untitled h1
8.1.3 unexpected adverse reaction

An adverse event or suspected adverse reaction is considered "unexpected" if it is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed; or, if an investigator brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application. "Unexpected", also refers to adverse events or suspected adverse reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned as occurring with the particular drug under investigation.
untitled h1
8.1.4 serious

An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 8.1.5 Serious Adverse Event An adverse event or suspected adverse reaction is considered serious if in the view of the investigator or the sponsor, it results in any of the following:
x Death, x A life-threatening adverse drug experience x Inpatient hospitalization or prolongation of existing hospitalization x A significant disability/incapacity
untitled h1
x a congenital anomaly/birth defect.

Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. 8.1.6 Disability A substantial disruption of a person's ability to conduct normal life functions. 8.1.7 Life-threatening adverse drug experience Any adverse event or suspected adverse reaction that places the patient or subject, in the view of the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that had it occurred in a more severe form, might have caused death. 8.1.8 Protocol Deviation (NIH Definition) Any change, divergence, or departure from the IRB approved research protocol 8.1.9 Non-compliance (NIH Definition) The failure to comply with applicable NIH Human Research Protections Program (HRPP) policies, IRB requirements, or regulatory requirements for the protection of human research subject. 8.1.10 Unanticipated Problem Any incident, experience, or outcome that:
x Is unexpected in terms of nature, severity, or frequency in relation to
(a) the research risks that are described in the IRB-approved research protocol and informed consent document; Investigator's Brochure or other study documents, and
(b) the characteristics of the subject population being studied; AND
x Is related or possibly related to participation in the research; AND  
x Suggests that the research places subjects or others at a *greater risk of harm* (including physical, psychological, economic, or social harm) than was previously known or recognized.
untitled h1
8.2 nci-irb and clinical director

8.2.1 NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths The Protocol PI will report in the NIH Problem Form to the NCI-IRB and NCI Clinical Director:  
x All deaths, except deaths due to progressive disease x All Protocol Deviations x All Unanticipated Problems x All non-compliance
Reports must be received within 7 days of PI awareness via iRIS.  
8.2.2 NCI-IRB Requirements for PI Reporting at Continuing Review The protocol PI will report to the NCI-IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the deviation occurred, a brief description of the deviation and any corrective action.  
2. A summary of any instances of non-compliance 3. A tabular summary of the following adverse events:
x All Grade 2 **unexpected** events that are possibly, probably, or definitely related to lupron or the IND;
x All Grade 3 and 4 events that are possibly, probably, or definitely related to the lupron or the IND;
x All Grade 5 events regardless of attribution; x All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be collected or reported. Note: With the exception of severe adverse events, AE that occur prior to the initiation of protocol directed therapy (to include standard of care chemotherapy that could be given due to delay in donor availability or for other reasons) will not be collected or reported. NOTE: Expected AE of transplantation that will be exempt from reporting (because they will not be related to research) include:
- Leukopenia, anemia, and thrombocytopenia until engraftment of these cellular populations. Should a patient not engraft, this will be captured as an AE.  
- Coagulation abnormalities - Electrolyte abnormalities including sodium, potassium, chloride, magnesium, calcium, phosphorus, bicarb, blood urea nitrogen, lactate dehydrogenase, creatinine kinase.  
- Endocrine abnormalities, bone mineralization abnormalities, avascular necrosis, delay in growth/development, and nutritional data (to include lipid levels, prealbumin, albumin).  
- Dermatology abnormalities (to include changes in nails, pigmentation) - Mucositis 8.2.3 NCI-IRB Reporting of IND Safety Reports Only IND Safety Reports that meet the definition of an unanticipated problem will need to be reported to the NCI IRB.
untitled h1
8.3 nci guidance for reporting

The site PI must immediately report to the coordinating center PI any serious adverse event, whether or not considered drug related, including those listed in the protocol or investigator brochure and must include an assessment of whether there is a reasonable possibility that the drug caused the event within 24 hours of PI awareness of the event. The Site PI must also report any protocol deviations to the coordinating center PI within 7 days of PI awareness. Participating centers must also submit the report to their IRB in accordance with their institutional policies.  
A participating site problem form (available in section **12.16**) is to be filled out and sent to the Coordinating Center's PI.
untitled h1
8.4 ind sponsor reporting criteria

During the first 30 days after the subject receives investigational agent/intervention, the investigator must immediately report to the sponsor using the mandatory MedWatch form 3500a, or equivalent any serious adverse event, whether or not considered drug related, including those listed in the protocol or investigator brochure and must include an assessment of whether there is a reasonable possibility that the drug caused the event. For serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention, only report those that have an attribution of at least possibly related to the agent/intervention. Required timing for reporting per the above guideline:
x Deaths (except death due to progressive disease) must be reported via email within 24 hours. A complete report must be submitted within one business day.  
x Other serious adverse events as well as deaths due to progressive disease must be reported within one business day Events will be submitted to the Center for Cancer Research (CCR) at: CCRsafety@mail.nih.gov and to the CCR PI and study coordinator.
untitled h1
8.5 data recording of unrelated

Per NMDP regulations, and to maintain donor confidentiality, unrelated donor source documents will not be sent to the NIH. The NMDP will maintain all required source documents in accordance with NMDP policies and procedures. The NMDP will confirm donor eligibility and will notify the NIH of any deviations in regard to protocol requirements.  
The National Marrow Donor Program (NMDP) IRB will be responsible for the review and continuing oversight of protocol procedures that relate only to NMDP unrelated donors.
untitled h1
8.6 data and safety monitoring

The clinical research team will meet on a regular basis weekly when patients are being actively treated on the trial to discuss each patient. All data will be collected in a timely manner and reviewed by the principal investigator or a lead associate investigator. Pertinent data includes: GVHD acute or chronic and characterization as per appendices and medications to treat this documented at day 30, 60, 100, 180, 270, 365, and yearly after this, infections and medications and disease response and therapies for recurrent disease also collected at these key time points. Ancillary medications taken at the time of these time points needs to be collected, however, ancillary medications not associated with the aforementioned that are started and stopped between key time points need not to be collected/recorded unless associated with adverse events. Adverse events will be reported as required above. Any safety concerns, new information that might affect either the ethical and or scientific conduct of the trial, or protocol deviations will be immediately reported to the IRB using iRIS. The site principal investigator will review adverse event and response data on each patient to ensure safety and data accuracy. The site principal investigator will personally conduct or supervise the investigation and provide appropriate delegation of responsibilities to other members of the research staff.
untitled h1
8.6.2 sponsor monitoring plan

As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring program. The CCR's program allows for confirmation of: study data, specifically data that could affect the interpretation of primary study endpoints; adherence to the protocol, regulations, and SOPs; and human subjects protection. This is done through independent verification of study data with source documentation focusing on: - Informed consent process - Eligibility confirmation - Drug administration and accountability  
- Adverse events monitoring
- Response assessment. The monitoring program also extends to multi-site research when the CCR is the coordinating center.  
8.6.3 This trial will be monitored by personnel employed by an NCI contractor. Monitors are qualified by training and experience to monitor the progress of clinical trials. Personnel monitoring this study will not be affiliated in any way with the trial conductSafety Monitoring Committee (SMC)
This protocol will require oversight from the Safety Monitoring Committee (SMC). Initial review will occur as soon as possible after the annual NCI-IRB continuing review date. Subsequently, each protocol will be reviewed as close to annually as the quarterly meeting schedule permits or more frequently as may be required by the SMC. For initial and subsequent reviews, protocols will not be reviewed if there is no accrual within the review period. Written outcome letters will be generated in response to the monitoring activities and submitted to the Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI.
untitled h1
9 multi-institutional guidelines

This is a multi-institutional trial with University of Oklahoma and National Institutes of Health, National Cancer Institute, and Children's National Medical Center.  
Children's National Medical Center will enroll only children and open only the FLT arm of the study. Univ. of Oklahoma will enroll only adults and open only the Lupron arm.
untitled h1
9.1.1 irb approvals

The PI will provide the NCI IRB and Central Registration Office with a copy of the participating institution's approved yearly continuing review. Registration will be halted at any participating institution in which a current continuing approval is not on file at the NCI IRB. 9.1.2 Amendments and Consents The PI will provide NIH IRB with any and all documentation of amendments, consents, and approvals from IRB reviews at all participating institutions. All amendments to the protocol or the NCI consent are to be approved by the NCI PI and the NCI IRB and then submitted to the participating institution's IRB for approval. 9.1.3 Data and Specimen Collection Procedures The NCI C3D data base will be utilized; data will only be collected at the time points specified in this trial. Participating sites will be trained in the use of C3D and directly enter data at these sites into C3D. Any questions or concerns should elicit immediate contact of the NCI PI or AI. . 9.1.4 Data Center Audits All participating sites will be monitored as per section **8.7.2.** Scans and data may also be reviewed of primary NIH or Children's National Medical Center patients at Univ of Oklahoma after de-identification for exploratory analyses. The NCI PI or AI will oversee the implementation of any necessary quality improvement measures that may be indicated as a result of these quality assurance activities. 9.1.5 Protocol Monitoring Committees The NCI PI or AI will have either a meeting or phone conversation with all IRB-approved participating institution PIs to discuss protocol progress at least monthly after the outside site as begun accrual.
untitled h1
10 pharmaceutical information 10.1 lupron

5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-Larginyl-N-ethyl-Lprolinamide acetate Lupron is a synthetic nonapeptide analog of naturally produced gonadotropin-releasing hormone (GnRH). 10.1.2 Chemical structure  
  
Supplied either daily or extended release injections. Daily formulation is a 2.8 mL multi-dose vial with 5 mg/mL Lupron, administered as 1 mg (0.2 mL) subcutaneously per day. Lupron also is supplied as Lupron Depot in either a 1, 3, or 4 month preparation with 3.75, 22.5 mg, or 30 mg leuprolide acetate respectively for adults and as 11.25 mg 3 month preparation for children. Lupron Depot is given as an intramuscular injection in a dual chamber syringe system that contains sterile lyophilized microspheres which become suspended in the carrier solution upon injection and continue drug release for the recommended timeframe. 10.1.4 Storage Room temperature
untitled h1
10.1.5 stability

Lupron remains stable when stored at 15-30 deg. Celsius. The product should be stored in the original container and away from light sources. 10.1.6 Route of administration Intramuscular injection. Emla may be given prior to injection to minimize discomfort at injection site.
untitled h1
10.1.7 dose

Lupron will be administered as 30 mg intramuscular injection once prior to stem cell transplant for adult patients and as an adult preparation 3 month extended release 11.25 mg intramusclular injection once prior to stem cell transplant for patients <18 years.
untitled h1
10.1.8 drug interactions

There are no reported drug interactions with Lupron. It is metabolized by peptidases and does not involve the P450 enzyme system. However, given the mechanism of action of sex hormone suppression, all sex hormones are contraindicated (including: testosterone, progesterone, and estrogen) in all preparations. 10.1.9 Known toxicities for patients >18 (see table below)
Version Date: December 28, 2017 Please utilize the table for the most accurate assessment of Lupron toxicities.  The most common side effects in large trials include headache and fatigue.  A toxicity table from the Lupron insert is included here:  
| Adverse Events Reported in ≥ 5% of Patients Regardless of Causality   |           |         |        |        |
|-----------------------------------------------------------------------|-----------|---------|--------|--------|
| LUPRON DEPOT-4 Month 30 mg                                            |           |         |        |        |
| Nonorchiectomized, | Orchiectomized,                                  |           |         |        |        |
| N=49                                                                  | N=24      |         |        |        |
| Study 013                                                             | Study 012 |         |        |        |
| N                                                                     | (&)       | N       | (%)    |        |
| Body As a Whole                                                       |           |         |        |        |
| Asthenia                                                              | (12.2)    |         |        |        |
| 6                                                                     | i         | (4.2)   |        |        |
| Flu Syndrome                                                          | 6         | (12.2). | 0      | (0.0)  |
| General Pain                                                          | 16        | (32.7)  | l      | (4.2)  |
| Headache                                                              | S         | (10.2)  | l      | (4.2)  |
| Injection Site Reaction                                               | 4         | (8.2)   | 9      | (7.5)  |
| Cardiovascular System                                                 |           |         |        |        |
| Hot flashes/Sweats*                                                   | 23        | (46.9)  | 2      | (8.3)  |
| Digestive System                                                      |           |         |        |        |
| GI Disorders                                                          | s         | (10.2)  | 3      | (12.5) |
| Metabolic and                                                         |           |         |        |        |
| Nutritional Disorders                                                 |           |         |        |        |
| Dchydration                                                           | 4         | (8.2)   | 0      | (0.0)  |
| Edema                                                                 | 4         | (8.2)   | s      | (20.8) |
| Musculoskeletal System                                                |           |         |        |        |
| Joint Disorder                                                        | 8         | (16.3)  | I      | (4.2)  |
| Myalgia                                                               | 4         | (8.2)   | o      | (0.0)  |
| Nervous System                                                        |           |         |        |        |
| Dizziness/Vertigo                                                     | (6.1)     |         |        |        |
| 3                                                                     | 2         | (8.3)   |        |        |
| Neuromuscular Disorders                                               | 3         | (6.1)   | I      | (4.2)  |
| Paresthesia                                                           | 4         | (8.2)   | l      | (4.2)  |
| Respiratory System                                                    |           |         |        |        |
| Respiratory Disorder                                                  | 4         | (8.2)   | (4.2)  |        |
| 1.                                                                    |           |         |        |        |
| Skin and Appendages                                                   |           |         |        |        |
| Skin Reaction                                                         | 6         | (12.2)  | (0.0)  |        |
| 0                                                                     |           |         |        |        |
| Urogenital System                                                     |           |         |        |        |
| Urinary Disorders                                                     | s         | (10.2)  | (16.7) |        |
| 4                                                                     |           |         |        |        |  
Table 2: Adverse Events in ≥ 5% of Patients Regardless of Causality 10.1.10Known toxicities for patients <18
untitled h1
(see table below)

In two studies of children with central precocious puberty, in 2% or more of the patients receiving the drug, the following adverse reactions were reported to have a possible or probable relationship to drug as ascribed by the treating physician. Reactions which are not considered drug related are excluded.  
| Table 3                                         | Number of Patients   |     |
|-------------------------------------------------|----------------------|-----|
| N = 421                                         | (%)                  |     |
| Body as a Whole                                 |                      |     |
| General Pain                                    | 12                   | (3) |
| Headache                                        | 11                   | (3) |
| Injection Site Reactions Including              | 37                   | (9) |
| Abscess*                                        |                      |     |
| Cardiovascular System                           |                      |     |
| Vasodilation                                    | 9                    | (2) |
| Integumentary System (Skin and                  |                      |     |
| Appendages)                                     |                      |     |
| Acne/Seborrhea                                  | 13                   | (3) |
| Rash Including Erythema                         | 12                   | (3) |
| Multiforme                                      |                      |     |
| Nervous System                                  |                      |     |
| Emotional Lability                              | 19                   | (5) |
| Urogenital System                               |                      |     |
| Vaginitis/Vaginal Bleeding/Vaginal              | 13                   | (3) |
| Discharge                                       |                      |     |
| *Most events were mild or moderate in severity. |                      |     |  
Table 3 10.2   C YCLOPHOSPHAMIDE
10.2.1  Chemical name 2-[bis(2-chloroethyl)amino] tetrahydro-2H-1,3,2-orxazaphosphorine 2-oxide monohydrate.  
Cyclophosphamide is a chemotherapy metabolized in the liver to an active alkylator that interferes with cell division through cross-linking of DNA.  
10.2.2 Chemical structure  
  
Version Date: December 28, 2017 10.2.3 Commercial Formulation Supplied as lyophilized powder that will be reconstituted with normal saline prior to intravenous administration. Oral tablets are available but not relevant to this trial.  
10.2.4 Storage Room temperature 10.2.5 Stability Cyclophosphamide reconstituted is stable for 24 hours at room temperature or for 6 days in the refrigerator. 10.2.6 Route of administration Intravenous injection 10.2.7 Dose Cyclophosphamide will be administered as per Section **12.4**.  
10.2.8 Drug Interactions The rate of metabolism and the activity of cyclophosphamide are increased with concomitant administration of Phenobarbital. Cyclophosphamide also increases the activity of succinylcholine chloride. If the patient has been treated with cyclophosphamide within 10 days of general anesthesia, the anesthesiologist should be alerted. 10.2.9 Known toxicities (see table below)
Table 4: Toxicity  
| Common                                                                                                                                 | Occasional                                              | Rare Transient blurred vision1 cardiac   |                                                      |
|----------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------|------------------------------------------|------------------------------------------------------|
| Immediate:                                                                                                                             | Anorexia (L), nausea                                    | Metallic taste (L),                      |                                                      |
| Within 1-2 days of receiving drug                                                                                                      | (L), vomiting(L)                                        | Inappropriate ADH1                       | toxicity with arrhythmias1 myocardial necrosis 2 (L) |
| Prompt: Within 2-3 weeks, prior to the next  course                                                                                    | Myelosuppression (L),                                   | Hemorrhagic cystitis (L)                 |                                                      |
| alopecia (L)                                                                                                                           | Pulmonary fibrosis3 (L)                                 |                                          |                                                      |
| Delayed: Any time later during therapy,  excluding the above conditions                                                                | Immunosuppression,  gonadal dysfunction  /sterility (L) |                                          |                                                      |
| Late: Any time after completion of  treatment                                                                                          | Secondary malignancy, bladder  fibrosis                 |                                          |                                                      |
| Unknown Frequency and Timing: **Fetal and teratogenic toxicities and toxicities in breast-fed children 1 Less common with lower doses. |                                                         |                                          |                                                      |  
2Only with very high doses.  
3 **Risk increased with chest radiation.**
(L) Toxicity may also occur later.  
**Fetal toxicities and teratogenic effects of cyclophosphamide (alone or in combination with other antineoplastic agents) have been noted in humans. Toxicities include: chromosome abnormalities, multiple anomalies, pancytopenia, and low birth weight. **Cyclophosphamide is excreted into breast milk. Neutropenia has been reported in breast-fed infants. Cyclophosphamide is considered to be contraindicated during breast feeding because of the reported cases of neutropenia and because of the potential adverse effects relating to immune suppression, growth, and carcinogenesis.
untitled h1
10.3 total body irradiation 10.3.1

10.3.2 Known toxicities The side effects of radiation have been well described. The most common include nausea and mucositis. There also exists a risk of hypothyroidism, cataracts, interstitial pneumonitis, nephropathy, and an unspecified long-term risk of developing secondary malignancies [63]. Importantly, the majority of the non-neoplastic effects were subclinical and/or reversible [64]. Studies attempting to evaluate the risk attributed to radiation within a preparative regimen have implicated secondary malignancies, however this is difficult to ascribe since secondary malignancies are also increased with cGVHD and other post-transplant complications [65] [66]. Pediatric patients who require sedation in order to undergo TBI will be asked to sign a separate consent outlining the risk of the selected anesthesia.
untitled h1
10.4 flt

10.4.1 Chemical Name 3'-deoxy-3 18F-fluorothymidine 10.4.2 Commercial Formulation FLT is supplied as a unit dose by intravenous injection.  
10.4.3 Storage Room Temperature 10.4.4 Chemical Structure  
  
10.4.5 Method of Administration
[**18F]** FLT is administered by intravenous injection over 15 seconds with a saline flush.  
Appropriate shielding will meet the Radiation Safety Guidelines of NIH.  
10.4.6 Availability
[**18F]** FLT will be synthesized and delivered to Building 21 by Cardinal Health, or PETnet Pharmacies. [**18F]** FLT will be synthesized and delivered Radiology Department located on 2nd floor of hospital at Children's National Medical Center by Cardinal Health or PETnet Pharmacies. 10.4.7 Known Toxicites No AEs attributable to 18F FLT administered at tracer levels have been reported in the published literature. While no related AEs are expected, patients will be monitored very closely with regards to hepatic, neurologic, and hematologic parameters following radiotracer injection.
untitled h1
10.5.2 supply

Fludarabine monophosphate will be purchased by the NIH Clinical Center Pharmacy Department from commercial sources and is supplied as a white, lyophilized powder. Each vial contains 50 mg of fludarabine phosphate, 50 mg of mannitol, and sodium hydroxide to adjust pH. Fludara is stored at room temperature.
untitled h1
10.5.3 preparation

FLUDARA IV should be prepared for parenteral use by aseptically adding Sterile Water for Injection, USP. When reconstituted with 2 ml of Sterile Water for Injection, each ml of the resulting solution will contain 25 mg of Fludarabine Phosphate, 25 mg of mannitol, and sodium hydroxide to adjust the pH to 7–8.5. Fludarabine will be diluted in 100 to 125ml of either 5%
dextrose in water or 0.9% sodium chloride, and infused IV over 30 minutes.  
10.5.4 Storage and Stability Reconstituted FLUDARA IV is chemically and physically stable for 24 hours at room temperature or for 48 hours if refrigerated. Because reconstituted FLUDARA IV contains no antimicrobial preservative, care must be taken to assure the sterility of the prepared solution; for this reason, reconstituted FLUDARA IV should be used or discarded within 8 hours. 10.5.5 Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. 10.5.6 Toxicities Fludarabine toxicities include myelosuppression (dose limiting toxicity), fever, nausea, vomiting, stomatitis, diarrhea, gastrointestinal bleeding, anorexia, edema, skin rashes, myalgia, headache, agitation, hearing loss, transient episodes of somnolence and fatigue, auto-immune hemolytic anemia, auto-immune thrombocytopenia, paresthesias, peripheral neuropathy, renal, and pulmonary toxicity (interstitial pneumonitis). Severe fatal CNS toxicity presenting with loss of vision and progressive deterioration of mental status were encountered almost exclusively after very high doses of fludarabine monophosphate. Such toxicity has only rarely been demonstrated at the 25-30 mg/m2/day dosage of fludarabine. Very rarely described complications include transfusion-associated graft-versus-host disease, thrombotic thrombocytopenic purpura, and liver failure. Tumor lysis syndrome following fludarabine administration has been observed, especially in patients with advanced bulky disease. Opportunistic infections (protozoan, viral, fungal, and bacterial) have been observed post-fludarabine, especially in heavily pre-treated individuals, and in individuals receiving fludarabine combined with other agents.
untitled h1
10.6 busulfan (busulfex)

Busulfan is a bifunctional alkylating agent approved for use as a conditioning agent prior to allogeneic hematopoieitc stem cell transplantation at NCI on protocol 10-c-0174 amendment M.The IV formulation is administered as Busulfan (Busulfex, Otsuka America Pharmaceutical, Inc.)
untitled h1
10.6.1 source

For patient administration, IV Busulfan is purchased by the NIH Clinical Center Pharmacy Department from commercial sources. The drug is supplied as a clear, colorless sterile solution in 10ml single use vials. Each vial of Busulfan contains 60 mg (6mg/ml) of busulfan. 10.6.2 Storage and Stability Unopened vials of Busulfan are stable until the date indicated on the package when stored under refrigeration at 2-6 degrees C (36-46 degrees F). 10.6.3 Administration Busulfan must be diluted prior to use with either 0.9% Sodium chloride or 5% Dextrose Injection.  
The diluent quantity should be 10 times the volume of Busulfan so that the final concentration of busulfan is approximately 0.5 mg/ml. Busulfan should be administered intravenously via a central venous catheter as a two-hour infusion every 24 hours for a total of 4 doses over four days.
untitled h1
10.6.4 toxicities

At the indicated dose and schedule Busulfan induces profound myelosuppression; 2) All patients should be given a seizure prophylaxis regimen (e.g. Clonazepam plus levetiracetam) since busulfan is known to cross the blood brain barrier and induce seizures; 3) Nausea, vomiting, and stomatitis are common side effects of busulfan.
untitled h1
10.6.5 drug interactions

Itraconazole increases the clearance of busulfan by up to 25%. Phenytoin increases the clearance of busulfan by 15%.
untitled h1
11 references

1. Hakim, F.T., et al., Constraints on CD4 recovery postchemotherapy in adults: thymic insufficiency and apoptotic decline of expanded peripheral CD4 cells. Blood, 1997.  
90(9): p. 3789-98.  
2. Hazenberg, M.D., et al., *T-cell receptor excision circle and T-cell dynamics after* allogeneic stem cell transplantation are related to clinical events. Blood, 2002. 99(9): p.  
3449-53.  
3. Storek, J., et al., Infectious morbidity in long-term survivors of allogeneic marrow transplantation is associated with low CD4 T cell counts. Am J Hematol, 1997. 54(2): p.  
131-8.  
4. Roux, E., et al., Recovery of immune reactivity after T-cell-depleted bone marrow transplantation depends on thymic activity. Blood, 2000. 96(6): p. 2299-303.  
5. Dumont-Girard, F., et al., *Reconstitution of the T-cell compartment after bone marrow* transplantation: restoration of the repertoire by thymic emigrants. Blood, 1998. 92(11):
p. 4464-71.  
6. Lewin, S.R., et al., *Direct evidence for new T-cell generation by patients after either Tcell-depleted or unmodified allogeneic hematopoietic stem cell transplantations.* Blood, 2002. 100(6): p. 2235-42.  
7. Novitzky, N., et al., *Immune reconstitution at 6 months following T-cell depleted* hematopoietic stem cell transplantation is predictive for treatment outcome.  
Transplantation, 2002. 74(11): p. 1551-9.  
8. Koehl, U., et al., Immune recovery in children undergoing allogeneic stem cell transplantation: absolute CD8+ CD3+ count reconstitution is associated with survival.  
Bone Marrow Transplant, 2007. 39(5): p. 269-78.  
10. Weinberg, K., et al., Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation. Blood, 2001. 97(5): p. 1458-66.  
11. Fallen, P.R., et al., *Factors affecting reconstitution of the T cell compartment in* allogeneic haematopoietic cell transplant recipients. Bone Marrow Transplant, 2003. 32(10): p. 1001-14.  
12. Jimenez, M., et al., *Clinical factors influencing T-cell receptor excision circle (TRECs)*
counts following allogeneic stem cell transplantation in adults. Transpl Immunol, 2006. 16(1): p. 52-9.  
13. Omazic, B., et al., Memory B lymphocytes determine repertoire oligoclonality early after haematopoietic stem cell transplantation. Clin Exp Immunol, 2003. 134(1): p. 159-66.  
9. Parkman, R., et al., *Successful immune reconstitution decreases leukemic relapse and* improves survival in recipients of unrelated cord blood transplantation. Biol Blood Marrow Transplant, 2006. 12(9): p. 919-27.
14. Marie-Cardine, A., et al., *Transitional B cells in humans: characterization and insight* from B lymphocyte reconstitution after hematopoietic stem cell transplantation. Clin Immunol, 2008. 127(1): p. 14-25.  
15. Omazic, B., et al., *Reconstitution of the Ig heavy chain CDR3 repertoire after allogeneic* haematopoietic stem cell transplantation with myeloablative or reduced-intensity conditioning regimens. Scand J Immunol, 2005. 61(1): p. 72-81.  
16. Parsons, R.F., et al., Acquisition of Humoral Transplantation Tolerance upon De Novo Emergence of B Lymphocytes. J Immunol, 2010.
17. Chu, R., et al., *Comparison of Outcomes after Transplantation of G-CSF Stimulated* Bone Marrow Grafts versus Bone Marrow or Peripheral Blood Grafts from HLAMatched Sibling Donors for Patients with Severe Aplastic Anemia. Biol Blood Marrow Transplant, 2010.  
18. Anderson, D., et al., A comparison of related donor peripheral blood and bone marrow transplants: importance of late-onset chronic graft-versus-host disease and infections.  
Biol Blood Marrow Transplant, 2003. 9(1): p. 52-9.  
19. Goldberg, G.L., et al., *Enhanced Immune Reconstitution by Sex Steroid Ablation* following Allogeneic Hemopoietic Stem Cell Transplantation. J Immunol, 2007. 178(11):
p. 7473-84.  
20. Leposavic, G., et al., Differential effects of gonadectomy on the thymocyte phenotypic profile in male and female rats. Pharmacol Biochem Behav, 1996. 54(1): p. 269-76.
21. Olsen, N.J. and W.J. Kovacs, *Effects of androgens on T and B lymphocyte development.*
Immunol Res, 2001. 23(2-3): p. 281-8.  
22. Olsen, N.J., et al., Induction of immature thymocyte proliferation after castration of normal male mice. Endocrinology, 1994. 134(1): p. 107-13.  
23. Sutherland, J.S., et al., *Activation of thymic regeneration in mice and humans following* androgen blockade. J Immunol, 2005. 175(4): p. 2741-53.  
24. Ellis, T.M., et al., *Alterations in peripheral B cells and B cell progenitors following* androgen ablation in mice. Int Immunol, 2001. 13(4): p. 553-8.  
25. Williams, K.M., et al., *CCL25 increases thymopoiesis after androgen withdrawal.* Blood, 2008. 112(8): p. 3255-63.  
26. Aragon-Ching, J.B., K.M. Williams, and J.L. Gulley, *Impact of androgen-deprivation* therapy on the immune system: implications for combination therapy of prostate cancer.  
Front Biosci, 2007. 12: p. 4957-71.  
27. Ghalie, R., et al., Prevention of hypermenorrhea with leuprolide in premenopausal women undergoing bone marrow transplantation. Am J Hematol, 1993. 42(4): p. 350-3.  
28. Vermeulen, A. and Oddens, *Androgens and the Aging Male*, in *Declining Androgens with* age: an overview, A. Vermeulen, Editor. 1996, Parthenon Publishing: New York. p. 3-14.  
29. Huang, C.X., L.Z. Chen, and J.G. Zhao, *[Influence of chemotherapy with FOLFOX*
protocol on sex hormones of male patients and the protective effect of herbal medicines
for reinforcing Shen and supplementing qi on it]. Zhongguo Zhong Xi Yi Jie He Za Zhi, 2008. 28(11): p. 986-9.  
30. Isasi, C.R., P. Lu, and M.D. Blaufox, *A metaanalysis of 18F-2-deoxy-2-fluoro-D-glucose* positron emission tomography in the staging and restaging of patients with lymphoma.  
Cancer, 2005. 104(5): p. 1066-74.  
31. Spaepen, K., et al., *Prognostic value of pretransplantation positron emission tomography* using fluorine 18-fluorodeoxyglucose in patients with aggressive lymphoma treated with high-dose chemotherapy and stem cell transplantation. Blood, 2003. 102(1): p. 53-9.  
32. Spaepen, K., et al., Can positron emission tomography with [(18)F]-fluorodeoxyglucose after first-line treatment distinguish Hodgkin's disease patients who need additional therapy from others in whom additional therapy would mean avoidable toxicity? Br J Haematol, 2001. 115(2): p. 272-8.  
33. Spaepen, K., et al., [(18)F]FDG PET monitoring of tumour response to chemotherapy:
does [(18)F]FDG uptake correlate with the viable tumour cell fraction? Eur J Nucl Med Mol Imaging, 2003. 30(5): p. 682-8.  
34. Schwartz, J.L., et al., *Monitoring tumor cell proliferation by targeting DNA synthetic* processes with thymidine and thymidine analogs. J Nucl Med, 2003. 44(12): p. 2027-32.  
35. Kasper, B., et al., *Functional diagnosis of residual lymphomas after radiochemotherapy* with positron emission tomography comparing FDG- and FLT-PET. Leuk Lymphoma, 2007. 48(4): p. 746-53.  
36. Buchmann, I., et al., [18F]3'-deoxy-3'-fluorothymidine-PET in NHL patients: whole-body biodistribution and imaging of lymphoma manifestations--a pilot study. Cancer Biother Radiopharm, 2004. 19(4): p. 436-42.  
37. Herrmann, K., et al., *Early response assessment using 3'-deoxy-3'-[18F]fluorothymidinepositron emission tomography in high-grade non-Hodgkin's lymphoma.* Clin Cancer Res, 2007. 13(12): p. 3552-8.
38. Buck, A.K., et al., *Molecular imaging of proliferation in malignant lymphoma.* Cancer Res, 2006. 66(22): p. 11055-61.  
39. Been, L.B., et al., Positron emission tomography in patients with breast cancer using
(18)F-3'-deoxy-3'-fluoro-l-thymidine ((18)F-FLT)-a pilot study. Eur J Surg Oncol, 2006. 32(1): p. 39-43.  
40. Kenny, L., et al., *Imaging early changes in proliferation at 1 week post chemotherapy: a* pilot study in breast cancer patients with 3'-deoxy-3'-[18F]fluorothymidine positron emission tomography. Eur J Nucl Med Mol Imaging, 2007. 34(9): p. 1339-47.  
41. Pio, B.S., et al., Usefulness of 3'-[F-18]fluoro-3'-deoxythymidine with positron emission tomography in predicting breast cancer response to therapy. Mol Imaging Biol, 2006. 8(1): p. 36-42.  
42. Cobben, D.C., et al., *Detection and grading of soft tissue sarcomas of the extremities with*
(18)F-3'-fluoro-3'-deoxy-L-thymidine. Clin Cancer Res, 2004. 10(5): p. 1685-90.
43. Buck, A.K., et al., First demonstration of leukemia imaging with the proliferation marker 18F-fluorodeoxythymidine. J Nucl Med, 2008. 49(11): p. 1756-62.  
44. Agool, A., et al., 18F-FLT PET in hematologic disorders: a novel technique to analyze the bone marrow compartment. J Nucl Med, 2006. 47(10): p. 1592-8.  
45. Agool, A., et al., Effect of radiotherapy and chemotherapy on bone marrow activity: a 18F-FLT-PET study. Nucl Med Commun, 2011. 32(1): p. 17-22.  
46. Awasthi, V., et al., *F-18-fluorothymidine-PET evaluation of bone marrow transplant in a* rat model. Nucl Med Commun. 31(2): p. 152-8.  
47. Flexner, C., et al., Relationship between plasma concentrations of 3'-deoxy-3'-
fluorothymidine (alovudine) and antiretroviral activity in two concentration-controlled trials. J Infect Dis, 1994. 170(6): p. 1394-403.  
48. Shields, A.F., et al., Imaging proliferation in vivo with [F-18]FLT and positron emission tomography. Nat Med, 1998. 4(11): p. 1334-6.
49. Kong, X.B., et al., Comparisons of anti-human immunodeficiency virus activities, cellular transport, and plasma and intracellular pharmacokinetics of 3'-fluoro-3'-
deoxythymidine and 3'-azido-3'-deoxythymidine. Antimicrob Agents Chemother, 1992. 36(4): p. 808-18.  
50. Goldstone, A.H., et al., *In adults with standard-risk acute lymphoblastic leukemia, the* greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood, 2008. 111(4): p. 1827-33.  
51. Stock, W., *Adolescents and young adults with acute lymphoblastic leukemia.* Hematology Am Soc Hematol Educ Program, 2010. **2010**: p. 21-9.  
52. Foran, J.M., *New prognostic markers in acute myeloid leukemia: perspective from the* clinic. Hematology Am Soc Hematol Educ Program, 2010. **2010**: p. 47-55.
53. Byrd, J.C., et al., *Pretreatment cytogenetic abnormalities are predictive of induction* success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB
8461). Blood, 2002. 100(13): p. 4325-36.  
54. Bornhauser, M., et al., *Improved outcome after stem-cell transplantation in FLT3/ITDpositive AML.* Blood, 2007. 109(5): p. 2264-5; author reply 2265.  
55. Scholl, S., et al., *Clinical impact of nucleophosmin mutations and Flt3 internal tandem* duplications in patients older than 60 yr with acute myeloid leukaemia. Eur J Haematol, 2008. 80(3): p. 208-15.
56. Thiede, C., et al., Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood, 2002. 99(12): p. 4326-35.  
57. Williams, K.M. and R.E. Gress, Immune reconstitution and implications for immunotherapy following haematopoietic stem cell transplantation. Best Pract Res Clin Haematol, 2008. 21(3): p. 579-96.  
58. Bishop, M.R., et al., *A randomized, double-blind trial of filgrastim (granulocyte colonystimulating factor) versus placebo following allogeneic blood stem cell transplantation.*
Blood, 2000. 96(1): p. 80-5.  
59. Ernst, P., et al., *A Phase 3, Randomized, Placebo-controlled Trial of Filgrastim in* Patients with Haematological Malignancies Undergoing Matched-related Allogeneic Bone Marrow Transplantation. Arch Drug Inf, 2008. 1(3): p. 89-96.  
60. Battiwalla, M. and P.L. McCarthy, Filgrastim support in allogeneic HSCT for myeloid malignancies: a review of the role of G-CSF and the implications for current practice.  
Bone Marrow Transplant, 2009. 43(5): p. 351-6.  
61. Rizzo, J.D., et al., Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, the Center for International Blood and Marrow Transplant Research, and the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant, 2006. 12(2): p. 138-51.  
62. Filipovich, A.H., et al., National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant, 2005. 11(12): p. 945-56.  
63. Buchali, A., et al., Immediate toxicity during fractionated total body irradiation as conditioning for bone marrow transplantation. Radiother Oncol, 2000. 54(2): p. 157-62.  
64. Thomas, O., et al., *Long-term complications of total body irradiation in adults.* Int J
Radiat Oncol Biol Phys, 2001. 49(1): p. 125-31.  
65. Curtis, R.E., et al., *Solid cancers after bone marrow transplantation.* N Engl J Med, 1997. 336(13): p. 897-904.  
66. Kolb, H.J., et al., Malignant neoplasms in long-term survivors of bone marrow transplantation. Late Effects Working Party of the European Cooperative Group for Blood and Marrow Transplantation and the European Late Effect Project Group. Ann Intern Med, 1999. 131(10): p. 738-44.
untitled h1
12 appendices

| %                       | Karnofsky†                                     | Status                    | Lansky Scale#   |
|-------------------------|------------------------------------------------|---------------------------|-----------------|
| 100                     | Normal; no complaints/ no  evidence of disease | 100                       | Fully Active    |
| Able to carry on normal | 90                                             | Minor restrictions in     |                 |
| 90                      | activity; minor signs or                       | physically strenuous play |                 |
| symptoms of disease     |                                                |                           |                 |  
| Version Date: December 28, 2017 Normal activity with effort;   | Restricted in strenuous                                                                        |                                                                                             |                                             |
|----------------------------------------------------------------|------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------|---------------------------------------------|
| 80                                                             | some signs or symptoms of                                                                      | 80                                                                                          | play, tires more easily,                    |
| disease                                                        | otherwise active                                                                               |                                                                                             |                                             |
| Cares for self; unable to                                      | Both greater restrictions of                                                                   |                                                                                             |                                             |
| 70                                                             | carry on normal activity or                                                                    | 70                                                                                          | and less time spent in                      |
| do active work                                                 | active play Ambulatory up to 50% of  time, limited active play  with assistance /  supervision |                                                                                             |                                             |
| Requires occasional                                            |                                                                                                |                                                                                             |                                             |
| 60                                                             | assistance but is able to care  60 for most of his needs                                       | Considerable assistance  required for any active  play; fully able to engage  in quiet play |                                             |
| Requires considerable                                          |                                                                                                |                                                                                             |                                             |
| 50                                                             | assistance and frequent                                                                        | 50                                                                                          |                                             |
| medical care                                                   |                                                                                                |                                                                                             |                                             |
| 40                                                             | Disabled, requires special  care and assistance                                                | 40                                                                                          | Able to initiate quiet  activities          |
| Severely disabled;                                             | 30                                                                                             | Needs considerable                                                                          |                                             |
| hospitalization is indicated                                   |                                                                                                |                                                                                             |                                             |
| 30                                                             | assistance for quiet activity                                                                  |                                                                                             |                                             |
| though death not imminent                                      | Limited to very passive  activity initiated by others  e.g. TV                                 |                                                                                             |                                             |
| 20                                                             | Very sick; hospitalization is  necessary                                                       | 20                                                                                          |                                             |
| 10                                                             | Moribund; fatal process  progressing rapidly                                                   | 10                                                                                          | Completely disabled, not  even passive play |
| 0                                                              | Unresponsive, coma                                                                             |                                                                                             |                                             |  
† Karnofsky = D.A., et al., Cancer 1: 634-656, 1948
\# Lansky Scale = Lansky, et. al., Cancer Oct 1; 60(7): 1651-1656, 1987 Version Date: December 28, 2017 12.2 APPENDIX 2A: RECIPIENT (ARM 1 **AND 2)** Name: ______________ Donor: _______________
DOB: ___/___/______ MR\#______________
Tentative Transplant Date ___/___/______ Pre-Tx W/u: Scheduled Date Done Comments H/P: __/__/__ __/__/__ CT Scans:
Head __/__/__ __/__/__ Sinus __/__/__ __/__/__ Chest __/__/__ __/__/__
Abd/Pel __/__/__ __/__/__
Echo __/__/__ __/__/__ EKG __/__/__ __/__/__ PFT
DLCO __/__/__ __/__/__ FEV1 __/__/__ __/__/__
Dental Ex __/__/__ __/__/__ Broviac p. __/__/__ __/__/__ Radiation __/__/__ __/__/__ BM/LP __/__/__ __/__/__ Nutrition __/__/__ __/__/__
Date Done Result CBC __/__/__
ABO Type __/__/__ _______
PT/PTT __/__/__
Acute care panel __/__/__ _______  
 Hepatic panel __/__/__ _______
Mineral Panel __/__/__ _______
CK and LDH __/__/__ _______ Uric Acid _/__/__ _______
Lipid/TRI __/__/__ _______ U Preg (F) __/__/__ _______
Hep A Ab __/__/__ _______ Hep B Ab __/__/__ _______ Hep C Ab __/__/__ _______
HIV Ab __/__/__ _______ Toxo IgG/IgM __/__/__ _______ CMV IgG/IgM __/__/__ _______ HTLV I/II IgG __/__/__ _______
HSV1,2 IgG/IgM __/__/__ _______ **Testosterone and Estrogen level**
Adenovirus IgG __/__/__ _______ Pre-Lupron for females and males. EBV IgM/IgG __/__/__ _______ Syphilis __/__/__ _______ Radiation records (prior)? Varicella IgG __/__/__ _______ T/B/NK __/__/__ _______
May need to repeated if chemo required.  
Disease diagnosis: CNS+ ever? ______________ Cytogenetics: Flow: ID?  
Should be completed within 45 days of BMT.  
Extra evaluations based on hx: Social work? Ophtho?  
Version Date: December 28, 2017  
24 hr CCL/GFR__/__/__ _______  
  
NMDP sample __/__/__ IgG, IgA, IgM__/__/__ RFLP __/__/__ TSH/FreeT4 __/__/__ _______ Urinalysis __/__/__ _______  
Version Date: December 28, 2017 12.3 APPENDIX 2B: DONOR (ARM 1 **AND 2)**
Name: ______________ Recipient: _______________  
  
DOB: ___/___/______ MR\#______________ Diagnosis: ___________ Tentative Transplant Date ___/___/______ Pre-Tx W/u: Scheduled Date Done Comments H/P: __/__/__ __/__/__ EKG __/__/__ __/__/__ CXR __/__/__ __/__/__ Anesthesia __/__/__ __/__/__
Date Done Result CBC __/__/__ _______ ABO Type __/__/__ _______ PT/PTT __/__/__ Acute care, hepatic, and mineral panel plus LDH __/__/__ _______ Lipid/TRI __/__/__ _______  
  
  
 U Preg (F) __/__/__ _______ Hep A Ab __/__/__ _______ Hep B Ab __/__/__ _______ Hep C Ab __/__/__ _______
HIV Ab __/__/__ _______
Toxo IgG/IgM __/__/__ _______ CMV IgG/IgM __/__/__ _______ HTLV I/II IgG __/__/__ _______ HSV1,2 IgG/IgM __/__/__ _______ Adenovirus IgG __/__/__ _______ EBV IgM/IgG __/__/__ _______ Syphilis __/__/__ _______ Varicella IgG __/__/__ _______ T/B/NK __/__/__ _______ NMDP sample __/__/__ _______ RFLP __/__/__ _______ Urinalysis __/__/__ _______
Should be completed within 30 days of BMT.  
May need to repeated if chemo required.  
Abbreviated Title: Lupron & 18F FLT in allo-HSCTVersion Date: *December 28, 2017*  
  
83 Abbreviated Title: Lupron & 18F FLT in allo-HSCTVersion Date: *December 28, 2017*  
  
Comments  
Appendix 3B: FLT (2nd BMT)Patient Name_____________
untitled h1
12.5 appendix 4a adult (>22

Bone Marrow Transplant with Total Body Irradiation and Cyclophosphamide  
This roadmap represents the general plan of care for this patient during the bone marrow transplant process. This is not an order sheet. Transplant Date:____________  
| process. This is not an order sheet. Transplant Date:____________ Patient/Diagnosis Basis for Dose  Transplant                                                                 | Donor    |              |              |           |              |               |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------|--------------|--------------|-----------|--------------|---------------|
| Calculations                                                                                                                                                                   |          |              |              |           |              |               |
| Name:                                                                                                                                                                          | Ht (cm): | Type of      | Name:        |           |              |               |
| Match:                                                                                                                                                                         |          |              |              |           |              |               |
| MR#:                                                                                                                                                                           | Wt (kg): | Prep         | TBI, Cytoxan | NMDP/MR#: |              |               |
| Regimen:                                                                                                                                                                       |          |              |              |           |              |               |
| Sex:                                                                                                                                                                           | BSA(m2): | Product:     | Marrow       | Sex:      |              |               |
| DOB:                                                                                                                                                                           | /        | /            | IBW          | GVH       | Methotrexate | Age:          |
| (kg):                                                                                                                                                                          | Regimen: | , Tacrolimus |              |           |              |               |
| Age:                                                                                                                                                                           | y/o      | Allergies:   | Day 0:       | /         | /            | Relationship: |
| ABO/Rh:                                                                                                                                                                        | Wt (kg): |              |              |           |              |               |
| CMV IgG:                                                                                                                                                                       | ABO/Rh:  |              |              |           |              |               |
| HSV (I/II):                                                                                                                                                                    | CMV IgG: |              |              |           |              |               |
| Toxo IgG:                                                                                                                                                                      | HLA:     | A (          | ,            |           |              |               |
| ), Cw (                                                                                                                                                                        | ,        |              |              |           |              |               |
| ), B (                                                                                                                                                                         | ,        |              |              |           |              |               |
| ), Bw ( ,  ), DRB1 (  , ),  DRB3 (  ), DQB1 (  , )                                                                                                                             |          |              |              |           |              |               |
| HLA:                                                                                                                                                                           | A (      | ,            | ),           |           |              |               |
| Cw (                                                                                                                                                                           | ,        | ),           |              |           |              |               |
| B (                                                                                                                                                                            | ,        | ),           |              |           |              |               |
| Bw ( , ),  DRB1 ( ,                                                                                                                                                            | ),       |              |              |           |              |               |
| DRB3 (                                                                                                                                                                         | ),       |              |              |           |              |               |
| DQB1 (                                                                                                                                                                         | ,        | )            |              |           |              |               |
| Diagnosis: Status:                                                                                                                                                             |          |              |              |           |              |               |
| Cytogenetics: Risk Factors: Performance  Score: Chemotherapy started on: (write in date) ______Was dose of prep regimen modified? If yes, explain: ___________________________ |          |              |              |           |              |               |  
Version Date: December 28, 2017  
| Ht (cm):   | Dx:           |                        | Prep Regimen: TBI/Cytoxan   | Type of Match:   |
|------------|---------------|------------------------|-----------------------------|------------------|
| Wt (kg):   | Status:       |                        | Product: Marrow             | Donor CMV:       |
| IBW (kg):  | Risk Factors: | GVH Regimen: MTX/tacro | Donor ABO/Rh:               |                  |
| BSA (m2):  | Day 0: / /    |                        |                             |                  |
| Age:       | ABO/Rh:       |                        |                             |                  |  
| Day#:                       | Date:                                  | Regimen:                            | Medications/Interventions:                                      | Notes:   |
|-----------------------------|----------------------------------------|-------------------------------------|-----------------------------------------------------------------|----------|
| -14 to day -7               | / /                                    | +/- male LUPRON (+females)          | One injection of 4 month  preparation.                          |          |
| -8                          | TBI                                    | Start Pneumocystis carinii (PCP)    | Weekly Fungitall, Asp ag, Adeno                                 |          |
| and Caspofungin prophylaxis | +/- Toxo (for positive patients).      |                                     |                                                                 |          |
| -7                          | TBI                                    |                                     |                                                                 |          |
| -6                          | TBI                                    |                                     |                                                                 |          |
| -5                          | TBI                                    |                                     |                                                                 |          |
| -4                          | CY                                     | Forced diuresis with IV hydration   |                                                                 |          |
| Mesna                       | to maintain UOP volume of 2- 3ml/kg/hr |                                     |                                                                 |          |
| -3                          | CY                                     | Discontinue PCP prophylaxis         | Forced diuresis with IV hydration  to maintain UOP volume of 2- |          |
| Mesna                       | 3ml/kg/hr                              |                                     |                                                                 |          |
| -1                          | +/- FLT (1st or                        | Tacro 0.02mg/kg/day IBW             | TAC trough at least weekly, adjust                              |          |
| 2nd BMT)                    | continuous infusion                    | to goal of 5-10ng/ml.               |                                                                 |          |
| 0                           | TX                                     | Start prophylactic antibiotics      | TAC trough at least weekly, adjust  to goal of 5-10ng/ml.       |          |
| +1                          | Methotrexate  10mg/m2 IV               |                                     |                                                                 |          |
| +3                          | Methotrexate                           | TAC trough at least weekly, adjust  |                                                                 |          |
| 5mg/m2 IV                   | to goal of 5-10ng/ml.                  |                                     |                                                                 |          |
| +5                          | +/- FLT (1st                           | FLT can be on either day 5 or day 9 |                                                                 |          |
| BMT)                        | (BMT# 1 only)                          |                                     |                                                                 |          |
| +6                          | Methotrexate  5mg/m2 IV                |                                     |                                                                 |          |
| +11                         | Methotrexate                           | TAC trough at least weekly,         |                                                                 |          |
| 5mg/m2 IV                   | adjust to goal of 5-10ng/ml.           |                                     |                                                                 |          |
| +14                         | - Research Blood                       |                                     |                                                                 |          |  
87  
Version Date: December 28, 2017  
| Version Date: December 28, 2017 +28 +/- FLT (1st or   | Restart PCP prophylaxis                                                                                                                               | -BMB, BMA morphology, RFLP,                                                                                                                  |
|-------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------|
| 2nd BMT)                                              | -BMA FISH, flow  -diagnostic LP, Research Pl/BM -Chimerism Bl/BM, -H/P aGVHD, IgGs, TBNK                                                              |                                                                                                                                              |
| +29                                                   | +/- FDG (1st or 2nd BMT)                                                                                                                              |                                                                                                                                              |
| +30                                                   | +/- FLT When  GVHD or  thymus                                                                                                                         |                                                                                                                                              |
| +60                                                   | +/- FLT & FDG (2nd BMT  only)                                                                                                                         | -BMB, BMA morphology, RFLP,  -BMA cytogenetics, FISH, flow  -diagnostic LP -Chimerism Bl/BM,  - Research blood/BM  -TBNK, H/p w/ AGVHD eval. |
| +100                                                  | Taper Tacrolimus if no signs of                                                                                                                       | -H/P w/a or cGVHD,                                                                                                                           |
| GVHD                                                  | -BMB, BMA morphology, RFLP  -BMA cytogenetics, FISH, flow  - diagnostic LP - Chimerism Bl/BM, - Research blood/BM, TBNK - LDH, IGs, - PFTs, CHEST CT. |                                                                                                                                              |
| +180                                                  | Taper Tacrolimus if no signs of                                                                                                                       | -H/P w/ cGVHD,                                                                                                                               |
| GVHD                                                  | - Chimerism Bl, - Research blood, TBNK - Ferritin, Fe, LDH, IGs, - PFTs. - Ophthalmology - Dental - LH/FSH, TSH/T4, U/A, Chem20                       |                                                                                                                                              |
| +270                                                  | -H/P w/ cGVHD,  - Chimerism Bl, - Research blood, TBNK - Ferritin, Fe, LDH, IGs, - PFTs. - LH/FSH, TSH/T4, Chem20                                     |                                                                                                                                              |
| +365                                                  | Consider Immunizations 6 months  after withdrawal of  immunosuppression.                                                                              | -H/P w/a or cGVHD,  -BMB, BMA morphology, RFLP  -BMA cytogenetics, FISH, flow  - diagnostic LP                                               |  
| - Chimerism Bl/BM, - Research blood/BM, TBNK - Ferritin, LDH, IGs, - PFTs, CHEST CT. - Ophthalmology - Dental - LH/FSH, TSH/T4, U/A, Chem20 - Echo - Dexa - GYN (female)   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
TBI twice daily fractionated with lung block on days -7, -6, -5, and -4. Cumulative dose = 1200 cGy/course. CNS boost if CNS positive at any time prior to HSCT.  
Cyclophosphamide 60mg/kg IV over 1 hour on days -3, -2. Cumulative dose =120mg/kg.  
***Note: Use a modified dose in obese patients that is defined as BMI > 35 and modified weight is half way between actual and ideal body weight for Cyclophosphamide and Mesna dosing Mesna IV 24 hour infusion = to total Cyclophosphamide dose on days -3, -2.  
Version Date: December 28, 2017
untitled h1
12.6 appendix 4b pediatric (<22

Bone Marrow Transplant with Total Body Irradiation and Cyclophosphamide This roadmap represents the general plan of care for this patient during the bone marrow transplant process. This is not an order sheet.  
| Transplant Date:____________ Patient/Diagnosis Basis for Dose                                                                                                                          | Transplant   | Donor        |        |          |              |                |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------|--------------|--------|----------|--------------|----------------|
| Calculations                                                                                                                                                                           |              |              |        |          |              |                |
| Name:                                                                                                                                                                                  | Ht (cm):     | Type of      | Name:  |          |              |                |
| Match:                                                                                                                                                                                 |              |              |        |          |              |                |
| MR#:                                                                                                                                                                                   | Wt (kg):     | Prep         | TBI,   | NMDP/MR# |              |                |
| Cytoxan                                                                                                                                                                                |              |              |        |          |              |                |
| Regimen:                                                                                                                                                                               | :            |              |        |          |              |                |
| Sex:                                                                                                                                                                                   | BSA(m2)      | Product:     | Marrow | Sex:     |              |                |
| :                                                                                                                                                                                      |              |              |        |          |              |                |
| DOB:                                                                                                                                                                                   | /            | /            | IBW    | GVH      | Methotrexate | Age:           |
| (kg):                                                                                                                                                                                  | Regimen:     | , Tacrolimus |        |          |              |                |
| Age:                                                                                                                                                                                   | y/o          | Allergies:   | Day 0: | /        | /            | Relationship : |
| ABO/Rh:                                                                                                                                                                                | Wt (kg):     |              |        |          |              |                |
| CMV IgG:                                                                                                                                                                               | ABO/Rh:      |              |        |          |              |                |
| HSV (I/II):                                                                                                                                                                            | CMV IgG:     |              |        |          |              |                |
| Toxo IgG:                                                                                                                                                                              | HLA:         | A (          | ,      | ),       |              |                |
| Cw (                                                                                                                                                                                   | ,            | ),           |        |          |              |                |
| B (                                                                                                                                                                                    | ,            |              |        |          |              |                |
| ), Bw ( ,                                                                                                                                                                              | ),           |              |        |          |              |                |
| DRB1 (                                                                                                                                                                                 | ,            |              |        |          |              |                |
| ), DRB3 (  ), DQB1 (                                                                                                                                                                   | ,            |              |        |          |              |                |
| )                                                                                                                                                                                      |              |              |        |          |              |                |
| HLA:                                                                                                                                                                                   | A (          | ,            | ),     |          |              |                |
| Cw (                                                                                                                                                                                   | ,            |              |        |          |              |                |
| ), B (                                                                                                                                                                                 | ,            |              |        |          |              |                |
| ), Bw ( , ),  DRB1 ( ,  ), DRB3 ( ),  DQB1 ( ,  )                                                                                                                                      |              |              |        |          |              |                |
| Diagnosis: Status:                                                                                                                                                                     |              |              |        |          |              |                |
| Cytogenetics: Risk Factors: Performance  Score: Chemotherapy started on: (write in date) _________________________________________ Was dose of prep regimen modified? If yes, explain: |              |              |        |          |              |                |  
Was dose of prep regimen modified? If yes, explain: ____________________________________________________________________  
90 Version Date: December 28, 2017  
| Ht (cm):   | Dx:           |                        | Prep Regimen: TBI/Cytoxan   | Type of Match:   |
|------------|---------------|------------------------|-----------------------------|------------------|
| Wt (kg):   | Status:       |                        | Product: Marrow             | Donor CMV:       |
| IBW (kg):  | Risk Factors: | GVH Regimen: MTX/tacro | Donor ABO/Rh:               |                  |
| BSA (m2):  | Day 0: / /    |                        |                             |                  |
| Age:       | ABO/Rh:       |                        |                             |                  |  
91  
Version Date: December 28, 2017  
| Version Date: December 28, 2017 Day#: Date: Regimen:   | Medications/Interventions:                                                                                                                   | Notes:                                        |                                                                                                                                     |
|--------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------|
| -14 to day -7                                          | / /                                                                                                                                          | +/- male                                      | One injection of 4 month preparation.                                                                                               |
| LUPRON (+females)                                      |                                                                                                                                              |                                               |                                                                                                                                     |
| -9                                                     | TBI                                                                                                                                          | Start Pneumocystis carinii (PCP)              | Weekly Fungitall, Asp ag, Adeno +/-                                                                                                 |
| and Caspofungin prophylaxis                            | Toxo (for positive patients).                                                                                                                |                                               |                                                                                                                                     |
| -8                                                     | TBI                                                                                                                                          |                                               |                                                                                                                                     |
| -7                                                     | TBI                                                                                                                                          |                                               |                                                                                                                                     |
| -6                                                     | TBI                                                                                                                                          |                                               |                                                                                                                                     |
| -5                                                     | CY                                                                                                                                           | Forced diuresis with IV hydration to maintain |                                                                                                                                     |
| Mesna                                                  | UOP volume of 2-3ml/kg/hr                                                                                                                    |                                               |                                                                                                                                     |
| -4                                                     | CY                                                                                                                                           | Forced diuresis with IV hydration to maintain |                                                                                                                                     |
| Mesna                                                  | UOP volume of 2-3ml/kg/hr                                                                                                                    |                                               |                                                                                                                                     |
| -3                                                     | CY                                                                                                                                           | Forced diuresis with IV hydration to maintain |                                                                                                                                     |
| Mesna                                                  | UOP volume of 2-3ml/kg/hr                                                                                                                    |                                               |                                                                                                                                     |
| -2                                                     | CY                                                                                                                                           | Discontinue PCP prophylaxis                   | Forced diuresis with IV hydration to maintain  UOP volume of 2-3ml/kg/hr                                                            |
| Mesna                                                  |                                                                                                                                              |                                               |                                                                                                                                     |
| -1                                                     | +/- FLT*                                                                                                                                     | Tacro 0.02mg/kg/day IBW                       | TAC trough at least weekly, adjust to goal                                                                                          |
| continuous infusion                                    | of 5-10ng/ml.                                                                                                                                |                                               |                                                                                                                                     |
| 0                                                      | TX                                                                                                                                           | Start prophylactic antibiotics                | TAC trough at least weekly, adjust to goal  of 5-10ng/ml.                                                                           |
| +1                                                     | Methotrexate  10mg/m2 IV                                                                                                                     |                                               |                                                                                                                                     |
| +3                                                     | Methotrexate                                                                                                                                 | TAC trough at least weekly, adjust to         |                                                                                                                                     |
| 5mg/m2 IV                                              | goal of 5-10ng/ml.                                                                                                                           |                                               |                                                                                                                                     |
| +5                                                     | +/- FLT                                                                                                                                      |                                               |                                                                                                                                     |
| +6                                                     | Methotrexate  5mg/m2 IV                                                                                                                      |                                               |                                                                                                                                     |
| +11                                                    | Methotrexate                                                                                                                                 | TAC trough at least weekly, adjust to         |                                                                                                                                     |
| 5mg/m2 IV                                              | goal of 5-10ng/ml.                                                                                                                           |                                               |                                                                                                                                     |
| +14                                                    | - Research Blood                                                                                                                             |                                               |                                                                                                                                     |
| +28                                                    | +/- FLT                                                                                                                                      | Restart PCP prophylaxis                       | -BMB, BMA morphology, RFLP,  -BMA cytogenetics, FISH, flow  -diagnostic LP, Research Pl/BM -Chimerism Bl/BM, -H/P aGVHD, IgGs, TBNK |
| +29                                                    | +/- FDG                                                                                                                                      |                                               |                                                                                                                                     |
| +30                                                    | +/- FLT When  GVHD or  thymus                                                                                                                |                                               |                                                                                                                                     |
| +60                                                    | -BMB, BMA morphology, RFLP,  -BMA cytogenetics, FISH, flow  -diagnostic LP -Chimerism Bl/BM,  - Research blood/BM  -TBNK, H/p w/ AGVHD eval. |                                               |                                                                                                                                     |
| +100                                                   | Taper Tacrolimus if no signs of                                                                                                              | -H/P w/a or cGVHD,                            |                                                                                                                                     |
| GVHD                                                   | -BMB, BMA morphology, RFLP  -BMA cytogenetics, FISH, flow  - diagnostic LP - Chimerism Bl/BM, - Research blood/BM, TBNK                      |                                               |                                                                                                                                     |  
Version Date: December 28, 2017  
| - Ferritin, LDH, IGs, - PFTs, CHEST CT.                                                                                                                       |                                                                                                                                 |                                                                                                                                                                                                                                                                         |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| +180                                                                                                                                                          | Taper Tacrolimus if no signs of                                                                                                 | -H/P w/ cGVHD,                                                                                                                                                                                                                                                          |
| GVHD                                                                                                                                                          | - Chimerism Bl, - Research blood, TBNK - Ferritin, Fe, LDH, IGs, - PFTs. - Ophthalmology - Dental - LH/FSH, TSH/T4, U/A, Chem20 |                                                                                                                                                                                                                                                                         |
| +270                                                                                                                                                          | -H/P w/ cGVHD,  - Chimerism Bl, - Research blood, TBNK - Ferritin, Fe, LDH, IGs, - PFTs. - LH/FSH, TSH/T4, Chem20               |                                                                                                                                                                                                                                                                         |
| +365                                                                                                                                                          | Consider Immunizations 6  months after withdrawal of  immunosuppression.                                                        | -H/P w/a or cGVHD,  -BMB, BMA morphology, RFLP  -BMA cytogenetics, FISH, flow  - diagnostic LP - Chimerism Bl/BM, - Research blood/BM, TBNK - Ferritin, LDH, IGs, - PFTs, CHEST CT. - Ophthalmology - Dental - LH/FSH, TSH/T4, U/A, Chem20 - Echo - Dexa - GYN (female) |
| TBI twice daily fractionated with lung block on days -8, -7, -6, -5. Cumulative dose = 1200 cGy/course. CNS boost if  CNS positive at any time prior to HSCT. |                                                                                                                                 |                                                                                                                                                                                                                                                                         |  
TBI twice daily fractionated with lung block on days -8, -7, -6, -5. Cumulative dose = 1200 cGy/course. CNS boost if CNS positive at any time prior to HSCT.  
Cyclophosphamide 50mg/kg IV over 1 hour on days -5, -4,-3, -2. Cumulative dose =200mg/kg.
untitled h1
version date december 28 2017

Please note that any extra clinical specimen taken from the patient on protocol may become a research specimen if the patient has agreed to this, to include: BAL, biopsies of lung, bone, or liver etc. Note total aliquot will not exceed 3 ml/kg/draw nor 7 ml/kg in 4 week period for research.  
| Note total aliquot will not exceed 3 ml/kg/draw nor 7 ml/kg in 4 week period for research. Day#: From: Source: Notes: - DONOR Donor marrow product 5 million total nucleated donor cells  (of marrow product)  -1 HOST Peripheral Blood - FLT patients TK for FLT 1st or 2nd BMT patients. 3 cc EDTA PB TK 3 cc EDTA PB for FLT 1st BMT  only patients. 20cc in red/green CPT PB 16 cc in EDTA PB +7, 14, 21 HOST Peripheral Blood - cells, EDTA,  20cc in red/green CPT PB HEP pl, TBNK 16 cc in EDTA PB +5 HOST Peripheral Blood - FLT patients Peripheral Blood - cells, EDTA,  HEP pl, TBNK +28 HOST Peripheral Blood - cells, EDTA,  HEP pl Bone marrow aspirate Bone marrow biopsy  Peripheral Blood - FLT patients 20cc in red/green CPT PB 16 cc in EDTA PB + TK 3 cc EDTA PB for FLT 1st or  2nd BMT patients  +45 HOST Peripheral Blood - cells, EDTA,  HEP pl, TBNK + 60 HOST Peripheral Blood - cells, EDTA,  HEP pl Bone marrow aspirate Bone marrow biopsy 20cc in red/green CPT PB 16 cc in EDTA PB + TK 3 cc EDTA PB for FLT 2nd BMT patients  +ONSET  HOST Peripheral Blood - cells, EDTA,  20cc in red/green CPT PB AGVHD  HEP pl 16 cc in EDTA PB +100 HOST Peripheral Blood - cells, EDTA,  HEP pl Bone marrow aspirate Bone marrow biopsy 20cc in red/green CPT PB 16 cc in EDTA PB +ONSET  HOST Peripheral Blood - cells, EDTA,  20cc in red/green CPT PB cGVHD HEP pl 16 cc in EDTA PB +180 HOST Peripheral Blood - cells, EDTA,  20cc in red/green CPT PB HEP pl 16 cc in EDTA PB +270 HOST Peripheral Blood - cells, EDTA,  HEP pl +365 HOST Peripheral Blood - cells, EDTA,  HEP pl Bone marrow aspirate Bone marrow biopsy +yearly on  study until 5  years HOST Peripheral Blood - cells, EDTA,  HEP pl   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
94 Version Date: December 28, 2017 12.8 APPENDIX 6: IMMUNIZATION POST-TRANSPLANT Immunizations: All recipients will receive immunizations after transplant, according to the BMT
consortium guidelines
(https://cccasper.cc.nih.gov/cvpn/aHR0cDovL2ludHJhbmV0LmNjLm5paC5nb3Y/bmt/clinicalc are/pdf/Table_II.pdf)
untitled h1
12.9 appendix 7 management of

Clinical Definition of Engraftment Syndrome A constellation of clinical symptoms and signs has been observed during neutrophil recovery following HSCT, most commonly termed "engraftment syndrome" (ES), sometimes "hyperacute" graft-versus-host reaction. Below are guidelines for diagnosis and treatment.  
| Major criteria:                                                                                                                              | x                                                     | Fever > 38.3q with no identifiable infectious etiology       |       |
|----------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------|--------------------------------------------------------------|-------|
| x                                                                                                                                            | Erythrodermatous rash involving more than 25% of body |                                                              |       |
| surface area and not attributable to a medication x Noncardiogenic pulmonary edema, manifested by diffuse  pulmonary infiltrates and hypoxia |                                                       |                                                              |       |
| Minor criteria                                                                                                                               | x                                                     | Hepatic dysfunction with either total bilirubin > 2 mg/dl or |       |
| transaminases levels > two times normal x Renal insufficiency (serum creatinine                                                              | >                                                     | two                                                          | times |
| baseline) x Weight gain > 2.5% of baseline body weight x Transient encephalopathy unexplainable by other causes                              |                                                       |                                                              |       |  
A diagnosis of ES is established by the presence of all three major criteria, or two major criteria and one or more minor criteria; the clinical signs and symptoms should appear within 96 hours of neutrophil recovery, according to the above proposed definition.  
Neutrophil recovery after transplantation may result in "engraftment syndrome" (which may include fever, rash, edema, hypoxia)
The following criteria will be utilized to diagnose engraftment syndrome (must have 3 major criteria or 2 major + 1 minor criteria):
To promote consistency of our clinical practice, the following will be the recommended therapy for engraftment syndrome. However, this schedule may be modified (taper either accelerated or delayed) for individual patients as clinical circumstances warrant. In particular, every attempt should be made to rapidly wean steroids due to infection and disease control issues in our patient population.  
Treatment of Engraftment Syndrome without pulmonary edema:
- attempt to use diuretics first. - If progression of edema, consider methylprednisolone at 0.5mg/kg/day x 3 days.
Treatment of Engraftment Syndrome if pulmonary edema is present  
| Day 1:     | Methylprednisolone 250 mg IV Q6 hours x 4 doses   |
|------------|---------------------------------------------------|
| Day 2:     | Methylprednisolone 250 mg IV Q8 hours x 3 doses   |
| Day 3:     | Methylprednisolone 250 mg IV Q12 hours x 2 doses  |
| Day 4:     | Methylprednisolone 125 mg IV Q12 hours x 2 doses  |
| Day 5:     | Methylprednisolone 60 mg IV Q12 hours x 2 doses   |
| Day 6:     | Methylprednisolone 30 mg IV Q12 hours x 2 doses   |
| Days 7-8:  | Prednisone 60 mg PO QD x 2 days                   |
| Days 9-10: | Prednisone 50 mg PO QD x 2 days                   |  
Version Date: December 28, 2017 Days 11-12: Prednisone 40 mg PO QD x 2 days Days 13-14: Prednisone 30 mg PO QD x 2 days Days 15-16: Prednisone 20 mg PO QD x 2 days Days 17-18: Prednisone 10 mg PO QD x 2 days Day 19: Discontinue prednisone In the event that symptoms or clinical signs of ES recur during the steroid taper, patients should be retreated with methylprednisolone at a minimum dose of 60 mg IV QD. This schema is intended to serve as a guideline and to promote consistency in our clinical practice; it may be modified for individual patients as clinical circumstances warrant. **In particular, steroid dosing**
for pediatric patients (< 18) will be determined on a case-by-case basis. 12.10 APPENDIX 8A: GRADING AND MANAGEMENT OF ACUTE GRAFT-VERSUS-HOST-DISEASE  
| Stage                   | Skin                       | Liver                            | Gut                  |       |
|-------------------------|----------------------------|----------------------------------|----------------------|-------|
| 1                       | Rash < 25% BSA             | Total bilirubin 2-3 mg/dl        | Diarrhea 500-999ml/d |       |
| 2                       | Rash 25-50% BSA            | Total bilirubin 3-6 mg/dl        | Diarrhea             | 1000- |
| 1499ml/d                |                            |                                  |                      |       |
| 3                       | Rash > 50% BSA             | Total bilirubin 6-15 mg/dl       | Diarrhea •1500ml/d                      |       |
| 4                       | Generalized  erythoderma   | with                             |                      |       |
| desquamation and bullae | Total bilirubin > 15 mg/dl | Severe abdominal pain  +/- ileus |                      |       |  
Clinical Staging of Acute GVHD to be done/documented day +28, +60, +100 at minimum BSA = body surface area; use "rule of nines" or burn chart to determine extent of rash.  
| Stage    |        |       |     |
|----------|--------|-------|-----|
| Grade    | Skin   | Liver | Gut |
| 0 (none) | 0      | 0     | 0   |
| I        | 1-2    | 0     | 0   |
| II       | 3 or   | 1 or  | 1   |
| III      | 2-3 or | 2-4   |     |
| IV       | 4 or   | 4     |     |  
Grade IV may also include lesser organ involvement but with an extreme decrease in performance status.
untitled h1
treatment of acute gvhd

This schema is intended to serve as a guideline and to promote consistency in our clinical practice; it may be modified for individual patients as clinical circumstances warrant.
untitled h1
grade i gvhd

1) Supportive care or topical corticosteroids (usually 0.1% triamcinolone; 1% hydrocortisone to face) applied to rash BID.
untitled h1
grade ii gvhd

1) Supportive care or topical corticosteroids or oral/IV corticosteroids as deemed necessary by the clinical providers.  
Grade III-IV GVHD: 1) Methylprednisolone (MP) 1 mg/kg per dose IV, BID for 3 consecutive days.  
2) If no response after 4 days, continue until response (7-day maximum trial) add second line therapy which could include: MMF, ECP, rituximab, sirolimus, and will be directed based on
organ and severity and patient co-morbidities. 3)Regardless of response within 7 days, taper as follows (note add other agents prior to taper for non-responders):  
a) 0.75 mg/kg per dose IV BID for 7 days.  
b) 0.5 mg/kg per dose IV BID for 7 days. c) 0.375 mg/kg per dose IV BID for 7 days. d) If clinically appropriate, change MP to oral prednisone to equivalent of IV dose) daily for 2 days. MP may be converted to prednisone later in the taper at the investigators' discretion.  
e) After this, steroids will be reduced by 10% of starting oral dose each week until a dose of 10 mg/day is reached. Subsequent reductions will be made at the investigators' discretion.  
f) If GVHD worsens during taper, steroids should be increased to previous dose. g) During steroid taper, maintain tacrolimus at therapeutic levels.
5) *Antifungal prophylaxis with agents effective against muld will be started when it is* anticipated that the patient will be receiving steroids at > 1 mg/kg/day of methylprednisolone (or equivalent) for > 2 weeks. Voriconazole, caspofungin, liposomal amphotericin B (Ambisome), posaconazole, or amphotericin B lipid complex (Abelcet) are valid alternatives. During prophylaxis with any of the above agents, fluconazole should be discontinued. In patients with therapeutic cyclosporine levels at the initiation of voriconazole therapy, the cyclosporine or tacrolimus dose should be decreased by approximately 50%. In patients with therapeutic sirolimus levels at the initiation of voriconazole therapy, the sirolimus dose should be decreased by approximately 90%.  
6) Determination of GVHD treatment response should be made within 96 hours of starting the treatment. The following are criteria to determine definitions of response to GVHD treatment: a) Complete response: Complete resolution of all clinical signs and symptoms of acute GVHD.  
b) Partial Response: 50% reduction in skin rash, stool volume or frequency, and/or total bilirubin. Maintenance of adequate performance status (Karnofsky Score > 70%).  
c) Non-responder: < 50% reduction in skin rash, stool volume or frequency, and/or total bilirubin. Failure to maintain adequate performance status (Karnofsky Score d 70%).  
d) Progressive disease: Further progression of signs and symptoms of acute GVHD, and/or decline in performance status after the initiation of therapy.  
Treatment This schema is intended to serve as a guideline and to promote consistency in our clinical practice; it may be modified for individual patients as clinical circumstances warrant.  
  
12.11 **APPENDIX 8B**
Abbreviated Title: Lupron & 18F FLT in allo-HSCTVersion Date: *December 28, 2017* 99  
| 0= no loose or liquid stools during the past week 1= occasional loose or liquid stools, on some days during the past week 2=intermittent loose or liquid stools throughout the day, on almost every day of the past week, without requiring intervention to prevent or correct  volume depletion 3=voluminous diarrhea on almost every day of the past week, requiring intervention to prevent or correct volume depletion   | Over the past month would you say that this patient's cGvHD is                                  | +3= Very much better  +2= Moderately better +1= A little better 0= About the same                                                                                                                                                                                                                                                    | -1=A little worse -2=Moderately worse  -3=Very much worse             |                                                                                                                             |                                                                                                  |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------|
| % Predicted                                                                                                                                                                                                                                                                                                                                                                                                                  | Karnofsky Performance Status Scale Definitions (circle  from 0-100) (persons 16 years or older) |                                                                                                                                                                                                                                                                                                                                      |                                                                       |                                                                                                                             |                                                                                                  |
| U/L                                                                                                                                                                                                                                                                                                                                                                                                                          | Single Breath DLCO (adjusted for hemoglobin)                                                    |                                                                                                                                                                                                                                                                                                                                      | 100 Fully active, normal Normal no complaints; no evidence of disease | 90 Minor restrictions in physically strenuous activity Able to carry on normal activity; minor signs or symptoms of disease | 80 Active, but tires more quickly Normal activity with effort; some signs or symptoms of disease |
| 0= no symptoms 1=mild, occasional symptoms, with little reduction in oral intake during the past week 2=moderate, intermittent symptoms, with some reduction in oral intake during the past week 3=more severe or persistent symptoms throughout the day, with marked reduction in oral intake, on almost every day of the past week                                                                                         |                                                                                                 |                                                                                                                                                                                                                                                                                                                                      |                                                                       |                                                                                                                             |                                                                                                  |
| % Eosinophils                                                                                                                                                                                                                                                                                                                                                                                                                | % K/uL ULN                                                                                      |                                                                                                                                                                                                                                                                                                                                      | Range of Motion:  o Not performed                                     | o Physical Therapy Report Attached                                                                                          |                                                                                                  |
| Alkaline Phosphatase                                                                                                                                                                                                                                                                                                                                                                                                         | U/L U/L                                                                                         | 0= no esophageal symptoms 1=Occasional dysphagia or odynophagia with solid food or pills during the past week 2=Intermittent dysphagia or odynophagia with solid foods or pills, but not for liquids or soft foods, during the past week 3=Dysphagia or odynophagia for almost all oral intake, on almost every day of the past week | % Predicted                                                           |                                                                                                                             |                                                                                                  |
| ULN                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                                 |                                                                                                                                                                                                                                                                                                                                      |                                                                       |                                                                                                                             |                                                                                                  |
| K/uL                                                                                                                                                                                                                                                                                                                                                                                                                         | Trial #3                                                                                        | psi                                                                                                                                                                                                                                                                                                                                  |                                                                       |                                                                                                                             |                                                                                                  |
| Trial #2                                                                                                                                                                                                                                                                                                                                                                                                                     | psi                                                                                             |                                                                                                                                                                                                                                                                                                                                      |                                                                       |                                                                                                                             |                                                                                                  |
| Trial #1                                                                                                                                                                                                                                                                                                                                                                                                                     | psi                                                                                             |                                                                                                                                                                                                                                                                                                                                      |                                                                       |                                                                                                                             |                                                                                                  |
| Most severe cGvHD                                                                                                                                                                                                                                                                                                                                                                                                            | Lansky Performance Status Scale Definitions (circle from 0-100) (persons < 16 years  old)       |                                                                                                                                                                                                                                                                                                                                      |                                                                       |                                                                                                                             |                                                                                                  |
| Where would you rate the severity of this patient's chronic GvHD symptoms on the following  scale, where 0 is cGVHD symptoms that are not at all severe and 10 is the most severe cGVHD  symptoms possible:                                                                                                                                                                                                                  |                                                                                                 | Grip Strength (Dominant Hand)                                                                                                                                                                                                                                                                                                        |                                                                       |                                                                                                                             |                                                                                                  |
| ULN                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                                 | not at all severe symptoms                                                                                                                                                                                                                                                                                                           | possible                                                              |                                                                                                                             |                                                                                                  |
| 0 1 2 3 4 5 6 7 8 9 10                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                 |                                                                                                                                                                                                                                                                                                                                      |                                                                       |                                                                                                                             |                                                                                                  |
| U/L                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                                 |                                                                                                                                                                                                                                                                                                                                      |                                                                       |                                                                                                                             |                                                                                                  |
| Total WBC                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                 |                                                                                                                                                                                                                                                                                                                                      |                                                                       |                                                                                                                             |                                                                                                  |
| K/uL                                                                                                                                                                                                                                                                                                                                                                                                                         | FEV-1 Pulmonary Function Tests with Diffusing  Capacity (attach report for person> 5 yrs old)   |                                                                                                                                                                                                                                                                                                                                      |                                                                       |                                                                                                                             |                                                                                                  |
| ALT                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                                 |                                                                                                                                                                                                                                                                                                                                      |                                                                       |                                                                                                                             |                                                                                                  |
| ULN                                                                                                                                                                                                                                                                                                                                                                                                                          | mg/dL                                                                                           | Total Distance Walked in 2 Minutes:                                                                                                                                                                                                                                                                                                  | Number of laps: _______ (x 50 feet) + final partial                   | lap: _____ feet = ______ feet walked in 2 minutes,                                                                          | 6min                                                                                             |
| ULN                                                                                                                                                                                                                                                                                                                                                                                                                          | K/uL Total serum bilirubin                                                                      | mg/dL                                                                                                                                                                                                                                                                                                                                | cGvHD symptoms                                                        |                                                                                                                             |                                                                                                  |
| Platelet Count                                                                                                                                                                                                                                                                                                                                                                                                               |                                                                                                 | Gastrointestinal-Esophageal x Dysphagia OR x Odynophagia                                                                                                                                                                                                                                                                             | Lungs x Bronchiolitis Obliterans                                      | Functional Performance (in  persons >4 years old) x Walk Time x Grip Strength                                               |                                                                                                  |
| Gastrointestinal-Upper GI  x Early satiety OR x Anorexia OR x Nausea & Vomiting                                                                                                                                                                                                                                                                                                                                              | Gastrointestinal-Lower GI x Diarrhea                                                            | Health Care Provider  Global Ratings: In your opinion, do you  think that this patient's  chronic GvHD is mild,  moderate or severe? 0=none 1= mild 2=moderate 3=severe                                                                                                                                                              |                                                                       |                                                                                                                             |                                                                                                  |
| Liver Function Tests                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                 |                                                                                                                                                                                                                                                                                                                                      |                                                                       |                                                                                                                             |                                                                                                  |
| Blood Counts                                                                                                                                                                                                                                                                                                                                                                                                                 | Score                                                                                           |                                                                                                                                                                                                                                                                                                                                      |                                                                       |                                                                                                                             |                                                                                                  |  
Abbreviated Title: Lupron & 18F FLT in allo-HSCTVersion Date: *December 28, 2017* 100 100 Abbreviated Title: Lupron & 18F FLT in allo-HSCTVersion Date: *December 28, 2017*  
| 70 Both greater restriction of and less time spent in play activity Cares for self; unable to carry on normal activity or to do active work   | 60 Up and around, but minimal active play; keeps busy with quieter activities Requires occasional assistance but is able to care for most personal needs   | 50 Gets dressed but lies around much of the day, no active play but able to participate in all quiet play and activities Requires considerable assistance and frequent medical care   | 40 Mostly in bed; participates in quiet activities Disabled; requires special care and assistance   | 30 In bed; needs assistance even for quiet play Severely disabled; hospital admission is indicated although death not  imminent 20 Often sleeping; play entirely limited to very passive activities Very sick; hospital admission necessary; active supportive treatment  necessary 10 No play; does not get out of bed Moribund; fatal processes progressing rapidly   | 0 Unresponsive Dead   |
|-----------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------|
untitled h1
version date december 28 2017

| 12.12 APPENDIX 8C: SIGNS AND SYMPTOMS OF CGVHD ORGAN OR  DIAGNOSTIC  SITE (Sufficient to  establish the  diagnosis of chronic  GVHD) DISTINCTIVE  (Seen in chronic GVHD, but  insufficient alone to establish a  diagnosis of chronic GVHD)   | OTHER                                                                                                                                                      | COMMON (Seen with both                                                                                                            |                                            |    |                                             |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------|----|---------------------------------------------|
| FEATURES*                                                                                                                                                                                                                                     | acute and  chronic GVHD)                                                                                                                                   |                                                                                                                                   |                                            |    |                                             |
| Skin                                                                                                                                                                                                                                          | Ɣ                                                                                                                                                          | Poikiloderma                                                                                                                      |                                            |    |                                             |
| Ɣ                                                                                                                                                                                                                                             | Lichen planus-like  features                                                                                                                               |                                                                                                                                   |                                            |    |                                             |
| Ɣ                                                                                                                                                                                                                                             | Sclerotic features                                                                                                                                         |                                                                                                                                   |                                            |    |                                             |
| Ɣ                                                                                                                                                                                                                                             | Morphea-like  features                                                                                                                                     |                                                                                                                                   |                                            |    |                                             |
| Ɣ                                                                                                                                                                                                                                             | Lichen sclerosuslike features                                                                                                                                                            | Ɣ                                                                                                                                 | Depigmentation                             | ƔSweat impairment Ɣ Ichthyosis ƔKeratosis pilaris ƔHypopigmentation ƔHyperpigmentation    | Ɣ Erythema Ɣ Maculopapular  rash Ɣ Pruritus |
| Nails                                                                                                                                                                                                                                         | Ɣ Dystrophy Ɣ Longitudinal ridging,  splitting or brittle features Ɣ Onycholysis Ɣ Pterygium unguis Ɣ Nail loss** (usually  symmetric, affects most nails) |                                                                                                                                   |                                            |    |                                             |
| Scalp and                                                                                                                                                                                                                                     | Ɣ New onset of scarring or nonscarring scalp alopecia, (after                                                                                                                                                            |                                                                                                                                   |                                            |    |                                             |
| Body Hair                                                                                                                                                                                                                                     | recovery from  chemoradiotherapy) Ɣ6FDOLQJSDSXORVTXDPRXV lesions                                                                                                                                                            | Ɣ Thinning scalp  hair, typically  patchy, coarse or  dull (not explained  by endocrine or  other causes),  Ɣ Premature gray hair |                                            |    |                                             |
| Mouth                                                                                                                                                                                                                                         | Ɣ Lichen-type  features Ɣ Hyperkeratotic  plaques Ɣ Restriction of  mouth opening from sclerosis                                                           | Ɣ Xerostomia Ɣ Mucocele Ɣ Mucosal Atrophy Ɣ Pseudomembranes** Ɣ Ulcers**                                                          | Ɣ Gingivitis Ɣ Mucositis Ɣ Erythema Ɣ Pain |    |                                             |
| Eyes                                                                                                                                                                                                                                          | Ɣ New onset dry, gritty, or  painful eyes† Ɣ Cicatricial conjunctivitis Ɣ Keratoconjunctivitis sicca† x Confluent areas of punctate  keratopathy           | Ɣ Photophobia Ɣ Periorbital  hyperpigmentation Ɣ Blepharitis  (erythema of the  eye lids with  edema)                             |                                            |    |                                             |
| Genitalia                                                                                                                                                                                                                                     | Ɣ                                                                                                                                                          | Lichen planus-like  features                                                                                                      |                                            |    |                                             |
| Ɣ                                                                                                                                                                                                                                             | Vaginal scarring  or stenosis                                                                                                                              | x Erosions** x Fissures** x Ulcers**                                                                                              |                                            |    |                                             |
| GI Tract                                                                                                                                                                                                                                      | x Esophageal web x Strictures or stenosis  in the upper to mid third of the  esophagus**                                                                   | x                                                                                                                                 | Exocrine                                   |    |                                             |
| pancreatic  insufficiency                                                                                                                                                                                                                     | x Anorexia x Nausea x Vomiting x Diarrhea x Weight loss                                                                                                    |                                                                                                                                   |                                            |    |                                             |  
Version Date: December 28, 2017  
| Version Date: December 28, 2017 ORGAN OR  DIAGNOSTIC  SITE (Sufficient to  establish the  diagnosis of chronic  GVHD)                                                          | DISTINCTIVE  (Seen in chronic GVHD, but  insufficient alone to establish a  diagnosis of chronic GVHD)                                                                | OTHER                                                 | COMMON                                                          |        |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------|-----------------------------------------------------------------|--------|
| FEATURES*                                                                                                                                                                      | (Seen with both  acute and  chronic GVHD) x Failure to  thrive (infants  and children                                                                                 |                                                       |                                                                 |        |
| Liver                                                                                                                                                                          | x Total bilirubin,  alkaline  phosphatase >  2 x upper limit  of normal† ƔALT or AST >  2x upper limit of  normal†                                                    |                                                       |                                                                 |        |
| Lung                                                                                                                                                                           | Ɣ                                                                                                                                                                     | Bronchiolitis  obliterans diagnosed  with lung biopsy | x Bronchiolitis obliterans  diagnosed with PFTs and  radiology† | x BOOP |
| Muscles,                                                                                                                                                                       | x Fasciitis                                                                                                                                                           |                                                       |                                                                 |        |
| Fascia, Joints                                                                                                                                                                 | x Joint stiffness or  contractures  secondary to sclerosis                                                                                                            | x Myositis or                                         | x Edema                                                         |        |
| polymyositis †                                                                                                                                                                 | x Muscle cramps x Arthralgia or  arthritis                                                                                                                            |                                                       |                                                                 |        |
| Hematopoietic                                                                                                                                                                  | x Thrombocytopenia                                                                                                                                                    |                                                       |                                                                 |        |
| and Immune                                                                                                                                                                     | x Eosinophilia x Lymphopenia x Hypo- or hypergammaglobulinemi a x Autoantibodies  (AIHA, ITP)                                                                                                                                                                       |                                                       |                                                                 |        |
| Other                                                                                                                                                                          | x Pericardial or  pleural effusions x Ascites x Peripheral  neuropathy x Nephrotic  syndrome x Myasthenia gravis x Cardiac conduction  abnormality or  cardiomyopathy |                                                       |                                                                 |        |
| *Can be acknowledged as part of the chronic GVHD symptomatology if diagnosis is confirmed **In all cases, infection, drug effect, malignancy or other causes must be excluded. |                                                                                                                                                                       |                                                       |                                                                 |        |  
*Can be acknowledged as part of the chronic GVHD symptomatology if diagnosis is confirmed **In all cases, infection, drug effect, malignancy or other causes must be excluded.  
†Diagnosis of chronic GVHD requires biopsy or radiology confirmation (or Schirmer's test foreyes).  
GVHD (graft versus host disease); ALT (alanine aminotransferase); AST (aspartate aminotransferase); BOOP (bronchiolitis obliterans organizing pneumonia); PFTs (pulmonary function tests); AIHA (autoimmune hemolytic anemia)  
| Please complete for new diagnosis and follow-up with cGVHD (and/or day +100, 180, 270, 365) SCORE 0 SCORE 1 SCORE 2 SCORE 3 ERFORMANCE  CORE Asymptomatic  and fully active  (ECOG 0; KPS or  LPS 100%) Symptomatic,  fully ambulatory,  restricted only in  physically strenuous  activity (ECOG 1,  KPS or LPS 80- 90%) Symptomatic,  ambulatory,  capable of selfcare, >50% of  waking hours out  of bed (ECOG 2,  KPS or LPS 60- 70%)  Symptomatic,  limited self-care,  >50% of waking  hours in bed (ECOG  3-4, KPS or LPS  <60%) KPS ECOG LPS KIN Clinical features: Maculopapular  rash Lichen planus-like  features Papulosquamous  lesions or ichthyosis Hyperpigmentation Hypopigmentation Keratosis pilaris Erythema Erythroderma  Poikiloderma Sclerotic features  Pruritus Hair involvement Nail involvement % BSA  involved No Symptoms 18% BSA with  disease signs but  NOsclerotic  features 19-50% BSA  OR involvement  with superficial  sclerotic features  "not hidebound"  (able to pinch) >50% BSA OR deep sclerotic  features "hidebound"  (unable to pinch) OR impaired mobility,  ulceration or severe  pruritus  Severe symptoms  with disease signs on  examination with major limitation of  oral intake YES OUTH No symptoms Mild symptoms  with disease signs  but not limiting oral  intake significantly Moderate  symptoms with  disease signs with partial limitation  of oral intake No symptoms Mild dry eye  symptoms not  affecting ADL  (requiring eyedrops  < 3 x per day) OR asymptomatic signs  of  keratoconjunctivitis  sicca Moderate dry  eye symptoms  partially affecting  ADL (requiring  drops > 3 x per  day or punctal  plugs),  WITHOUT vision impairment Severe dry eye  symptoms  significantly  affecting ADL  (special eyeware to  relieve pain) OR unable to work  because of ocular  symptoms ORloss  of vision caused by  keratoconjunctivitis  siccaMean tear test (mm): >10 6-10 <5 Not done   |
|---|  
Version Date: December 28, 2017  
| SCORE 0                                                                                                                                                                                                                                                                                                                         | SCORE 1         | SCORE 2           | SCORE 3   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------|-------------------|-----------|
| GI TRACT                                                                                                                                                                                                                                                                                                                        | No symptoms     | Symptoms such     |           |
| as dysphagia,  anorexia, nausea,  vomiting, abdominal  pain or diarrhea  without significant  weight loss (<5%)                                                                                                                                                                                                                 | Symptoms        |                   |           |
| associated with  significant weight  loss >15%, requires  nutritional  supplement for most  calorie needs OR esophageal dilation                                                                                                                                                                                                |                 |                   |           |
| IVER                                                                                                                                                                                                                                                                                                                            | Normal LFT      | Elevated          |           |
| Bilirubin, AP*, AST  or ALT <2 x ULN                                                                                                                                                                                                                                                                                            | Symptoms        |                   |           |
| associated with  mild to moderate  weight loss (5- 15%) Bilirubin >3  mg/dl or Bilirubin,  enzymes 2-5 x  ULN                                                                                                                                                                                                                   | Bilirubin or    |                   |           |
| enzymes > 5 x ULN                                                                                                                                                                                                                                                                                                               |                 |                   |           |
| UNGS                                                                                                                                                                                                                                                                                                                            | No symptoms     | Mild symptoms     |           |
| (shortness of breath  after climbing one  flight of steps)                                                                                                                                                                                                                                                                      | Moderate        |                   |           |
| symptoms  (shortness of  breath after  walking on flat  ground)                                                                                                                                                                                                                                                                 | Severe symptoms |                   |           |
| (shortness of breath  at rest; requiring 0                                                                                                                                                                                                                                                                                      |                 |                   |           |
| FEV1                                                                                                                                                                                                                                                                                                                            | FEV1 > 80%      |                   |           |
| ORLFS=2                                                                                                                                                                                                                                                                                                                         | FEV1 60-79%     |                   |           |
| ORLFS 3-5                                                                                                                                                                                                                                                                                                                       | FEV1 <39% OR    |                   |           |
| LFS 10-12                                                                                                                                                                                                                                                                                                                       |                 |                   |           |
| DLCO                                                                                                                                                                                                                                                                                                                            | FEV1 40-59%     |                   |           |
| ORLFS 6-9                                                                                                                                                                                                                                                                                                                       |                 |                   |           |
| OINTS AND ASCIA                                                                                                                                                                                                                                                                                                                 | No symptoms     | Mild tightness of |           |
| arms or legs, normal  or mild decreased  range of motion  (ROM) ANDnot  affecting ADL                                                                                                                                                                                                                                           | Tightness of    |                   |           |
| arms or legs OR joint contractures,  erythema due to  fasciitis, moderate  decrease ROM  ANDmild to  moderate  limitation of ADL                                                                                                                                                                                                | Contractures    |                   |           |
| WITH significant  decrease of ROM AND significant  limitation of ADL  (unable to tie shoes,  button shirts, dress  self etc.)  Symptomatic  WITH advanced  signs (stricture,  labial agglutination  or severe ulceration)  ANDsevere pain  with coitus or  inability to insert  vaginal speculum                                |                 |                   |           |
| AP may be elevated in growing children, and not reflective of liver dysfunction ENITAL RACT No symptoms Symptomatic with  mild signs on exam  ANDno effect on  coitus and minimal  discomfort with  gynecologic exam Symptomatic  with moderate  signs on exam  ANDwith mild  dyspareunia or  discomfort with  gynecologic exam |                 |                   |           |
untitled h1
other indicators clinical manifestations or

| Esophageal stricture or web___            | Pericardial Effusion___       | Pleural Effusion(s)___         |      |
|-------------------------------------------|-------------------------------|--------------------------------|------|
| Ascites (serositis)___                    | Nephrotic syndrome___         | Peripheral Neuropathy___       |      |
| Myasthenia Gravis___                      | Cardiomyopathy___             | Eosinophilia >                 | l___ |
| Polymyositis___                           | Cardiac conduction defects___ | Coronary artery involvement___ |      |
| Platelets <100,000/l ___Progressive onset |                               |                                |      |  
106 Version Date: December 28, 2017 Լ **OTHERS:** ___________
untitled h1
12.14 appendix 9 etib policy

Experimental Transplantation and Immunology Branch Preclinical Service Policy for Sample Handling 12.14.1Sample Processing
untitled h1
edta plasma

Spin down cells at 1500 rpm, 10 min, 10°C. Draw off plasma. Store >6 ml of plasma in 1ml conical tubes, labeled as EDTA plasma. Store at -80°C.Heparinized Blood: Heparinized whole blood is collected for analysis of relevant cytokine/chemokines content. Separate plasma by centrifugation and freeze > 6ml samples in 1ml conical tubes, labeled as heparinized plasma. Store at –80°C. If whole blood is being processed for flow cytometry: Place 1 ml of well mixed whole blood in a 15ml tube. Add 10ml ACK. Mix well by repeatedly inverting tube. Hold 5 min RT. Spin down (1500 rpm, 10 min, 10°C), Resuspend in 0.5ml FACS buffer. Distribute to staining tubes. If whole blood is cryopreserved Ficoll blood and cryopreserve cells, divided into two 1ml aliquots. Store in LN2. Our freezing protocol is attached, but any commercial cryopreserve media will suffice.
untitled h1
12.14.2labeling

All samples are to be labeled with an anonymized Patient identifier such as the patient \# in the protocol\#), date, content (EDTA or heparinized plasma, PBMC with cell number,) and preferably stage (pre, 3m, 6m). We need to be able to link all timepoints collected on a single patient but not an identity.  
12.14.3Storage/Tracking in the Preclinical Development and Clinical Monitoring Facility
untitled h1
(pdcmf)

Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. Should a CRIS screen not be available, the CRIS downtime procedures will be followed. Samples will not be sent outside NIH without IRB notification and an executed MTA. Normal donor and patient blood and tissue samples, collected for the purpose of research under IRB approved protocols of the Experimental Transplantation and Immunology Branch, may be archived by the ETIB Preclinical Service. All data associated with archived clinical research samples is entered into the ETIB Preclinical Services's Microsoft Excel databases on frozen cells and plasma. These databases are stored on the NCI group drive in the ETIB Preclinical Service folder. Access to this folder is limited to ETIB clinical staff, requiring individual login and password. All staff in the Preclinical Service laboratory have received annually updated NIH/CIT training and maintain standards of computer security. Only NIH PI and Adjunct PI may appropriate samples for use and interpret data in the context of the endpoints of this trial. The data recorded for each sample includes the patient ID, name, trial name/protocol number, date drawn, treatment cycle/post transplant time point, cell source (e. g. peripheral blood, lymphapheresis, mobilized peripheral blood stem cells, marrow, pleural fluid) as well as box and freezer location. Patient demographics that correlate treatment outcomes and therapies with the samples can be obtained only through the NCI/ETIB clinical records or NCI C3D. As of January 2007, all newly received samples will receive a unique bar code number, which will be added to the sample Preclinical Service database. Only this bar code will be recorded on the sample vial and the vials will not be traceable back to patients without authorized access to the Preclinical Service database. All non-coded samples previously archived will be stripped of identifiers prior to distribution for any use other than as a primary objective of the protocol under which they were collected. Samples are stored in locked freezers. All samples will be labeled solely with a bar code (which includes the date, and serially determined individual sample identifier). The key will be available to a restricted number of ETIB investigators and associate investigators on the protocol. Coded samples will be stored frozen at -20°, -80° or liquid nitrogen vapor phase according to the stability requirements under the restricted control of the PDCM Facility of ETIB.. Access to samples from a protocol for research purposes will be by permission of the Principal Investigator of that protocol in order to be used (1) for research purposes associated with protocol objectives for which the samples were collected, or (2) for a new research activity following submission and IRB approval of a new protocol and consent, or (3) for use only as unlinked or coded samples under the OHSRP Exemption Form guidelines stipulating that the activity is exempt from IRB review. Unused samples must be returned to the PDCMF laboratory. Samples, and associated data, will be stored permanently unless the patient withdraws consent. If researchers have samples remaining once they have completed all studies associated with the protocol, they must be returned to the PDCMF laboratory. These freezers are located onsite at the PDCMF laboratory (12C216) or in ETIB common equipment space (CRC/3-3273). 12.14.4Protocol Completion/Sample Destruction Once primary research objectives for the protocol are achieved, researchers can request access to remaining samples, providing they have both approval of the Principal Investigator of the original protocol under which the samples or data were collected and either an IRB approved protocol and patient consent or the OHSRP Exemption Form stipulating that the activity is exempt from IRB review.. The PDCMF staff will report to the Principal Investigators any destroyed samples, if samples become unsalvageable because of environmental factors (ex. broken freezer or lack of dry ice in a shipping container), lost in transit between facilities or misplaced by a researcher. The PI will report destroyed samples to the IRB if samples become unsalvageable because of environmental factors (ex. broken freezer or lack of dry ice in a shipping container) or if a patient withdraws consent. Samples will also be reported as lost if they are lost in transit between facilities or misplaced by a researcher. Freezer problems, lost samples or other problems associated with samples will also be reported to the IRB, the NCI Clinical Director, and the office of the CCR, NCI. 12.14.5Handling for subjects at other Participating Institutions x Blood speciman obtained from University of Oklahoma and Children's National Medical Center may be frozen as above, stored, and shipped in batch to NCI. The specimens should be shipped to arrive Monday-Friday, to Dr. Fran Hakim's ETIB Core lab (Bldg 10, room 12C216. Attention Jeremy Rose phone: 301-594 5339, 10 Center Drive, CRC 3-3330, Bethesda, MD 20892.  
12.15 APPENDIX 10: DATA COLLECTION ELEMENTS REQUIRED BY PROTOCOL
All of the following elements will be recorded in the C3D database.  
A. Patient Enrollment
untitled h1
recipient donor

x Date of birth, age, gender, race, ethnicity x Height x Weight x Baseline History/Physical (Y/N)
x Serology (CMV) x ABO
B. Study Drug administration and response for each course of therapy given x Dates study drugs given x Dose level, actual dose, schedule and route given x Height, weight, and body surface area at start of each course x Response assessment for each restaging performed x For women, the administration of estrogen supplementation will be captured.  
C. Laboratory and Diagnostic Test Data x All Clinical laboratory and diagnostic test results done at screening (recipient and donor) and until day 365 post transplant with the following exceptions:
x Date of birth, age, gender, race, ethnicity x Height x Weight x Performance Status x Date of original diagnosis x Stage at diagnosis x Stage at study entry x Sites of disease at diagnosis and study entry x Tumor Histology and date of confirmation x Date of Informed Consent signature, consent version and date of registration x Baseline History/Physical x Baseline Symptoms x Prior therapy x Prior surgery x Findings of consultations done at screening x ABO
o Diagnostic tests which are not specified in the protocol, and if the results are not needed to document the start or end of an adverse event that requires reporting.  
x All clinical laboratory and diagnostic tests done after day 100 that support a possible, probable or definite diagnosis of GVHD, infection or secondary malignancy and those done to document a change in grade and the end of these adverse events.  
x All tests done to document resolution of adverse events that occurred in the first 100 days post transplant x HLA data (patient and donor).  
x Serologies-CMV, HSV, EBV, toxoplasmosis, adenovirus (patient and donor)
x TTV data (patient and donor)
x Blood, bone marrow, and tumor chimerism data x FEV1, DLCO (adjusted but not /VA) pre-transplant x EF pre-transplant x Acute care, hepatic, and mineral panel plus LDH at transplant x GFR or CrCL pre-transplant x Complete blood count pre-transplant x Lymphocyte total number, % CBC, and TBNK at research time points for primary endpoint x IgA, IgM, IGG at research primary endpoints x Engraftment endpoints: neutrophil, plt, hbg x LH/FSH/sex hormone levels x Vaccine serologies.
untitled h1
d. adverse events

x All grade 2, 3, or 4 adverse events possibly, probably, or definitely attributable to lupron or the IND and all serious adverse events will be recorded.  
x Data will also be reported to the Center for International Bone Marrow Transplant Registry E. Concomitant Measures x Baseline medications x Antibiotics x GVHD prophylaxis and treatment x Other therapy for recorded adverse events F. Treatment of Persistent/Progressive Disease with Standard Therapy x Chemotherapy x Immunotherapy x Radiation therapy x Donor Lymphocyte Infusion G. Tumor response and measurements x Restaging studies performed at protocol specified time points and as clinically indicated.  
H. Off study x Date and reason for off study x Date and cause of death x Autopsy findings x PI decision to end this study Version Date: December 28, 2017  
| 12.16 APPENDIX 11: PROBLEM REPORT FORM NCI Protocol #: Protocol Title:  Report version: (select one) ____Initial Report  ____Revised Report ____Follow-up Site Principal Investigator: Date of problem: Location of problem: (e.g., patient's home,  doctor's office ) Who identified the problem? (provide role (not name of person): nurse, investigator,  monitor, etc…) Brief Description of Subject (if  applicable) (Do NOT include personal  identifiers) Sex: ___ Male ___ Female Age: ___ Not applicable (more than subject is involved) Diagnosis under study:  Name the problem: (select all that apply) [ ] Adverse drug reaction  [ ] Abnormal lab value  [ ] Death  [ ] Cardiac Arrest/ code  [ ] Anaphylaxis  [ ] Sepsis/Infection  [ ] Blood product reaction [ ] Unanticipated surgery/procedure  [ ] Change in status (e.g. increased level of care required)  [ ] Allergy (non-medication)  [ ] Fall  [ ] Injury/Accident (not fall)  [ ] Specimen collection issue  [ ] Informed consent issue  [ ] Ineligible for enrollment  [ ] Breach of PII   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Version Date: December 28, 2017
[ ] Tests/procedures not performed on schedule [ ] Other, brief 1-2 word description: _________________________
Detailed Description of the problem: (Include any relevant treatment, outcomes or pertinent history):
*Is this problem unexpected? *(see the definition of unexpected in the protocol))* __YES __NO Please explain:
*Is this problem related or possibly related to participation in the research?  
__YES __NO Please explain:
*Does the problem suggest the research places subjects or others at a greater risk of harm than was previously known or recognized? __YES __NO
Please explain:
Is this problem? (*select all that apply*)
[ ] An Unanticipated Problem* that is: [ ] Serious [ ] Not Serious [ ] A Protocol Deviation that is: [ ] Serious [ ] Not Serious [ ] Non-compliance *Note if the 3 criteria starred above are answered, "YES", then this event is also a UP.  
Is the problem also *(select one)* [ ] AE [ ] Non-AE Have similar problems occurred on this protocol at your site? __YES __NO
If "Yes", how many? ____ **Please describe:**
Describe what steps you have already taken as a result of this problem:
In addition to the NCI IRB, this problem is also being reported to: (*select all that* apply)
[ ] Local IRB [ ] Study Sponsor [ ] Manufacturer : ____________________ [ ] Institutional Biosafety Committee [ ] Data Safety Monitoring Board [ ] Other: ____________________________________ [ ] None of the above, not applicable Version Date: December 28, 2017 INVESTIGATOR'S SIGNATURE: DATE: