Targeting plasma cells with daratumumab aids in the treatment of post-transplant autoimmune-like hepatitis

Rebecca Epperly1, Teresa Santiago2, Cara E. Morin3, Kurt Patton4

Abstract

Antibody-mediated autoimmune-like hepatitis is a rare and challenging occurrence after hematopoietic cell transplant (HCT). We present the case of a 16-year-old male patient with Ph+ ALL who underwent matched sibling donor HCT and developed autoimmune-like hepatitis after receiving ponatinib for post-HCT maintenance, evidenced by marked plasma cell infiltrate on liver biopsy. He was successfully treated with steroids and daratumumab, an anti-CD38-monoclonal antibody. The dramatic response in this patient warrants expanded investigation of daratumumab for plasma cell-mediated disorders post-HCT. It further highlights that identifying mechanisms of immune-mediated injury can allow for directed therapy and limit exposure to broad immune suppression.

KEYWORDS
autoimmune hepatitis, daratumumab, hematopoietic cell transplant

1 INTRODUCTION

Hepatic complications frequently occur after hematopoietic cell transplant (HCT), and the etiology is often complex and multifactorial. Among these, classic hepatic graft versus host disease (GVHD) mediated by an allogeneic T-cell response has been well described.1 However, other immune-mediated complications, including antibody-mediated autoimmune-like hepatitis, are exceedingly rare.2 Autoimmune-like hepatitis is defined by portal eosinophilia steroids, though given the rarity of this condition, there is no established standard treatment.5–7 CD38 is predominantly expressed on plasma cells and at lower levels on other lymphoid and myeloid subsets.8 Daratumumab, a CD38– targeted monoclonal antibody, was initially developed for use in multiple myeloma,9–11 but it has also been effective in other plasma cell–mediated disorders as well. In the post-HCT setting, the use of daratumumab has been described in pediatric and adult patients with delayed red blood cell engraftment after HCT, associated with major ABO mismatch between donor and the recipient12,13 and for autoimmune cytopenias.14–17 We report the novel use of daratumumab to treat post-HCT autoimmune hepatitis in a pediatric patient after HCT for relapsed B cell acute lymphoblastic leukemia (B-ALL).

2 RESULTS: CASE DESCRIPTION

A 16-year-old male patient with a history of relapsed BCR-ABL fusionpositive (Philadelphia, Ph+) B-ALL underwent matched sibling donor HCT. He received a myeloablative conditioning regimen with total body irradiation (12 Gy) and cyclophosphamide (120 mg/kg cumulative dose) followed by an unmanipulated bone marrow graft. He had no evidence of acute GVHD, and GVHD prophylaxis with cyclosporine was tapered and discontinued on day +85 after HCT. Due to history of BCR-ABL fusion-positive ALL, he was started on ponatinib maintenance therapy on day +92. One month after initiation of ponatinib, he presented with acute liver injury with an abrupt increase in serum bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and alkaline phosphatase (ALP). Because of the temporal relationship with the initiation of ponatinib and concern that it may be causative, ponatinib was discontinued. A liver biopsy showed acute lobular hepatitis with hepatocellular dropout, focal bridging necrosis, and marked lobular regeneration (Figure 1A-B). There was a prominent ductular reaction and inflammatory infiltrate containing many plasma cells and portal eosinophils, most consistent with a diagnosis of drug-induced autoimmune hepatitis (Figure 1C-E).3 There was a brisk portal and lobular T-cell infiltrate accompanying the polyclonal plasmacellular inflammation (Supporting Information Figure S1). Immunoglobulin G (IgG) level increased in parallel with AST/ALT and peaked at 4112 mg/deciliter (dL) (upper limit of normal (ULN) 2190 mg/dL) (Figure 2A), predominantly IgG subclass 1, in addition to increased gamma globulin by serum protein electrophoresis. No specific autoantibodies were identified, and there was no increase in plasma cells in bone marrow specimen obtained concurrently. No acute infectious etiology was identified and magnetic resonance cholangiopancreatography (MRCP) showed no parenchymal signal abnormality, structural deformity, or biliary obstruction (Figure 2B-D).
He required supportive care for decreased hepatic synthetic function and had peak INR of 1.7, which did not completely correct with vitamin K. Given the rapid increase in AST (peak 2670 U/L, ULN 40 U/L) and ALT (peak 1098 U/L, ULN 40 U/L) 7 weeks after discontinuation of ponatinib (Figure 2A) with plasma cell infiltrate, plasma cell–directed therapy with daratumumab was initiated, along with systemic steroids. He received five weekly doses of daratumumab (16 mg/kg/dose), which were well tolerated. He had a dramatic decline in AST and ALT, followed by a decrease in bilirubin and improvement in his hepatic synthetic function. Prednisone was initiated at 60 mg daily (usual adult dosing) along with daratumumab and weaned with improvement in liver enzymes to a stable low dose of 5 mg daily (< 0.2 mg/kg) within 4 weeks, and was continued for a total of three months of initial steroid therapy. To preserve graft function in the post-HCT setting, additional maintenance therapies with potentially myelosuppressive effects were avoided.
He had a waxing and waning course of hepatitis for the first six months after initial therapy. This was accompanied by increased liver stiffness on ultrasound elastography, which can indicate inflammation in the acute setting and fibrosis in the chronic setting.18,19 MRCP showed narrowing of the common hepatic bile duct and dilation of the intrahepatic bile ducts. The liver demonstrated parenchymal scarring, hypertrophy of the caudate lobe, and ascites (Figure 2C-E). Follow-up liver biopsy showed increased fibrosis and reduction in plasma cell infiltrate with prominent lobular regeneration, indicating ongoing healing after initial acute injury (Figure 1F-J). Seven months after initial diagnosis, due to increase in AST/ALT (Figure 2A), a follow-up liver biopsy was obtained showing ongoing hepatocellular injury but with decreased fibrosis and overall improved liver architecture (Figure 1K-O). Prednisone was resumed at 20 mg daily, which resulted in normalization of liver enzymes, and then weaned to 5 mg daily and continued for a total of three months of additional steroid therapy. IgG levels returned to normal range with treatment, along with IgA and IgM. He did not require intravenous immunoglobulin supplementation and maintained CD19+ B cell count within normal range. The patient is now 17 months from HCT and has discontinued prednisone. He remains in complete remission, with negative minimal residual disease by flow cytometry and no detectable BCR-ABL fusion transcript. He has robust graft function with 100% donor chimerism.

3 DISCUSSION

Although antibody-mediated autoimmune-like hepatitis after HCT is rare, recognition of this unique mechanism of immune-mediated injury can allow for directed therapy, potentially sparing effects of broader immune suppression. Delineation of the etiology of hepatic dysfunction post-HCT is challenging, as an array of factors, including medications, sinusoidal obstruction syndrome/veno-occlusive disease, infections, and GVHD, can contribute.1 In this case, biopsy evidence of ductular reaction with plasma cell infiltrate and elevated gamma globulin were consistent with autoimmune hepatitis rather than classic hepatic GVHD.3,7 Though CD3+ T cells were detected, the predominance of plasma cells in the liver biopsy specimen (as evidenced by kappa and lambda light chains in the in situ hybridization) further supports the diagnosis of a plasma cell–driven process, rather than GVHD. Although BCR-ABL fusion has rarely been reported in myeloma, the lack of detectable bone marrow BCR-ABL transcript and absence of kappa/lambda light chain restriction make a malignant plasma cell proliferation unlikely in this case.20
In general pediatric patients with autoimmune hepatitis, treatment typically entails steroids, which are continued for several months to years, along with maintenance agents such as azathioprine or 6mercaptopurine.4 In refractory patients, additional immune suppression or liver transplant may be required.4 In the rare reported cases of post-HCT autoimmune hepatitis, treatment regimens had included prolonged systemic steroids with or without the addition of ursodiol or azathioprine.5–7 Considering implications for the integrity of the bone marrow graft and risk of infection in patients post-HCT, the incorporation of targeted immune therapies that enhance initial response and limit overall immune suppression would be of benefit. In our patient who continued to have worsening of acute hepatitis despite removing the potentially inciting agent ponatinib, the addition of daratumumab to generally accepted steroid therapy resulted in a rapid improvement in the laboratory and functional markers of liver function. Though the contribution of daratumumab as a single agent cannot be ascertained, this patient was able to wean systemic steroid dose quickly and now has stable hepatic function without any additional immune suppression. Overall, his cumulative steroid exposure was less than would have been expected for post-HCT autoimmune hepatitis.
Daratumumab was well tolerated in our patient post-HCT, as has been observed in the emerging experience with daratumumab for autoimmune cytopenias in this population.14,15,17 Beyond hematologic conditions, treatment with daratumumab has shown a reduction in autoantibodies21 and is being investigated for other autoimmune conditions.22,23 Considerations when administering daratumumab include infusion reaction, potential bone marrow suppression, viral reactivation, and interference with serologic blood bank testing.11,24 The dramatic response to and tolerability of daratumumab reported in this single patient experience of autoimmune-like hepatitis post-HCT warrants further investigation into the expanded role of targeted immune therapies for post-HCT autoimmune conditions.

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