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| ID | Type | Description | Link |
|---|---|---|---|
| NCI-2011-03805 | Registry Identifier | CTRP (Clinical Trial Reporting Program) | |
| 2571 | |||
| 2571.00 | Other Identifier | Fred Hutch/University of Washington Cancer Consortium | |
| P01HL036444 | U.S. NIH Grant/Contract | View source | |
| P30CA015704 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Cancer Institute (NCI) | NIH |
| National Heart, Lung, and Blood Institute (NHLBI) | NIH |
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This phase I/II trial evaluates the efficacy and adverse effects of alpha 1 anti-trypsin (AAT) for the treatment of acute graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation.
PRIMARY OBJECTIVES:
I. Determine the safety and tolerability of AAT in patients with steroid non-responsive acute GVHD.
II. Characterize pharmacodynamic effects of AAT on pro-inflammatory cytokines, heparan sulfate, and the spectrum of peripheral blood T cells.
III. Determine clinical responses of GVHD to AAT in patients with steroid non-responsive acute GVHD.
OUTLINE: This is a phase I/II dose-escalation study of AAT.
Patients will receive AAT intravenously (IV) on study days 1, 3, 5, and 7. Patients who experience no toxicity and in whom GVHD is stable or improved after the day 7 dose can continue therapy with AAT on days 9, 11, 13 and 15 for a total of 8 doses.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cohort 1 (30 mg/kg) | Other | Alpha 1 anti-trypsin (AAT) will be administered intravenously at a dose of 90 mg/kg (loading dose) on day 1 followed by 30mg/kg (maintenance dose) every other day (QOD) on days 3, 5, 7, 9, 11, 13 & 15. |
|
| Cohort 2 (60 mg/kg) | Other | AAT will be administered intravenously at a dose of 90 mg/kg (loading dose) on day 1 followed by 60 mg/kg (maintenance dose) QOD on days 3, 5, 7, 9, 11, 13 & 15. |
|
| Cohort 3 (90 mg/kg) | Other | AAT will be administered intravenously at a dose of 90 mg/kg on days 1, 3, 5, 7, 9, 11, 13 & 15. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia] | Drug | Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia] at various levels over different days |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number (Percentage) of Patients at Each Dosing Cohort Who Experience no Toxicity and in Whom Graft Versus Host Disease (GVHD) is Stable or Improved | Toxicity and adverse events were assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. All adverse events were reported regardless of attribution to alpha 1 anti-trypsin (AAT). GVHD response was defined per standard criteria for improvement, no change or progression of signs/symptoms in skin rash (% body surface area), GI (nausea, vomiting, anorexia, diarrhea, GI bleeding, abdominal cramping) and hepatic function (serum bilirubin levels). For this outcome measure, the requirement for additional GVHD treatment beyond AAT was not included in the criteria for response (i.e patients who may have required additional GVHD treatment before study day 28 were not automatically categorized as non-responders or as having progressive GVHD). | Adverse events were reported through 15 days after the last dose of AAT. GVHD response assessed at study day 28. |
| Measure | Description | Time Frame |
|---|---|---|
| Number (Percentage) of Patients at Each Dosing Cohort Experiencing an Unexpected Serious Adverse Event (SAE) | Serious adverse events included death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/ incapacity, or congenital anomaly/birth defect. Significant events that do not meet these criteria may be considered serious if they jeopardize the patient and require a medical intervention to prevent one of the outcomes above. An "unexpected" adverse event is defined as an event that is not identified in nature, severity or frequency in the current investigator brochure/package insert/product information. |
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Inclusion Criteria:
Exclusion Criteria:
Patients who have received any systemic agents in addition to steroids for treatment of GVHD
Patients unable to give informed consent
Patients with manifestations of classic chronic GVHD
Patients with evidence of recurrent malignancy
Patients with acute/chronic GVHD overlap syndrome
Patients whose GVHD developed after donor lymphocyte infusion (DLI)
Patients with severe organ dysfunction, defined as
Patients with uncontrolled infections
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| Name | Affiliation | Role |
|---|---|---|
| H. Joachim Deeg | Fred Hutch/University of Washington Cancer Consortium | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Fred Hutch/University of Washington Cancer Consortium | Seattle | Washington | 98109 | United States |
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Patients signed IRB-approved consents during the period of 12/11/13 to 12/22/16. Treatment with alpha 1 anti-trypsin (AAT) typically started within 24 hours of consent. Patients were identified by clinical staff as needing additional treatment for acute graft versus his disease (GVHD) following initial therapy with corticosteroids.
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| ID | Title | Description |
|---|---|---|
| FG000 | Cohort 1 (30 mg/kg) | AAT will administered intravenously at a dose of 90 mg/kg (loading dose) on day 1 followed by 30mg/kg (maintenance dose) QOD on days 3, 5, 7, 9, 11, 13 & 15. Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia] |
| FG001 | Cohort 2 (60 mg/kg) | AAT will be administered intravenously at a dose of 90 mg/kg (loading dose) on day 1 followed by 60 mg/kg (maintenance dose) QOD on days 3, 5, 7, 9, 11, 13 & 15. Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia] |
| FG002 | Cohort 3 (90 mg/kg) | AAT will be administered intravenously at a dose of 90 mg/kg on days 1, 3, 5, 7, 9, 11, 13 & 15. Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia] |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Cohort 1 (30 mg/kg) | AAT will be administered intravenously at a dose of 90 mg/kg (loading dose) on day 1 followed by 30mg/kg (maintenance dose) QOD on days 3, 5, 7, 9, 11, 13 & 15. Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia] |
| BG001 | Cohort 2 (60 mg/kg) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number (Percentage) of Patients at Each Dosing Cohort Who Experience no Toxicity and in Whom Graft Versus Host Disease (GVHD) is Stable or Improved | Toxicity and adverse events were assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. All adverse events were reported regardless of attribution to alpha 1 anti-trypsin (AAT). GVHD response was defined per standard criteria for improvement, no change or progression of signs/symptoms in skin rash (% body surface area), GI (nausea, vomiting, anorexia, diarrhea, GI bleeding, abdominal cramping) and hepatic function (serum bilirubin levels). For this outcome measure, the requirement for additional GVHD treatment beyond AAT was not included in the criteria for response (i.e patients who may have required additional GVHD treatment before study day 28 were not automatically categorized as non-responders or as having progressive GVHD). | Posted | Count of Participants | Participants | Adverse events were reported through 15 days after the last dose of AAT. GVHD response assessed at study day 28. |
|
Adverse events were reported through 15 days after the last dose of AAT. Serious adverse events were reported if they occurred within 30 days after the last dose of AAT.
All adverse events were collected regardless of attribution to AAT. Included are events that worsened from baseline.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Cohort 1 (30 mg/kg) | AAT will administered intravenously at a dose of 90 mg/kg (loading dose) on day 1 followed by 30mg/kg (maintenance dose) QOD on days 3, 5, 7, 9, 11, 13 & 15. Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia] |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| acute graft-versus-host disease | Immune system disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| thrombocytopenia | Blood and lymphatic system disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| H. Joachim Deeg, MD | Fred Hutchinson Cancer Research Center | 206-667-5985 | jdeeg@fredhutch.org |
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| ID | Term |
|---|---|
| D006086 | Graft vs Host Disease |
| ID | Term |
|---|---|
| D007154 | Immune System Diseases |
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| ID | Term |
|---|---|
| D000515 | alpha 1-Antitrypsin |
| ID | Term |
|---|---|
| D006023 | Glycoproteins |
| D006001 | Glycoconjugates |
| D002241 | Carbohydrates |
| D015843 | Serpins |
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The study will have three escalating alpha 1 anti-trypsin (AAT) dose cohorts with six patients in each cohort (Phase I). Based on response and toxicity, an additional six patients will be enrolled in the optimal dose (Phase II).
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| SAEs were reported through 30 days after the last dose of alpha 1 anti-trypsin (AAT). |
| Number (Percentage) of Patients at Each Dosing Cohort Who Experience One or More Suspected Serious Adverse Reactions (Infusion Related Reactions) | Serious adverse reactions were assessed by the NCI CTCAE v4.0. | Within 48 hours after each infusion |
| Number (Percentage) of Patients at Each Dosing Cohort Who Experience One or More Thrombotic or Thrombo-embolic Events | Events were assessed using the NCI CTCAE v4.0. | Events were reported through 15 days after the last dose of AAT. |
| Number (Percentage) of Patients at Each Dosing Cohort With Occurrence of Infections | Infections were assessed using NCI CTCAE v4.0. | Infections were reported through 15 days after the last dose of AAT. |
| Number (Percentage) of Patients at Each Dosing Cohort With Progression of GVHD | GVHD responses were assessed using criteria established by the Center for International Blood and Marrow Transplant Research and criteria from the Acute GVHD Activity Index. Patients who required additional systemic GVHD treatment beyond AAT before study day 28 were defined as having progressive GVHD. | GVHD responses were assessed on day 28 after starting AAT therapy or at time of death if patient died before study day 28. |
AAT will be administered intravenously at a dose of 90 mg/kg (loading dose) on day 1 followed by 60 mg/kg (maintenance dose) QOD on days 3, 5, 7, 9, 11, 13 & 15. Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia] |
| BG002 | Cohort 3 (90 mg/kg) | AAT will be administered intravenously at a dose of 90 mg/kg on days 1, 3, 5, 7, 9, 11, 13 & 15. Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia] |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Median | Full Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG000 |
| Cohort 1 (30 mg/kg) |
AAT will administered intravenously at a dose of 90 mg/kg (loading dose) on day 1 followed by 30mg/kg (maintenance dose) QOD on days 3, 5, 7, 9, 11, 13 & 15. Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia] |
| OG001 | Cohort 2 (60 mg/kg) | AAT will be administered intravenously at a dose of 90 mg/kg (loading dose) on day 1 followed by 60 mg/kg (maintenance dose) QOD on days 3, 5, 7, 9, 11, 13 & 15. Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia] |
| OG002 | Cohort 3 (90 mg/kg) | AAT will be administered intravenously at a dose of 90 mg/kg on days 1, 3, 5, 7, 9, 11, 13 & 15. Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia] |
|
|
| Secondary | Number (Percentage) of Patients at Each Dosing Cohort Experiencing an Unexpected Serious Adverse Event (SAE) | Serious adverse events included death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/ incapacity, or congenital anomaly/birth defect. Significant events that do not meet these criteria may be considered serious if they jeopardize the patient and require a medical intervention to prevent one of the outcomes above. An "unexpected" adverse event is defined as an event that is not identified in nature, severity or frequency in the current investigator brochure/package insert/product information. | Posted | Count of Participants | Participants | SAEs were reported through 30 days after the last dose of alpha 1 anti-trypsin (AAT). |
|
|
|
| Secondary | Number (Percentage) of Patients at Each Dosing Cohort Who Experience One or More Suspected Serious Adverse Reactions (Infusion Related Reactions) | Serious adverse reactions were assessed by the NCI CTCAE v4.0. | Posted | Count of Participants | Participants | Within 48 hours after each infusion |
|
|
|
| Secondary | Number (Percentage) of Patients at Each Dosing Cohort Who Experience One or More Thrombotic or Thrombo-embolic Events | Events were assessed using the NCI CTCAE v4.0. | Posted | Count of Participants | Participants | Events were reported through 15 days after the last dose of AAT. |
|
|
|
| Secondary | Number (Percentage) of Patients at Each Dosing Cohort With Occurrence of Infections | Infections were assessed using NCI CTCAE v4.0. | Posted | Count of Participants | Participants | Infections were reported through 15 days after the last dose of AAT. |
|
|
|
| Secondary | Number (Percentage) of Patients at Each Dosing Cohort With Progression of GVHD | GVHD responses were assessed using criteria established by the Center for International Blood and Marrow Transplant Research and criteria from the Acute GVHD Activity Index. Patients who required additional systemic GVHD treatment beyond AAT before study day 28 were defined as having progressive GVHD. | Posted | Count of Participants | Participants | GVHD responses were assessed on day 28 after starting AAT therapy or at time of death if patient died before study day 28. |
|
|
|
| 6 |
| 8 |
| 8 |
| 8 |
| 8 |
| 8 |
| EG001 | Cohort 2 (60 mg/kg) | AAT will be administered intravenously at a dose of 90 mg/kg (loading dose) on day 1 followed by 60 mg/kg (maintenance dose) QOD on days 3, 5, 7, 9, 11, 13 & 15. Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia] | 4 | 6 | 5 | 6 | 6 | 6 |
| EG002 | Cohort 3 (90 mg/kg) | AAT will be administered intravenously at a dose of 90 mg/kg on days 1, 3, 5, 7, 9, 11, 13 & 15. Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia] | 4 | 6 | 4 | 6 | 6 | 6 |
| infection | Infections and infestations | Systematic Assessment |
|
| perirectal abbess | Gastrointestinal disorders | Systematic Assessment |
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| bowel perforation | Gastrointestinal disorders | Systematic Assessment |
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| liver failure | Hepatobiliary disorders | Systematic Assessment |
|
| diffuse alveolar hemorrhage | Reproductive system and breast disorders | Systematic Assessment |
|
| cranial hemorrhage | Nervous system disorders | Systematic Assessment |
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| hypogammaglobulinemia | Blood and lymphatic system disorders | Systematic Assessment |
|
| neutropenia | Blood and lymphatic system disorders | Systematic Assessment |
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| anemia | Blood and lymphatic system disorders | Systematic Assessment |
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| leukocytosis | Blood and lymphatic system disorders | Systematic Assessment |
|
| HUS/microangiopathy | Blood and lymphatic system disorders | Systematic Assessment |
|
| hyperglycemia | Metabolism and nutrition disorders | Systematic Assessment |
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| hypokalemia | Metabolism and nutrition disorders | Systematic Assessment |
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| hyperkalemia | Metabolism and nutrition disorders | Systematic Assessment |
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| hypomagnesemia | Metabolism and nutrition disorders | Systematic Assessment |
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| hyponatremia | Metabolism and nutrition disorders | Systematic Assessment |
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| elevated LDH | Metabolism and nutrition disorders | Systematic Assessment |
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| hypocalcemia | Metabolism and nutrition disorders | Systematic Assessment |
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| hypoglycemia | Metabolism and nutrition disorders | Systematic Assessment |
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| hypophosphatemia | Metabolism and nutrition disorders | Systematic Assessment |
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| weakness | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| joint pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| fall | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| edema/fluid overload | Cardiac disorders | Systematic Assessment |
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| hypotension | Cardiac disorders | Systematic Assessment |
|
| orthostatic hypotension | Cardiac disorders | Systematic Assessment |
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| bradycardia | Cardiac disorders | Systematic Assessment |
|
| hypertension | Cardiac disorders | Systematic Assessment |
|
| tachycardia | Cardiac disorders | Systematic Assessment |
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| dehydration | Cardiac disorders | Systematic Assessment |
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| atrial fibrillation | Cardiac disorders | Systematic Assessment |
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| gall bladder sludge | Hepatobiliary disorders | Systematic Assessment |
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| elevated liver function tests | Hepatobiliary disorders | Systematic Assessment |
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| iron overload | Hepatobiliary disorders | Systematic Assessment |
|
| ascites | Hepatobiliary disorders | Systematic Assessment |
|
| dizziness | Nervous system disorders | Systematic Assessment |
|
| neuropathy | Nervous system disorders | Systematic Assessment |
|
| tremor | Nervous system disorders | Systematic Assessment |
|
| altered mental status | Nervous system disorders | Systematic Assessment |
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| seizure | Nervous system disorders | Systematic Assessment |
|
| headache | Nervous system disorders | Systematic Assessment |
|
| somnolence | Nervous system disorders | Systematic Assessment |
|
| numbness (leg) | Nervous system disorders | Systematic Assessment |
|
| blister/excoriation | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| dry skin | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| rash/erythema | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| striae | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| wound | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| pain (all sites combined) | General disorders | Systematic Assessment |
|
| anxiety/stress | Psychiatric disorders | Systematic Assessment |
|
| depression | Psychiatric disorders | Systematic Assessment |
|
| delirium | Psychiatric disorders | Systematic Assessment |
|
| lethargy | Psychiatric disorders | Systematic Assessment |
|
| gastroesophageal reflux | Gastrointestinal disorders | Systematic Assessment |
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| constipation | Gastrointestinal disorders | Systematic Assessment |
|
| diarrhea | Gastrointestinal disorders | Systematic Assessment |
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| nausea | Gastrointestinal disorders | Systematic Assessment |
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| hemorrhoids | Gastrointestinal disorders | Systematic Assessment |
|
| peri-rectal abcess | Gastrointestinal disorders | Systematic Assessment |
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| gastroparesis | Gastrointestinal disorders | Systematic Assessment |
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| peri-rectal irritation | Gastrointestinal disorders | Systematic Assessment |
|
| hepatomegaly | Hepatobiliary disorders | Systematic Assessment |
|
| hypoxia | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| cough | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| pneumonia | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| consolidation (on CXR) | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| dry mouth | Gastrointestinal disorders | Systematic Assessment |
|
| oral lesion/ulcer | Gastrointestinal disorders | Systematic Assessment |
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| oral plaques | Gastrointestinal disorders | Systematic Assessment |
|
| dry eyes | Eye disorders | Systematic Assessment |
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| blurred vision | Eye disorders | Systematic Assessment |
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| scleral discharge | Eye disorders | Systematic Assessment |
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| corneal abrasion | Eye disorders | Systematic Assessment |
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| hearing loss | Ear and labyrinth disorders | Systematic Assessment |
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| facial/neck swelling | General disorders | Systematic Assessment |
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| fatigue | General disorders | Systematic Assessment |
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| chills | General disorders | Systematic Assessment |
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| insomnia | General disorders | Systematic Assessment |
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| hiccups | General disorders | Systematic Assessment |
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| dysuria | Renal and urinary disorders | Systematic Assessment |
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| penile lesion | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| scrotal edema | Renal and urinary disorders | Systematic Assessment |
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| hematuria | Renal and urinary disorders | Systematic Assessment |
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| acute kidney injury | Renal and urinary disorders | Systematic Assessment |
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| acute graft versus host disease (GVHD) | Immune system disorders | Systematic Assessment |
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| liver failure | Hepatobiliary disorders | Systematic Assessment |
|
| bowel perforation | Gastrointestinal disorders | Systematic Assessment |
|
| diffuse alveolar hemorrhage | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| cranial hemorrhage | Nervous system disorders | Systematic Assessment |
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| infection | Infections and infestations | Systematic Assessment |
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| acute myelogenous leukemia | Blood and lymphatic system disorders | Systematic Assessment |
|
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| D010455 |
| Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D000209 | Acute-Phase Proteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000510 | Alpha-Globulins |
| D012712 | Serum Globulins |
| D005916 | Globulins |