Q51-193: Toxicities

!Reporting Toxicities
Report only toxicities (e.g. CRS, neurotoxicity, etc.) that are directly attributed to the CAR-T product / infusion associated with the event date of this form. Treatment given post-infusion (including immunotherapies or other CAR-T products) may have the effect of re-activating the product and inducing toxicities (e.g. CRS), these toxicities should NOT be captured in this section of the form. Contact CIBMTR Center Support with questions.

!Reporting Toxicities
Do not report any toxicities that were present prior to the infusion and persisted post-infusion.
Do not report any toxicities associated with an event where the Pre-CTED (4000) Form has been made “NRQ” (not required).
Contact CIBMTR Center Support with questions.

*Reporting Toxicities
Report the applicable toxicity (e.g ICANS, parkinsonism) based on either clear documentation of the toxicity diagnosis by a physician or documentation of the symptoms of the toxicity.

*TED vs CRF reporting
All toxicities are listed on the Post-CTED (4100) Form, however, some questions will be disabled for TED reporting level, and will only be enabled for the CRF reporting level (where an associated F4101 is due with the F4100). For more information on TED vs CRF level reporting for cellular therapy see the Cell Therapy section of the Data Management Guide. Questions that are disabled for TED reporting level are noted.

*Combined follow up
In scenarios where both HCT and cellular therapy forms are being completed, these questions should still be answered when an HCT follows a cellular therapy.

Question 51: Did the recipient experience Cytokine Release Syndrome (CRS)?

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 the classic symptoms of fever (≥100.4F or ≥38C), hypotension and hypoxia, and also, but not limited to, nausea, chills, tachycardia, asthenia, headache, rash, sore throat, respiratory failure or death.¹

Indicate Yes if CRS occurred or persisted into the current reporting period.

¹ Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, Maus MV, Park JH, Mead E, Pavletic S, Go WY, Eldjerou L, Gardner RA, Frey N, Curran KJ, Peggs K, Pasquini M, DiPersio JF, van den Brink MRM, Komanduri KV, Grupp SA, Neelapu SS. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019 Apr;25(4):625-638. doi: 10.1016/j.bbmt.2018.12.758. Epub 2018 Dec 25. PMID: 30592986; PMCID: PMC12180426.

*Reporting Multiple CRS Events
Report only CRS events that are directly attributed to the CAR-T product / infusion associated with the event date of this form. If more than one CRS event occurred in the reporting period, complete the CRS questions for each event by adding an additional instance in the FormsNet3^SM application.
Refer to the definition of resolution to determine if there is a new reportable event.

Question 52: Was the date of diagnosis previously reported?

Specify if the diagnosis date of CRS was previously reported. If the CRS event was diagnosed in a previous reporting period, and the symptoms continue into this reporting period, and the date has already been reported, select Yes. If the CRS event was diagnosed in this reporting period, report No.

Question 53: Date of diagnosis

Report the date when the first symptom of CRS was documented by a physician or other health care provider in the progress note or chart.

For more information regarding reporting partial or unknown dates, see General Instructions, General Guidelines for Completing Forms.

Questions 54-57: Specify therapy given for CRS (check all that apply)

Indicate which therapies were given to treat the CRS event in the current reporting period. Pulse dose of corticosteroids are intravenous (IV) high doses given intermittently over a short time period. Specify the therapy if Other therapy is selected.

*Supportive Care
Supportive care treatments should not be reported as treatment for CRS. Examples of what not to report as Other therapy include, but are not limited to, acetaminophen (Tylenol®), albumin, antibiotics, IV fluids, or any brand name or specific corticosteroids administered (select Corticosteroids or Corticosteroids – pulse dose as applicable).

Of the drugs selected as therapy given for CRS, report the date of the first therapy given to treat CRS. Do not report the start date of fluids or supportive care.

If Tocilizumab was given to treat the CRS, report the number of doses given in the current reporting period.

If therapy was not given to treat the CRS event, select No therapy given.

Question 58: Indicate symptoms of CRS (check all that apply)

Specify the symptoms occurring in the current reporting period as a result of the CRS event.

If CRS persists from a prior reporting period, report the symptoms that worsened or carried over in this reporting period.

Fevers (≥100.4F or ≥38C): A disorder characterized by elevation of the body’s temperature above the upper limit of normal. Fever less than 100.4°F / 38°C does not qualify as a symptom of CRS on its own, unless the physician note indicates the recipient is being treated for CRS.

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. Do not report hypotension if treatment was not required.

*Hypoxia
If recipient receives supplemental oxygen via a low-flow nasal cannula then transfers to a high-flow nasal cannula in this reporting period, select only hypoxia requiring more than minimal supplemental oxygen (FiO2>40%) as the symptom

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.

Onset dates of each symptom are reported in the subsequent questions and are used to determine worsening of the CRS event and the maximum grade of the event.

¹ Source: Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, Maus MV, Park JH, Mead E, Pavletic S, Go WY, Eldjerou L, Gardner RA, Frey N, Curran KJ, Peggs K, Pasquini M, DiPersio JF, van den Brink MRM, Komanduri KV, Grupp SA, Neelapu SS. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019 Apr;25(4):625-638. doi: 10.1016/j.bbmt.2018.12.758. Epub 2018 Dec 25. PMID: 30592986; PMCID: PMC12180426.

Question 59: Date of fever onset

Report the date of onset of the fever. If there were multiple fevers in the reporting period, report the first occurrence. If the recipient self-reported a fever from a home test, and the date is documented in the medical records, report the date of the home test.

For more information regarding reporting partial or unknown dates, see General Instructions, General Guidelines for Completing Forms.

Question 60: Date of hypotension onset

Report the date of onset as the date that the hypotension required therapy. If there were multiple occurrences of hypotension requiring treatment, report the first occurrence.

For more information regarding reporting partial or unknown dates, see General Instructions, General Guidelines for Completing Forms.

Questions 61-65: Specify therapy given for hypotension (check all that apply)

Specify the therapy used to treat hypotension. Select all that apply:
Intravenous fluids
Vasopressor(s): If vasopressor(s) were given, report the number of vasopressors used and specify the drugs used. Options for number of vasopressors include 1 or >2 and can be used to determine the grade.

• In order to assess severity, only recipients who received two or more vasopressor agents at the same time, excluding vasopressin, should be marked as >2 vasopressors.
  

*Vasopressin
Vasopressin can be used with fluids or other vasopressors to stabilize the blood pressure. Addition of vasopressin to any other vasopressor agents does not reflect the same level of acuity compared to a recipient requiring two or more vasopressors without vasopressin.

Other therapy: Examples of what not to report as Other therapy include, but are not limited to, antibiotics, corticosteroids, any brand names, hypertension or antiarrhythmic drugs, or any drug used for CRS treatment (e.g. Anakinra, Tocilizumab).

Question 66: Was hypotension controlled with therapy?

Specify 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.

Question 67: Date of hypoxia onset for minimal supplemental oxygen (FiO2 < 40%)

Report the date of onset. If there were multiple occurrences of hypoxia requiring minimal supplemental oxygen, report the first occurrence.

For more information regarding reporting partial or unknown dates, see General Instructions, General Guidelines for Completing Forms.

Question 68: Date of hypoxia onset for more than minimal supplemental oxygen (FiO2 ≥ 40%)

Report the date of onset. If there were multiple occurrences of hypoxia requiring more than minimal supplemental oxygen, report the first occurrence.

For more information regarding reporting partial or unknown dates, see General Instructions, General Guidelines for Completing Forms.

Questions 69-76: Specify the laboratory values collected (check all that apply)

Disabled for TED level reporting

Report the maximum laboratory results obtained during the CRS event in the current reporting period. Maximum values should be between diagnosis and resolution dates, or diagnosis and current contact date if not resolved. If none of the labs listed on the form were assessed in the current reporting period, select None.

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. Specify the maximum value during the CRS event, the date the sample was collected, and the upper limit of normal for the lab report. If the maximum value occurred multiple times during the CRS event, report the date of the first occurrence.

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. Specify the maximum value during the CRS event, the units of measurement, and the date the sample was collected.

Total serum ferritin: Ferritin is an acute phase reactant and is often found in high concentration in highly inflammatory conditions. Report the maximum value during the CRS event and the date the sample was collected. If the maximum value occurred multiple times during the CRS event, report the date of the first occurrence.

Questions 77-78: 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.

!BiPAP and CPAP for Sleep Apena
Recipients 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.

If positive pressure ventilatory support was required due to the CRS event, select Yes and report the start date. If the recipient required multiple types of positive ventilatory support, report the start date of the first method. If positive pressure ventilatory support was not required, or it is unknown if it was required, report No or Unknown.

Questions 79-80: Did cytokine release syndrome resolve?

The resolution date is defined as the first date when all signs and symptoms leading to the diagnosis of CRS have resolved. If the CRS event reported in this instance is resolved in this reporting period, select Yes and report the resolution date.

!CRS resolution
If the recipient has symptoms again within 3-5 days after a resolution date, refer to the treating physician to determine if it’s a continuation of the same event or a new event.

If CRS did not resolve during the reporting period or it is not known, select No.

For more information regarding reporting partial or unknown dates, see General Instructions, General Guidelines for Completing Forms.

Question 81: Were features consistent with immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) present?

Immune effector cell-associated hemophagocytic lymphohistiocytosis(HLH)-like syndrome (IEC-HS) is defined as a pathological and biochemical hyperinflammatory syndrome that manifests with features of macrophage activation/HLH, is attributable to IEC therapy, and is associated with progression or new onset of cytopenias, hyperferritinemia, coagulopathy with hypofibrinogenemia, and/or transaminitis. Although HLH-like manifestations are frequently seen in patients with severe CRS, IEC-HS is often of delayed onset and manifests as CRS is resolved/resolving, and should not be used to describe only manifestations of severe CRS. Typical onset time of IEC-HS can occur as early as Day +7 and up to Day +28. Hyperferritinemia is a required criterion, and other supportive criteria are listed below in Table 1.

Indicate Yes if IEC-HS occurred or persisted into the current reporting period.

Table 1. Definition and identification of IEC-HS

¹ Source: Hines MR, Knight TE, McNerney KO, et al. Immune effector cell associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). Transplant Cell Ther. 2023;29(7):438.e1-438.e16.

Question 82: Date of IEC-HS onset

Report the date when the first symptom of IEC-HS was documented by a physician or other health care provider in the progress note or chart. Refer to Table 1 above for the criteria of IEC-HS diagnosis. IEC-HS can overlap with CRS but generally occurs after the diagnosis of CRS, most often CRS has begun to improve or has resolved. Refer to the treating physician if there are any questions regarding onset date.

If the IEC-HS event was diagnosed in a previous reporting period, and the symptoms continue into this reporting period, and the date has already been reported, leave the question blank and override the error using the code “Not Answered.”

For more information regarding reporting partial or unknown dates, see General Instructions, General Guidelines for Completing Forms.

Questions 83-85: Specify therapy given for IEC-HS toxicities (check all that apply)

Indicate which therapies were given to treat IEC-HS in the current reporting period. Pulse dose of corticosteroids are intravenous (IV) high doses given intermittently over a short time period. Specify the therapy if Other therapy is selected.

*Supportive Care
Supportive care treatments should not be reported as treatment for IEC-HS. Examples of what not to report as Other therapy include, but are not limited to, acetaminophen (Tylenol®) albumin, antibiotics, IV fluids, or any brand name or specific corticosteroids administered (select Corticosteroids or Corticosteroids – pulse dose as applicable).

If the recipient experiences CRS and IEC-HS events at the same time, report any therapy(s) that began after the diagnosis date of IEC-HS. This may include reporting a therapy as both CRS and IEC-HS treatment.

Of the drugs selected, report the date of the last dose therapy given to treat IEC-HS after the diagnosis of the event. Do not report the date of fluids or supportive care. This date is to help capture treatment duration of the IEC-HS event.

If therapy was not given to treat the IEC-HS event, select No therapy given.

Questions 86: Did the recipient have splenomegaly?

Indicate if the recipient has new onset splenomegaly (i.e., abnormal enlargement of the spleen) that could be attributed to the IEC-HS event. Splenomegaly due to baseline disease prior to IEC-HS diagnosis would not be counted towards IEC-HS criteria.

Splenomegaly is often documented during the physician’s physical assessment of the recipient and represents an abnormal finding. Splenomegaly can also be detected by imaging techniques such as ultrasonography, CT or MRI.

Questions 87: Was hemophagocytosis confirmed by a bone marrow biopsy or a bone marrow aspirate?

The pathognomonic feature of IEC-HS is a bone marrow examination that reveals numerous well differentiated macrophages actively phagocytosing hematopoietic cells. A bone marrow aspirate and biopsy may be performed to look for microscopic evidence of hemophagocytosis as part of the diagnostic work-up.

*Hemophagocytosis
Hemophagocytosis can be confirmed via a PB smear and CSF and reported below.

Report Yes if a bone marrow biopsy or bone marrow aspirate was obtained to confirm IEC-HS.

Questions 88-108: Specify the laboratory values collected (check all that apply)

Report the laboratory values obtained during the IEC-HS event in the current reporting period. Review below to determine which values to report for each lab (maximum vs lowest). Values should be between diagnosis and resolution dates, or diagnosis and current contact date if not resolved. If none of the labs listed on the form were assessed during the current reporting period, select None.

AST (SGOT): Aspartate aminotransferase, or serum glutamic oxalic transaminase, is an enzyme measured in serum or plasma that reflects liver function and liver cell integrity. Elevated levels of AST may indicate liver damage. Report the maximum value during the IEC-HS event, the units of measurement, and the upper limit of normal for your institution.

ALT (SGPT): Alanine aminotransferase, or serum glutamic pyruvic transaminase, is an enzyme measured in the blood that reflects liver function. Elevated levels of ALT may indicate liver injury, minor or severe. Report the maximum value during the IEC-HS event, the units of measurement, and the upper limit of normal for your institution.

CXCL9: a chemokine that plays a crucial role in the immune system by attracting and activating specific immune cells, particularly T lymphocytes. Also known as CMK, HuMIG, MIG, SCYB9, crg-10, C-X-C motif chemokine ligand 9. Report the maximum value during the IEC-HS event and the upper limit of normal for your institution.

Direct bilirubin: Bilirubin is a pigment that is formed from the breakdown of hemoglobin in red blood cells. Serum bilirubin is a test of liver function that reflects the ability of the liver to take up, process, and secrete bilirubin. Direct bilirubin is also known as conjugated bilirubin. Report the maximum value during the IEC-HS event, the units of measurement, and the upper limit of normal for your institution. Do not report a total bilirubin result.

Fibrinogen: a protein that plays a crucial role in blood clotting. Report the lowest value during the IEC-HS event and specify the units of measurement.

LDH: Lactate dehydrogenase is an enzyme found in the cytoplasm of almost all tissues, which converts L-lactate into pyruvate, or pyruvate into L-lactate depending on the oxygen level. Report the maximum value during the IEC-HS event, the units of measurement, and the upper limit of normal for your institution.

Prothrombin time (PT): Prothrombin is a protein made by the liver. It is one of several substances known as clotting (coagulation) factors. A PT test measures how many seconds it takes for a clot to form in a blood sample. Report the maximum value during the IEC-HS event and the upper limit of normal for your institution.

Partial thromboplastin (PTT): measure how long it takes for your blood to make a clot. Report the maximum value during the IEC-HS event and the upper limit of normal for your institution. Activated PTT results are comparable and can be reported here.

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. Report the maximum value during the IEC-HS event, the units of measurement, and the date the sample was collected. If both sIL2RA and CD25 are both performed, report the sIL2RA value.

Total serum ferritin: Ferritin is an acute phase reactant and is often found in high concentration in highly inflammatory conditions. Report the maximum value during the IEC-HS event and the date the sample was collected.

Triglyceride: a type of fat found in the bloodstream. Report the maximum value during the IEC-HS event and the units of measurement.

Question 109: Was there a fever associated with IEC-HS?

The intent of this question is to know if there was a fever (≥100.4F or ≥38C) after the IEC-HS diagnosis date.

Fever is a symptom of both CRS and IEC-HS. If the recipient experiences CRS with fever as a symptom, and the fever continues after the diagnosis of IEC-HS, the fever is also reported here.

Question 110: Were there organ toxicities associated with IEC-HS? (check all that apply)

Check all that apply for the organ toxicities the recipient experienced in the current reporting period associated with the IEC-HS event.

!IEC-HS and CRS
When a recipient experiences both CRS and IEC-HS, report any organ toxicities that occurred or persisted after the IEC-HS diagnosis date.

• Direct hyperbilirubinemia: abnormally high level of direct or conjugated bilirubin in the blood, typically this is >1-1.5 x ULN from baseline
• Hepatic transaminase elevation: AST/ALT values >5 X ULN (if baseline was normal) or >5 x baseline if baseline was abnormal
• Hypoxia: a disorder characterized by a decrease in the level of oxygen in the body¹.
• Pulmonary edema: a disorder characterized by accumulation of fluid in the lung tissues that causes a disturbance of the gas exchange that may lead to respiratory failure
• Pulmonary infiltrates: New onset of fluid, pus, blood, or protein that accumulate in the lung parenchyma
• Renal insufficiency: new onset of acute loss of renal function identified by an increase level of creatinine in the blood, typically this is >1.5 x ULN from baseline

¹ Common Terminology Criteria for Adverse Events (CTCAE) v6.0

Questions 111-112: Did IEC-HS resolve?

The resolution date is defined as the first date when all signs and symptoms leading to the diagnosis of IEC-HS8 have resolved. If the IEC-HS event reported in this instance is resolved in this reporting period, select Yes and report the resolution date.

If IEC-HS did not resolve during the reporting period or it is not known, select No.

!IEC-HS resolution
If the recipient has symptoms again within 3-5 days after a resolution date, refer to the treating physician to determine if it’s a continuation of the same event or a new event.

For more information regarding reporting partial or unknown dates, see General Instructions, General Guidelines for Completing Forms.

Question 113: Did the recipient experience immune effector cell-associated neurotoxicity syndrome (ICANS)?

ICANS (Immune effector Cell-associated Neurotoxicity Syndrome) is a disorder characterized by a pathologic process involving the central nervous system following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells¹. This was initially thought to be part of CRS, but it was also observed in the absence of any other signs of CRS. This section attempts to collect different clinical and laboratory information to understand the severity of this event.

Indicate Yes if ICANS occurred or persisted into the current reporting period. Any new or different manifestation seen after a prior resolution date would be reported as a new ICANS event.

¹ Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, Maus MV, Park JH, Mead E, Pavletic S, Go WY, Eldjerou L, Gardner RA, Frey N, Curran KJ, Peggs K, Pasquini M, DiPersio JF, van den Brink MRM, Komanduri KV, Grupp SA, Neelapu SS. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019 Apr;25(4):625-638. doi: 10.1016/j.bbmt.2018.12.758. Epub 2018 Dec 25. PMID: 30592986; PMCID: PMC12180426.

*Reporting Multiple ICANS Events
Report only ICANS events that are directly attributed to the CAR-T product / infusion associated with the event date of this form. If more than one ICANS event occurred in the reporting period, complete the ICANS questions for each event by adding an additional instance in the FormsNet3^SM application.
Refer to the definition of resolution to determine whether there is a new reportable event.

Question 114: Was the date of onset previously reported?

Specify if the diagnosis date of ICANS was previously reported. If the ICANS event was diagnosed in a previous reporting period, the symptoms continue into this reporting period, and the date has already been reported, select Yes. If the ICANS event was diagnosed in this reporting period, report No.

Question 115: Date of ICANS onset

Report the date when the first symptom of ICANS was documented by a physician or other health care provider in the progress note or chart.

For more information regarding reporting partial or unknown dates, see General Instructions, General Guidelines for Completing Forms.

Questions 116-117: Specify therapy given for ICANS (check all that apply)

Indicate which therapies were given to treat the ICANS event in the current reporting period. Pulse dose of corticosteroids are intravenous (IV) high doses given intermittently over a short time period. Specify the therapy if Other therapy is selected.

*Supportive Care
Supportive care treatments should not be reported as treatment for ICANS. Examples of what not to report as Other therapy include, but are not limited to, antibiotics (e.g., amoxicillin, cefepime, ciprofloxacin, piperacillin), antipsychotics (e.g., Risperdal) narcotics/opioids, other pain killers or any brand name or specific corticosteroids administered (select Corticosteroids or Corticosteroids – pulse dose as applicable).

If a drug was started as planned prophylaxis but the recipient develops neurotoxicity and the drug is continued as treatment, this is considered a change in intent from prophylaxis to treatment and the drug should also be reported here as therapy for ICANS.

If therapy was not given to treat the ICANS event, select No therapy given.

Question 118: What was the lowest ICE score?

The Immune Effector Cell-Associated Encephalopathy (ICE) score provides for the object grading of multiple overlapping encephalopathy terms. A score of 10 is normal. This screening tool assesses 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.

Unresponsive patients score 0 for all scales. Some centers perform these evaluations multiple times a day. These questions attempt to capture the worst score.

Lower scores are associated with a higher level of encephalopathy. Report the lowest score of any evaluation from the reporting period.

Unable to complete assessment should be selected when an assessment was started and couldn’t be finished for any reason or the recipient couldn’t perform the evaluation. This should be used rarely since evaluations may be given multiple times a day.

For children under the age of 12, the Cornell Assessment of Pediatric Delirium (CAPD) is recommended to aid in the overall grading of ICANS. A conversion chart is provided below to convert to an ICE score.

*ICANS Manifestations
For manifestations of ICANS, report the MAXIMUM grade observed for this event.

Questions 119-124: Indicate the manifestations of ICANS (check all that apply)

Specify the manifestations occurring in the current reporting period as a result of the ICANS event.

*ICE Score and ICANS Manifestations
Do not report the components of the ICE score as symptoms of ICANS.

!Other ICANS Manifestations
Post-CTED (4100) Form revision 10 does not include a field for Specify other manifestation of ICANS. If the recipient experiences another manifestation of ICANS that is not an option listed on the form, report the other manifestation in Other neurotoxicity.
If the recipient experiences ICANS and did not have any of the listed symptoms, leave blank Indicate the manifestations of ICANS and use the override code “Verified Correct” and report all manifestations in Other neurotoxicity.

Cerebral edema: A swelling in the brain caused by the presence of excessive fluid. Specify the type of cerebral edema.

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. Should be attributable to no other cause (e.g. no sedating medication). Specify the most severe level during the reported ICANS event.

Motor findings: neurological disorder affecting motor neurons that control muscle activity. Specify the type of motor neuron disorder.

• Hemiparesis: Weakness on one side of the body (hemiplegic), or other sudden loss of connectivity between the CNS and muscles.
• Paraparesis: Weakness affecting both lower extremities and is considered an incomplete paralysis, distinguishing it from paraplegia, which refers to complete paralysis of the lower extremities.
• Other motor neuron disorder: Other motor neuron disorder not included in above options. Examples include, but are not limited to, facial weakness/paralysis, etc. Do not report cranial nerve palsy (III, VI, VII), Guillain-Barre syndrome, or myelitis here.
  

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 severity (grade). If multiple seizures occurred with different grading, report the worst grade of the seizure the recipient experienced during the ICANS event.

Questions 125-126: Did ICANS resolve?

Resolution means complete normalization of neurologic function. It is possible that recipients might remain with residual neurologic dysfunction which would not qualify as complete resolution of this complication. If the ICANS event resolved during the reporting period, select Yes and report the resolution date.

For more information regarding reporting partial or unknown dates, see General Instructions, General Guidelines for Completing Forms.

Question 127: Did the recipient experience parkinsonism?

Parkinsonism is a non-ICANS neurotoxicities (NINTs), a clinical syndrome that occurs with disruption of dopaminergic signaling in the brain. This is distinct from ICANS, and possibly results from on-target, off-tumor activity. Median time to onset is 27 days (range 14-108) versus ICANS onset in 8 days (range 6-8). Parkinsonism is typically seen after CRS and/or ICANS resolution.¹

Indicate Yes if parkinsonism occurred or persisted into the current reporting period.

¹ Juliane Gust, BCMA-CAR T-cell treatment–associated parkinsonism, Blood, Volume 142, Issue 14, 2023, Pages 1181-1183, ISSN 0006-4971, https://doi.org/10.1182/blood.2023021860. (https://www.sciencedirect.com/science/article/pii/S0006497123019134)

*Reporting Multiple Parkinsonism Events
Report only parkinsonism events that are directly attributed to the CAR-T product / infusion associated with the event date of this form. If more than one parkinsonism event occurred in the reporting period, complete the parkinsonism questions for each event by adding an additional instance in the FormsNet3^SM application.
Refer to the definition of resolution to determine whether there is a new reportable event.

Question 128: Was the date of onset previously reported?

Specify if the diagnosis date of parkinsonism was previously reported. If the parkinsonism event was diagnosed in a previous reporting period, and the symptoms continue into this reporting period, and the date has already been reported, select Yes. If parkinsonism event was diagnosed in this reporting period, report No.

Question 129: Date of parkinsonism onset

Report the date when the first symptom of parkinsonism was documented by a physician or other health care provider in the progress note or chart.

For more information regarding reporting partial or unknown dates, see General Instructions, General Guidelines for Completing Forms.

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

Indicate which therapies were given to treat the parkinsonism event in the current reporting period. Pulse dose of corticosteroids are intravenous (IV) high doses given intermittently over a short time period. Specify the therapy if Other therapy is selected.

*Supportive Care
Supportive care treatments should not be reported as treatment for parkinsonism. Examples of what not to report as Other therapy include, but are not limited to, acetaminophen (Tylenol®) albumin, antibiotics, IV fluids, or any brand name or specific corticosteroids administered (select Corticosteroids or Corticosteroids – pulse dose as applicable).

If therapy was not given to treat the parkinsonism event, select No therapy given.

Questions 132-133: Indicate the manifestations of parkinsonism (check all that apply)

Specify the symptoms occurring in the current reporting period as a result of parkinsonism. If parkinsonism persists from a prior reporting period, report the symptoms that worsened or carried over in this reporting period. Do not report any symptom experienced by the recipient but independent of the parkinsonism diagnosis.

• Anosmia: a disorder characterized by a change in the sense of smell.
• Bradykinesia: slowed movement.
• Dyskinesia: abnormal, involuntary movements.
• Flat affect: lack of emotional expression.
• Gait disturbance: A disorder characterized by walking difficulties.
• Impaired swallowing: dysphagia, difficulty or pain moving food/liquids from mouth to stomach.
• Resting tremor: A disorder caused by the rapid alternating contraction and relaxation of muscles (involuntary) while the body is at rest against gravity and is a common symptom of diseases of the nervous system.
• Rigidity: stiffness or inflexibility in muscles.
• Other manifestation: If the recipient experienced a symptom of parkinsonism not listed above, select Other and specify the symptom.

¹ 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 134-135: Did parkinsonism resolve?

Resolution means complete normalization of neurologic function. It is possible that recipients might remain with residual neurologic dysfunction which would not qualify as complete resolution of this complication. If the parkinsonism event resolved during the reporting period, select Yes and report the resolution date.

For more information regarding reporting partial or unknown dates, see General Instructions, General Guidelines for Completing Forms.

Question 136: Did the recipient experience cranial nerve palsy (III, VI, VII)?

Cranial nerve palsy occurs when one or more of the 12 cranial nerves, often those controlling eye movement (III, IV, VI) or facial movement (VII), do not function properly.

Indicate Yes if cranial nerve palsy (III, VI, VII) occurred or persisted into the current reporting period.

!Cranial Nerve Palsy (III, VI, VII)
The following questions are disabled for TED level reporting: Onset date, Specify therapy, and Date resolved.

Question 137: Was the date of onset previously reported?

Specify if the diagnosis date of cranial nerve palsy (III, VI, VII) was previously reported. If the cranial nerve palsy (III, VI, VII) was diagnosed in a previous reporting period, and the symptoms continue into this reporting period, and the date has already been reported, select Yes. If cranial nerve palsy (III, VI, VII) was diagnosed in this reporting period, report No.

Question 138: Date of cranial nerve palsy onset

Report the date when the first symptom of cranial nerve palsy (III, VI, VII) was documented by a physician or other health care provider in the progress note or chart.

For more information regarding reporting partial or unknown dates, see General Instructions, General Guidelines for Completing Forms.

Questions 139-140: Specify therapy given for cranial nerve palsy (III, VI, VII) (check all that apply)

Indicate which therapies were given to treat cranial nerve palsy (III, VI, VII) in the current reporting period. Pulse dose of corticosteroids are intravenous (IV) high doses given intermittently over a short time period. Specify the therapy if Other therapy is selected.

*Supportive Care
Supportive care treatments should not be reported as treatment for cranial nerve palsy (III, VI, VII). Examples of what not to report as Other therapy include, but are not limited to, eye protection or physical therapy.

If therapy was not given to treat cranial nerve palsy (III, VI, VII), select No therapy given.

Questions 141-142: Did cranial nerve palsy (III, VI, VII) resolve?

Resolution means normalization of the palsy. It is possible that recipients might remain with residual neurologic dysfunction which would not qualify as complete resolution of this complication. If the cranial nerve palsy (III, VI, VII) resolved, select Yes and report the resolution date.

For more information regarding reporting partial or unknown dates, see General Instructions, General Guidelines for Completing Forms.

!Tumor Inflammation-Associated Neurotoxicity (TIAN)
TIAN related questions only apply to CAR-T products for brain tumors.
Report No to Did the recipient experience tumor inflammation-associated neurotoxicity (TIAN)? if the product is not a CAR-T for brain tumor.

Question 143: Did the recipient experience tumor inflammation-associated neurotoxicity (TIAN)?

Emerging preclinical and clinical experiences with cell therapies for CNS tumors have demonstrated a syndrome of localized neurotoxicity, termed tumor inflammation-associated neurotoxicity (TIAN), that is distinct from the systemic CRS and ICANS toxicity syndromes. TIAN occurs secondary to local, on-target tumor associated inflammation that is unique to neuroanatomy of the tumor itself. TIAN is relevant not only to cellular therapies, but also to other immunotherapies for CNS tumors. TIAN causes transient worsening of baseline neurologic deficits and/or clinical signs/symptoms of increased intracranial pressure.¹

Typical onset will vary based on the product infused, but it is usually seen within the first four weeks post-infusion. A TIAN event may resolve in a single day or last as long as two to three weeks.

Indicate Yes if TIAN occurred in the current reporting period or persisted into the current reporting period. TIAN as the diagnosis should be documented. There may also be documentation of the individual symptoms. If unclear that TIAN occurred, refer to the treating physician.

¹ Mahdi J, Dietrich J, Straathof K, Roddie C, Scott BJ, Davidson TB, Prolo LM, Batchelor TT, Campen CJ, Davis KL, Gust J, Lim M, Majzner RG, Park JR, Partap S, Ramakrishna S, Richards R, Schultz L, Vitanza NA, Wang LD, Mackall CL, Monje M. Tumor inflammation-associated neurotoxicity. Nat Med. 2023 Apr;29(4):803-810. doi: 10.1038/s41591-023-02276-w. Epub 2023 Apr 6. PMID: 37024595; PMCID: PMC10166099.

*Reporting Multiple TIAN Events
Report only TIAN events that are directly attributed to the CAR-T product / infusion associated with the event date of this form. If more than one TIAN event occurred in the reporting period, complete the TIAN questions for each event by adding an additional instance in the FormsNet3^SM application.
Refer to the definition of resolution to determine if there is a new reportable event.

!When to report a new instance of TIAN
If a prior instance of TIAN has completely resolved and the inflammation appeared to completely resolve off anti-inflammatory agents and then new neurological symptoms developed with concerns for a second wave of inflammation, then that would be considered a new event.

!Tumor Inflammation-Associated Neurotoxicity
The following questions are disabled for TED level reporting: Onset date, Specify therapy, and Date resolved.

Question 144: Was the date of onset previously reported?

Specify if the diagnosis date of TIAN was previously reported. If the TIAN event was diagnosed in a previous reporting period, and the symptoms continue into this reporting period, and the date has already been reported, select Yes. If the TIAN event was diagnosed in this reporting period, report No.

Question 145: Date of TIAN onset

At this time, the neurological exam remains the most sensitive diagnostic tool for the assessment and treatment of TIAN¹. Report the date when the first symptom of TIAN event was documented either by MRI or in the physician’s notes.

If a prior instance of TIAN has completely resolved and the inflammation appeared to completely resolve off anti-inflammatory agents and then new neurological symptoms developed with concerns for a second wave of inflammation, then that would be considered a new event.

For more information regarding reporting partial or unknown dates, see General Instructions, General Guidelines for Completing Forms.

¹ Mahdi J, Dietrich J, Straathof K, Roddie C, Scott BJ, Davidson TB, Prolo LM, Batchelor TT, Campen CJ, Davis KL, Gust J, Lim M, Majzner RG, Park JR, Partap S, Ramakrishna S, Richards R, Schultz L, Vitanza NA, Wang LD, Mackall CL, Monje M. Tumor inflammation-associated neurotoxicity. Nat Med. 2023 Apr;29(4):803-810. doi: 10.1038/s41591-023-02276-w. Epub 2023 Apr 6. PMID: 37024595; PMCID: PMC10166099.

Questions 146-147: Specify therapy given for TIAN (check all that apply)

Indicate which therapies were given to treat the TIAN event in the current reporting period. Pulse dose of corticosteroids are intravenous (IV) high doses given intermittently over a short time period. Specify the therapy if Other therapy is selected.

*Supportive Care
Supportive care treatments should not be reported as treatment for TIAN. Examples of what not to report as Other therapy include, but are not limited to, acetaminophen (Tylenol®) albumin, antibiotics, IV fluids, or any brand name or specific corticosteroids administered (select Corticosteroids or Corticosteroids – pulse dose as applicable).

If therapy was not given to treat TIAN, select No therapy given.

Questions 148-149: Did TIAN resolve?

Resolution means the recipient has returned to their neurologic baseline. Recipients with CNS tumors often have neurologic deficits at baseline as a direct result of their tumors or previous therapy. In this case, the comparison should be made to the recipient’s baseline neurologic exam before immunotherapy to determine if the TIAN has resolved. The TIAN resolution should be clearly documented and can only be determined by the physician/APP.

If inflammation persists, appears to resolve for a few days, but then returns or the recipient is not off anti-inflammatory agents, do not report TIAN resolution.

If the TIAN event resolved in the current reporting period, select Yes and report the resolution date.

For more information regarding reporting partial or unknown dates, see General Instructions, General Guidelines for Completing Forms.

Question 150: Did the recipient experience Guillain-Barre syndrome?

Guillain-Barre syndrome (GBS) is a disorder characterized by the body’s immune system attacking the peripheral nervous system causing ascending paralysis¹. GBS typically presents as progressive, symmetric, ascending muscle weakness, often accompanied by sensory disturbances, areflexia, dysautonomia, and in severe cases, respiratory compromise². It is more common in adults than pediatric patients. Average range to GBS symptom onset is 5-78 days (mean 27.1 days), and it is frequently preceded by CRS².

Indicate Yes if GBS occurred or persisted into the current reporting period. Also report if it’s documented as “Guillain-Barre-like symptoms”.

¹ 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
fn2. Kilroe KM, Clarke JE, Ann P, Salamon N, Acharya J. Guillain-Barre syndrome in patients receiving chimeric antigen receptor T-cell therapy: an individual participant data meta-analysis. Front Neurol. 2025 Nov 13;16:1704826. doi: 10.3389/fneur.2025.1704826. PMID: 41323217; PMCID: PMC12658458.

!Guillain-Barre syndrome
The following questions are disabled for TED level reporting: Onset date, Specify therapy, and Date resolved.

Question 151: Was the date of onset previously reported?

Specify if the diagnosis date of Guillain-Barre syndrome (GBS) was previously reported. If the GBS was diagnosed in a previous reporting period, and the symptoms continue into this reporting period, and the date has already been reported, select Yes. If GBS was diagnosed in this reporting period, report No.

Question 152: Date of Guillain-Barre syndrome onset

Report the date when the first symptom of Guillain-Barre syndrome was documented by a physician or other health care provider in the progress note or chart. The diagnosis is primarily clinical but may be supported by cerebrospinal fluid analysis¹.

For more information regarding reporting partial or unknown dates, see General Instructions, General Guidelines for Completing Forms.

¹ Kilroe KM, Clarke JE, Ann P, Salamon N, Acharya J. Guillain-Barre syndrome in patients receiving chimeric antigen receptor T-cell therapy: an individual participant data meta-analysis. Front Neurol. 2025 Nov 13;16:1704826. doi: 10.3389/fneur.2025.1704826. PMID: 41323217; PMCID: PMC12658458.

Questions 153-154: Specify therapy given for Guillain-Barre syndrome (check all that apply)

Indicate which therapies were given to treat Guillain-Barre syndrome (GBS) in the current reporting period. Specify the therapy if Other therapy is selected.

*Supportive Care
Supportive care treatments should not be reported as treatment for Guillain-Barre syndrome. Examples of what not to report as other therapy include, but are not limited to, physical therapy or occupational therapy.

Guillain-Barre syndrome is rarely left untreated. If therapy was not given to treat GBS, leave the question blank and leave the question blank and override the error using the code “Unable to Answer.”

Questions 155-156: Did Guillain-Barre syndrome resolve?

Resolution means complete normalization of neurologic function. It is possible that recipients might remain with residual neurologic dysfunction which would not qualify as complete resolution of this complication. If GBS resolved in this reporting period, select Yes and report the resolution date.

For more information regarding reporting partial or unknown dates, see General Instructions, General Guidelines for Completing Forms.

*Reporting Multiple Other Neurotoxicity Events
Report only other neurotoxicity events that are directly attributed to the CAR-T product/infusion. If more than one other neurotoxicity event occurred in the reporting period, complete the other neurotoxicity questions for each event by adding an additional instance in the FormsNet3^SM application.

Questions 157-158: Other neurotoxicity

These neurotoxicities do not fit into a category above, but are still important to capture:

• Ataxia: A disorder characterized by lack of coordination of muscle movements resulting in the impairment or inability to perform voluntary activities
• Cerebrovascular 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. 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).
• Dysmetria: a specific type of ataxia, improper accuracy in voluntary movements.
• Leukoencephalopathy: A disorder characterized by diffuse reactive astrocytosis with multiple areas of necrotic foci without inflammation as determined by neuroimaging (i.e., brain MRI).
• Myelitis: Inflammation of the spinal cord

Indicate Yes if another neurotoxicity occurred or persisted into the current reporting period.

Question 159: Date of onset

Report the date when the first symptom of the other neurotoxicity was documented by a physician or other health care provider in the progress note or chart.

For more information regarding reporting partial or unknown dates, see General Instructions, General Guidelines for Completing Forms.

Question 160: Specify type of cerebrovascular accident

Disabled for TED reporting level

Cerebral vascular accident (stroke) is 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.

Specify the type of cerebrovascular accident:

• 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 stroke occurs when the arteries to your brain become narrowed or blocked, causing severely reduced blood flow (ischemia).
  

A recipient may experience both hemorrhagic and ischemic stroke in the same reporting period. Report each as a separate instance.

Other toxicities

Questions 161-162: Did the recipient receive immunoglobulin replacement therapy?

Replacement therapy is given to prevent infections. If the recipient received immunoglobulin replacement therapy (includes, but not limited to, IVIG or SCIG) regardless of hypogammaglobulinemia that developed post-infusion, select Yes.

Specify the reason the recipient received immunoglobulin therapy. Select Prophylaxis if the recipient did not fulfill the hypogammaglobulinemia criteria but still received immunoglobulin therapy. If the recipient was initially given IVIG as prophylaxis but it becomes replacement therapy, still report as Prophylaxis since that was the original intent. Select Replacement if the recipient did fulfill the hypogammaglobulinemia criteria (as noted below).

!Immunoglobulin Therapy Date
This question can only be completed on the Day 100 follow-up form. This question will be skipped for all subsequent reporting periods

Question 163: Date of first administration of immunoglobulin therapy

Report the date of the first administration of immunoglobulin therapy given to the recipient.

For more information regarding reporting partial or unknown dates, see General Instructions, General Guidelines for Completing Forms.

Questions 164-165: Did the immunoglobulin therapy stop?

Specify Yes or No if the immunoglobulin therapy stopped in this reporting period and report the date of last immunoglobulin therapy infusion given.

For more information regarding reporting partial or unknown dates, see General Instructions, General Guidelines for Completing Forms.

Questions 166-167: Has the recipient’s immunoglobulin level recovered?

Hypogammaglobulinemia refers to low levels of circulating gammaglobulins, or immunoglobulins, in the blood and often determined by quantitative levels of immunoglobulins G (IgG), A (IgA) and M (IgM), or most commonly IgG only. 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. Immunoglobulin replacement therapy is given to prevent infections.

Hypogammaglobulinemia can be reported as resolved if there are sustained normal levels of IgG in the blood without the need for IG infusions for six consecutive months.

Normal limits of IgG concentration in the blood vary with age. For adults, levels lower than 600 mg/dL of circulating IgG are considered to be hypogammaglobulinemia. Children ages four to 18, levels lower than 500 mg/dL are considered hypogammaglobulinemia. Children younger than four 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.

Example 1. IgG levels were 450 mg/dL on June 1; immunoglobulin replacement therapy was given on June 15. IgG levels were monitored for the next 7 months, and no further immunoglobulin replacement therapy was given. IgG levels went above 600 mg/dL on December 15 and continued to rise. Report the resolution date as the first test result that was greater than 600 mg/dL (December 15).

Example 2. IgG levels were 450 mg/dL on May 15, no immunoglobulin replacement therapy is given. IgG levels were monitored and went above 600 mg/dL on June 3 and normal levels were sustained. Report resolution date as the first test result that was greater than 600 mg/dL (June 3).

Example 3. IgG levels were 450 mg/dL on June 1; immunoglobulin replacement therapy was given on June 15. IgG levels were not monitored, and the recipient has returned to their primary oncologist. In the absence of any testing, the resolution date can be reported as the date 6 months after the last IG infusion.

Example 4. For an adult recipient, IgG levels were 450 mg/dL on June 1; immunoglobulin replacement therapy was given on June 15. IgG levels were monitored over the next six and a half months and no further immunoglobulin replacement therapy was given. IgG levels were tested, and measured greater than 600 mg/dL, on November 29 (5.2 months after last IG infusion) and December 25 (6.2 months after the last IG infusion). The resolution date should be greater than or equal to 6 months after the last IG infusion; therefore December 25 should be reported as the resolution date.

Example 5. For an adult recipient, IgG levels were 450 mg/dL on June 1; immunoglobulin replacement therapy was given on June 15. IgG levels were monitored over the next six and a half months and no further immunoglobulin replacement therapy was given. IgG levels were tested, and measured greater than 600 mg/dL, on November 29 (5.5 months after last IVIG infusion). IgG levels were measured at 450 mg/dL on December 25 (6.2 months after the last IG infusion). Hypogammaglobulinemia cannot be reported as resolved in this case.

If the IgG was assessed in the reporting period and hypogammaglobulinemia resolved without the need for IG infusions for six consecutive months, select Yes and report the resolution date as documented by a physician or other health care provider in the progress note or chart.

Select Not applicable when:

• The recipient never got immunoglobulin replacement therapy because their IgG levels were never decreased
  Or
• There was no decline in IgG levels in this reporting period
  Or
• IgG levels were never tested in this reporting period

Question 168: Tumor lysis syndrome

Disabled for TED reporting level

Tumor lysis syndrome (TLS) is a disorder characterized by metabolic abnormalities that result from a spontaneous or therapy-related cytolysis of tumor cells. Indicate if TLS occurred or persisted into the current reporting period.

Indicate Yes, No, or Unknown if tumor lysis syndrome occurred or persisted into the current reporting period.

Question 169: Was the date of onset previously reported?

Specify if the diagnosis date of tumor lysis syndrome was previously reported. If the tumor lysis syndrome was diagnosed in a previous reporting period, and the symptoms continue into this reporting period, and the date has already been reported, select Yes. If tumor lysis syndrome was diagnosed in this reporting period, report No.

Question 170: Date of onset

Report the date when the first symptom of tumor lysis syndrome documented by a physician or other health care provider in the progress note or chart.

For more information regarding reporting partial or unknown dates, see General Instructions, General Guidelines for Completing Forms.

Question 171: Tumor lysis syndrome

Report the most severe grade of the tumor lysis syndrome in the reporting period 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 172-173: Tumor lysis syndrome

If the tumor lysis syndrome resolved, select Yes and report the resolution date as documented by a physician or other health care provider in the progress note or chart.

For more information regarding reporting partial or unknown dates, see General Instructions, General Guidelines for Completing Forms.

Questions 174-175: Other toxicity

Disabled for TED reporting level

To reduce the reporting burden, other toxicities 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 and specify the other toxicity.

If the recipient did not experience other toxicities or it is unknown, select No.

*Reporting multiple other toxicities
If more than one other toxicity occurred in the reporting period, complete the other toxicity questions for each event by adding an additional instance in the FormsNet3^SM application.

Question 176: Was the date of onset previously reported?

Specify if the other toxicity was diagnosed in a previous reporting period. If the other toxicity was diagnosed in a previous reporting period, and the symptoms continue into this reporting period, and the date has already been reported, select Yes. If the other toxicity was not diagnosed in a previous reporting period, report No.

Question 177 Date of onset

Report the date when the first symptom of the other toxicity was documented by a physician or other health care provider in the progress note or chart.

For more information regarding reporting partial or unknown dates, see General Instructions, General Guidelines for Completing Forms.

Questions 178-179: Did the other toxicity resolve?

Resolution means complete normalization of function. It is possible that recipients might remain with residual dysfunction which would not qualify as complete resolution of this complication. If the other toxicity resolved, select Yes and report the resolution date.

For more information regarding reporting partial or unknown dates, see General Instructions, General Guidelines for Completing Forms.

!Grade 3 and 4 Organ Toxicities
This question will enable only for commercially available products Abecma®, Breyanzi®, or Carvykti®, or Kymriah® AND the CRID is enrolled into the applicable study.

!Grade 3 and 4 Organ Toxicities
If the recipient experiences a grade 3 organ toxicity that progresses to a grade 4 organ toxicity, report only the highest grade (e.g. grade 4) and report the onset date when it became grade 4.

!Grade 3 Organ Toxicities
These questions can only be completed on the Day 100 and six-month follow-up forms. These questions will be skipped for all subsequent reporting periods

Questions 180-186: Has the recipient experienced a 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. If Other is selected, then the 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.

Indicate Yes, No, or Unknown if the recipient experienced a grade 3 organ toxicity in the current reporting period that is directly attributed to the CAR-T product / infusion associated with the event date of this form.

*Reporting multiple Grade 3 toxicities
If more than one grade 3 organ toxicity occurred in the reporting period, complete the grade 3 organ toxicity questions for each event by adding an additional instance in the FormsNet3^SM application.

Specify the organ affected and specify the toxicity of that organ. The list of symptoms will dynamically filter based on the organ selected. The table below shows all option values.

Organ / System	Symptom or Event
Cardiovascular	Capillary leak syndrome, cardiac arrhythmia, hypertension, hypotension, left ventricular systolic dysfunction, myocardial infarction, new or worsening heart failure, pericardial effusion, pericarditis, restrictive cardiomyopathy, thromboembolic event
Gastrointestinal	Abdominal pain, constipation, diarrhea, dyspepsia (heartburn), gastroenteritis, intestinal obstruction (includes small intestine and colonic), mucositis oral, nausea, vomiting
Kidneys	Acute kidney injury, chronic kidney disease, cystitis noninfective
Liver	Alanine aminotransferase increased (ALT), alkaline phosphatase increased, aspartate aminotransferase increased (AST), blood bilirubin increased, hepatic failure, hepatitis
Lungs	Acute respiratory distress syndrome, dyspnea, productive cough, pulmonary edema, respiratory edema, respiratory failure
Musculoskeletal	Arthralgia (joint pain), muscle weakness, generalized or specific area (not due to neuropathy), myalgia (muscle pain)
Nervous system	Dizziness, encephalopathy, headache, tremor
Other	Anorexia, chills, dysgeusia (taste alternation), edema limbs, fatigue

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 to the question Was the date of onset previously reported and report the date when the grade 3 organ toxicity was documented by either a physician/ health care provider or determined by lab results. Else select No and report the date of grade 3 organ toxicity diagnosis..

If the grade 3 organ toxicity resolved, select Yes to the question Did the grade 3 organ toxicity resolve? and report the date as documented by a physician or other health care provider in the progress note or chart.

Questions 187-193: Has the recipient experienced a grade 4 organ toxicity?

!Grade 4 Organ Toxicities
These questions can only be completed on the Day 100 and six-month follow-up forms. These questions will be skipped for all subsequent reporting periods

Disabled for TED reporting level

As defined by the CTCAE criteria, grade 4 toxicity represents life-threatening consequences and urgent intervention is indicated. If Other is selected, then the 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.

Indicate Yes, No, or Unknown if the recipient experienced a grade 4 organ toxicity in the current reporting period that is directly attributed to the CAR-T product / infusion associated with the event date of this form.

*Reporting multiple Grade 4 toxicities
If more than one grade 4 organ toxicity occurred in the reporting period, complete the grade 4 organ toxicity questions for each event by adding an additional instance in the FormsNet3^SM application.

Specify the organ affected and specify the toxicity of that organ. The list of symptoms will dynamically filter based on the organ selected. The table below shows all option values.

Organ / System	Symptom or Event
Cardiovascular	Capillary leak syndrome, cardiac arrhythmia, hypertension, hypotension, left ventricular systolic dysfunction, myocardial infarction, new or worsening heart failure, pericardial effusion, pericarditis, restrictive cardiomyopathy, thromboembolic event
Gastrointestinal	Abdominal pain, constipation, diarrhea, dyspepsia (heartburn), gastroenteritis, intestinal obstruction (includes small intestine and colonic), mucositis oral, nausea, vomiting
Kidneys	Acute kidney injury, chronic kidney disease, cystitis noninfective
Liver	Alanine aminotransferase increased (ALT), alkaline phosphatase increased, aspartate aminotransferase increased (AST), blood bilirubin increased, hepatic failure, hepatitis
Lungs	Acute respiratory distress syndrome, dyspnea, productive cough, pulmonary edema, respiratory edema, respiratory failure
Musculoskeletal	Arthralgia (joint pain), muscle weakness, generalized or specific area (not due to neuropathy), myalgia (muscle pain)
Nervous system	Dizziness, encephalopathy, headache, tremor
Other	Anorexia, chills, dysgeusia (taste alternation), edema limbs, fatigue

Specify if the diagnosis date of the grade 4 organ toxicity was previously reported. If the grade 4 organ toxicity was diagnosed in a previous reporting period, and the symptoms continue into this reporting period, and the date has already been reported, select Yes. If the grade 4 organ toxicity was diagnosed in this reporting period, report No. Report the date when the grade 4 organ toxicity was documented by either a physician/ health care provider or determined by lab results.

For more information regarding reporting partial or unknown dates, see General Instructions, General Guidelines for Completing Forms.

If the grade 4 organ toxicity resolved, select Yes and report the date as documented by a physician or other health care provider in the progress note or chart.

Section Updates:

Question Number	Date of Change	Add/Remove/Modify	Description	Reasoning (If applicable)
.	.	.	.	.

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CIBMTR® (Center for International Blood and Marrow Transplant Research) is a research collaboration between the Medical College of Wisconsin and NMDP.