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appendices 11 11.1 a ppendix

| Folstein Mini Mental Status Examination                                       |                                              |                            |    |
|-------------------------------------------------------------------------------|----------------------------------------------|----------------------------|----|
| Task                                                                          | Instructions                                 | Scoring                    |    |
| One point each for year,                                                      |                                              |                            |    |
| Date                                                                          | Tell me the date?" Ask for omitted items.    | season, date, day of       |    |
| Orientation                                                                   | week, and month                              |                            |    |
| One point each for                                                            |                                              |                            |    |
| Place                                                                         | state, county, town,                         |                            |    |
| "here are you?" Ask for omitted items.                                        | 5                                            |                            |    |
| Orientation                                                                   | building, and floor or                       |                            |    |
| room                                                                          |                                              |                            |    |
| Register 3                                                                    | Name three objects slowly and clearly. Ask   | One point for each item    |    |
| Objects                                                                       | the patient to repeat them.                  | correctly repeated         |    |
| Ask the patient to count backwards from                                       | One point for each                           |                            |    |
| Serial                                                                        | 100 by 7. Stop after five answers. (Or ask   | correct answer (or         | 5  |
| Sevens                                                                        | them to spell "world" backwards.)            | letter)                    |    |
| Recall 3                                                                      | Ask the patient to recall the objects        | One point for each item    |    |
| Objects                                                                       | mentioned above.                             | correctly remembered       |    |
| Point to your watch and ask the patient                                       | One point for each                           |                            |    |
| Naming                                                                        | "what is this?" Repeat with a pencil.        | correct answer             |    |
| Repeating a                                                                   | One point if successful                      |                            |    |
| Ask the patient to say "no ifs, ands, or buts."                               |                                              |                            |    |
| Phrase                                                                        | on first try                                 |                            |    |
| Give the patient a plain piece of paper and                                   |                                              |                            |    |
| Verbal                                                                        | One point for each                           |                            |    |
| say "Take this paper in your right hand, fold                                 | 3                                            |                            |    |
| correct action                                                                |                                              |                            |    |
| Commands                                                                      | it in half, and put it on the floor.'        |                            |    |
| Written                                                                       | Show the patient a piece of paper with       | One point if the patient's |    |
| "CLOSE YOUR EYES" printed on it.                                              |                                              |                            |    |
| Commands                                                                      | es close                                     |                            |    |
| One point if sentence                                                         |                                              |                            |    |
| Writing                                                                       | Ask the patient to write a sentence.         | has a subject, a verb,     |    |
| and makes sense                                                               |                                              |                            |    |
| Ask the patient to copy a                                                     | One point if the figure                      |                            |    |
| pair of intersecting                                                          |                                              |                            |    |
| Drawing                                                                       | has ten comers and two                       |                            |    |
| pentagons onto a piece of                                                     | intersecting lines                           |                            |    |
| ppper.                                                                        |                                              |                            |    |
| Scoring                                                                       | A score of 24 or above is considered normal. | 30                         |    |
| Adapted from Folstein et al. Mini Mental State, J PSYCH RES 12:196-198 (1975) |                                              |                            |    |
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11.2 appendix 2 neurological function

1. Able to work and perform normal activities. Neurological findings minor or absent. 2. Able to carry out normal activities with minimal difficulty. Neurological impairment does not require nursing care or hospitalization.  
3. Seriously limited in performing normal activities; requires nursing care or hospitalization. Patient confined to bed or wheelchair or with significant intellectual impairment.  
4. Unable to perform even minimal normal activities. Requires hospitalization and/or constant nursing care. Patient unable to communicate or in a coma.  
| 1. Repeat if abnormal at baseline. H&P= History and Physical, including ECOG; Ophtho Exam = Ophthalmology exam for orbital involvement; Clin. Labs = CBC with differential and Retic, Chem. 20, PT/PTT, Urine: UA, E-hCG  (women); Cr. Cl. = estimated creatinine clearance by Cockcroft-Gault formula (Appendix 4), Serology = Hepatitis and Toxoplasmosis serologies, RPR; CSF = CSF cell count, glucose, protein, EBV,  molecular pathology, flow cytometry ; HIV/CD4 = Baseline HIV Serology, genotype if indicated, HIV viral load, and lymphocyte subset TBNK; EBV = EBV quantitative PCR, blood; Neuropsych, See  Appendix 5; Adherence, see Appendix 6. BL = Baseline Studies; End Rx = End of therapy, Cycle 8, Day 28 (Month 1 follow-up). For patients that relapse, re-staging will include: MRI-brain with contrast, CNS FDG-PET, CSF studies, quantitative EBV-PCR, and ophthalmologic examination. See Section 3.8.5.   |                                                                                                                                                            |                       |           |             |         |         |       |       |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------|-----------|-------------|---------|---------|-------|-------|
| Neuropsych Adherence                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | XX X X X X X X                                                                                                                                             | X X X X X             | X X X X X | X X X X X   | X X     | X X X X |       |       |
| EBV Research  Blood Screen MRI PET CSF HIV/ CD4 Cr. Cl. MMSE Clin.  Labs Toxicity  Assess H&P Ophtho  Exam X2 X2 X2 X2 X X                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | X X X                                                                                                                                                      | X X X                 | X X X     | X X X X X X | X X X   | X X X   | X X X | X X X |
| X X                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | X X                                                                                                                                                        |                       |           |             |         |         |       |       |
| X1 X X                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                            |                       |           |             |         |         |       |       |
| X                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | X X                                                                                                                                                        |                       |           |             |         |         |       |       |
| X                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | X                                                                                                                                                          | X                     | X X X     | X           | X X X X | X X     |       |       |
| X X X X X X X X X X X X X X X X X X X X                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                                                                                                                            |                       |           |             |         |         |       |       |
| 11.3 APPENDIX 3: ON-STUDY EVALUATIONS                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Cycle/  Visit                                                                                                                                              | X X1 X X X            | X X X     | X X X X X X | X X     | X X     |       |       |
| (Optional Clinical Follow up)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                                                                                            |                       |           |             |         |         |       |       |
| X X X X X X                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                                                            |                       |           |             |         |         |       |       |
| Cycle 1 X Cycle 2 X Cycle 3 X Cycle 4 X Cycle 5 X Cycle 6 X Cycle 7 X Cycle 8 X                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Follow-up Q2 mo x3 Month 2 X Month 4 X Month 6 X Q3 mo x6 Month 9 X Month 12 X Month 15 X Month 18 X Month 21 X Month 24 X Q6 mo x 2 Month 30 X Month 36 X | Month 48 X Month 60 X |           |             |         |         |       |       |
| CR by MRI                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Q12 mo x2                                                                                                                                                  |                       |           |             |         |         |       |       |
| End Rx                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                            |                       |           |             |         |         |       |       |  
| 1. Repeat if abnormal at baseline. H&P= History and Physical, including ECOG; Ophtho Exam = Ophthalmology exam for orbital involvement; Clin. Labs = CBC with differential and Retic, Chem. 20, PT/PTT, Urine: UA, E-hCG (women); Cr. Cl. = estimated  creatinine clearance by Cockcroft-Gault formula (Appendix 4), Serology = Hepatitis and Toxoplasmosis serologies, RPR; CSF = CSF cell count, glucose, protein, EBV, molecular pathology, flow cytometry ; HIV/CD4 =  Baseline HIV Serology, genotype if indicated, HIV viral load, and lymphocyte subset TBNK; EBV = EBV quantitative PCR, blood; Neuropsych, See Appendix 5; Adherence, see Appendix 6. BL = Baseline Studies; End Rx =  End of therapy, Day 28 (Week 1 follow-up.)  For patients that relapse, re-staging will include: MRI-brain with contrast, CNS FDG-PET, CSF studies, quantitative EBV-PCR, and ophthalmologic examination.   |                                                                                                                                                                              |                       |           |             |             |         |       |       |       |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------|-----------|-------------|-------------|---------|-------|-------|-------|
| Neuropsych Adherence                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | XX X X X X X X                                                                                                                                                               | X X X X X             | X X X X X | X X X X X   | X X         | X X X X |       |       |       |
| EBV Research  Blood Serology MRI PET CSF HIV/ CD4 Cr. Cl. MMSE Clin.  Labs Toxicity  Assess H&P Ophtho  Exam                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | X X X                                                                                                                                                                        | X X X                 | X X X     | X X X       | X X X X X X | X X X   | X X X | X X X | X X X |
| On-Study Evaluations for Best Available Radiation Sparing Therapy (no Methotrexate) Cycle/  Visit                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | X X                                                                                                                                                                          |                       |           |             |             |         |       |       |       |
| X X X X X X X                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | X X                                                                                                                                                                          |                       |           |             |             |         |       |       |       |
| X1 X X                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                              |                       |           |             |             |         |       |       |       |
| X                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | X X                                                                                                                                                                          |                       |           |             |             |         |       |       |       |
| X                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | X X X                                                                                                                                                                        | X                     | X X X X   | X X         |             |         |       |       |       |
| X X X X X X X X X X X X X X X                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | X X1 X X X                                                                                                                                                                   | X X                   | X X X     | X X X X X X | X X         | X X     |       |       |       |
| (Optional Clinical Follow up)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                                                                                                              |                       |           |             |             |         |       |       |       |
| X X                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | X X                                                                                                                                                                          |                       |           |             |             |         |       |       |       |
| Screen/BL X X Day 1 X Day 3 X Day 5 X Day 8 X Day 15 X Day 21 X                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Follow-up Week 2 X Week 4 X Q2 mo x3 Month 2 X Month 4 X Month 6 X Q3 mo x6 Month 9 X Month 12 X Month 15 X Month 18 X Month 21 X Month 24 X Q6 mo x 2 Month 30 X Month 36 X | Month 48 X Month 60 X |           |             |             |         |       |       |       |
| CR by MRI                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | Q12 mo x2                                                                                                                                                                    |                       |           |             |             |         |       |       |       |
| End Rx                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                              |                       |           |             |             |         |       |       |       |
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11.4 appendix 4 calculation of

I. Calculation: Cockcroft-Gault formula for Creatinine Clearance (CrCl)
estimate A. Male CrCl = (140 - age) x (weight) / (sCr x 72)
B. Female CrCl = (140 - age) x (weight) x 0.85 / (sCr x 72) C. Annotation 1. Where creatinine clearance is expressed in mL/min 2. Where age is in years 3. Where weight is Actual Body Weight in kilograms 4. Where sCr is Serum Creatinine in mg/dL
D. Efficacy 1. As accurate as CrCl measured from a 24-hour urine collection in many cases 2. Exceptions: See 24-hour CrCl indications below 3. For estimated creatinine clearance of <100 mL/min, a 24-hour urine collection should be obtained *plus* a serum creatinine at the end of the collection period to determine a measured creatinine clearance (per section 3.4.2.1.1).  
E. Resources: http://www.kidney.org/professionals/
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ii. calculation measured creatinine clearance

B. Annotation 1. Where CrCl is Creatinine clearance in mL/min 2. Where uCr is Urine Creatinine in mg/dL 3. Where sCr is Serum Creatinine in mg/dL 4. Where uV is 24-hour urine volume in mL 5. Where 1440 represents number of minutes in 24 hours C. Indications (where calculation above is inaccurate)
1. Altered protein intake a. Vegetarian diet b. Creatine Supplementation 2. Altered muscle mass and muscle injury a. Malnutrition, muscle wasting, muscle trauma b. Amputation 3. Females 4. Unstable renal function (changing serum creatinine) 5. Obesity
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11.5 appendix 5 neuropsychological test

At entry into the study, patients will be administered a comprehensive neuropsychological battery of tests. The major domains of functioning to be evaluated for the comprehensive and monitoring assessment batteries are indicated below. The specific tests to be used for the protocol will be selected by the NCI/MICC neuropsychology group. Such tests have been shown to provide an effective assessment of functioning in similar chronically ill populations. The tests do not require complicated instrumentation and can be done with high reliability and validity by trained personnel. Repeated neuropsychological assessments will be administered to the patient according to the schedule specified in the protocol. The monitoring battery, which may be administered at shorter intervals, includes tests less subject to practice effects. The same domains should be assessed using the same test instruments throughout the study.  
Comprehensive Assessment General Cognitive Language/Verbal Visual-Perceptual Processing Speed Memory (working, immediate and delayed, visual and auditory) Executive Function Attention Fine Motor Mood/QOL
Monitoring assessment General Cognitive Language/Verbal Visual-Perceptual Processing Speed Working memory Executive Function Attention Fine motor Mood/QOL
--Additional neuropsychological tests may be administered to more comprehensively assess the patients if needed to further explore specific areas of functioning --The comprehensive assessment is administered at baseline and then annually, whereas the monitoring assessment is administered at the half-year assessments.
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11.6 appendix 6 adherence assessment

| Baseline, 6, and 12 months                                  | Estimated Time                                  |
|-------------------------------------------------------------|-------------------------------------------------|
| Knowledge Questionnaire Pills Identification Test Interview | 5 minutes 5 minutes 10 minutes 20 minutes total |
| Baseline, 3 and 9 months Interview                          | 10 minutes 10 minutes total                     |
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11.7 appendix 7 knowledge questionnaire

| Hosp #:   | Protocol:   |
|-----------|-------------|
| Name:     | Date:       |  
Please circle the best response for the questions below. Circle *one and only one*
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response for each question.

1. HIV is a virus that:
a) can be cured with a vaccine. b) cannot be controlled with medication. c) can often be controlled with antiretroviral medicine taken the way it is prescribed.  
d) can be controlled with antiretroviral medication in people who have received the vaccine.  
2. It is important for people to take HIV medicine the way it is prescribed because this will help the body:
a) get a higher viral load. b) build up resistance to the medicine. c) keep a strong immune system. d) all of the above.  
3. Resistance means:
a) HIV resists the process of changing into AIDS. b) immune cells fight with HIV cells. c) HIV learns to grow even with medicine in the body. d) HIV is killed by the medicine.  
4. A measure of "viral load" tells us:
a) How many different viruses are in someone's blood.  
b) How many T-cells a person has. c) How much HIV is in someone's blood. d) What kinds of HIV cells are in someone's saliva.  
5. If you run out of HIV medicine, you should:
a) schedule an appointment at NIH to get more. b) call the nurse or doctor right away to get more. c) borrow some pills from a friend until you can get more from the pharmacy.  
d) both B and C are correct.  
6. The best thing to have is:
a) high viral load and low T-cells. b) low viral load and low T-cells. c) high viral load and high T-cells. d) low viral load and high T-cells.  
7. The best way to fight HIV is:
a) take HIV medicines the way they are prescribed.  
b) eat healthy foods.  
c) get the HIV vaccine. d) exercise every day.  
8. Which of these statements is NOT true?  
a) A person can only be resistant to one medicine at a time.  
b) Doctors can do a test to see which HIV
medicines work best for a person.  
c) If you become resistant to a medicine, the medicine probably won't work for you.  
d) There are many different types or "strains" of HIV.  
9. If a person doesn't take his medicine every day, a) the medicine will work better. b) his red blood cells will be destroyed.  
c) his T-cells will become resistant to the medicine.  
d) the HIV will become resistant to the medicine.  
10. If a person skips doses of her HIV medicine, a) her viral load will probably go to zero. b) she will probably gain weight. c) her CD4 cells will probably double. d) her body could become resistant to the medicine.  
11.8 APPENDIX 8: RECRUITMENT ANNOUNCEMENT
Clinical Trial for AIDS-related Primary Central Nervous System Lymphoma
hiv and aids malignancy branch
national institutes of health bethesda

Individuals with AIDS-related primary central nervous system (brain) lymphoma are invited to participate in a clinical trial designed to study the feasibility of treating this cancer without using the radiation therapy approaches traditionally used in this setting. Patients are invited to contact the NCI if they are HIV-infected and have a brain mass, even if the diagnosis for the cause of the brain mass has not been made. In certain circumstances, the diagnostic procedures may also be done at the National Institutes of Health. AIDS-related primary brain lymphoma is a serious and life threatening complication of HIV infection. Few individuals with this cancer survive for one year. Radiation therapy to the brain is the treatment commonly administered. Radiation therapy can make the lymphoma go away. However, many patients have recurrence of the lymphoma after radiation therapy, or develop other AIDS complications that limit survival. With the availability of highly active antiretroviral therapy, many individuals with AIDS-related primary brain lymphoma may be able to control the HIV infection long-term and go on to good health if the lymphoma can be cured. Many not HIV-infected people treated with radiation therapy for brain lymphoma survive several years, but have severe brain problems related to the radiation treatment. Therefore, in not HIV-infected people, chemotherapy has become the standard of care for treating this cancer. Survival with a healthy brain in such people is improved with this strategy. This clinical trial will assess whether chemotherapy will lead to several years or longer survival without brain problems in people with AIDS-related primary brain lymphoma.  
The treatment being studied in this experimental trial is to give a combination of highdose methotrexate, leucovorin, rituximab, and highly active antiretroviral therapy. This treatment is designed to treat the lymphoma without causing additional toxicity to the CD4+ lymphocytes. CD4+ lymphocyte recovery is essential for the long-term survival prospects of people with advanced AIDS. High-dose methotrexate is the core of most treatments for this tumor in HIV-unrelated primary brain lymphoma and it is used in that setting in conjunction with other medications. When given with leucovorin, high-dose methotrexate can usually be given without causing the expected toxicity to the bone marrow and to the immune system. Rituximab is being given because it is a monoclonal antibody that targets the lymphoma cells and helps the methotrexate kill the cancer cells. Since rituximab does not attach to the CD4+ lymphocytes, it may be possible to give methotrexate, leucovorin, and rituximab along with highly active antiretroviral therapy and simultaneously treat the cancer and the HIV. Some patients may not be able to receive high-dose methotrexate due to problems with their kidneys or heart. In such cases, treatment may still be possible, and will generally include rituximab and antiretroviral therapy. It may be possible to commence immune system recovery during the lymphoma therapy. Immune system recovery may be essential not only to prevention of other AIDS complications, but also to prevention of recurrent brain lymphoma. The study is designed to test the ability of this treatment to make the cancer go away, to see the extent of immune recovery that is feasible with the treatment, and to see whether the cancer comes back or not. Also, a series of tests will be done to measure the effects of this therapy on brain function, to see whether this therapy is less toxic to the brain than would be potentially expected with radiation therapy. Frequent visits and prolonged stays at the NIH may be necessary since this disease is a very serious condition causing many complications. Each treatment will require a week or longer in the hospital. The treatments will be repeated up to 8 times depending on how well it is tolerated, and the effects on the tumor. All of the diagnostic tests and medical treatments administered at the National Institutes of Health are free of charge. If the cancer goes away, treatment for HIV may continue for up to three years while additional tests on your immune system and brain function are made. Transportation costs to the NIH will be paid for those who do not live close to the NIH campus. For further information about coming to the NIH for consultation and possible enrollment into this clinical trial, contact Dr. Robert Yarchoan at 240-760-6075, or 1.800.243.2732, and then hit 4.
hiv and aids malignancy branch
11.9 appendix 9 rituximab combined

LEUCOVORIN RESCUE HAART AND CHEMOTHERAPY ADMINISTRATION, METHOTREXATE MONITORING AND SUPPORTIVE CARE GUIDELINES
hiv and aids malignancy branch
baseline/admission

1. Determine HAART regimen. Tenofovir sparing regimens preferred due to potential overlapping renal toxicity. Pharmacogenetic testing for abacavir; check HLA B*5701 2. PCP prophylaxis; monthly pentamidine or atovaquone preferred 3. MAC prophylaxis: azithromycin 1200 mg /m2 weekly for CD4 < 100 cells/microL
4. HSV prophylaxis: Valacyclovir 1000 mg/daily 5. Evaluate for thrush daily 6. Check Cockcroft-Gault estimate of creatinine clearance. If < 100mL/min, order 24 hour urine collection for creatinine clearance 7. Daily weights
hiv and aids malignancy branch
day -1 each cycle

1. Check Cockcroft-Gault estimate of Creatinine clearance. If < 100mL/min, order 24-hour creatinine clearance.  
2. Confirm at least 7 days serum methotrexate mcmol/L from previous cycle to next dose of methotrexate.  
3. Evaluate for possible methotrexate dose adjustments based on toxicities from previous cycle.
hiv and aids malignancy branch
day 1 of each cycle

1. Review all concomitantmedications prior to day 1 of each cycle. Discontinue any drug that would have interaction with methotrexate excretion. See list below. No filgrastim within 24 hours before methotrexate administration.  
2. Rituximab 375 mg/m2 3. Start IV fluid hydration by 18:00, using one of the protocol specified alkalinized IVF order sets in CRIS for 06-C-0051 4. Order q6 hour urine pH > 7.0 (00:00, 6:00, 12:00, 18:00) and **STRICT URINE**
OUTPUT monitoring record urine output every hour 5. Draw the following blood work until methotrexate level is < or equal to 0.05 mcmol/L:
a. Hepatic panel every other day b. CBC/Diff, Chem 7 daily
hiv and aids malignancy branch
day 2

1. 7 am: notify MD of urine pH and hourly UOP. If UOP < 100mL/hour or urine pH
<7 or >8, adjust IVF.  
2. Methotrexate 6000 mg/m2. Order within the 06-C-0051 CRIS order set. Include Sodium Bicarbonate 45mEq as an additive. (May be adjusted between 25-75mEq depending on individual patient needs).  
a. For creatinine clearance 60-100 mL, adjust methotrexate dose using formula: (Creatinine Clearance)/100 x 6000 mg/m2 b. For creatinine clearance < 60ml/min, methotrexate will NOT be administered.  
c. If episodic AST/ALT elevation > 10X upper limit normal on previous cycle, decrease methotrexate by 25%
3. Goal Start time: administer methotrexate starting between 9:00-10:00 am
hiv and aids malignancy branch
day 3-end leucovorin rescue

1. Start leucovorin 100 mg/m2 IV q6 hours starting 24 hours **AFTER INITIATION**
of methotrexate administration.  
2. Serum methotrexate monitoring levels is now performed at Children's Hospital 7 days a week at 2 p.m. Specimens collected for methotrexate monitoring must be delivered to the NIH CC Department of Laboratory Medicine's Chemistry Service in the morning so they can be delivered to Washington's Children's Hospital and processed in a timely manner. This process is designed to obtain same day results for patients on 06-C-0051 so the clinical team can make protocol defined treatment decisions, such as stopping leucovorin or IV fluids, or implementing treatment of delayed methotrexate clearance with glucarpidase (Voraxaze®).  
3. 24 hours **AFTER INITIATION** of methotrexate, draw red top tube for serum methotrexate level. Methotrexate Levels need to be **drawn at scheduled time.**
4. Repeat every 24 hours: 48 hr, 72 hr, 96 hr, until methotrexate monitoring no longer required.  
5. Check methotrexate levels same day, evaluate for delayed methotrexate clearance.  
Notify Research team for:
a. Methotrexate > 10 mcmol/L at 24 hours b. Methotrexate > 1 mcmol/L at 48 hours c. Methotrexate > 0.1 mcmol /L at 72/hours d. For **delayed methotrexate** elimination see pages 26 and 27 3.4.3), Table 1
(Leucovorin dose at 24, 48, 60 and 72 hours), and 3.4.4 for use of glucarpidase guidelines.  
6. Stop **intravenous** leucovorin and switch to oral leucovorin 25 mg PO (Alternative 10 mg/m2 PO) q6 hours a. If methotrexate level is <0.5 mcmol/L, see section 3.3.4.3.2 b. Patient does NOT have delayed methotrexate clearance (Defined, Point 5 above.)
c. Discuss discontinuing IVF research team 7. Stop **oral** leucovorin and urine monitoring once serum methotrexate OHYHOLV
0.05 mcmol/L
Medications to avoid during Methotrexate administration: 1. Asparaginase 2. Aspirin 3. Acidic drugs 4. Amoxicillin 5. Cephalosporins 6. Chloramphenicol 7. Cholestyramine 8. Cotrimoxazole 9. Cyclosporine 10. Diclofenac 11. Ibuprofen 12. Indomethacin 13. Ketoprofen 14. Mercaptopurine 15. Mezlocillin 16. Naproxen 17. Non-steroidal anti-inflammatory drugs 18. Omeprazole 19. Penicillins 20. Piperacillin (±tazobactam) 21. Probenecid 22. Proton pump inhibitors (e.g., dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole)
23. Pyrimethamine 24. Salicylates 25. Sulfonamides 26. Sulindac 27. Tetracyclines 28. Tolmetin 29. Trimethoprim 30. Trimethoprim/sulfamethoxazole 31. Vaccines, Live (viral and bacterial)