Question 77: Did the recipient develop Cytokine Release Syndrome (CRS) since the date of last report?

Cytokine Release Syndrome (CRS) is defined by development of a constellation of signs and symptoms that are seen after the infusion of monoclonal antibodies or cellular therapy products. It results from the rapid release of several inflammatory cytokines as a consequence of immune response triggered by a drug (i.e. monoclonal antibody) or cellular product. This rapid cytokine release into the circulation results in fever (must be ≥100.4F or ≥38C), nausea, chills, hypotension, tachycardia, asthenia, headache, rash, sore throat, respiratory failure or death. This section attempts to collect different clinical and laboratory information to understand the severity of this event.

If the recipient developed CRS since the date of last report, select “yes” and continue with question 78. If the recipient did not develop CRS, continue with question 101.

Question 78: Was the date of diagnosis previously reported?

If the CRS was diagnosed in a previous reporting period and symptoms continue into this reporting period and the date has already been reported, select “yes” and continue with question 80. Else select “no” and report the date of CRS diagnosis in question 79.

Question 79: Date of diagnosis:

Report the date (YYYY-MM-DD) when the first symptom of CRS was documented by a physician or other health care provider in the progress note or chart.

If the exact date is unknown, please view General Instructions, General Guidelines for Completing Forms for more information on reporting partial and unknown dates.

Question 80: Was therapy given? (for CRS)

Indicate “yes” if the recipient received therapy for CRS and continue with question 81. Indicate “no” if no therapy was given for CRS and continue with question 83. Report any prophylactic drugs as therapy for CRS if they were continued after the date of diagnosis.

Questions 81-82: Specify therapy given for CRS: (check all that apply)

Check all that apply from the list if given to treat the CRS. If “other therapy” is selected, specify the therapy in question 82.

Questions 83-98: Symptoms of CRS

Indicate which symptoms of CRS the recipient experienced. For each symptom reported, also report the date of onset. If there were multiple occurrences of a symptom (e.g. fever), report the first occurrence.

Fevers (≥100.4F or ≥38C): A disorder characterized by elevation of the body’s temperature above the upper limit of normal. Do not report fever less if than 100.4F or 38C in this field. Fever less than 100.4F or
38C does not qualify as a symptom of CRS. Report the date of fever onset in question 84. If there were multiple fevers in the reporting period, report the first occurrence.

Hypotension requiring therapy: Abnormally low blood pressure requiring treatment with volume resuscitation using intravenous isotonic fluids or vasopressors such as norepinephrine, dopamine, dobutamine, epinephrine, phenylephrine, or vasopressin. The use of vasopressors to control blood pressure is an indirect assessment of severity of CRS.

Options for number of vasopressors include 1 or >2 and can be used to determine the grade. One important consideration here is the use of vasopressin, which can be used with fluids or other vasopressors to stabilize the blood pressure. In order to assess severity, only patients who received two or more vasopressor agents excluding vasopressin, should be marked as >2 vasopressors. Addition of vasopressin to other vasopressor agents does not reflect the same level of acuity compared to a patient requiring 2 or more vasopressors without vasopressin. Only use the option of number of vasopressors as >2 for patients who are receiving multiple vasopressors excluding vasopressin.

Specify therapy given for hypotension (intravenous fluids, vasopressors, other) and if hypotension was controlled with therapy. Controlled means not worsening clinically or resolving the hypotension / managing it without the need for additional agents such as pressors.

Hypoxia requiring minimal supplemental oxygen (FiO2<40%): A lower than normal concentration of oxygen in arterial blood requiring supplemental oxygen of <40% FiO2. One example here is the delivery of supplemental oxygen with a low-flow nasal cannula or blow-by device.

Hypoxia requiring more than minimal supplemental oxygen (FiO2>40%): A lower than normal concentration of oxygen in arterial blood requiring supplemental oxygen of >40% FiO2. Also specify if positive pressure ventilatory support is required, such as CPAP, BiPAP, intubation or mechanical ventilation. Do not report use of CPAP for sleep apnea. Examples here include the requirement of supplemental oxygen delivered through a high-flow nasal cannula, facemask, opti-flow, non-rebreather mask or Venturi mask.

Was positive pressure ventilatory support required (CPAP, BiPAP, intubation, and mechanical ventilation): This option outlines the need of devices considered as positive pressure ventilation which could be non-invasive like continuous positive airway pressure (CPAP), bilevel positive airway pressure (BiPAP or BPAP), or invasive, which requires endotracheal intubation with mechanical ventilation.
Patients who use BiPAP or CPAP for obstructive sleep apnea are not considered the same here and should not be reported in this question. The intent of this question is the treatment of respiratory insufficiency or failure.

Source: Common Terminology Criteria for Adverse Events ( CTCAE) v5.0

Questions 99-100: Did cytokine release syndrome resolve?

If the cytokine release syndrome resolved, select “yes” and report the date (YYYY-MM-DD) in question 100.

If the exact date is unknown, please view General Instructions, General Guidelines for Completing Forms for more information on reporting partial and unknown dates.

If the cytokine release syndrome did not resolve, select “no” and continue with question 101.

Questions 101: Neurotoxicity:

Neurotoxicity is the development of different neurologic signs and symptoms reported after the infusion of genetically modified lymphocytes. This was initially thought to be part of CRS, but it was also observed in the absence of any other signs of CRS. Neurotoxicity also appears to be a spectrum of signs and symptoms that vary from fine tremors and word finding difficulties to seizure and loss of conscience. This section collects different neurologic signs that have been described after cellular therapy infusions.

Indicate “yes” if neurotoxicity occurred and continue with question 102. Indicate “no” if neurotoxicity did not occur or “unknown” if unsure whether neurotoxicity occurred and continue with question 132.

Questions 102: Was the date of onset previously reported?

If the neurotoxicity was diagnosed in a previous reporting period and symptoms continue into this reporting period and the date has already been reported, select “yes” and continue with question 104. Else select “no” and report the date of neurotoxicty diagnosis in question 103.

Question 103: Date of onset:

Report the date (YYYY-MM-DD) when the first symptom of neurotoxicity was documented by a physician or other health care provider in the progress note or chart.

If the exact date is unknown, please view General Instructions, General Guidelines for Completing Forms for more information on reporting partial and unknown dates.

Question 104: Was a cognitive assessment performed?

A cognitive assessment is an examination conducted to determine someone’s level of cognition. Indicate “yes” if a cognitive assessment was performed and continue with queston 105. If a cognitive assessment was not performed continue with question 107.

Question 105: Which assessment was performed?

The CAR Toxicity (CARTOX) 10-point neurologic assessment assigns one point for each task performed correctly. A score of 10 is normal. These scales assess cognition and the level of encephalopathy more precisely. They include assessments of orientation, naming, writing, and attention with a score associated with each positive answer. Lower scores are associated with a higher level of encephalopathy.
Unresponsive patients score 0 for all scales. Some centers performed these evaluations multiple times a day. These questions attempt to capture the worst score.

The Immune Effector Cell-Associated Encephalopathy (ICE) assessment is a slightly modified version of the CARTOX-10 assessment. It includes an element for command following.

If another assessment was performed, convert to CARTOX or ICE to report here. See question 106 for a conversion of the Cornell Assessment of Pediatric Delirium (CAPD) to CARTOX or ICE

Question 106: What was the lowest score? (e.g. CARTOX-10, ICE)

Tables for answering question 106 of form 4100.

Questions 107-126: Specify symptoms of neurotoxicity.

Indicate which symptoms of neurotoxicity the recipient experienced.

Depressed level of consciousness: A disruption in how the brain works that causes a change in behavior. This change can happen suddenly or over days and ranges from increased sleepiness to coma.
Specify the most severe level in question 108.

Dysphasia (speech impairment): The loss of ability to understand or express speech, caused by brain damage. Report the grade of dysphasia in question 110.

Aphasia (speech impairment): Note that grade 3 dysphasia is defined as aphasia.

Seizure: Uncontrolled electrical activity in the brain, which may produce a physical convulsion, minor physical signs, thought disturbances or a combination of symptoms. Specify the type of seizure and severity (grade) in questions 113-115.

Hemiparesis / paraparesis / other motor deficit: Weakness on one side of the body (hemiplegic, partial paralysis of the lower limbs (legs), or other sudden loss of connectivity between the CNS and muscles.
Cerebral edema: A swelling in the brain caused by the presence of excessive fluid. Specify the type of cerebral edema in question 118.

Hallucinations: A disorder characterized by a false sensory perception in the absence of an external stimulus (visual or other type).

Tremors: A disorder caused by the rapid alternating contraction and relaxation of muscles (involuntary) and is a common symptom of diseases of the nervous system.

Cerebral vascular accident (stroke): A disorder characterized by a decrease or absence of blood supply to the brain caused by obstruction (thrombosis or embolism) of an artery resulting in neurological damage. Also report the date of onset and the type of stroke. Hemorrhagic stroke occurs when a weakened blood vessel ruptures. Two types of weakened blood vessels usually cause hemorrhagic stroke: aneurysms and arteriovenous malformations (AVMs). Ischemic strokes occur when the arteries to your brain become narrowed or blocked, causing severely reduced blood flow (ischemia). Report the date of onset and type in questions 122 and 123.

Leukoencephalopathy: A disorder characterized by diffuse reactive astrocytosis with multiple areas of necrotic foci without inflammation.

Other symptom: If the recipient experienced a symptom of neurotoxicity not listed above, report here and specify the symptom in question 126.

Source: Common Terminology Criteria for Adverse Events ( CTCAE) v5.0 and ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biology of Blood and Marrow Transplantation, Volume 25, Issue 4, April 2019, Pages 625-638

Questions 127-128: Did neurotoxicity resolve?

If the cellular therapy associated neurotoxicity resolved, select “yes” and report the date (YYYY-MM-DD) in question 128. Resolution means complete normalization of neurologic function. It is possible that patients might remain with residual neurologic dysfunction which would not qualify as complete resolution of this complication.

If the exact date is unknown, please view General Instructions, General Guidelines for Completing Forms for more information on reporting partial and unknown dates.

Questions 129: Was therapy given? (for neurotoxicity)

Indicate “yes” if the recipient received therapy for neurotoxicity and continue with question 130. Indicate “no” if no therapy was given for neurotoxicity and continue with question 132. Report any prophylactic drugs as therapy for neurotoxicity if they were continued after the date of diagnosis.

Questions 130-131: Specify all therapy given for neurotoxicity: (check all that apply)

Check all that apply from the list if given to treat the neurotoxicity. If “other therapy” is selected, specify the therapy in question 131.

Other toxicities

Questions 132: Hypogammaglobulinemia

Hypogammaglobulinemia refers to low levels of circulating gammaglobulins, or immunoglobulins, in the blood and often determined by quantitative levels of immunoglobulins G (Ig G), A (IgA) and M (IgM); or most commonly IgG only. Levels lower than 600mg/dL of circulating IgG are considered to be hypogammaglobulinemia. Normal limits of IgG concentration in the blood vary with age. Children ages 4 to 10, levels lower than 500mg/dL are considered hypogammaglobulinemia. Children younger than 4 years, as levels of IgG can be much lower and still be within normal ranges for the age, the diagnosis of hypogammaglobulinemia needs to be confirmed with the treating physician.

Hypogammaglobulinemia is common after CAR-T infusions that target CD19+ cells, which produce immunoglobulins. The degree of hypogammaglobulinemia is associated with a higher risk of infection. Only report the hypogammaglobulinemia if it occurred after the cellular therapy infusion.

If hypogammaglobulinemia developed in this reporting period, select “yes” and continue with question 133. If hypogammaglobulinemia did not develop in this reporting period, select “no” and continue with question 139.

Questions 133: Was the date of onset previously reported?

If the hypogammaglobulinemia was diagnosed in a previous reporting period and symptoms continue into this reporting period and the date has already been reported, select “yes” and continue with question 135. Else select “no” and report the date of hypogammaglobulinemia diagnosis in question 134.

Questions 134: Date of onset:

Report the date (YYYY-MM-DD) when the hypogammaglobulinemia was documented by either a physician/health care provider or determined by lab results.

If the exact date is unknown, please view General Instructions, General Guidelines for Completing Forms for more information on reporting partial and unknown dates.

Questions 135-136: Did hypogammaglobulinemia resolve?

If the hypogammaglobulinemia resolved, select “yes” in question 135 and report the date (YYYY-MM-DD) in question 136 as documented by a physician or other health care provider in the progress note or chart.

Questions 137-138: Did recipient require immunoglobulin replacement therapy?

Replacement therapy is given to prevent infections. If the recipient required immunoglobulin replacement therapy as a result of hypogammaglobulinemia, select “yes” in question 137, and indicate if the recipient is still requiring the therapy at the time of this report in question 138.

Questions 139: Tumor lysis syndrome

Tumor lysis syndrome (TLS) is a disorder characterized by metabolic abnormalities that result from a
spontaneous or therapy-related cytolysis of tumor cells.

If tumor lysis syndrome developed in this reporting period, select “yes” and continue with question 140. If tumor lysis syndrome did not develop in this reporting period, select “no” and continue with question 145.

Questions 140: Was the date of onset previously reported?

If the tumor lysis syndrome was diagnosed in a previous reporting period and symptoms continue into this reporting period and the date has already been reported, select “yes” and continue with question 142. Else select “no” and report the date of hypogammaglobulinemia diagnosis in question 141.

Questions 141: Date of onset:

Report the date (YYYY-MM-DD) when the tumor lysis syndrome was documented by a physician or other health care provider in the progress note or chart.

If the exact date is unknown, please view General Instructions, General Guidelines for Completing Forms for more information on reporting partial and unknown dates.

Questions 142: Grade:

Report the most severe grade of the tumor lysis syndrome as documented by a physician or other health care provider in the progress note or chart.

  • Grade 3: Present
  • Grade 4: life-threatening consequences: urgent intervention indicated
  • Grade 5: death

Questions 143-144: Did tumor lysis syndrome resolve?

If the tumor lysis syndrome resolved, select “yes” in question 143 and report the date (YYYY-MM-DD) in question 144 as documented by a physician or other health care provider in the progress note or chart.

Questions 145-146: Other toxicity:

Copy and complete questions 146-150 to report more than one other organ toxicity during this reporting period. Other toxicities that are reported should be related to the cellular therapy infusion that are documented in the medical record as clinically important and relevant and do not fit into another category listed on this form.

If the recipient experienced a toxicity that does not fit in a category above, select “yes” in question 145 and specify the other toxicity in question 146.

Questions 147: Was the date of onset previously reported?

If the other toxicity was diagnosed in a previous reporting period and symptoms continue into this reporting period and the date has already been reported, select “yes” and continue with question 149. Else select “no” and report the date of the other toxicity diagnosis in question 148.

Questions 148: Date of onset:

Report the date (YYYY-MM-DD) when the other toxicity was documented by either a physician/health care provider or determined by lab results.

If the exact date is unknown, please view General Instructions, General Guidelines for Completing Forms for more information on reporting partial and unknown dates.

Questions 149-150: Did other toxicity resolve?

If the other toxicity resolved, select “yes” in question 149 and report the date (YYYY-MM-DD) in question 150 as documented by a physician or other health care provider in the progress note or chart.

Reporting multiple other toxicities
FormsNet3 application: Complete questions 146-150 for each other toxicity by adding additional instance(s) in the FormsNet application.
Paper form submission: Copy question 146-150 and complete for each other toxicity being reported.

Questions 151-153: Grade 3 organ toxicity

As defined by the CTCAE criteria, grade 3 toxicity represents severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care Activities of Daily Living (ADL), which refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. Other grade 3 toxicities / symptoms that are reported should be related to the cellular therapy infusion that are documented in the medical record as clinically important and relevant and do not fit into another category listed on this form.

Specify the organ affected in question 152.
Specify the toxicity of that organ in question 153. The list of symptoms will dynamically filter based on the organ selected in question 152.

Organ / System Symptom or Event
Cardiovascular Cardiac arrhythmia, capillary leak syndrome, hypotension, new or worsening heart failure, left ventricular systolic dysfunction, myocardial infarction, pericardial effusion, pericarditis, restricttive cardiomyopathy, hypertension, thromboembolic event
Gastrointestinal Abdominal pain, constipation, diarrhea, dyspepsia (heartburn), gastroenteritis, intestinal obstruction, nausea, vomitting, oral mucositis
Liver Alkaline phosphatase, alanine aminotransferase increased (ALT), aspartate aminotransferase increased (AST), blood bilirubin increased, hepatitis viral, liver failure
Kidneys Cysititis noninfective, chronic kidney disease, acute kidney injury
Musculoskeletal Arthralgia (joint pain), muscle weakness, generalized or specific area (not due to neuropathy), myalgia (muscle pain)
Other Anorexia, peripheral edema or edema limbs, dysgeusia (taste alternation)

Questions 154: Was the date of onset previously reported?

If the grade 3 organ toxicity was diagnosed in a previous reporting period and symptoms continue into this reporting period and the date has already been reported, select “yes” and continue with question 156. Else select “no” and report the date of grade 3 organ toxicity diagnosis in question 155.

Questions 155: Date of onset:

Report the date (YYYY-MM-DD) when the grade 3 organ toxicity was documented by either a physician/health care provider or determined by lab results.

If the exact date is unknown, please view General Instructions, General Guidelines for Completing Forms for more information on reporting partial and unknown dates.

Questions 156-157: Did the grade 3 organ toxicity resolve?

If the grade 3 organ toxicity resolved, select “yes” in question 156 and report the date (YYYY-MM-DD) in question 157 as documented by a physician or other health care provider in the progress note or chart.

Questions 158-160: Grade 4 organ toxicity

As defined by the CTCAE criteria, grade 4 toxicity represents life-threatening consequences and urgent intervention is indicated. Other grade 4 toxicities / symptoms that are reported should be related to the cellular therapy infusion that are documented in the medical record as clinically important and relevant and do not fit into another category listed on this form.

Specify the organ affected in question 159.
Specify the toxicity of that organ in question 160. The list of symptoms will dynamically filter based on the organ selected in question 159.

Organ / System Symptom or Event
Cardiovascular Cardiac arrhythmia, capillary leak syndrome, hypotension, new or worsening heart failure, left ventricular systolic dysfunction, myocardial infarction, pericardial effusion, pericarditis, restricttive cardiomyopathy, hypertension, thromboembolic event
Gastrointestinal Abdominal pain, constipation, diarrhea, dyspepsia (heartburn), gastroenteritis, intestinal obstruction, nausea, vomitting, oral mucositis
Liver Alkaline phosphatase, alanine aminotransferase increased (ALT), aspartate aminotransferase increased (AST), blood bilirubin increased, hepatitis viral, liver failure
Kidneys Cysititis noninfective, chronic kidney disease, acute kidney injury
Musculoskeletal Arthralgia (joint pain), muscle weakness, generalized or specific area (not due to neuropathy), myalgia (muscle pain)
Other Anorexia, peripheral edema or edema limbs, dysgeusia (taste alternation)

Questions 161: Was the date of onset previously reported?

If the grade 4 organ toxicity was diagnosed in a previous reporting period and symptoms continue into this reporting period and the date has already been reported, select “yes” and continue with question 163. Else select “no” and report the date of hypogammaglobulinemia diagnosis in question 162.

Questions 162: Date of onset:

Report the date (YYYY-MM-DD) when the grade 4 organ toxicity was documented by either a physician/health care provider or determined by lab results.

If the exact date is unknown, please view General Instructions, General Guidelines for Completing Forms for more information on reporting partial and unknown dates.

Questions 163-164: Did the grade 4 organ toxicity resolve?

If the grade 4 organ toxicity resolved, select “yes” in question 163 and report the date (YYYY-MM-DD) in question 164 as documented by a physician or other health care provider in the progress note or chart.

Specify the maximum lab results since the date of last report

If there is the same maximum lab value across multiple days, report the first date.

Questions 165-167: Interleukin-6:

Interleukin-6 is a pro-inflammatory cytokine derived from macrophages and endothelial cells that increases synthesis and secretion of immunoglobulins by B lymphocytes.

Indicate if the lab value is “known” or “unknown” in question 165. If known, report the value in question 166 and the date (YYYY-MM-DD) the sample was collected in question 167.

If the exact date is unknown, please view General Instructions, General Guidelines for Completing Forms for more information on reporting partial and unknown dates.

Questions 168-170: Interferon gamma IFN-γ:

Interferon gamma is a pro-inflammatory cytokine produced by macrophages and T-cells that is involved in the regulation of the immune system and activation of phagocytes.

Indicate if the lab value is “known” or “unknown” in question 168. If known, report the value in question 169 and the date (YYYY-MM-DD) the sample was collected in question 170.

If the exact date is unknown, please view General Instructions, General Guidelines for Completing Forms for more information on reporting partial and unknown dates.

Questions 171-173: Soluble interleukin-2 receptor α (sIL2RA or soluble CD25):

Interleukin-2 receptor alpha or CD25 can shed from the surface of cells during inflammatory conditions. This test detects soluble or circulating sIL2RA.

Indicate if the lab value is “known” or “unknown” in question 171. If known, report the value in question 172 and the date (YYYY-MM-DD) the sample was collected in question 173.

If the exact date is unknown, please view General Instructions, General Guidelines for Completing Forms for more information on reporting partial and unknown dates.

Questions 174-176: Total serum ferritin:

Ferritin is an acute phase reactant and is often found in high concentration in highly inflammatory conditions.

Indicate if the lab value is “known” or “unknown” in question 174. If known, report the value in question 175 and the date (YYYY-MM-DD) the sample was collected in question 176.

If the exact date is unknown, please view General Instructions, General Guidelines for Completing Forms for more information on reporting partial and unknown dates.

Questions 177-179: C-reactive protein:

C-reactive protein (CRP) is a protein produced by the liver and found in the blood. CRP levels increase with tissue injury or trauma, infection or inflammation. CRP is also highly associated with IL-6 levels.

Indicate if the lab value is “known” or “unknown” in question 177. If known, report the value in question 178 and the date (YYYY-MM-DD) the sample was collected in question 179.

If the exact date is unknown, please view General Instructions, General Guidelines for Completing Forms for more information on reporting partial and unknown dates.

Last modified: Nov 17, 2020

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