites that are more difficult to access surgically, or patients who cannot undergo surgery. These lesions have a very high tendency to recur, and morbidity rates are therefore also high. We present a case of supraglottic myofibroblastic tumor in which we elected high-dose corticosteroid therapy as the only form of treatment. With this new therapeutic approach, we avoided the undesirable effects of the usual type of surgery. At the 12-month follow-up, the patient is in complete remission.

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