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

Question 81: Was the date of diagnosis previously reported?

If the CRS was diagnosed in a previous reporting period, the symptoms continue into this reporting period, and the date has already been reported, select Yes and continue with question 83. If CRS was not diagnosed in a prior reporting period, report No.

Question 82: 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 83-85: 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 84.

If Tocilizumab was given to treat the CRS, report the number of doses given in question 85. This information is important in the grading of the CRS event.

Questions 86-96: 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 less if than 100.4F or 38C in this field. Fever less than 100.4F or 38C does not qualify as a symptom of CRS. Report the date of fever onset in question 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 88.

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.

Specify any vasopressor(s) used at the same time as a single therapy to treat hypotension in question 92 and 93. And report if hypotension was controlled with therapy in question 94. 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 95.

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 96.

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

Questions 97-98: 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 98. 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, report No and continue with question 99.

Questions 99-100: 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. MAS/HLH is within the spectrum of CRS. Some patients may present with CRS and progress into this more aggressive syndrome.

Report the date (YYYY-MM-DD) 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)

Questions 101: 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.

Questions 102: 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 103-107: 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.

Report the lowest fibrinogen level in question 104 and the date the sample was collected in question 105.

Report the highest triglyceride level in question 106 and the date the sample was collected in question 107.

Questions 108-109: Did cytokine release syndrome resolve?

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

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: 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 129.

Questions 111: 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 117. If neurotoxicity (ICANS) was not diagnosed in a prior reporting period, report No and enter the date of neurotoxicity (ICANS) diagnosis in question 114.

Question 112: 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 113-114: 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. If Other therapy is selected, specify the therapy in question 114.

Question 115: 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 120 for a conversion of the Cornell Assessment of Pediatric Delirium (CAPD) to CARTOX or ICE.

Question 116: What was the lowest score? (e.g. CARTOX-10, ICE)

Tables for answering question 106 of form 4100.

Questions 117-126: Indicate the symptoms of neurotoxicity (ICANS) (check all that apply)

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

Cerebral edema: A swelling in the brain caused by the presence of excessive fluid. Specify the type of cerebral edema in question 119.

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 120 and 121.

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 122.

Dysphasia (speech impairment): The loss of ability to understand or express speech, caused by brain damage. Report the grade of dysphasia in question 123.

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

Hemiparesis / paraparesis / other motor deficit: Weakness on one side of the body (hemiplegic, partial paralysis of the lower limbs (legs), or other sudden loss of connectivity between the CNS and muscles.

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

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 124-126. Report the worst type of seizure if multiple types were experienced in a single reporting period.

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

Other symptom: If the recipient experienced a symptom of neurotoxicity not listed above, report here and specify the symptom in question 118.

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

Questions 127-128: Did neurotoxicity resolve?

If the cellular therapy associated neurotoxicity resolved, select Yes and report the resolution date (YYYY-MM-DD) in question 127. 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 129: 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 500mg/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

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 136.

Report Unknown if the IgG levels were not tested in the reporting period.

Questions 130: 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 136. If hypogammaglobulinemia was not diagnosed in a prior reporting period, report No and enter the date of hypogammaglobulinemia diagnosis in question 131.

Questions 131: 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.

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 132-133: 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 132 and report the resolution date (YYYY-MM-DD) in question 133 as documented by a physician or other health care provider in the progress note or chart.

Questions 134-135: Did recipient require immunoglobulin replacement therapy?

Replacement therapy is given to prevent infections. If the recipient required immunoglobulin replacement therapy (IVIG) as a result 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 136: 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 142.

Questions 137: 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 139. 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 138.

Questions 138: 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 139: 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 140-141: Did tumor lysis syndrome resolve?

If the tumor lysis syndrome resolved, select Yes in question 140 and report the resolution date (YYYY-MM-DD) in question 141 as documented by a physician or other health care provider in the progress note or chart.

Questions 142-143: Other toxicity:

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 143.

Questions 144: 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 146. 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 145.

Questions 145: 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 146-147: Did other toxicity resolve?

Indicate Yes or No if the other toxicity resolved. If Yes, report the resolution date (YYYY-MM-DD) question 147 as documented by a physician or other health care provider in the progress note or chart.

Questions 148-150: 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 149.

Specify the toxicity of that organ in question 150. The list of symptoms will dynamically filter based on the organ selected in question 149.

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 151: 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 153. Else select No and report the date of grade 3 organ toxicity diagnosis in question 152.

Questions 152: 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 153-154: Did the grade 3 organ toxicity resolve?

If the grade 3 organ toxicity resolved, select “yes” in question 153 and report the date (YYYY-MM-DD) in question 154 as documented by a physician or other health care provider in the progress note or chart.

Questions 155-161: 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 156.

Specify the toxicity of that organ in question 157. The list of symptoms will dynamically filter based on the organ selected in question 156.

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 159: 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 160-161: Did the grade 4 organ toxicity resolve?

If the grade 4 organ toxicity resolved, select Yes in question 160 and report the date (YYYY-MM-DD) in question 161 as documented by a physician or other health care provider in the progress note or chart.

Questions 162-170: 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 163 and the date the sample was collected in question 164.

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 165 and the date the sample was collected in question 166.

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 167 and the date the sample was collected in question 168.

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 169 and the date the sample was collected in question 170.

None: None of the specified laboratory tests above were performed

Section Updates:

Question Number Date of Change Add/Remove/Modify Description Reasoning (If applicable)
132 5/12/2021 Add Added new example 4 for determining hypogammaglobulinemia resolution date Provide clarity to reporting resolution date.
132 1/7/2021 Add Added examples of when to report or not report hypogammaglobulinemia Provide clarity of when to report hypogammaglobulinemia.
134 1/7/2020 Add Added examples for hypogammaglobulinemia onset date Provide clarity to reporting onset date.
135 1/7/2020 Add Added examples for hypogammaglobulinemia resolution date Provide clarity to reporting resolution date.
137 1/7/2020 Add Clarified how to report continuation of IVIG therapy with this sentence: 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. Provide clarity of reporting IVIG continuation near the end of the reporting period.
Last modified: May 12, 2021

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