First use of ibrutinib for the treatment of post‐transplant central nervous system graft‐versus‐host disease

Chronic graft-versus-host disease (cGVHD) represents a serious complication of allogeneic haematopoietic stem cell transplant that occurs in 20%–80% of patients. cGVHD likely arises from interactions between different components of the adaptive immune system, including alloreactive dysregulated T and B cells, and the innate immune system, including macrophages, dendritic cells and neutrophils, which ultimately promote the formation of profibrotic lesions.1 On rare occasions, these profibrotic pathways may end up being activated in the central nervous system, resulting in central nervous system graft-versus-host disease (CNS-GVHD).2 CNS-GVHD is characterized by cerebrovascular damage and demyelination, causing diverse and non-specific symptoms such as motor and sensory deficits, weakness or aphasia. CNS-GVHD is difficult to distinguish from other chronic neurologic disorders and is considered a diagnosis of exclusion.2 Treating CNS-GVHD is an even greater challenge due to the rarity and paucity of data on its management. Corticosteroids and other immunosuppressive agents are most often used as first-line treatment for CNS-GVHD; however, the prognosis for patients with CNS-GHVD that is unresponsive to such therapies remains poor.2, 3 Here, we report a case of CNS-GVHD refractory to steroids, intravenous immunoglobulin (IVIG), plasmapheresis and rituximab, which was successfully treated with ibrutinib. A 74-year-old female with a history of chronic myeloid leukaemia refractory to numerous tyrosine kinase inhibitors underwent a reduced-intensity haploidentical allogeneic transplant with fludarabine, busulfan, cyclophosphamide and total body irradiation. GVHD prophylaxis consisted of post-transplant cyclophosphamide, tacrolimus and mycophenolate mofetil. Three months post-transplant, a bone marrow biopsy showed no evidence of CML and BCR-ABL p210 was undetectable on repeat qPCR. However, 11 months post-transplant, she presented to the oncology clinic with right face numbness and left-sided ataxia. On neurologic exam, she displayed decreased sensation to light touch and cold on her right face, dysmetria and dysdiadochokinesia of the left upper extremity, decreased vibration sense in her feet and difficulty with tandem gait. Testing of other cranial nerve, motor and sensory functions was unremarkable. Magnetic resonance imaging (MRI) of her brain demonstrated active demyelination of the subcortical white matter, precentral gyrus, midbrain, internal capsule and pons (Figure 1A,B). Lumbar puncture revealed borderline pleocytosis (8 white blood cells) with elevated myelin basic protein (20.7 ng/mL) and negative oligoclonal bands. Infectious workup (including meningitis/encephalitis PCR panel, cerebrospinal fluid (CSF) culture and next generation sequencing pathogen testing) were negative. Haematopathological evaluation of CSF revealed no myeloblasts, and flow cytometry revealed no monotypic myeloid population. Serum myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies were not detected. As the findings did not support an aetiology for her neurologic condition, she was diagnosed with post-transplant CNS-GVHD. She was started on a short course of methylprednisolone (1000 mg × 3 days), which resulted in partial symptom reduction. However, within a month, her balance and weakness problems recurred with a repeat brain MRI confirming ongoing demyelination. Over the next month, additional treatment attempts included 5 rounds of plasmapheresis followed by IVIG, as well as rituximab (1000 mg × 2 days) plus methylprednisolone (1000 mg × 5 days), all of which failed to prevent progressive demyelination on MRI (Figure 1C). After being tapered off steroids for 2 months, she had worsening eye, mouth and skin cGVHD. She was started on ibrutinib (420 mg daily) for steroid refractory cGVHD with the involvement of the CNS. However, the dose was lowered due to patient-reported side effects, including stiff joints and ecchymosis. Within 2 months, her symptoms improved, and follow-up brain MRI demonstrated no further active demyelination. She has been on ibrutinib for over a year (maintaining a stable dose of 280 mg daily for the last 3 months) with an ongoing response both clinically and radiographically (Figure 1A–C). The majority of case studies on CNS-GVHD to date have shown that the administration of corticosteroids alone can effectively and quickly improve neurological symptoms.4-6 However, it remains unclear how to best manage CNS-GVHD that is refractory to front-line immunosuppressive therapies. To our knowledge, our case represents the first-ever report of using ibrutinib to treat CNS-GVHD. In a review of 34 patients with CNS-GVHD who received immunosuppressive therapy, Ruggiu et al.3 highlight other treatments besides corticosteroids that have been administered, including plasmapheresis, IVIG, cyclophosphamide, mycophenolic acid, methotrexate, etoposide and calcineurin inhibitors; these attempts were associated with varying degrees of response. Our patient had a significant response to ibrutinib. Therefore, we believe ibrutinib is another important salvage therapy option available to patients with CNS-GVHD. Our patient was unresponsive to traditional means of treating cGVHD. For multiple reasons, ibrutinib, a Bruton tyrosine kinase inhibitor (BTKi), was chosen as an alternative therapy. First, ibrutinib achieves significant CNS penetrance, with one preclinical study suggesting that it can cross the blood–brain barrier in less than 0.3 h.7 Furthermore, it has the unique ability to inhibit both BTK in B cells and interleukin-2–inducible T-cell kinase in T cells. It has a wide range of applications in immune-mediated disorders: it is FDA-approved for use in steroid refractory cGVHD and also has activity in primary CNS lymphoma.8, 9 BTKi's are now being studied in multiple sclerosis, another chronic neuroinflammatory disorder, for their possible remyelination effect.10 Ibrutinib possesses a combination of qualities that are ideal for treating a CNS demyelinating disease, as it can rapidly enter the CNS, systemically temper an overactive immune response and potentially even reverse neuronal damage. The pathogenesis of chronic CNS-GVHD is still being elucidated. A leading hypothesis posits that chronic CNS-GHVD onset stems from sequential CNS infiltration of donor CD8+ T cells, donor CD4+ T cells and donor bone marrow–derived macrophages (BMDMs). Due to this activation of lymphocytes in the brain, IFN-γ is upregulated, which increases major histocompatibility complex II expression on BMDMs, promoting synaptic attack.11 One reason why ibrutinib may be particularly beneficial in CNS-GVHD is its capacity to modulate macrophage function, which also relies on BTK pathways. In fact, a separate study was able to show that ibrutinib limited the phagocytosis of rituximab-coated chronic lymphocytic leukaemia cells by macrophages.12 It is feasible that ibrutinib could exert a similar effect on host BMDMs to alleviate neuroinflammation in CNS-GVHD as well. Overall, further basic research studies to elucidate the actual therapeutic mechanism of ibrutinib and prospective clinical studies to delineate the role of BTKi's in treating rare cases of steroid refractory CNS-GVHD are warranted. Aaron Trando designed and wrote the first draft of the paper, interpreted the results, organized the figure and compiled the reference list. Anastasie Dunn-Pirio interpreted the results, gathered images for the figure and provided clinical care for the patient described. Divya Koura interpreted the results and edited the paper. Aaron M. Goodman interpreted the results, edited the paper and provided clinical care for the patient described. All authors were involved in the revision of the manuscript and approved the final version. The authors did not receive funding from any organization for the submitted work. The authors declare no competing financial interests. This case report was conducted in accordance with the Declaration of Helsinki. The collection and evaluation of all protected health information were performed in a Health Insurance Portability and Accountability Act (HIPAA)-compliant manner. Written informed consent was obtained from the patient, including permission for the publication of images. No material created by others, including images and text, was used.