Introduction
Adult patients with B-precursor acute lymphoblastic leukemia (ALL) often achieve complete remissions (CRs) with conventional first-line treatment [
1‐
3]. However, relapse rates are high despite allogeneic hematopoietic stem cell transplantation (alloHSCT) in high-risk patients [
1]. Those who relapse, or are refractory to initial treatment, have a poor prognosis, with the likelihood of achieving a subsequent CR declining with each relapse [
2,
3]. Novel treatment strategies employing immunotherapy agents are one means of addressing medical need for these patients. Blinatumomab is a 54-kDa bispecific T cell engager (BiTE®) antibody construct comprising CD19- and CD3-binding regions that link CD3-positive T lymphocytes with CD19-positive B cells, resulting in the serial lysis of target cells [
4]. In a phase 2 study of blinatumomab (
N = 189), 43% of adult patients with relapsed/refractory ALL achieved CR or CR with partial hematologic recovery of peripheral blood cells (CRh), allowing 40% of patients in remission to undergo alloHSCT [
5]. In a recent randomized phase 3 study, blinatumomab significantly prolonged overall survival of adult patients with relapsed/refractory ALL compared with existing chemotherapy [
6].
Blinatumomab treatment is associated with certain adverse events (AEs), such as pyrexia, fatigue, and headache, along with less frequent AEs like cytokine release syndrome (CRS), consistent with its effect on T cell function. Clinical studies exploring blinatumomab (60 μg/m
2/day or 112 μg/day) in adult patients with ALL or non-Hodgkin lymphoma (NHL) have shown that treatment is also regularly associated with neurologic events (NEs), which represent the most frequent reasons for dose interruptions and discontinuations [
4,
5,
7‐
9]. Given the nature of such events, their management requirements, and their impact on blinatumomab infusion, NEs represent a unique challenge during blinatumomab treatment.
We describe the occurrence patterns of NEs, their management, and the associated clinical risk factors in adult patients (
n = 189) with relapsed/refractory ALL who received treatment with blinatumomab in a large phase 2 study. The primary analysis of this study is reported elsewhere [
5].
Methods
Patients
Detailed eligibility requirements have been described previously; the protocol was approved by each center’s institutional review board or ethics committee, and all patients provided written informed consent [
5]. Briefly, adults (≥ 18 years) with Philadelphia chromosome-negative B-precursor ALL whose disease was refractory to standard chemotherapy or had relapsed (first salvage with remission duration ≤ 12 months, or second or greater salvage) and who had ≥ 10% bone marrow blasts were eligible. Patients with alloHSCT < 3 months before starting blinatumomab and those with active ALL in the central nervous system (CNS) or with clinically relevant CNS pathology (e.g., epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, or psychosis) were excluded from the study. However, enrollment of patients with a history of NEs was permitted at the investigator’s discretion if the NE was fully resolved at the time of screening.
Study design and treatment
This single-arm, open-label, phase 2 study (
n = 189) has been described in detail elsewhere [
5]. The study followed a Simon two-stage design, with a third stage. A study amendment in June 2013 allowed enrollment of an additional evaluation cohort to examine neurologic symptoms and putative prognostic factors for NEs. In cycle 1, blinatumomab was administered at 9 μg/day on days 1 to 7 and then at 28 μg/day from days 8 to 29 via continuous intravenous infusion (IV). In the following cycles, blinatumomab was administered at 28 μg/day in 4-week cycles. There were two treatment-free weeks between cycles. Based on pharmacokinetic observations in previous studies, there was no adjustment of dose for body size [
10]. Prephase dexamethasone treatment in patients with high tumor burden to mitigate risk of severe CRS and dexamethasone premedication before each cycle and dose step (cycle 1 only) to control infusion reactions was required [
5]. Patients who achieved CR or CRh within the first two infusion cycles and those with hematologic relapse during follow-up could receive up to three additional cycles of treatment.
Blinatumomab infusion was stopped immediately in case of grade 3 NEs or serious NEs. If the NE returned to grade ≤ 1, blinatumomab could be restarted at 9 μg/day (dose escalation was not permitted) after a 2-week treatment-free interval. Before restarting blinatumomab, patients were premedicated with dexamethasone (and prophylactic anticonvulsant, if applicable). Blinatumomab treatment was permanently discontinued in case of grade 4 NEs, grade 3 NEs requiring infusion interruption at a dose of 9 μg/day, NEs requiring > 1 week to resolve to grade ≤ 1, or if a patient experienced more than one seizure.
Assessments
AEs, including NEs, occurring during the core study (
n = 189; from treatment start until 30 days after last treatment or before HSCT) were recorded and graded per the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 [
11]. NEs were defined as previously reported [
5]. Extended neurologic examinations assessing level of consciousness, orientation, vision, motor and sensory function, reflexes, muscle tone, coordination, and neuropsychological findings (e.g., speech, cognition, emotion) were performed at screening, at the start of each treatment cycle, at the end-of-core-study visit, and at the investigators’ discretion. NEs occurring during the core study or between the first infusion of the first retreatment cycle and 30 days after the last retreatment infusion are reported. Events that began before infusion start and worsened later were considered NEs.
In the additional evaluation cohort (n = 36), the following supplementary assessments were performed: extended neurologic examinations in cycle 1, including after the dose step, and daily when grade ≥ 2 NEs occurred (until resolution to grade ≤ 1 and once after resolution); a cranial magnetic resonance imaging (MRI) scan at screening, the end of the core study, grade ≥ 3 NE occurrence, and before retreatment after infusion interruption.
Blinatumomab concentrations in serum following continuous IV infusion were determined using a validated bioassay with a lower limit of quantitation of 50 pg/mL [
4]. Samples were collected before IV infusion, on day 3 during infusion, on day 8 (before dose increase to 28 μg/day in cycle 1 and during 28 μg/day in cycle 2), and on days 15, 22, and 29 during IV infusion in cycles 1 and 2.
Statistical analyses
The primary study endpoint was the rate of CR/CRh within the first two treatment cycles. Overall incidence and severity of AEs was a secondary endpoint. Time to onset and duration of NEs were summarized using descriptive statistics for patients who had at least one NE. Kaplan-Meier estimates and 95% confidence intervals were used to summarize data for all patients. Exploratory analyses using Cox proportional hazard models assessed the characteristics associated with time to the first occurrence of a NE. A stepwise regression method was used to construct a multivariate model, using 0.1 as inclusion and exclusion criteria for prespecified baseline characteristics. All data refer to the original evaluation cohort (n = 189) except where noted. No combined analysis of the two cohorts was performed.
Discussion
Treatment with the CD19-targeted immunotherapy blinatumomab is associated with NEs [
4,
5,
7‐
9]. In this analysis of a large phase 2 study of blinatumomab in adults with relapsed/refractory ALL [
5], the most frequent on-study NEs (e.g., tremor, dizziness, confusional state, and encephalopathy) have been reported consistently across blinatumomab studies, including the recent phase 3 TOWER study in patients with ALL [
4‐
9]. Notably, most NEs were grade 1 or 2 and occurred early in cycle 1 when patients received the initial blinatumomab dose step in the hospital.
The NE incidence appeared to increase with increasing blinatumomab exposure at a given dose but factors other than drug concentration may have affected the results. In a recent publication, higher C
ss with blinatumomab at a dose of 9 μg/day was associated with a greater incidence of NE events in the univariate analysis but not in the multivariate analysis [
13]. Other disease- or treatment-related factors, such as more than two prior salvage therapies, may have affected the occurrence of NEs. The present study showed that there was no difference in median exposure between patients experiencing grade ≤ 2 and grade ≥ 3 NEs, suggesting that blinatumomab concentrations may not be a key driver of NE severity.
NEs were successfully managed by blinatumomab dose interruptions or discontinuations in 29 patients. The occurrence of NEs did not appear to hinder achievement of remission. Of the 29 patients with treatment interruptions or discontinuations due to NEs, 10 achieved CR/CRh before interruption, and 8 achieved CR/CRh after restarting treatment [
5]. Blinatumomab dose interruption with dexamethasone was also successful for the management in patients who experienced additional NEs after previously delaying blinatumomab due to NEs, as well as for more serious NEs, including seizures, encephalopathy, and aphasia. Although the protocol did not mandate primary seizure prophylaxis, it recommended secondary prophylaxis with phenytoin or levetiracetam, which was administered to all four patients who experienced seizures, allowing three of them to continue treatment. The data show that close monitoring with early appropriate intervention supported successful management of NEs with minimal impact on the treatment course for most of the patients.
Although previous analyses of phase 2 data have shown that patients aged ≥ 65 years with relapsed/refractory ALL had a greater incidence of NEs [
12], the multivariate model in this study did not demonstrate older age alone as a significant risk factor for time to first on-study NE. Furthermore, the types of NEs seen more frequently in older patients were consistent with those expected in this population, and older patients were more likely to have treatment interruptions as a result. The results of the multivariate analysis suggest that prior history of neurologic disorders should be considered before initiation of blinatumomab treatment. However, given the small number of patients in the analysis and considering that such measures may simply reflect disease severity—healthier patients are less likely to experience NEs—these prognostic evaluations should be interpreted with caution.
Based on the blinatumomab mode of action, T cell activation and subsequent cytokine release are known to play a role in the development of certain blinatumomab-associated AEs, such as pyrexia, fatigue, headache, and CRS [
14]. In contrast, the mechanism underlying the development of NEs is not yet understood but likely multifactorial. Tumor burden may not contribute to the development of NEs given the similarity in rates of grade 3/4 NEs in patients with minimal residual disease [
15]. Similar NEs, such as encephalopathy and seizures, have been reported in patients receiving CD19-targeted chimeric antigen receptor (CAR) T cells, including severe and fatal events [
16‐
18], suggesting a possible target dependence. Although more patients with NEs also had CRS, we did not find an association between NEs, CRS, and/or peak cytokine levels, especially interleukin (IL)-6, unlike recent reports with CD19 CAR T cells in which patients with severe neurotoxicity also developed CRS characterized by elevated IL-6 and interferon gamma [
18]. In other studies of CAR T cells, CAR T cells were detected in the spinal fluid of nearly all patients regardless of the occurrence of NEs [
17,
19]. B and T cells, as well as blinatumomab, have been detected in the spinal fluid of adult and pediatric patients treated with blinatumomab for ALL and NHL; however, these were independent of blood–CSF barrier integrity [
20]. Expression of CD19 in the CNS has been investigated as a potential factor in the development of motor aphasia in patients receiving CD19 CAR T cells for hematologic malignancies [
21]. Unfortunately, the MRI data in the current study were insufficient to investigate where pathologic changes in the CNS may have contributed to the development of NEs associated with blinatumomab. Further research in this area is required.
In this analysis of patients with relapsed/refractory ALL who received blinatumomab, NEs occurred early during treatment and could be managed with dose interruption or medication, even after recurrence. Increased exposure to blinatumomab and older age appeared to increase the incidence of certain NEs but not the severity. In a post hoc multivariate analysis, race, prior salvage therapy, and history of NEs were risk factors for time to first on-study NE. Unlike CAR T cells, peak interleukin levels and CRS do not appear to contribute to the development of NEs with blinatumomab treatment. Further investigation of the underlying mechanisms of NEs during blinatumomab treatment is warranted.
Acknowledgments
The authors thank Ben Scott, PhD (Scott Medical Communications, LLC), Geoff Smith, PhD (Amgen Inc.), and Beate D. Quednau, PhD (Amgen Inc.), for medical writing assistance.
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