Case report of neurotoxicity with blinatumomab and concurrent intrathecal chemotherapy in second relapse of acute lymphoblastic leukemia with central nervous system disease

Introduction

Blinatumomab is a first-in-class bispecific T-cell engager (BiTE) that is approved for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). Blinatumomab binds to the CD3 antigen on T-cells and the CD19 antigen on B-cells, ultimately resulting in a cytotoxic T-cell response against malignant B-cells. Blinatumomab is given as a continuous infusion in 28-day cycles, with two weeks in between each cycle. The dose starts with 9 µg/day in the first seven days of the first cycle, but is escalated to 28 µg/day for days 8 to 28 of the first cycle and days 1 to 28 of all future cycles. Although blinatumomab has shown promising efficacy, it can cause life-threatening cytokine release syndrome and neurologic toxicities, both of which are included as black box warnings in the package insert. ¹ Cytokine release syndrome usually occurs within 48 h of blinatumomab administration and is characterized by flu-like symptoms, including pyrexia, chills, and hypotension and elevated cytokine levels. Blinatumomab-induced neurotoxicity usually occurs within 14 days of blinatumomab administration and can manifest as encephalopathy, seizures, altered mental status, and balance disorders.

In 2014, blinatumomab was granted breakthrough therapy status and accelerated approval by the U.S. Food and Drug Administration (FDA) for the treatment of Philadelphia chromosome-negative relapsed or refractory B-cell ALL based on a multicenter, single-arm, open-label phase II trial with 189 patients that demonstrated a 43% complete remission rate and a median duration of response of 6.9 months. Dose-limiting neurological toxicities occurred in 23% of the patients, with the most common neurological events being tremor, dizziness, confusion, and encephalopathy. ² In 2017, the FDA expanded the indication of blinatumomab to include relapsed or refractory B-cell ALL, regardless of Philadelphia chromosome status based on a multicenter, single-arm, open-label phase II trial with 45 Philadelphia chromosome-positive patients who progressed on tyrosine kinase inhibitor therapy. The complete remission rate was 36%, and median duration of response was 6.7 months. The rate of dose-limiting neurological toxicity did not exceed that of previous clinical studies (3%). ³ The mechanism of this neurotoxicity is unclear but has been attributed to the local release of inflammatory cytokines at the blood brain barrier by blinatumomab-activated T-cells. ⁴

Intrathecal (IT) therapy is usually administered to patients with ALL for prophylaxis and/or treatment of central nervous system (CNS) involvement because the CNS is a common sanctuary site in adult ALL patients, and most systemic chemotherapies do not penetrate the blood brain barrier. However, the direct instillation of chemotherapy into the cerebrospinal fluid can also increase the risk of CNS toxicities, e.g. chemical arachnoiditis. ⁵ There is a theoretical risk for additive neurotoxicity when administering IT chemotherapy with other neurotoxic agents simultaneously. There are no data in the literature that has explored the additive risk of neurotoxicity with concurrent use of blinatumomab and IT chemotherapy. This is the first published case report, to our knowledge, of a patient developing severe neurotoxicity from the concurrent administration of blinatumomab and IT chemotherapy.

Case presentation

A 26-year-old male was initially diagnosed at age three with pre-B cell ALL in 1993 and completed three years of chemotherapy. Treatment was complicated by a CNS event (CNS bleed versus thrombotic event) and seizures. Following completion of his chemotherapy, he continued to have seizures, but did have a prolonged seizure-free period at one point. In 2012, he suffered an isolated CNS relapse with blasts in the cerebrospinal fluid (CSF), which was the first relapse, 19 years after the initial diagnosis. The frequency and intensity of his seizures increased approximately six months prior to his first relapse. He completed the AALL0232 regimen in 2015 with multiple modifications due to chemotherapy-induced pancytopenia. In 2016, he was diagnosed with second relapse of pre-B cell ALL with CNS disease after being evaluated for severe right leg pain. His initial labs after second relapse included: WBC 15.6 × 10⁹/L, platelets 131 × 10⁹/L, serum creatinine 0.74 mg/dL, total bilirubin 1.0 mg/dL, AST 46 units/L, and ALT 111 units/L. CSF showed protein 251 mg/dL and WBC 737 × 10⁶/L (98% blasts) with 0.3% minimal residual disease (MRD) in the bone marrow biopsy. Brain magnetic resonance imaging (MRI) showed evidence for significant leptomeningeal disease involving the cerebrum and cerebellum, increased cerebral atrophy, and reduction in cystic encephalomalacia of the right temporal lobe. The patient has a history of refractory seizures which were being treated with a combination of clonazepam, lacosamide, levetiracetam, and lorazepam (for breakthrough seizures).

The patient initially received three doses of triple IT chemotherapy with cytarabine, methotrexate, and hydrocortisone to treat second CNS relapse of ALL. Subsequent CSF showed an improvement in WBC to 38 × 10⁶/L (50% blasts) and protein to 104 mg/dL. One month later, he was admitted for blinatumomab administration and Ommaya reservoir placement to allow for ease of frequent intrathecal chemotherapy administration given his significant leptomeningeal disease involving the cerebrum and cerebellum. He received seven days of blinatumomab 9 µg daily, and blinatumomab was successfully escalated to 28 µg daily on day 8. He also received triple IT chemotherapy through his Ommaya reservoir with midazolam and propofol sedation on days 4, 8, and 11. CSF on day 11 showed further improvement in WBC to <1 × 10⁶/L (3% blasts) and protein to 27 mg/dL. On day 12, he developed CNS toxicity consisting of delayed speech, confusion, disorientation, and mild hypoxia, and blinatumomab was discontinued. In the following 24 h, he became non-verbal with significant non-responsiveness and urinary/fecal incontinence. Computed tomography (CT) of the brain showed increased densities in the brain that were possibly related to leptomeningeal leukemic infiltrates with subarachnoid hemorrhage. Magnetic resonance venography of the brain was performed to rule out cerebral venous thrombosis but because the patient refused to complete the study, the venogram only showed that his sagittal sinus appeared to be patent. MRI of the circle of Willis, which supplies blood to the brain and its surroundings, was unremarkable.

Following blinatumomab neurologic toxicity, goal of treatment was changed to palliative care because this was second CNS relapse of the patient’s ALL and he had multiple tolerability issues with systemic chemotherapy in the past. He was started and continued for a month on dexamethasone 8 mg intravenously every 8 h which was slowly tapered off to 8 mg twice daily and then to 4 mg twice daily for two days before being discontinued. In the following weeks, his cognitive status improved slowly with minimal recovery to baseline. He continued to have altered mental status, seizures, incontinence, and developed diffuse weakness from the long duration of bed rest. His antiepileptic regimen was maintained with clonazepam, lacosamide, levetiracetam, and valproic acid was also added during this hospitalization for the increased seizure activity. His oral intake decreased due to neurologic depression with failure of multiple swallow evaluations, so nasogastric tube was placed for nutritional support. Follow-up CSF showed disease remission with no evidence of WBC or blasts and protein 13 mg/dL. Electroencephalogram showed moderate diffuse encephalopathy with seizure activity, so valproic acid was added to the patient’s anti-epileptic regimen. His hospitalization was also complicated with febrile neutropenia, aspiration pneumonia, oral thrush, and significant bradycardia.

The patient was discharged from the hospital and completed rehabilitation therapy at an outside institution. Within the next six months, his neurologic status significantly improved and he became capable of performing all of his baseline activities without limitation. His anti-epileptic regimen for his chronic complex convulsive disorder was managed and adjusted by an outside neurologist. Repeat CSF testing showed remission until the patient presented in 2017 with fever and pancytopenia: WBC 2.4 × 10⁹/L (37% blasts), absolute neutrophil count (ANC) 0.3 × 10⁹/L, platelets 35 × 10⁹/L, serum creatinine 0.79 mg/dL, and liver function within normal limits. Unfortunately, bone marrow biopsy showed relapsed B-cell leukemia with 70% blasts for which he was started on re-induction chemotherapy with daily 6-mercaptopurine, weekly methotrexate, monthly vincristine, and prednisone. The patient ultimately passed away after being on three months of chemotherapy.

Discussion

This case is significant because it is the first documented occurrence of additive neurotoxicity with blinatumomab and IT chemotherapy in the literature. Outcomes are generally poor in adult patients with relapsed ALL, with one analysis of data from the PETHEMA trials showing a median survival of 4.5 months and a 5-year overall survival of 10%. ⁶ This patient’s ALL had already relapsed twice as an adult before he had received blinatumomab. In addition, his second relapse occurred with CNS involvement less than a year from his first relapse, and he had experienced multiple tolerability issues with systemic chemotherapy during treatment for his initial relapse. Before even considering treatment, his disease history already limited his treatment options and likely placed him in a high-risk category with a poor long-term prognosis.

Blinatumomab was deemed to be the optimal treatment option for this patient given his failure and intolerance of systemic chemotherapy, but he also had to receive IT chemotherapy for his CNS disease. Because of the imperative need for both therapies and the fact that blinatumomab is a continuous infusion, it was impossible to avoid concurrent administration of the two. The package insert does not provide any recommendations regarding when to administer IT chemotherapy relative to blinatumomab administration. Clinical trials also do not address this issue as IT chemotherapy was administered either before or following blinatumomab administration.^2,5 One randomized, phase 3 blinatumomab trial did, however, allow IT chemotherapy to be administered per institutional or national guidelines, but the details are unknown, and the study did not report higher rates of neurotoxicity compared to previous studies. ⁷ In addition, all blinatumomab pivotal trials excluded patients with active leukemia in the CNS, so data and guidance related to the use of blinatumomab in relapsed ALL with CNS involvement are limited. Patients with other active CNS conditions were also excluded, possibly because it is unclear how pre-existing CNS pathologies would contribute to blinatumomab-induced neurotoxicity.^2,3,7 It is difficult to analyze what caused the neurotoxicity in this specific patient due to the pre-existing neurological deficits, presence of complex seizure disorder, and the unusually long interval from initial diagnosis and time of his first relapse (19 years). This patient had a history of seizures and continued to have seizures during his treatment, further complicating the clinical picture and making it almost impossible to extrapolate the data from the blinatumomab trials to treat his relapsed ALL. The package insert does indicate that cranial MRI changes showing leukoencephalopathy has been observed in blinatumomab patients who have received IT chemotherapy in the past, but the clinical significance is unknown. ¹

Because the CNS is a common sanctuary site in ALL, IT chemotherapy is a standard of care for patients with ALL who are at risk for CNS relapse or with active CNS disease. ⁸ One strategy to avoid the additive toxicity of blinatumomab with IT chemotherapy is to separate their administration by 24 h, which is what was done in most clinical trials. That was not possible in this patient given that he had active CNS disease. There are no data in the literature that quantifies the capacity of blinatumomab to enter into the CNS. Blinatumomab is not expected to cross the blood-brain barrier because it is a large monoclonal antibody. However, the ability to cause neurologic toxicity suggests that blinatumomab may penetrate into the CNS and exert its clinical effects, albeit to a limited degree only. One pre-clinical study showed that treatment with a BiTE antibody targeting an epidermal growth factor receptor mutation in mice with glioblastoma resulted in complete cure rates of up to 75% (p < 0.05). ⁹ Intrathecal chemotherapy, especially methotrexate, can trigger an inflammation of the meninges within days of administration, resulting in an acute chemical arachnoiditis. This arachnoiditis is usually characterized by headache, neck rigidity, back pain, fever, vomiting, and CSF pleocytosis. The mechanism is unclear but may be related to a methotrexate-induced imbalance of folate pathways in the CNS. Intrathecal chemotherapy usually includes hydrocortisone to augment the elimination of leukemic cells and minimize the incidence of arachnoiditis. ¹⁰ The inflammatory CNS effects of blinatumomab and intrathecal chemotherapy may partially explain the additive neurotoxicity caused by the concurrent administration of both agents.

Neurologic toxicity consisting of altered mental status, speech impairment, incontinence, and diffuse weakness developed in a patient who received concurrent blinatumomab and IT chemotherapy for second relapse of ALL with CNS disease. Although CNS disease was undetectable, and the patient eventually recovered, this case suggests that additive neurotoxicity can occur when blinatumomab is given concurrently with IT chemotherapy. We recommend that this combination should be avoided when possible. However, there may be clinical situations similar to this one in which it is not possible to separate administration of the blinatumomab with IT chemotherapy. Further research and studies are needed to evaluate the necessity to control aggressive disease against the potential risk for additive neurotoxicity.