HK40081722A - Neurologic toxicity assessment methods and systems for documenting changes in handwriting - Google Patents

Description

Neurotoxicity assessment method and system for recording changes in handwriting

Technical Field

The present invention relates to methods and systems for assessing and recording neurotoxic adverse events associated with medical treatments or procedures, and in particular to ranking criteria for changes in handwritten adverse events related to neurotoxicity.

Background

New prescription drugs must be approved by regulatory agencies, such as the U.S. Food and Drug Administration (FDA), which to some extent requires manufacturers to demonstrate the safety and effectiveness of drugs under legal and regulatory standards. The drug development process begins with a basic laboratory study, followed by preclinical development, which typically involves testing in animals to determine the pharmacodynamics, pharmacokinetics, metabolism (ADME), and/or toxicology of the drug. The drug then enters clinical testing in humans, where regulatory bodies participate.

Generally, clinical development of a drug involves three clinical trial phases. Phase I clinical trials involve a relatively small population of individuals and evaluate the safety and ideal dosage of the drug-e.g., to determine the highest dose that can be safely administered without serious side effects. Phase II involves a larger population of individuals (e.g., < 100) with the disorder for which the drug is intended and assessing the effectiveness of the drug. Testing of larger populations of individuals may also reveal less common side effects. Phase III involves a population of at least a few hundred individuals and further assesses the safety and efficacy of the drug compared to existing treatment methods-i.e. whether the new drug is at least as safe and effective as current standard treatment. As with phases I and II, the individual is closely monitored for side effects, and if the side effects become too severe, treatment is discontinued.

The clinical trial is initiated by a sponsor (e.g., pharmaceutical company) who is responsible for and selects the primary investigator(s) conducting the clinical study. The sponsor must submit an Investigational New Drug (IND) application to the FDA that requires the sponsor to inform the FDA in the form of a written report of any serious and unexpected adverse events that are or are reasonably suspected to be caused by the drug. An adverse reaction is generally defined as an Adverse Event (AE) associated with a drug or medical treatment or any adverse and unexpected sign, symptom or disease, whether or not the adverse event is considered to be associated with the drug or medical treatment.

To promote consistency in the assessment and reporting of adverse events in clinical trials, and to promote comparisons among different clinical studies, it is useful to have standardized terms and scales to provide a framework for documenting the severity of adverse events. For example, the national cancer institute issued a universal term for adverse events standard (CTCAE) that provides a grading criterion for assessing the severity of organ toxicity associated with cancer treatment. CTCAE comprises a broad term list of adverse events commonly seen in oncology-related clinical trials, and defines a scale of 1-5 that describes the symptoms of increased severity associated with adverse events. Generally, grade 1 corresponds to no or mild symptoms, grade 2 moderate, grade 3 severe or medically requiring hospitalization, grade 4 life-threatening, and grade 5 death.

CTCAE grading standards provide standardization and consistency in defining and reporting treatment-related toxicities in clinical trials and different clinical studies. However, the CTCAE standard provides guidance for a portion of toxicity, and becomes limited as new drugs and medical treatments are developed, such as cell therapy which may involve new toxicity that physicians must learn to monitor and properly treat.

For example, immune effector cell therapy includes autologous Chimeric Antigen Receptor (CAR) T cell therapy, a novel treatment that involves harvesting and genetically engineering a patient's own T cells to recognize specific antigens on the surface of tumor cells. The genetically engineered T cells are reintroduced into the patient where they specifically bind to and initiate an immune response in the patient to kill the tumor cells. The side effect profile of these CAR T cell therapies is different from classical therapies (such as conventional chemotherapy) or even more recently developed therapies (such as treatment with monoclonal antibodies). Common toxicities associated with CAR T-cell therapy include Cytokine Release Syndrome (CRS) and neurotoxicity. The grading standards for CRS are provided by CTCAE and have also been established by the American Society for Transplantation and Cell Therapy (ASTCT). However, there is a lack of sufficient tools for the description and classification of adverse events associated with neurotoxicity, where symptoms may include headache, confusion, delirium, language disorders (e.g., aphasia), seizures, and in rare cases acute cerebral edema.

ASTCT has established a standard for immune effector cell associated neurotoxic syndrome (ICANS) which includes a 10-point grading tool for immune effector cell associated encephalopathy (ICE). The ICE tool comprises a weighted sum of five elements: direction (4 points), naming (3 points), follow command (1 point), writing (1 point) and attention (1 point). However, further advances in CAR T cell therapy and other types of therapy may present unique toxicities where the ICE tool does not provide appropriate weighting and/or sufficient detail to effectively describe and report the associated adverse events. For example, changes in handwriting may have greater significance in (early) detection and assessment of CAR T cell-associated neurotoxicity, but there are no general criteria for assessing and recording these types of adverse events. Therefore, additional standardized grading criteria are needed for defining and reporting neurotoxicity-related adverse events associated with immune effector cell therapy.

Disclosure of Invention

The present invention meets these needs and others by providing an assessment and grading system for assessing changes in handwriting associated with immune effector cell therapy of a patient.

In one embodiment, a system for assessing neurotoxicity of a subject associated with medical therapy includes at least two staging criteria selected from the group consisting of: handwriting disorders, gait disorders, other movement disorders of the limbs, disorders of the ability to perform self-care activities of daily life, and disorders of expression or motivation. Each grading criterion defines at least one symptom of an adverse event. The ranking criteria are stored in a non-transitory computer readable medium.

In one embodiment, a system for assessing neurotoxicity of a subject associated with a medical treatment comprises: a grading criterion for a handwriting disorder, the grading criterion defining symptoms of at least one adverse event selected from the group consisting of: underscore writing, impaired writing and loss of writing; a grading criterion for gait disorders, the grading criterion defining symptoms of at least one adverse event selected from the group consisting of: parkinson's gait, gait disturbance, gait disability and postural abnormalities; a grading criterion for other motor abnormalities of the limbs defining the symptoms of at least one adverse event selected from the group consisting of: tremor, muscle stiffness, gear stiffness, restlessness, akathisia, bradykinesia, hypokinesia, dyssynergia, ataxia and dysbalance; a grading criterion for a disability in performing self-care activities of daily life, the grading criterion defining symptoms of at least one adverse event selected from the group consisting of: autonomic dysfunction, dysphagia, movement disorders and apraxia; and a grading criterion for an expression or motivational disorder, the grading criterion defining symptoms of at least one adverse event selected from the group consisting of: apathy, diminished facial expressions, inability to express, apathy, ignorance, communication disorders, slow speech and dysarthria. The ranking criteria are stored in a non-transitory computer readable medium. In further embodiments, the grading criteria for a handwriting disorder defines at least two severity levels of symptoms for an adverse event, including: a first level, which is defined as slightly smaller or slower writing or difficulty in completing the writing task relative to the baseline, but most words are legible; and a second level, which is defined as writing less or slower than moderate to severe relative to baseline or difficult to accomplish, and most words are illegible. Grading criteria for gait disorders define at least four severity grades of symptoms of adverse events, including: a first level, defined as slower walking without assistance and no walking urge or a hungry gait; a second level, defined as difficult walking with little help; a third grade, defined as severe gait disorder requiring assistance; and a fourth level, which is defined as not walking even with help. Grading criteria for other motor abnormalities of the extremities define at least three severity levels of symptoms of adverse events, including: a first grade defined as mild symptoms of tremor at rest, stiffness, slowed movement, restlessness, dys coordination, or balance; a second grade, defined as moderate symptoms of tremor at rest, stiffness, slowed movement, restlessness, dys coordination, or disturbance of balance; and a third grade, defined as severe symptoms of tremor at rest, stiffness, slowed movement, restlessness, dys coordination, or balance disorders. The grading criteria for disability to perform daily life self-care activities define at least four severity grades of symptoms for adverse events, including: a first level, defined as performing daily self-care activities slightly slower than baseline, but self-care does not require help; a second level defined as when daily life self-care activities occasionally require assistance; a third level, which is defined as requiring considerable help to perform daily life self-care activities, but can do something alone; and a fourth level, which is defined as disabled and requires full care. The grading criteria for expression or motivational disorders define at least two severity levels of symptoms for adverse events, including: a first level defined as mild apathy, reduced facial expression or emotional response, less communication, slower speaking rate or ambiguity, or disinterest in non-daily activities; and a second level defined as moderate to severe apathy, lack of facial expression or emotional response, answers of several words, monotony or slurred mouth, or disinterest in daily activity.

In one embodiment, the method of assessing neurotoxicity of a subject associated with medical therapy comprises the step of determining a toxicity rating according to at least one ranking criterion selected from the group consisting of: grading standards for handwriting disorder and grading standards for gait disorder; grading criteria for other motor abnormalities of the limbs; a grading criterion for the disability to perform the daily life self-care activities; and grading criteria for expression or motivational disorders.

Drawings

The foregoing summary, as well as the following detailed description of preferred embodiments of the present patent application, will be better understood when read in conjunction with the appended drawings. It should be understood, however, that the application is not limited to the precise embodiments shown in the drawings.

FIG. 1 is a table including grading criteria embodying a system for assessing and grading handwritten neurotoxicity of individuals.

Fig. 2 illustrates a handwriting log for recording, assessing and grading handwritten neurotoxicity in an individual for use with the system and grading criteria of fig. 1.

Fig. 3A and 3B include tables containing grading criteria embodying a system for assessing and grading neurotoxic symptoms of an individual that are associated with immune effector cell therapy.

Detailed Description

The present invention describes methods and systems for recording and assessing adverse events associated with neurotoxicity in clinical trials for new drugs and medical treatments. Common symptoms associated with neurotoxicity include headache, confusion, delirium, language disorders (e.g., aphasia), seizures, and, in rare cases, acute cerebral edema. Other common symptoms of immune effector cell-associated neurotoxicity include handwritten changes. CTCAE (version 5.0) does not define any grading criteria for adverse events on handwriting, nor any other standardized toxicity grading criteria can be used to assess changes in handwriting.

The international human drug technical requirements coordination committee (ICH) has formulated a regulatory activity medical dictionary (MedDRA) that provides standardized medical terms for sharing regulatory information related to human medical products. MedDRA has a hierarchical structure in which higher level terms are composed of groups of related lower level terms that increase in specificity. The lowest, most specific level consists of the lowest level terms, which reflect the terms used in practice-e.g., "feeling nausea". The next level consists of preferred terms, which are terms that represent the medical concept of a group of one or more related lowest level terms-e.g., "nausea". Higher levels also include terms that represent lower level sets of terms that are related to anatomy, pathology, physiology, etiology, or function.

The preferred terms for MedDRA versus handwriting variation are: hypomnesia, writing disorder and academia. The underscore handwriting is a disease characterized by abnormal or sloppy handwriting, or progresses to increasingly smaller handwriting. A writing disorder is a transcription disorder characterized by illegible writing, requiring significant effort or an unreasonable amount of time to complete and/or exhibiting poor spelling. Apraxia is the inability to communicate by writing and is characterized by the inability to write meaningful words and/or slow writing, writing requiring extreme effort and distortion or incompleteness.

In one embodiment, a system for assessing and recording adverse events associated with neurotoxicity in a subject includes one or more ranking criteria for handwritten adverse events. In one embodiment, adverse events correspond to one or more MedDRA lowest level terms and/or preferred terms, such as the preferred terms understylosis, dyslexia, and apraxia. In a preferred embodiment, the handwriting grading criteria define at least two severity levels of symptoms of the adverse event. The grading criteria preferably correspond to the CTCAE grading system-i.e. asymptomatic or mild (grade 1) and moderate (grade 2). An additional level for the severity of the adverse event may be provided. However, a higher toxicity rating according to the CTCAE guidelines is not suitable for assessing changes in handwriting-i.e. adverse events defined as involving hospitalization (grade 3), life-threatening (grade 4), disability or leading to death (grade 5).

In one embodiment, the grading criteria define at least two severity levels of symptoms of understylosis. Level 1 is defined as handwriting that exhibits less than a 50% reduction in letter size or word spacing in the sentence as compared to the baseline handwriting sample. Level 2 is defined as handwriting that exhibits a 50% or more reduction in size or spacing compared to the baseline.

In one embodiment, the grading criteria define at least two severity levels of symptoms of the writing disorder. Level 1 is defined as the handwriting of a predetermined sentence that exhibits symptoms (including a somewhat slower writing speed, straight line obstacles, difficulty in completing the sentence, and most but not all words in the sentence being legible) compared to the baseline handwriting sample. Level 2 is defined as handwriting that exhibits level 1 symptoms but is moderate to severe in writing speed and illegible for most of the words of the sentence, compared to baseline.

In one embodiment, the grading criterion defines symptoms of at least two severity grades of atopy. Level 1 is defined as a handwriting of a predetermined sentence that exhibits symptoms including words that fail to write the same number of sentences as the baseline but at least 3 words, as compared to the baseline handwriting sample. Level 2 is defined as handwriting that exhibits level 1 symptoms but cannot write more than 2 words compared to baseline.

Figure 1 illustrates one embodiment of a handwritten neurotoxicity ranking criterion in the form of a reference guide for use in evaluating changes in a subject's handwriting. Preferably, a copy of the handwritten neurotoxicity ranking criteria is stored in digital form, such as in a non-transitory computer readable medium. The grading criteria provide consistency in assessing and reporting clinical trials and handwritten adverse events in different clinical trial groups. The system may also include a form for recording adverse events, such as a handwriting log for taking handwritten samples of the subject over time. Preferably, the copy of the handwritten log is stored in digital form, such as in a non-transitory computer readable medium. FIG. 2 illustrates one embodiment of a handwriting log for use with handwriting ranking criteria. In a preferred embodiment, the table provides records of: (1) an identifier of the clinical trial, (2) an identifier of the test subject, (3) a baseline sample and one or more additional samples handwritten by the subject; (4) Date of sample, (5) rating scale (1 or 2) of three adverse event categories (hypo-written, dys-written, apraxia), and (6) rating date and identifier of person performing the rating.

The system may also include protocols and instructions for conducting handwritten assessments performed by the primary investigator of its designated personnel in the clinical trial. The test subject is asked to provide a handwritten sample of the test phrase that may be spontaneous or predetermined. In one embodiment, the test phrase is a relatively short predetermined standard phrase comprised of common words. In a preferred embodiment, the standard phrase includes about 10 words, and more preferably includes all or most of the letters. An example of a suitable standard phrase is "agile brown fox skipping a lazy-sleeping dog" (The quick brown fox jumped over The lazy sleeping dog). In one embodiment, the standard phrases may be printed on a record table for transcription by the test subjects, as shown in fig. 2.

In practice, an initial or baseline handwritten sample is taken at the beginning of a clinical trial, prior to administration or medical treatment. Subsequent handwritten samples taken during the clinical trial may be compared to the baseline to assess any changes in the subject's handwriting. A subject's handwriting sample is preferably collected at the beginning of each visit, prior to any intervention. The subject is provided with a writing instrument that he feels comfortable with and placed in a comfortable position to write (e.g., sitting at a table or sitting in a bed using a bedside table). If a handwritten sample is recorded in the log, the previous handwritten sample will be covered or otherwise hidden from the subject's view during the current evaluation. All subsequent writing samples preferably use the same brand and type of writing instrument. The use of erasable writing instruments (e.g., pencils) is generally not recommended, or may require some skill or familiarity to comfortably use a writing instrument (e.g., a pen or a pen with a large grip). In one embodiment, the writing instrument is a black or blue ballpoint pen. Preferably, the copy of the handwritten sample is stored in digital form, such as in a non-transitory computer readable medium.

Individuals (test takers) evaluating the handwritten sample should observe the subject while writing the test phrase to allow a comprehensive assessment of changes in ease of writing relative to baseline-e.g., pauses between words (larger), increased number of strokes, or word breaks. The evaluation of the handwritten sample is preferably applied by the same individual to ensure consistency of the grading and reporting. Adverse events in the under-written, dyswritten, and apraxia categories of the handwritten sample were evaluated according to the grading criteria provided in the reference guidelines. Assessment of the writing disorder can include subjective components based on the recollections of the examiner, self-reports by the subject (e.g., subject notes are written more slowly and more difficult to perform), and/or observations of others (e.g., the subject's caregiver).

In the event that the subject has a condition that would prevent an effective comparison of the handwritten sample to baseline (e.g., a general condition or low level of consciousness, such as hand injury, peripheral neuropathy, muscle spasm, flu, etc.), the counselor should record the condition associated with the handwritten sample in a log. The primary investigator in a clinical trial may choose to omit such written samples from the assessment.

Preferably, the copies of the ranked handwritten samples are stored in digital form, such as in a non-transitory computer readable medium. The handwritten neurotoxicity ranking criteria, the handwriting log, the handwritten sample, and/or the digital copy of the ranked handwritten sample may each be stored in a separate non-transitory computer-readable medium, or more preferably, in the same non-transitory computer-readable medium.

Depending on the severity of the adverse event (e.g., grade 1 or 2) and the nature of the clinical trial (e.g., the type of drug or other medical treatment, and the medical condition being investigated), the detection of handwritten neurotoxicity may prompt different actions to be taken. For example, detection of handwritten neurotoxicity may indicate a need to closely observe the subject, further examine the subject, and/or assess other symptoms of neurotoxicity. Alternatively, detection of handwriting neurotoxicity may indicate a need for intervention and/or cessation of treatment.

In one embodiment, the above-described systems and methods for recording and assessing adverse events using handwritten neurotoxicity staging criteria are applied to a subject undergoing medical treatment for malignancy. In a preferred embodiment, the medical treatment is immune effector cell therapy, more preferably CAR T cell therapy targeting B Cell Maturation Antigen (BCMA). Common neurological toxicities associated with CAR T cell therapy include aphasia and disorientation. anti-BCMA CAR-T cell therapy has been found to be associated with neurotoxicity, which may be unique and has not been reported publicly in other existing CAR-T products. These novel toxicities occur later than typical CAR-T associated neurotoxicity (i.e., after CRS withdrawal) and are not typically manifested by neurocognitive and/or motor symptoms. Accordingly, it is desirable to provide standardized grading standards to define and report additional neurotoxic adverse events, including handwritten changes. In addition, the detection of adverse handwriting events (such as underswritings, writing disorders, and apraxia) can provide the patient with an early indication of other potential risks of more severe neurotoxicity. Early detection will allow these high risk patients to be closely monitored for early treatment and may be critical to achieving better outcomes.

Preferably, subjects in a clinical trial or other clinical study involving immune effector cell therapy are evaluated for handwritten adverse events using handwritten neurotoxicity grading criteria. When these handwritten changes are detected, as well as other immune effector cell-associated neurotoxicity (e.g., ICANS or other neurotoxicity), grade 1 or grade 2 hypolites, dyslexia, and/or apraxia adverse events should be reported immediately. This information should facilitate further assessment of other neurotoxic symptoms, further examination, and potential initiation of intervention.

Grading criteria for handwritten adverse events may be incorporated into a system for assessing and grading neurotoxic symptoms associated with immune effector cell therapy (such as CAR T cell therapy) that may not be recognized or easily documented using conventional CTCAE guidelines. In one embodiment, a system for assessing and recording adverse events associated with neurotoxicity in a subject comprises a grading criterion for one or more symptoms associated with immune effector cell-associated movement and neurocognitive impairment (icand). The preferred term for MedDRA, which generally encompasses such motor and neurocognitive disorders, is parkinson's disease, which is defined as motor symptom disorders, cognitive disorders, and/or personality changes. The symptoms of dyskinesia are a general slowing down and stiffness of movement. Large loss of motor control is characterized by difficulty walking, poor balance, restlessness, and gait changes, including a dragging, rapid walking, or panicked gait. Loss of fine motor control is characterized by difficulty in writing or performing daily self care Activities (ADLs), coordination impairment, and tremors. Examples of ADLs include, but are not limited to, dressing, eating, taking medicine, and sanitation. Cognitive disorders are general mental retardation characterized by short-term memory impairment, amnesia, difficulty in finding words, slow speech, inattention, and difficulty in solving problems or learning new things. Character changes are often characterized by apathy and diminished emotional response, which may include apathy, lethargy, neglect, communication barriers, loss of motivation or interest, and diminished facial expression or emotional response.

The icamed classification criteria define symptoms of adverse events in at least one, and preferably at least two, symptom domains, including: (1) handwriting disorders, (2) gait disorders, (3) other movement disorders of the limbs, (4) disorders of the ability to execute ADL, and (5) disorders of expression or motivation. Each symptom domain contains at least one adverse event consistent with the applicable MedDRA lowest level term and/or preferred term. The grading criteria define at least two severity levels of symptoms of an adverse event that are assessed as changes from baseline. In one embodiment, the ranking criteria reflects a CTCAE ranking system and includes: mild (grade 1), no intervention indicated; (level 2) moderate, non-invasive intervention indication; (grade 3) severe or medically significant but not immediately life threatening, including indicated disability and/or hospitalization or prolonged hospitalization; (level 4) life-threatening or severe disability, including indicated interventions for prevention of indicated permanent injury, persistent disability or death, hospitalization or prolonged hospitalization, including professional care facilities. CTCAE grade 5 corresponds to mortality associated with adverse events and is generally not applicable to ICAMAND grading standards.

Grading criteria for handwriting obstacles are discussed above. In one embodiment, adverse events related to handwriting disorders are reported consistent with at least one of the MedDRA preferred terms: underscore writing, impaired writing and loss of writing. In a preferred embodiment, the grading criteria include two grades of handwriting impediments. Level 1 is defined as a slightly smaller or slower writing relative to baseline or difficulty in completing the writing task, but most words are clearly legible. Level 2 is defined as a writing or task that is moderately to less severe or slow relative to baseline, and most words are illegible. Levels 3 and 4 are not applicable.

As described above, the evaluation of the change in handwriting may be performed using a form for recording a handwritten sample of the subject's standard phrase. In one embodiment, the standard phrases may be omitted from the record table. Although suitable for handwriting evaluation, transcription may not allow for evaluation of adverse events in other symptom domains, such as communication impairment.

In one embodiment, adverse events related to gait disorders are reported consistent with at least one of the MedDRA preferred terms: gait, gait disturbance, gait disability and abnormal posture in Parkinson's disease. In a preferred embodiment, the grading criteria include four severity levels of symptoms for gait disorders. Level 1 is defined as a slower walk that does not require assistance; and may include arm swing, a gait of walking, or a stooping posture, but no gait jerky or hungry. Level 2 is defined as a difficult walk requiring little help; and may include some walking jerky or hungry gait with a dragging gait or stooping posture. Grade 3 is defined as severe gait disorder requiring assistance. Level 4 is defined as the inability to walk even with assistance-e.g., the subject is bedridden or sitting in a wheelchair.

In one embodiment, adverse events associated with other motor abnormalities of the extremities include motor abnormalities that are not included in the symptom domains (1) and (2) -i.e., adverse events associated with handwriting and gait disorders are excluded. Adverse events related to other motor abnormalities of the extremities were reported to be consistent with at least one of the MedDRA preferred terms: tremor, muscle stiffness, gear stiffness, restlessness, akathisia, bradykinesia, hypokinesia, dyssynergia, ataxia and dyshomeostasis. Gear-like stiffness is a stiffness in which the muscles react in a gear-like twitch to the use of force to bend the limb. Sedentary seating cannot be a movement disorder characterized by difficulty in remaining still. Hypokinesia is another dyskinesia, meaning little movement. Bradykinesia describes slow movement and response, often a symptom of a medical condition (e.g., parkinson's disease). Ataxia is a symptom of dysfunction of the nervous system characterized by a lack of coordination of muscle control or voluntary movement. Subjects with ataxia may exhibit symptoms such as slurred mouth, stumbling, falls, and incoordination. Balance disorder is a condition that causes instability or dizziness in humans.

In a preferred embodiment, the grading criteria include three severity levels of symptoms for other movement abnormalities of the extremities. Grade 1 is defined as mild symptoms of tremor, stiffness, slowed movement, restlessness, dyscoordination or disturbance of balance at rest. Grade 2 is defined as moderate symptoms of tremor at rest, stiffness, slowed movement, restlessness, dyscoordination, or disturbance of balance. Grade 3 is defined as severe symptoms of tremor, stiffness, slowed movement, restlessness, dyscoordination or disturbance of balance at rest. Level 4 not applicable.

In one embodiment, adverse events associated with disability to conduct ADL are reported consistent with at least one of the MedDRA preferred terms: autonomic dysfunction, dysphagia, movement disorders and apraxia. Dysphagia is a disease characterized by dysphagia which may be associated with pain. Dyskinesia is a motor learning disorder, including difficulty in fine motor skills, large motor skills, motor planning and coordination. Apraxia is a neurological disorder characterized by the inability to perform familiar actions on command despite the fact that the command is understood and has a willingness to perform the action.

In a preferred embodiment, the grading criteria include four severity grades of symptoms of the disability for self care ADL. Level 1 is defined as performing self-care ADL slightly slower than baseline, but self-care does not need help. Level 2 is defined to occasionally need assistance in self-care ADL, including buttoning, cutting food, brushing teeth, combing hair, and/or self-feeding. Level 3 is defined as requiring considerable help to perform self-care ADL, but can do something alone and may include significant voluntary eating or swallowing difficulties. Level 4 is defined as disabled and requires full care.

In one embodiment, adverse events related to expression or motivational disorders are reported to be consistent with at least one of the preferred terms MedDRA: apathy, diminished facial expression, inability to express, apathy, ignorance, communication barriers, slow speech and dysarthria. An expression cannot be an inability to use or understand gestures or body language. Indifference and ignorance refer to a lack of interest in activity and/or social interaction. Communication disorders are neurocognitive disorders characterized by disorders that transmit, receive, process or understand speech, non-speech or graphical language, speech and/or communication. Dysarthria is a motor-driven speech disorder in which the muscles used to produce speech are damaged, paralyzed or weakened.

In a preferred embodiment, the grading criteria define two severity levels of symptoms for the expression or motivational disorder. Level 1 is defined as mild apathy, reduced facial expression or emotional response, less communication, slower or ambiguous speech, or disinterest in non-daily activities. Level 2 is defined as moderate to severe apathy, lack of facial expression or emotional response, answers by a few words (terse), monotony or slurred mouth, or disinterest in daily activity. Levels 3 and 4 are not applicable.

Adverse events corresponding to the symptom domain are not limited to the MedDRA preferred term. In alternative embodiments, an adverse event may be reported consistent with the lowest level term and/or a combination of the preferred term and the lowest level term.

Fig. 3 illustrates an embodiment of the icand classification criteria in the form of a reference guide. Copies of the icamed rating standard may be stored in digital form, such as in a non-transitory computer readable medium. The system may also include a table or log for recording adverse events. A copy of the journal may also be stored in digital form, such as in a non-transitory computer readable medium.

Disorders of regression of CRS or ICANS should be noted in the absence of other clear causes of neurocognitive decline, such as fever, infection, tumors, cerebrovascular disease, pre-existing neurological disease, drug abuse, and the like. In one embodiment, neurotoxicity of a subject is assessed by determining a toxicity rating according to one or more symptom domain grading criteria. The overall ICAMAND toxicity rating was determined as the toxicity rating for the most severe disorder symptom domain. In a preferred embodiment, the diagnosis of immune effector cell-associated motor and neurocognitive disorders preferably requires that at least 2 domains are affected and that symptoms are present for at least 1 week.

At the first sign of neurotoxicity, neurologic consultation and evaluation should be considered. In practice, cognitive disorders and personality changes are common in icand and may occur in a insidious manner. For subjects who present with cognitive changes and report observed symptoms, cognitive assessment and evaluation should be considered. In one embodiment, all observed symptoms are reported, including adverse events not represented under the MedDRA preferred terminology. Examples of reportable symptoms include cognitive disorders, short-term memory disorders, thought retardation, amnesia, mental disorders, difficulty in finding words, inattention, attentiveness disorders, problem solving disorders, personality changes, social withdrawal, lethargy, and sleep disorders, including sleep movement disorders.

Example 1: neurotoxicity patient case study detected using a handwriting assessment tool

One CAR-T associated motor and neurocognitive (mand) case was determined by using this handwriting tool (the only new mand case reported by the study product since the handwriting tool was implemented in a clinical trial). This patient was pre-determined to be at risk for CAMAND due to baseline risk factors (male, high disease burden, limited response to bridging therapy) and significant toxicity (grade 3 CRS) associated with increased risk following CAR-T infusion. The subject returned home from the hospital approximately 28 days after CAR-T infusion, after which the patient's spouse observed daytime sleepiness, fatigue, apathy and some handwritten changes at home between study visits on day 28 and day 56. The use of a handwriting tool during the study visit on day 56 helped the investigator diagnose grade 1 hypotypy, which prompted further neurological assessments based on the study protocol. During this visit, in addition to character changes (such as apathy, veining, less communication, and apathy), changes in balance and coordination, bradykinesia, rigidity, and parkinsonian gait and posture were noted. This case demonstrates that handwriting monitoring and early detection of changes in handwriting by this tool facilitates further neurological assessment and enables efficient recognition of CAR-T associated motor and neurocognitive disorders.

While particular embodiments of the present disclosure have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the disclosure. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this disclosure.

Claims (23)

1. A system for assessing neurotoxicity of a subject associated with a medical treatment, the system comprising:

at least two grading criteria selected from the group consisting of: handwriting disorders, gait disorders, other movement disorders of the extremities, disorders of the ability to perform self-care activities of daily life, disorders of expression or motivation;

wherein each grading criterion defines symptoms of at least one adverse event, and wherein the grading criterion is stored in a non-transitory computer readable medium.

2. The system of claim 1, comprising a grading criterion for a handwriting disorder, the grading criterion defining a symptom of at least one adverse event selected from the group consisting of: hypomnesia, writing disorder and academia.

3. The system of claim 2, wherein the grading criteria for a handwriting disorder defines symptoms of at least two severity grades of the adverse event, comprising:

a first level, defined as lightly small or slow writing relative to baseline or difficult to complete writing tasks, but most words are legible; and

a second level, defined as writing less or slower than moderate to severe relative to baseline or difficult to accomplish, and most words illegible.

4. The system of claim 1, comprising grading criteria for gait disorders that define symptoms of at least one adverse event selected from the group consisting of: gait, gait disturbance, gait disability and abnormal posture in Parkinson's disease.

5. The system of claim 4, wherein the grading criteria for gait disorders define at least four severity grades of symptoms for the adverse event, including:

a first level defined as slower walking without assistance and no walking jerk or panicking gait;

a second level defined as difficult walking with little help;

a third level defined as a severe gait disorder requiring assistance; and

a fourth level defined as not walking even with assistance.

6. The system of claim 1, comprising a grading criterion for other motor abnormalities of the limbs, the grading criterion defining symptoms of at least one adverse event selected from the group consisting of: tremor, muscle stiffness, gear stiffness, restlessness, akathisia, bradykinesia, hypokinesia, dyssynergia, ataxia and dyshomeostasis.

7. The system of claim 6, wherein the grading criteria for other movement abnormalities of the extremities defines at least three severity levels of symptoms for the adverse event, including:

a first grade defined as mild symptoms of tremor at rest, stiffness, slowed movement, restlessness, dys coordination, or disturbance of balance;

a second grade defined as tremor at rest, rigidity, slowed movement, restlessness, moderate symptoms of dys coordination or balance; and

a third grade defined as tremor at rest, stiffness, slowed movement, restlessness, dys coordination, or severe symptoms of balance disorder.

8. The system of claim 1, comprising a grading criterion for the disability of performing self-care activities of daily living, the grading criterion defining symptoms of at least one adverse event selected from the group consisting of: autonomic dysfunction, dysphagia, movement disorders and apraxia.

9. The system of claim 8, wherein the grading criteria for an disability to perform self-care activities of daily living defines symptoms of at least four levels of severity for the adverse event, comprising:

a first level defined as performing self-care activities of daily living slightly slower than baseline, but self-care does not require assistance;

a second level defined as the daily self-care activities needing occasional assistance;

a third level, defined as requiring considerable help to perform daily life self-care activities, but can do something alone; and

a fourth level, defined as disability and requiring full care.

10. The system of claim 1, comprising a grading criterion for expression or motivational disorders, the grading criterion defining symptoms of at least one adverse event selected from the group consisting of: apathy, diminished facial expressions, inability to express, apathy, ignorance, less communication, slow speech and dysarthria.

11. The system of claim 10, wherein the grading criteria for expression or motivational disorders define at least two severity levels of symptoms for the adverse event, including:

a first level defined as mild apathy, reduced facial expression or emotional response, less communication, slower or ambiguous speech, or disinterest in non-daily activities; and

a second level, defined as moderate to severe apathy, lack of facial expression or emotional response, answers of a few words, monotony or slurred or disinterest in daily activities.

12. The method of claim 1, wherein the medical treatment is immune effector cell therapy.

13. The method of claim 1, wherein the medical treatment is chimeric antigen receptor T cell therapy.

14. A system for assessing neurotoxicity of a subject associated with a medical treatment, the system comprising:

a grading criterion for a handwriting disorder, the grading criterion defining symptoms of at least one adverse event selected from the group consisting of: underscore writing, impaired writing and loss of writing;

a grading criterion for gait disorders, the grading criterion defining symptoms of at least one adverse event selected from the group consisting of: parkinson's gait, gait disturbance, gait disability and postural abnormalities;

a grading criterion for other motor abnormalities of the limbs, said grading criterion defining the symptoms of at least one adverse event selected from the group consisting of: tremor, muscle stiffness, gear stiffness, restlessness, akathisia, bradykinesia, hypokinesia, dyssynergia, ataxia and dysbalance;

a grading criterion for a disability to perform a daily lifestyle activity, the grading criterion defining symptoms of at least one adverse event selected from the group consisting of: autonomic dysfunction, dysphagia, movement disorders and apraxia; and

a grading criterion for an expression or motivational disorder, the grading criterion defining symptoms of at least one adverse event selected from the group consisting of: apathy, decreased facial expression, inability to express, apathy, neglect, communication barriers, slow speech rate, and dysarthria;

wherein the ranking criteria are stored in a non-transitory computer readable medium.

15. The system of claim 14, wherein:

the grading criteria for a handwriting disorder defines at least two severity levels of symptoms for the adverse event, including:

a first level defined as a slightly smaller or slower writing or difficult to complete writing task relative to baseline, but most words are clearly legible; and

a second level defined as less or slower writing or difficult to accomplish task than moderate to severe relative to baseline, and most words illegible;

the grading criteria for gait disorders define at least four severity grades of symptoms for the adverse event, including:

a first level defined as slower walking without assistance and no walking urge or a hungry gait;

a second level defined as difficult walking with little help;

a third level defined as a severe gait disorder requiring assistance; and

a fourth level defined as not walking even with assistance;

the grading criteria for other motor abnormalities of the limbs defines at least three severity levels of symptoms for the adverse event, including:

a first grade defined as mild symptoms of tremor at rest, stiffness, slowed movement, restlessness, dys coordination, or disturbance of balance;

a second grade defined as moderate symptoms of tremor, stiffness, slowed movement, restlessness, disturbance of coordination or disturbance of balance at rest; and

a third grade defined as tremor at rest, stiffness, slowed movement, restlessness, dys coordination, or severe symptoms of balance disorder;

the grading criteria for the disability to perform self-care activities of daily life define at least four severity levels of symptoms for the adverse event, including:

a first level defined as performing self-care activities of daily living slightly slower than baseline, but self-care does not require assistance;

a second level defined as the daily self-care activities needing occasional assistance;

a third level, defined as requiring considerable help to perform daily life self-care activities, but can do something alone; and

a fourth level, defined as a disability and requiring full care; and is

Said grading criteria for expression or motivational disorders define at least two severity levels of symptoms for said adverse event, including:

a first level defined as mild apathy, reduced facial expression or emotional response, less communication, slower or ambiguous speech, or disinterest in non-daily activities; and

a second level defined as moderate to severe apathy, lack of facial expression or emotional response, answers of a few words, monotony or slurred mouth, or disinterest in daily activity.

16. The system of claim 14, wherein the medical treatment is immune effector cell therapy.

17. The system of claim 14, wherein the medical treatment is chimeric antigen receptor T cell therapy.

18. A method of assessing neurotoxicity of a subject associated with medical therapy comprising the step of determining a toxicity rating according to at least one rating criterion selected from the group consisting of: grading criteria for handwriting obstacles; grading criteria for gait disorders; grading criteria for other motor abnormalities of the limbs; a grading criterion for the disability to perform the daily life self-care activities; and grading criteria for expression or motivational disorders.

19. The method of claim 18, wherein:

the grading criterion for handwriting disorders defines symptoms of at least one adverse event selected from the group consisting of: underscore writing, impaired writing and loss of writing;

the grading criterion for gait disorders defines symptoms of at least one adverse event selected from the group consisting of: parkinson's gait, gait disturbance, gait disability and postural abnormalities;

the grading criterion for other motor abnormalities of the limbs defines the symptoms of at least one adverse event selected from the group consisting of: tremor, muscle stiffness, gear stiffness, restlessness, akathisia, bradykinesia, hypokinesia, dyssynergia, ataxia and dysbalance;

the grading criteria for impaired ability to perform self-care activities of daily life define symptoms of at least one adverse event selected from the group consisting of: autonomic dysfunction, dysphagia, movement disorders and apraxia; and is provided with

The grading criteria for expression or motivational disorders define symptoms of at least one adverse event selected from the group consisting of: apathy, diminished facial expressions, inability to express, apathy, ignorance, communication disorders, slow speech and dysarthria.

20. The method of claim 19, wherein:

the grading criteria for a handwriting disorder define at least two severity grades of symptoms for the adverse event, including:

a first level defined as a slightly smaller or slower writing or difficult to complete writing task relative to baseline, but most words are clearly legible; and

a second level defined as less or slower writing or difficult to accomplish task than moderate to severe relative to baseline, and most words illegible;

the grading criteria for gait disorders define at least four levels of severity of symptoms for the adverse event, including:

a first level defined as slower walking without assistance and no walking jerk or panicking gait;

a second level defined as difficult walking with little help;

a third level defined as a severe gait disorder requiring assistance; and

a fourth level defined as not walking even with assistance;

the grading criteria for other motor abnormalities of the limbs defines at least three severity levels of symptoms for the adverse event, including:

a first grade defined as mild symptoms of tremor, stiffness, slowed movement, restlessness, dyscoordination, or disturbance of balance at rest;

a second grade defined as tremor at rest, rigidity, slowed movement, restlessness, moderate symptoms of dys coordination or balance; and

a third grade defined as tremor at rest, stiffness, slowed movement, restlessness, dys coordination, or severe symptoms of balance disorder;

the grading criteria for the disability to perform daily lifestyle activities define at least four severity grades of symptoms for the adverse event, including:

a first level defined as performing self-care activities of daily living slightly slower than baseline, but self-care does not require assistance;

a second level defined as the daily life self-care activities needing occasional assistance;

a third level, defined as requiring considerable help to perform daily life self-care activities, but being able to do something alone; and

a fourth level, defined as a disability and requiring full care; and is

The grading criteria for expression or motivational disorders define at least two severity grades of symptoms for the adverse event, including:

a first level defined as mild apathy, reduced facial expression or emotional response, less communication, slower or ambiguous speech, or disinterest in non-daily activities; and

a second level, defined as moderate to severe apathy, lack of facial expression or emotional response, answers of a few words, monotony or slurred or disinterest in daily activities.

21. The method of claim 18, wherein the toxicity rating is determined according to at least two grading criteria, and further comprising the step of determining the overall toxicity rating as the toxicity rating for the most severe disorder grading criteria.

22. The method of claim 18, wherein the medical treatment is immune effector cell therapy.

23. The method of claim 18, wherein the medical treatment is chimeric antigen receptor T cell therapy.