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Abstract
Bleeding diathesis is an uncommon side effect of ibrutinib use and is seen in less than 5% of the population. We describe a case of an elderly woman with ibrutinib-induced spontaneous major extradural haematoma presenting as acute compressive myelopathy. She is a known case of splenic marginal zone lymphoma with multiple extramedullary relapses and presented to the emergency department with acute-onset low backache, followed by urinary retention. MRI revealed extradural haemorrhage. After possible evaluation, she was diagnosed with ibrutinib-induced extradural haematoma.
- Haematology (drugs and medicines)
- Spinal cord
- Chemotherapy
- Unwanted effects / adverse reactions
- Tyrosine Kinase Inhibitor
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- Haematology (drugs and medicines)
- Spinal cord
- Chemotherapy
- Unwanted effects / adverse reactions
- Tyrosine Kinase Inhibitor
Background
Ibrutinib is an orally available revolutionary bruton kinase inhibitor widely used for the treatment of various B-cell malignancies such as mantle cell lymphoma, refractory/relapsed chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma and Waldenstrom’s macroglobulinaemia.1 Major bleeding diathesis following ibrutinib is seen in 4%–8% of the population when followed for a year.2–4 Fatal bleeding like intracranial bleeding is extremely rare and is seen in less than 1% of the population.5 Subdural haematoma is the most common form of intracranial bleeding.6 We report a case of concomitant spontaneous intraspinal-spinal extradural and subarachnoid haemorrhage (SAH) in an elderly woman on ibrutinib for marginal zone lymphoma (MZL). This case report can create increased awareness about the undesirable effects of the drug, leading to careful patient monitoring. Treating physicians will also be prompted to exercise a high level of suspicion at the earliest signs of spinal subdural haematoma.
Case presentation
This is a woman in her 80s with hypertension, hypothyroidism, immune thrombocytopaenia (ITP) (in remission), recently excised left forearm melanoma, and splenic MZL on ibrutinib therapy who presented to our emergency department (ED) with acute-onset bilateral lower limb weakness. The patient stated that she developed sudden severe lower back pain that progressed to weakness in both lower limbs and inability to urinate. She denied any tingling, numbness, bowel, or bladder incontinence, or any recent trauma. On examination, power was 1/5 with areflexia in both lower limbs. Power was normal at 5/5 in both upper limbs. Bowel and bladder sphincter tone were normal. Sensory examinations like fine touch, crude touch and two point discrimination were normal. She was diagnosed with MZL in 2010 and was managed with rituximab for six cycles. She had extramedullary relapses, which were managed with only rituximab subsequently. Given multiple extramedullary relapses, she was started on ibrutinib maintenance therapy after a 6-month relapse-free interval. She was on an oral ibrutinib tablet 560 mg once daily. After a year of being on ibrutinib, she presented with the above symptoms (figure 1).
Timeline of the index patient showing extramedullary relapses since diagnosis. (Drawn by NV).
Investigations
Blood investigations revealed normal complete blood counts and a normal platelet count (258 x 10∧9/L). Renal function tests and liver function tests were normal. Serum albumin was 3.9 g/dL and total protein was 6 g/dL. Given low back pain with red flag symptoms, an urgent MRI of the thoracolumbar spine was done which revealed T5–L1 extradural bleed with cord compression (figure 2A,B). Coagulation studies like international normalised ratio was 1.2 and activated partial thromboplastin time was 28 s.
(A) T1-weighted sagittal MRI showing linear hyperintense signal within the spinal canal. (B) T2-weighted sagittal MRI showing lobular lesion in the dorsal spine (white pointed arrow) extending from T5 to L1 pointing to extradural haematoma.
Differential diagnosis
Possible aetiologies considered included haemorrhagic metastasis due to melanoma (given a history of melanoma) and spinal cord arterio-venous malformation. The patient underwent urgent decompressive laminectomy with haematoma evacuation. The patient had no prior history of spinal procedures including exploratory lumbar puncture thus ruling out iatrogenic aetiology. Histopathological evaluation showed haematoma with no evidence of malignancy. The day after surgery, the patient developed a new-onset altered sensorium. A CT scan of the head showed multifocal acute SAH (figure 3A,B). The patient’s son recalled that the patient had excess bleeding after the melanoma excision as well. Because of multiple episodes of bleeding, an underlying bleeding disorder was suspected; however, systemic studies such as platelet count, coagulation studies, von Willebrand factor (VWF) function and coagulation factor levels were normal. Metastatic melanoma was ruled out by histopathology. Spinal cord arterio-venous malformations were ruled out with neuroimaging. After a complete negative workup, she was diagnosed with ibrutinib-induced major bleeding diathesis. After discussion with the family, the decision was made to stop ibrutinib, as her MZL was in remission.
(A) Axial non-contrast CT scan head showing subarachnoid haemorrhage. (B) Axial CT scan head done after 2 days showing resolution of the previous blood products in the subarachnoid space.
Treatment
She underwent urgent decompressive laminectomy with haematoma evacuation followed by intensive physical therapy at subacute rehabilitation centre.
Outcome and follow-up
The patient was transitioned to subacute rehabilitation, and during follow-up, she did not have any new recurrence of bleeding diathesis. She is undergoing physical therapy and occupational therapy in the rehabilitation.
Discussion
Bruton tyrosine kinase-mediated intracellular mechanism is sought to be essential for B-cell maturation and production of antibodies.7 This led to the creation of blocking agents which thereby halted the B cell maturation. The first of its kind to gain approval by the FDA (Federal Drug Administration) was ibrutinib in 2009.8 After its approval, there has been widespread use of this molecule. As its use increased so has its adverse effect profile. Two important side effects of Ibrutinib are (1) increased risk of atrial fibrillation and (2) bleeding diathesis. Interestingly, bleeding diathesis though common with ibrutinib grade 3 and grade 4 bleeding is extremely rare and limited to case reports and trials. In an open-label phase 2 trial of 111 patients with a median follow-up of 26.7 months, only two patients had subdural bleeding requiring treatment discontinuation.2 SAH and intraspinal bleeding as in our case are further rare entities that require quick recognition and prompt action. It is well established that the geriatric population is at an increased risk of bleeding. This is mainly due to changes associated with ageing, or secondary to another underlying cause which include, but are not limited to thrombocytopenia, malignancy, drug-induced bleeding, acquired VWF disease, acquired haemophilia and renal dysfunction. Thrombocytopaenia can be caused by ITP, drug-induced, hypersplenism, disseminated intravascular coagulation, malignancy and aplastic anaemia. The patient in our case has immune thrombocytopaenic purpura, in addition to her old age, which predisposed her to episodes of spinal epidural haematoma and SAH.9
Ibrutinib-induced bleeding diathesis is thought to be due to platelet dysfunction occurring through multiple mechanisms in all phases of platelet-mediated clotting, like activation, adhesion, aggregation and clot retraction. BTK (Bruton's Tyrosine Kinase) inhibitors prevent factor VI-mediated platelet activation and release of alpha granules. Additionally, they also decrease VWF activation and prevent platelet adhesion by inhibiting GP-Ib causing destabilisation of the clot (figure 4). Finally, these agents also prevent clot retraction.10–13 Because of their multiple mechanisms, no single diagnostic test will possibly be used to predict bleeding diathesis underscoring the utility of the commonly available diagnostic tests. Hence, the idea of testing platelet sensitivity was proposed before the initiation of ibrutinib though is not widely practised clinically.12 As of now, there are no recommended tests to diagnose patients with ibrutinib-induced bleeding and it is mainly a diagnosis of exclusion. However, patients undergoing ibrutinib treatment should be monitored for adverse effects, including signs and symptoms of bleeding.
Proposed mechanism of how ibrutinib causes platelet dysfunction through multiple mechanisms. (Drawn using BioRender by NV and FR).
Immune-mediated cytopenia and the use of ibrutinib go hand-in-hand, especially in patients with CLL. Though autoimmune haemolytic anaemia is most commonly seen in 10% of CLL patients, clinically significant ITP accounts for 2% of patients.14–16 There has been significant reluctance among haematologists to use ibrutinib, especially when baseline platelet counts are critically low due to the heightened risk of bleeding even after the results from the RESONATE trial regarding the safety of this molecule have matured enough.17 However, a recent study showed promising results in the use of ibrutinib for treating autoimmune cytopenias (AIC) among patients with CLL. A retrospective cohort study analysed 193 CLL patients, 29 with AIC, who were started on ibrutinib. 12 patients needed AIC treatment before the initiation of ibrutinib. Of the 193 patients, 1 in 17 patients developed acute AIC. Out of the 12 patients who were treated for AIC, Two-thirds of the patients were able to discontinue their AIC treatment or decrease the treatment dose. These data show promising results in the treatment of AIC secondary to CLL, however, worsening of the AIC can still happen.18 Indeed, in a phase 2 trial with a specific BTK inhibitor that acts only on B-cells and macrophages, rilzabrutinib had positive effects in patients with ITP without affecting haemostasis.13 Lastly, a study conducted on two patients with CLL and mantle cell lymphoma with life-threatening-ibrutinib-induced bleeding showed that platelet transfusion led to the cessation of bleeding despite having a normal or near normal platelet count. Therefore, this study suggested that platelet transfusion can be one way to manage ibrutinib-induced bleeding.19 In summary, although more research is needed to determine the prevention and management of ibrutinib-induced bleeding, there are multiple ways of reducing the risk of ibrutinib-induced immune cytopenia for patients with B cell malignancies.
Neurological complications like compressive myelopathy are extremely rare and under-reported complications with the use of ibrutinib. Prompt identification and timely discontinuation of therapy are crucial. Currently, there are no specific tests used to diagnose ibrutinib-induced bleeding. As in our patient’s case, we came to the diagnosis of ibrutinib-induced bleeding based on excluding all other potential causes of bleeding. Will ibrutinib increase the risk of bleeding in patients with chronic ITP despite having a normal platelet count is a question of future research. Consideration for prophylactic platelet transfusion should be done on a case-to-case basis after expert consultation.
Learning points
While ibrutinib is an effective treatment for various B-cell malignancies, it can lead to major bleeding diathesis, with significant complications.
Although fatal bleeding, such as intracranial bleeding, is extremely rare (less than 1%), subdural haematoma and other intracranial haemorrhages can occur and require prompt recognition and management.
Geriatric patients and patients with underlying conditions like immune thrombocytopaenic purpura are at increased risk of bleeding.
Ethics statements
Patient consent for publication
References
Footnotes
Contributors The following authors were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content: NV and FR. The following authors gave final approval of the manuscript: SKY and GK.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.