Multi-organ failure induced by Nivolumab in the context of allo-stem cell transplantation

Abstract

Background Immune checkpoint inhibitors have radically changed the landscape of anti-tumor therapies in several malignancies. However the adverse events associated with immune checkpoint blockade in combination with other treatments remains to be thoroughly documented. Here we report the case of a 33-year-old male with classical Hodgkin lymphoma who was successfully treated for lymphoma but experienced serious and eventually fatal multisystem organ failure following nivolumab administration and allogeneic stem cell transplantation. Case presentation The patient was diagnosed with stage IIIa nodular sclerosing Hodgkin lymphoma. Originally treated by chemotherapy and autologous stem cell transplantation, he subsequently received two allogeneic stem cell transplants from matched and haplo-identical siblings upon successive disease recurrences. Nivolumab treatment was administered prior to the second allograft, after which complete remission of lymphoma was achieved (year 10), as evidenced by clinical and radiographic examination. However within the next 3 months, the patient went on to develop a constellation of symptoms affecting multiple organs, including acute pneumonia with no evidence of bacterial infection, widespread cutaneous eruptions on trunk and lower limbs, mucosal ulcerations, myositis, diarrhea and colitis. Further complications included hepatic cytolysis, acute renal failure, pancreatitis, as well as complete heart block. Some of these injuries being suggestive of graft-versus-host disease, the patient was administered immunosuppressive therapy (mycophenolate, steroids and polyvalent immunoglobulins), but died shortly afterwards. Tissue biopsies revealed extensive lymphocytic infiltration (mostly CD3 + T cells) in skin, liver, and most peculiarly in muscles, including the myocardium. Massive lymphoid-histiocytic infiltration of muscle fibers was accompanied by acute necrotizing myositis and endomysial inflammation. Conclusions Multi-organ failure represents a rare but potentially fatal outcome of immune checkpoint blockade in patients receiving allogeneic stem cell grafts. Nivolumab may induce atypical immune-mediated tissue inflammation and damage, such as the extensive muscular polymyositis described here in a patient with Hodgkin lymphoma. Nivolumab might also worsen GVHD symptoms in the context of allogeneic stem cell transplantation. Irrespective of the actual pathological mechanisms, clinicians should be alerted to these fatal drug-related toxicities. Electronic supplementary material The online version of this article (10.1186/s40164-019-0132-2) contains supplementary material, which is available to authorized users.

Immune Checkpoint Inhibitor-Associated Cardiotoxicity: Current Understanding on Its Mechanism, Diagnosis and Management

“…cTnI, cardiac troponin I; cTnT, cardiac troponin T; BNP, brain natriuretic peptide; TTE, transthoracic echocardiogram; ECG, electrocardiogram; CMR, cardiovascular magnetic resonance; CK-MB, creatine kinase-myocardial band; NT-pro BNP, N-terminal pro-brain natriuretic peptide; CPK, creatine phosphokinase; CK, creatine kinase; CRP, C-reactive protein; AChR Ab, acetylcholine receptor antibody; EF, ejection fraction; LV, left ventricular; LVEF, left ventricular ejection fraction; PE, pericardial effusion; MR, mitral regurgitation; AR, aortic regurgitation; BVD, bi-ventricular dilatation; BAD, bi-atrial dilatation; LVD, left ventricle dilatation; RVD, right ventricle dilatation; TR, tricuspid regurgitation; LAFB, left anterior fascicular block; LBBB, left bundle branch block; RBBB, right bundle branch block; LVH, left ventricular hypertrophy; RAE, right atrial enlargement; LAE, left atrial enlargement; GBF, global biventricular failure; LGE, late gadolinium enhancement; EGE, early gadolinium enhancement AF, atrial fibrillation; PAP, pulmonary artery pressure; LVSF, left ventricular systolic function; RVSF, right ventricular systolic function; RHF, right heart failure; CHB, complete heart block; MI, myocardial infarction; MAB, multiple apical thrombi; CAB, complete atrioventricular block(a* = 9 (Norwood et al, 2017; Ganatra and Neilan, 2018; Katsume et al, 2018; Monge et al, 2018; Thibault et al, 2018; Agrawal et al, 2019; Charles et al, 2019; Sakai et al, 2019; Sharma et al, 2019). (b* = 7) (Ederhy et al, 2018; Frigeri et al, 2018; Matson et al, 2018; Agrawal et al, 2019; Charles et al, 2019; Fazel and Jedlowski, 2019; Khoury et al, 2019). (c* = 8) (Johnson et al, 2016a; Arangalage et al, 2017; Chen et al, 2018; Martin Huertas et al, 2019; Salem et al, 2019).…”

“…(a* = 9 (Norwood et al, 2017; Ganatra and Neilan, 2018; Katsume et al, 2018; Monge et al, 2018; Thibault et al, 2018; Agrawal et al, 2019; Charles et al, 2019; Sakai et al, 2019; Sharma et al, 2019).…”

“…(b* = 7) (Ederhy et al, 2018; Frigeri et al, 2018; Matson et al, 2018; Agrawal et al, 2019; Charles et al, 2019; Fazel and Jedlowski, 2019; Khoury et al, 2019).…”

Graft Versus Host Disease Associated with Immune Checkpoint Inhibitors: A Pharmacovigilance Study and Systematic Literature Review

“…In case reports extracted from literature (Singh et al, 2016;Boekstegers et al, 2017;Braun et al, 2017;Haverkos et al, 2017;Klobuch et al, 2017;Onizuka et al, 2017;Herbaux et al, 2018;Charles et al, 2019;Kim et al, 2019;Minson et al, 2019), when mentioned, ICI was indicated for disease relapse after allo-HSCT in 17/22, 77.3%. In one case of nivolumab-associated GVHD, biopsy showed PD-L1 expression in skin, liver and muscular tissues (those with active GVHD) (Charles et al, 2019).…”

Case Report: Fatal Multiorgan Failure and Heterochronous Pneumonitis Following Pembrolizumab Treatment in a Patient With Large-Cell Neuroendocrine Carcinoma of Lung

“…The incidence of myocarditis is ∼0.06% in nivolumab treatment and relatively higher with combination blockade (0.27%) of ipilimumab (Johnson et al, 2016). To our knowledge, fatal simultaneous multiorgan failure has rarely been reported (Charles et al, 2019;Hyun et al, 2019). Here, we reported a case where cardiac pacemaker and high-dose steroids successfully controlled the simultaneous fulminant myocarditis, myasthenia gravis crisis, and hepatic dysfunction, and delayed pneumonitis in a patient with lung LCNEC caused by pembrolizumab plus chemotherapy.…”