Combined follow up
In scenarios where both HCT and cellular therapy forms are being completed, toxicities should still be reported when an HCT follows a cellular therapy. It is possible to have CAR-T cell reactivation post-HCT.

Question 89: 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 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.

Indicate Yes if CRS occurred or persisted into the current reporting period and continue with question 80.
Indicate No if CRS did not occur or persist into the current reporting period and continue with question 110.

Question 90: Was the date of diagnosis previously reported?

If the CRS was diagnosed in a previous reporting period, and the symptoms continue into this reporting period, and the date has already been reported, select Yes and continue with question 92. If CRS was not diagnosed in a prior reporting period, report No and continue with question 91.

Question 91: 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.

Questions 92-94: Specify therapy given for CRS: (check all that apply)

Check all that apply from the list of the drug(s) given to treat CRS in this reporting period. If Other therapy is selected, specify the therapy in question 93. Supportive care treatments should not be reported as treatment for CRS. Examples of what not to report include, but are not limited to, acetaminophen (Tylenol®) albumin, or antibiotics,

If Tocilizumab was given to treat the CRS, report the number of doses given in question 94. This information is important in the grading of the CRS event.

Questions 95-105: Indicate symptoms of CRS (check all that apply)

Indicate which symptoms of CRS the recipient experienced in the current reporting period, check all symptoms that apply. 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.

If CRS is persisting 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. Do not report fever if less 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 87. 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. Report the date of hypotension onset in question 97. Report therapy given for hypotension in question 98.

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 at the same time 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 at the same time excluding vasopressin. Select the number of vasopressors used for therapy in question 100.

Specify any vasopressor(s) used at the same time as a single therapy to treat hypotension in question 101 and 102. And report if hypotension was controlled with therapy in question 103. 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. Report the date of onset in question 104.

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. Report the date of onset in question 105.

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

Questions 106-107: 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.

If positive pressure ventilatory support was required, select Yes and report the start date in question 107. 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 unknown if it was required, report No or Unknown and continue with question 108.

Questions 108-109: Did cytokine release syndrome resolve?

If the cytokine release syndrome resolved, select Yes and report the resolution date (YYYY-MM-DD) in question 109.

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 110.

It is possible a patient could experience CRS like symptoms after the CRS event has previously resolved. In these situations, please report the date of onset, the worst grade of both events, and the resolution of the second event if applicable. Please contact CIBMTR Center Support for a review of these types of scenarios.

Questions 110-111: Were there features related to macrophage activation syndrome (MAS) / hemophagocytic lymphohistiocytosis (HLH)?

Macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH) are a severe systematic inflammatory syndromes caused by excessive activation and expansion of T lymphocytes and macrophagic histiocytes. HLH is recognized as both a familial disorder and a sporadic disorder associated with an infection, malignancy, and rheumatologic disorders1. Diagnostic clinical criteria for MAS/HLH include fever, cytopenias, high triglyceride levels, high ferritin levels, high soluble IL-2 receptor levels, low fibrinogen levels or organomegaly. MAS/HLH has also been reported following chimeric antigen receptor (CAR) T-cell therapy. Some patients may present with CRS and progress into this more aggressive syndrome, where the MAS/HLH falls into the spectrum of CRS. But MAS/HLH may also develop independently which can be due to the recipient’s underlying disease (especially lymphoma1). The intent of this question is to capture whether MAS/HLH occurred in the recipient regardless of CRS occurring.

1. Jordan, MB, Allen, CE, Greenberg, J, et al. Challenges in the diagnosis of hemophagocytic lymphohistiocytosis: recommendations from the North American Consortium for Histiocytosis (NACHO). Pediatr Blood Cancer. 2019; 66:e27929.

Report the date (YYYY-MM-DD) in question 111 when the first symptom of MAS/HLH was documented by either the date of the pathological confirmation of MAS/HLH (bone marrow or other organ biopsy) or the first date of a ferritin level > 100,000 ng/mL among patients without pathologic confirmation but with high clinical suspicion (persistent high fevers, ongoing cytopenias, high triglyceride levels, low fibrinogen levels or organomegaly). Continue with question 112.

Questions 112: Did the recipient have splenomegaly?

Indicate if the recipient had splenomegaly (i.e., abnormal enlargement of the spleen) that could be attributed to MAS/HLH. 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. Continue with question 113.

Questions 113: Was MAS/HLH confirmed by a bone marrow biopsy?

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

Report Yes if a bone marrow biopsy was obtained to confirm MAS/HLH. Report No if a bone marrow biopsy was not obtained to confirm MAS/HLH.

Questions 114-118: Specify the laboratory values collected (check all that apply)

Hypofibrinogenemia and hypertriglyceridemia support the diagnosis of HLH. The laboratory values should be at the time of diagnosis of MAS/HLH.

If Fibrinogen is selected in question 114, report the lowest fibrinogen level in question 115 and the date the sample was collected in question 116.

If Triglyceride is selected in question 114, report the highest triglyceride level in question 117 and the date the sample was collected in question 118.

Questions 119-120: Did macrophage activation syndrome (MAS) / hemophagocytic lymphohistiocytosis (HLH) resolve?

If the macrophage activation syndrome (MAS) / hemophagocytic lymphohistiocytosis (HLH) resolved, select Yes and report the resolution date (YYYY-MM-DD) in question 120.

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 macrophage activation syndrome (MAS) / hemophagocytic lymphohistiocytosis (HLH) did not resolve, select No and continue with question 121.

Questions 121: Did the recipient experience neurotoxicity (ICANS)?

ICANS (Immune effector Cell-associated Neurotoxicity Syndrome) 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 or No if neurotoxicity occurred or persisted in the current reporting period. If neurotoxicity did not occur / persist into the current reporting period or it is not known, select No or Unknown, respectively then continue with question 160.

Questions 122: 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 124. If neurotoxicity (ICANS) was not diagnosed in a prior reporting period, report No and enter the date of neurotoxicity (ICANS) diagnosis in question 123.

Question 123: Date of neurotoxicity (ICANS) onset:

Report the date (YYYY-MM-DD) when the first symptom of neurotoxicity (ICANS) 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 124-125: Specify therapy given for neurotoxicity: (check all that apply)

Check all that apply from the list of drug(s) given to treat neurotoxicity (ICANS) in this reporting period. Pulse dose of corticosteroids are intravenous (IV) high doses given intermittently over a short time period. If Other therapy is selected, specify the therapy in question 125.

Question 126: Which cognitive 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 127 for a conversion of the Cornell Assessment of Pediatric Delirium (CAPD) to CARTOX or ICE.

Question 127: What was the lowest score? (e.g. CARTOX-10, ICE)

Tables for answering question 106 of form 4100.

Questions 128-158: Indicate the symptoms of neurotoxicity (ICANS) (check all that apply)

Cerebral edema: A swelling in the brain caused by the presence of excessive fluid. Specify the type of cerebral edema in question 130, report if the cerebral edema resolved in question 131, and the date of resolution in question 132 (if applicable).

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 133 and 134.

Cognitive impairment: A disorder characterized by a conspicuous change in cognitive functiona. Specify the type of cognitive impairment in question 135, report if the cognitive impairment resolved in question 137, and the date of resolution in question 138 (if applicable). The date of resolution should be the for the category as a whole, e.g. when the last symptom resolved.

  • Amnesia: A disorder characterized by systematic and extensive loss of memorya
  • Cognitive disorder: A disorder characterized by a conspicuous change in cognitive functiona
  • Confusional state: A disorder characterized by a lack of clear and orderly thought and behaviora
  • Concentration impairment: A disorder characterized by a deterioration in the ability to concentratea
  • Encephalopathy: A disorder characterized by a pathologic process involving the braina
  • Hallucination: A disorder characterized by a false sensory perception in the absence of an external stimulusa
  • Leukoencephalopathy: A disorder characterized by diffuse reactive astrocytosis with multiple areas of necrotic foci without inflammation* as determined by neuroimaging (i.e. brain MRI).
  • Loss of consciousness: A disorder characterized by a decrease in ability to perceive and responda
  • Mental status changes: a change in a person’s mood, behavior, psychomotor skills, and/or cognition
  • Non-infective encephalitis: inflammation of the brain not caused by infection
  • Psychomotor retardation: slowing of mental and physical activity
  • Other cognitive impairment: other decline in mental abilities not included in above options

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 139, report if the depressed level on consciousness resolved in question 140, and the date of resolution in question 141 (if applicable).

Motor neuron disorder: neurological disorder effecting motor neurons that control muscle activity. Specify the type of motor neuron disorder in question 142, report if the motor neuron disorder resolved in question 144, and the date of resolution in question 145 (if applicable). The date of resolution should be the for the category as a whole, e.g. when the last symptom resolved.

  • Facial weakness/paralysis: weakness or inability to move facial musculature
  • Hemiparesis: 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.
  • Paraparesis: 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.
  • Guillain-Barre syndrome: A disorder characterized by the body’s immune system attacking the peripheral nervous system causing ascending paralysisa
  • Myelitis: Inflammation of the spinal cord
  • Other motor neuron disorder: other motor neuron disorder not included in above options

Movement disorder: neurologic disorder causing excess movement or lack of voluntary movement. Specify the type of movement disorder in question 146, report if the movement disorder resolved in question 148, and the date of resolution in question 149 (if applicable). The date of resolution should be the for the category as a whole, e.g. when the last symptom resolved.

  • Action tremor: A disorder caused by the rapid alternating contraction and relaxation of muscles with the voluntary movement of a muscle and is a common symptom of diseases of the nervous system.
  • Ataxia: A disorder characterized by lack of coordination of muscle movements resulting in the impairment or inability to perform voluntary activities
  • Cogwheel rigidity: muscular rigidity causing cogwheel jerks to passive movement of limbs
  • Dysgraphia: neurologic disorder causing writing disabilities
  • Dyskinesia: abnormal, involuntary movements
  • Dysmetria: improper accuracy in voluntary movements
  • Gait disturbance: A disorder characterized by walking difficulties
  • Myoclonus: involuntary and sudden movement of muscle
  • 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.
  • Other movement disorder: other movement disorder not included in above options

Personality change: deviation from the patient’s normal behavior patterns. Specify the type of personality change in question 150, report if the personality change resolved in question 151, and the date of resolution in question 152 (if applicable). The date of resolution should be the for the category as a whole, e.g. when the last symptom resolved.

  • Flat affect: lack of emotional expression
  • Personality change: A disorder characterized by a conspicuous change in a person’s behavior and thinkinga
  • Other personality change: other personality change not included in above options

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 154-156. Report the worst type of seizure if multiple types were experienced in a single reporting period.
Speech impairment: neurologic disorder causing disruption of normal speech. Specify the type of speed impairment in question 157 and specify the grade of dysphasia in question 158 (if applicable)

  • Dysphasia: The loss of ability to understand or express speech, caused by brain damage.
  • Aphasia: Grade 3 dysphasia is defined as aphasia

Other symptom: If the recipient experienced a symptom of neurotoxicity not listed above, report here and specify the symptom in question 129.

aCommon 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 159-160: Did neurotoxicity resolve?

If the cellular therapy associated neurotoxicity resolved, select Yes and report the resolution date (YYYY-MM-DD) in question 160. 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.

Other toxicities

Questions 161: Hypogammaglobulinemia

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. Levels lower than 600 mg/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 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.

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.

Example 1. For an adult recipient, IgG levels were below 600 mg/dL pre-cellular therapy infusion and continue to be low post-infusion. This is reported as a toxicity, even though IgG level were below 600 mg/dL pre-infusion.

Example 2. For an adult recipient, IgG levels were below 600 mg/dL pre-cellular therapy infusion and continues to be low post-infusion and immunoglobulin replacement therapy (IVIG) was given post-infusion. This is reported as a toxicity, even though IgG level were below 600 mg/dL pre-infusion.

Example 3. For an adult recipient, IgG levels were never below 600 mg/dL, but levels were decreasing post-infusion and immunoglobulin replacement therapy (IVIG) was given. This is not reported as a toxicity since the IgG levels were never below 600 mg/dL, even though immunoglobulin replacement therapy was given.

Example 4. For an adult recipient, IVIG was administered prophylactically, but IgG levels were never below 600 mg/dL. This is not reported as a toxicity since the IgG levels were never below 600 mg/dL

Example 5. For an adult recipient, IgG levels were below 600 mg/dL pre-infusion and immunoglobulin replacement therapy (IVIG) was given pre-infusion. Post-infusion, all IgG values were greater than 600 mg/dL and never dropped below 600 mg/mL. This is not reported as a toxicity since the IgG levels were never below 600 mg/dL after infusion.

If IgG dropped below 600 (or 500 for children ages 4 – 10) in the reporting period, regardless if the IgG was below 600 prior to infusion, or if the IgG was below 600 (or 500 for children ages 4 – 10) and persistent into the current reporting period, report hypogammaglobulinemia developed or persisted in this reporting period, by selecting Yes. If hypogammaglobulinemia did not develop in this reporting period, select No and continue with question 166.

Report Unknown if the IgG levels were not tested in the reporting period and continue with question 166.

Questions 162: Was the date of onset previously reported?

If the hypogammaglobulinemia was diagnosed in a previous reporting period, symptoms continue into this reporting period, and the date has already been reported, select Yes and continue with question 162. If hypogammaglobulinemia was not diagnosed in a prior reporting period, report No and enter the date of hypogammaglobulinemia diagnosis in question 163.

Questions 163: 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. Immunoglobulin replacement therapy (IVIG) is not required for the diagnosis of hypogammaglobulinemia

Example 1. IgG levels were measures at 450 mg/dL on June 1; however, immunoglobulin replacement therapy (IVIG) was not given and on June 15, IgG levels had dropped to 400, immunoglobulin replacement therapy was given as this time. Report the onset date as June 1.

Example 2. IgG levels were measures at 450 mg/dL on May 15, no immunoglobulin replacement therapy (IVIG). Report the onset date as May 15.

Example 3. For an adult recipient, IgG levels were below 600 mg/dL pre-cellular therapy infusion and continue to be low post-infusion Report the onset date as first day values are low post-infusion.

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 164-165: Did hypogammaglobulinemia resolve?

Hypogammaglobulinemia can be reported as resolved if there are sustained normal levels of IgG in the blood without the need for IVIG infusions for 3 consecutive months.

Example 1. IgG levels were measures at 450 mg/dL on June 1; immunoglobulin replacement therapy (IVIG) was given on June 15. IgG levels were monitored for the next 4 months and no further immunoglobulin replacement therapy (IVIG) was given. IgG levels went above 600 mg/dL on September 15 and continued to rise. Report the resolution date as the first test result that was greater than 600 mg/dL (September 15).

Example 2. IgG levels were measures at 450 mg/dL on May 15, no immunoglobulin replacement therapy (IVIG) 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 measures at 450 mg/dL on June 1; immunoglobulin replacement therapy (IVIG) 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 3 months after the last IVIG infusion.

Example 4. For an adult recipient, IgG levels were measured at 450 mg/dL on June 1; immunoglobulin replacement therapy (IVIG) was given on June 15. IgG levels were monitored over the next three and a half months and no further immunoglobulin replacement therapy (IVIG) was given. IgG levels were tested, and measured greater than 600 mg/dL, on August 29 (2.5 months after last IVIG infusion) and September 25 (3.2 months after the last IVIG infusion). The resolution date should be greater than or equal to 3 months after the last IVIG infusion; therefor September 25 should be reported as the resolution date.

If the hypogammaglobulinemia resolved, select Yes in question 164 and report the resolution date (YYYY-MM-DD) in question 165 as documented by a physician or other health care provider in the progress note or chart.

Questions 166-167: Did recipient require immunoglobulin replacement therapy?

Replacement therapy is given to prevent infections. If the recipient required immunoglobulin replacement therapy (IVIG) regardless of hypogammaglobulinemia that developed post-infusion, select Yes and indicate if the recipient is still requiring the therapy on the contact date for this reporting period. If the last immunoglobulin replacement therapy (IVIG) was given less than 3 months from the date of contact, report Yes unless it’s clearly stated in the medical record that no more immunoglobulin replacement therapy is required.

Questions 168: 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.

Indicate Yes or No if tumor lysis syndrome developed in the current reporting period. If tumor lysis syndrome did not develop in this reporting period or it’s unknown if tumor lysis syndrome developed, select No or Unknown respectively and continue with question 174.

Questions 169: Was the date of onset previously reported?

If the tumor lysis syndrome was diagnosed in a previous reporting period, symptoms continue into this reporting period, and the date has already been reported, select Yes and continue with question 170. If tumor lysis syndrome was not diagnosed in a prior reporting period, report No and enter the date of tumor lysis syndrome diagnosis in question 169.

Questions 170: 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 171: 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 172-173: Did tumor lysis syndrome resolve?

If the tumor lysis syndrome resolved, select Yes in question 172 and report the resolution date (YYYY-MM-DD) in question 173 as documented by a physician or other health care provider in the progress note or chart.

Questions 147-175: Other toxicity:

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 in question 175.

If the recipient did not experience other toxicities, select No and continue with question 180.

Questions 176: Was the date of onset previously reported?

If the other toxicity was diagnosed in a previous reporting period, symptoms continue into this reporting period, and the date has already been reported, select Yes and continue with question 178. If the other toxicity being reported was not diagnosed in a prior reporting period, report No and enter the date of the other toxicity diagnosis in question 177.

Questions 177: 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 178-179: Did other toxicity resolve?

Indicate Yes or No if the other toxicity resolved. If Yes, report the resolution date (YYYY-MM-DD) question 179 as documented by a physician or other health care provider in the progress note or chart.

Questions 180-182: 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. 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 181.

Specify the toxicity of that organ in question 182. The list of symptoms will dynamically filter based on the organ selected in question 181.

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

Questions 183: Was the date of onset previously reported?

If the grade 3 organ toxicity was diagnosed in a previous reporting period, symptoms continue into this reporting period, and the date has already been reported, select Yes and continue with question 185. Else select No and report the date of grade 3 organ toxicity diagnosis in question 184.

Questions 184: 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 185-186: Did the grade 3 organ toxicity resolve?

If the grade 3 organ toxicity resolved, select Yes in question 184 and report the date (YYYY-MM-DD) in question 186 as documented by a physician or other health care provider in the progress note or chart.

Questions 187-188: Has the recipient experienced a 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 188.

Specify the toxicity of that organ in question 189. The list of symptoms will dynamically filter based on the organ selected in question 188.

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

Questions 158: 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 160. Else select No and report the date of grade 4 organ toxicity diagnosis in question 159.

Questions 191: 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 192-193: Did the grade 4 organ toxicity resolve?

If the grade 4 organ toxicity resolved, select Yes in question 192 and report the date (YYYY-MM-DD) in question 193 as documented by a physician or other health care provider in the progress note or chart.

Questions 194-203: Specify the laboratory values collected (check all that apply)

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 since the date of the last report in question 195, the date the sample was collected in question 196, and the upper limit of normal for your institution in question 197.

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 since the date of the last report in question 198 and the date the sample was collected in question 199.

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 since the date of the last report in question 200 and the date the sample was collected in question 201.

Total serum ferritin: Ferritin is an acute phase reactant and is often found in high concentration in highly inflammatory conditions. Report the maximum value since the date of the last report in question 202 and the date the sample was collected in question 203.

None: None of the specified laboratory tests above were performed

Section Updates:

Question Number Date of Change Add/Remove/Modify Description Reasoning (If applicable)
161 4/11/2022 Add Additional example added to clarify hypogammaglobulinemia reporting: Example 5. For an adult recipient, IgG levels were below 600 mg/dL pre-infusion and immunoglobulin replacement therapy (IVIG) was given pre-infusion. Post-infusion, all IgG values were greater than 600 mg/dL and never dropped below 600 mg/mL. This is not reported as a toxicity since the IgG levels were never below 600 mg/dL after infusion. Added for clarification
Last modified: May 10, 2022

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