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10 human subjects protections 10.1

x The patients to be entered in this protocol have multiple myeloma which is an almost always incurable disease; moreover, patients will have progressive or relapsed myeloma despite at least 3 prior therapies. These patients have limited life expectancies. Subjects from both genders and all racial/ethnic groups are eligible for this study if they meet the eligibility criteria. To date, there is no information that suggests that differences in disease response would be expected in one group compared to another. Efforts will be made to extend accrual to a representative population, but in this preliminary study, a balance must be struck between patient safety considerations and limitations on the number of individuals exposed to potentially toxic and/or ineffective treatments on the one hand and the need to explore gender and ethnic aspects of clinical research on the other hand. If differences in outcome that correlate to gender or to ethnic identity are noted, accrual may be expanded or a follow-up study may be written to investigate those differences more fully.  
x Multiple myeloma (MM) remains an incurable disease despite recent advances in therapy.  
x Over the last 40 years and throughout the most recent era of improved therapy with novel agents, the depth of the disease response to therapy (including T- cells targeting B-cell maturation antigen) has remained the single most predictive factor for event free and overall survival in MM
x Therefore, improving the rate and depth of responses remains a high priority for clinical research in MM.  
x This justifies the enrollment of all subjects with MM eligible for T- cells targeting B-cell maturation antigen in this phase I/II study in an attempt to improve the clinical outcome while feasibility and safety are being evaluated.  
x Because patients on previous trials of CAR T cells have experienced hypotension, tachycardia, prolonged fevers, neurological toxicities, and depressed myocardial function. In many cases these toxicities were severe enough to require intensive care unit admission. We will limit enrollment to patients 70 years of age or less because based on our admittedly limited experience with prior CAR-T cell clinical trials, younger patients tolerate and recover from these toxicities better than elderly patients.
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10.2 participation of children

Children will not be enrolled on this study. Multiple myeloma is extremely uncommon in children; moreover, since the efficacy of this experimental procedure is unknown, it does not seem reasonable to expose children to this risk without further evidence of benefit.
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10.3 participation of subjects unable

Adults unable to give consent are excluded from enrolling in the protocol. However re-consent may be necessary and there is a possibility, though unlikely, that subjects could become decisionally impaired. For this reason and because there is a prospect of direct benefit from research participation (section **10.4** DOOVXEMHFWVDJHZLOOEHRIIHUHGWKHRSSRUWXQLW\WRILOO in their wishes for research and care, and assign a substitute decision maker on the "NIH Advance Directive for Health Care and Medical Research Participation" form so that another person can make decisions about their medical care in the event that they become incapacitated or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent Assessment Team for evaluation. For those subjects that become incapacitated and do not have pre-determined substitute decision maker, the procedures described in MEC Policy 87-4 for appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of attorney, will be followed.
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10.4 evaluation of benefits and

The experimental treatment has a chance to provide clinical benefit though this is unknown. A goal of this study is to improve upon the number of patients who may benefit from adoptive cell therapy by using genetically-modified T-cells. This specific protocol is being performed to evaluate a genetically modified T-cell therapy for multiple myeloma, which is an almost always incurable disease. Only patients with multiple myeloma who have progressive or relapsed myeloma despite at least 3 prior lines of therapy will be enrolled. The risks of the study fall into 3 general categories. First, chemotherapy that could cause cytopenias is part of the protocol. As with any chemotherapy that causes neutropenia and thrombocytopenia, this chemotherapy could cause toxicities such as infections and bleeding. The second category of toxicity is cytokinerelease type toxicities such as high fevers, hypotension and neurological toxicities such as delirium, obtundation, myoclonus, seizures, headache, and transient focal neurological toxicities including aphasia and focal paresis. These cytokine-release-type toxicities have been detected in other clinical trials of CAR T cells during the first 2 weeks after anti-BCMA CAR T cells were infused.4,95 The third main category of toxicity is direct damage to normal tissues by the CAR T
cells. This could happen because of unexpected expression of BCMA on normal cells or because of unexpected cross-reactivity of the anti-BCMA CAR with proteins other than BCMA in vivo. Another potential toxicity of anti-BCMA CAR T cells is hypogammaglobulinemia due to depletion of plasma cells and mature B cells. Hypogammaglobulinemia has been a complication of many patients on clinical trials of anti-BCMA CAR-expressing T cells.4,32 Hypogammaglobulinemia in these patients was routinely treated with infusions of intravenous immunoglobulins.4 The gammaretroviral vector used in this trial inserts into the T-cell DNA of patients, so in theory, insertional mutagenesis could occur, but insertional mutagenesis has not occurred in any of the hundreds of patients treated with mature T cells that were genetically modified by gammaretroviral vectors.34-36 The success of this clinical trial cannot be predicted at this time. Because all patients in this protocol have advanced multiple myeloma and limited life expectancies the potential benefit is thought to outweigh the potential risks. It is also anticipated that this study will provide scientific information relevant to tumor immunotherapy.
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10.5 consent and assent process

The patient, along with family members or friends, will be presented with a detailed description of the protocol treatment. The specific requirements, objectives, and potential advantages and disadvantages will be presented. The Informed Consent document is given to the patient who is requested to review it and to ask questions prior to agreeing to participate in the treatment portion of this protocol. The patient will be reassured that participation on trial is entirely voluntary and that he/she can withdraw or decide against treatment at any time without adverse consequences.The permission for additional biopsies for research will be obtained from patients at the time of the biopsy procedure. The research nurse, Principal Investigator or his designee is responsible for obtaining written informed consent from the patient. 10.5.1 Telephone re-consent procedure Reconsent on this study may be obtained via telephone according to the following procedure: the informed consent document will be sent to the subject. An explanation of the study will be provided over the telephone after the subject has had the opportunity to read the consent form. The subject will sign and date the informed consent. A witness to the subject's signature will sign and date the consent. The original informed consent document will be sent back to the consenting investigator who will sign and date the consent form with the date the consent was obtained via telephone. A fully executed copy will be returned via mail for the subject's records. The informed consent process will be documented on a progress note by the consenting investigator and a copy of the informed consent document and note will be kept in the subject's research record. 10.5.2 Short form consent process for non-English speaking patients If there is an unexpected enrollment of a research participant for whom there is no translated extant IRB approved consent document, the principal investigator and/or those authorized to obtain informed consent will use the Short Form Oral Consent Process as described in MAS Policy M77-2, OHSRP SOP 12, 45 CFR 46.117 (b) (2) and 21 CFR 50.27 (b) (2). The summary that will be used is the English version of the extant IRB approved consent document. Signed copies of both the English version of the consent and the translated short form will be given to the subject or their legally authorized representative and the signed original will be filed in the medical record. Unless the PI is fluent in the prospective subject's language, an interpreter will be present to facilitate the conversation. Preferably someone who is independent of the subject (i.e., not a family member) will assist in presenting information and obtaining consent. Whenever possible, interpreters will be provided copies of the relevant consent documents well before the consent conversation with the subject (24 to 48 hours if possible). We request prospective IRB approval of the use of the short form process and will notify the IRB at the time of continuing review of the frequency of the use of the Short Form.
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11 pharmaceutical information 11.1 retroviral

The retroviral vector supernatant (PG13-MSGV-11D5-3CD828Z B1) encoding a chimeric antigen receptor (CAR) directed against B-cell maturation antigen (BCMA) was prepared and preserved following cGMP conditions in the Surgery Branch Vector Production Facility (SBVPF). The retroviral vector utilizes the MSGV retroviral vector backbone and consists of 7007 bps including the 5' LTR from the murine stem cell virus (promoter), packaging signal including the splicing donor (SD) and splicing acceptor sites, the anti-BCMA CAR protein containing a signal peptide from human CD8-alpha, 11D5-3 light chain variable region (11D5-3 VL), linker peptide, 11D5-3 heavy chain variable region (11D5-3 VH), CD8 (hinge and transmembrane), CD28 (cytoplasmic region), and TCR zeta (cytoplasmic region), followed by the murine stem cell virus 3'LTR. The physical titer was determined by RNA dot blot according to sponsor certificate. The supernatant will be stored at –80 C or shipped on dry ice and stored in the Dept. of Transfusion Medicine, NIH or at Cryonix, Rockville, MD. Both storage facilities are equipped with around-the-clock temperature monitoring. Upon request, supernatant will be delivered on dry ice to be used in *in vitro* transductions of T cells. There will be no re-use of the same unit of supernatant for different patients. Retroviral titer has been shown to be stable after immediate thawing and immediate use. Handling of the vector should follow the guidelines of Biosafety Level-2 (BSL-2). The specific guidelines for Biosafety Level-2 (BSL-2) can be viewed at http://bmbl.od.nih.gov/sect3bsl2.htm
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11.2 cyclophosphamide 11.2.1 source

Cyclophosphamide will be purchased by the NIH Clinical Center Pharmacy Department from commercial sources and is supplied as a lyophilized powder in various vial sizes. 11.2.2 Toxicities 1) Nausea and vomiting - variable; symptomatically improved with standard anti-emetics and/or benzodiazepines [e.g., lorazepam].  
2) Water retention - cyclophosphamide may rarely provoke the syndrome of inappropriate antidiuretic hormone secretion and resultant hyponatremia, usually manifested 12-48 hours after IV administration, necessitating frequent accurate assessment [q 1-2 hours] of intake, urine output and urine specific gravity. This effect can be counteracted by furosemide. Fluid restriction is not feasible during administration of high dose cyclophosphamide.  
3) Cardiomyopathy - cyclophosphamide may cause severe, sometimes lethal, hemorrhagic myocardial necrosis or congestive cardiomyopathy. Patients may present with congestive cardiomyopathy as late as 2 weeks after the last dose of cyclophosphamide. The clinical syndrome has been observed in patients receiving the dose of cyclophosphamide used in this protocol. In an attempt to minimize this complication, patients with significant cardiac dysfunction are excluded from this protocol [see patient eligibility]. Congestive failure is managed according to standard medical therapeutics.  
4) Hemorrhagic cystitis - this is a serious, potentially life-threatening complication related to injury of the bladder epithelium by cyclophosphamide metabolites.  
5) Although sub-clinical hematuria is not uncommon at this dose level, clinically significant hematuria or serious hemorrhage can usually be avoided by maintaining a high urine volume and frequent voidings and the administration of Mesna. Diuresis is maintained for 24 hours after completion of last dose by parenteral infusions of normal saline with potassium chloride. Careful monitoring of serum and urine electrolytes is mandated. Furosemide may be required to ensure this diuresis. Continuous bladder irrigation may be used for control of significant hematuria.  
6) Sterility 7) Less common but serious complications include pulmonary fibrosis and secondary malignancies. Less common but reversible toxicities include alopecia and skin rash.
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11.2.3 formulation and preparation

Reconstituted with sterile water for injection to yield a final concentration of 20 mg/ml as described in the package insert.
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11.2.4 stability and storage

Vials are stored at room temperature. Following reconstitution as directed with sterile water for injection, cyclophosphamide is stable for 24 hours at room temperature or 6 days when kept at 28°C. Once diluted for administration, cyclophosphamide will be provided an expiration date based on the standards set by the NIH CC Pharmacy Department.
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11.2.5 administration procedures

The cyclophosphamide used in this regimen will be given as Intravenous infusion over 30 minutes.
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11.3 fludarabine 11.3.1 source

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. Fludarabine is stored at room temperature.
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11.3.2 toxicity

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 agent.
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11.3.3 formulation and 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.
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11.3.4 stability and storage

Reconstituted FLUDARA IV should be stored in the refrigerator between 36 and 46 degrees F. Because reconstituted FLUDARA IV contains no antimicrobial preservative, care must be taken to assure the sterility of the prepared solution. Once diluted for administration, fludarbine will be provided an expiration date based on the standards set by the NIH CC Pharmacy DepartmentAdministration procedures Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Fludarabine is administered as an IV infusion in 100 ml 0.9% sodium chloride, USP over 15 to 30 minutes. Dose reduction for renal impairment For Creatinine Clearance of 30-70 mL/min/1.73m2 there will be a 20% dose reduction. If the Creatinine Clearance is less than 30mL/min/1.73m2, Fludarabine will not be administered.
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75. O'Connor BP, Raman VS, Erickson LD, et al. BCMA Is Essential for the Survival of Long-lived Bone Marrow Plasma Cells. *Journal of Experimental Medicine.* 2004;199(1):91-97.  
76. Ng LG, Sutherland APR, Newton R, et al. B cell-activating factor belonging to the TNF
family (BAFF)-R is the principal BAFF receptor facilitating BAFF costimulation of circulating T and B cells. *Journal of Immunology.* 2004;173(2):807-817.  
77. Xu S, Lam KP. B-cell maturation protein, which binds the tumor necrosis factor family members BAFF and APRIL, is dispensable for humoral immune responses. *Molecular* and Cellular Biology. 2001;21(12):4067-4074.  
78. Schiemann B, Gommerman JL, Vora K, et al. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. *Science.* 2001;293(5537):2111-2114.  
79. Brandtzaeg P. Function of mucosa-associated lymphoid tissue in antibody formation.  
Immunological Investigations. 2010;39(4-5):303-355.  
80. Soutar CA. Distribution of plasma cells and other cells containing immunoglobulin in the respiratory tract of normal man and class of immunoglobulin contained therein. *Thorax.* 1976;31(2):158-166.  
81. Kalled SL, Hsu Y. Anti-BCMA Antibodies. World Intellectual Property Organization Patent. Filing date 10 March 2010;International Publicaton Number WO 2010/104949 A2(Patent Applicant Biogen Idec, Cambridge MA, USA).  
82. Rubio V, Stuge TB, Singh N, et al. Ex vivo identification, isolation and analysis of tumor-cytolytic T cells. *Nature Medicine.* 2003;9(11):1377-1382.  
83. Muranski P, Boni A, Wrzesinski C, et al. Increased intensity lymphodepletion and adoptive immunotherapy - How far can we go? *Nature Clinical Practice Oncology.* 2006;3(12):668-681.  
84. Klebanoff CA, Khong HT, Antony PA, Palmer DC, Restifo NP. Sinks, suppressors and antigen presenters: How lymphodepletion enhances T cell-mediated tumor immunotherapy. *Trends in Immunology.* 2005;26(2):111-117.  
85. Dumitru CA, Moses K, Trellakis S, Lang S, Brandau S. Neutrophils and granulocytic myeloid-derived suppressor cells: Immunophenotyping, cell biology and clinical relevance in human oncology. *Cancer Immunology, Immunotherapy.* 2012;61(8):11551167.  
86. Lee JC, Hayman E, Pegram HJ, et al. In vivo inhibition of human CD19-targeted effector T cells by natural T regulatory cells in a xenotransplant murine model of B cell malignancy. *Cancer Research.* 2011;71(8):2871-2881.  
87. Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. *Science.* Oct 25 2002;298(5594):850-854.  
88. Dudley ME, Yang JC, Sherry R, et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. Journal of Clinical Oncology. Nov 10 2008;26(32):5233-5239.  
89. O'Brien SM, Kantarjian HM, Cortes J, et al. Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia. *Journal of* Clinical Oncology. 2001;19(5):1414-1420.  
90. Klebanoff CA, Gattinoni L, Palmer DC, et al. Determinants of successful CD8 + T-cell adoptive immunotherapy for large established tumors in mice. *Clinical Cancer Research.* 2011;17(16):5343-5352.  
91. Overwijk WW, Theoret MR, Finkelstein SE, et al. Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells. Journal of Experimental Medicine. 2003;198(4):569-580.  
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13 appendices 13.1 appendix a-performance

| ECOG Performance Status Scale*                                                             |                                                                                                                                                                                       |
|--------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade                                                                                      | Descriptions                                                                                                                                                                          |
| 0                                                                                          | Normal activity. Fully active, able to carry on all pre-disease  performance without restriction. Symptoms, but ambulatory. Restricted in physically strenuous activity,              |
| 1                                                                                          | but ambulatory and able to carry out work of a light or sedentary nature  (e.g., light housework, office work). In bed <50% of the time. Ambulatory and capable of all self-care, but |
| 2                                                                                          | unable to carry out any work activities. Up and about more than 50%  of waking hours.                                                                                                 |
| 3                                                                                          | In bed >50% of the time. Capable of only limited self-care, confined to  bed or chair more than 50% of waking hours.                                                                  |
| 4                                                                                          | 100% bedridden. Completely disabled. Cannot carry on any self-care.  Totally confined to bed or chair.                                                                                |
| 5                                                                                          | Dead.                                                                                                                                                                                 |
| * As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., |                                                                                                                                                                                       |  
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982.
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13.2 appendix b data collection

All of the following elements will be recorded in the C3D database:
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a. patient enrollment

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 Plasmacytoma present: Yes or No x Tumor Histology and date of confirmation x BCMA expression by tumor type of tissue studied 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 radiation x Prior Bone Marrow Biopsy that includes the percent of plasma cells and the percent of BCMA cells x Findings of consultations done at screening B. Study Drug administration and response for each course of therapy given x Dates anti-BCMA-CAR-transduced T cells 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 Concomitant medications will not be collected in C3D
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c. laboratory and diagnostic test

1. All Clinical laboratory and diagnostic test results done at screening and until day 30 post infusion with the following exceptions: 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. Serologies-CMV, HSV, EBV, toxoplasmosis, adenovirus (patient and donor) TTV data 2. All staging studies including serum protein electrophoresis, urine protein electrophoresis, serum free light chains, bone marrow biopsy reports, flow cytometry reports, serum immunoglobulin reports including beta-2 microglobulin, complete blood count and differential reports, serum creatinine reports, TBNK results, serum protein, urine albumin, serum calcium (including ionized), ESR and CRP results. MRI, X-ray (including skeletal survey), and CT scan results will only be reported if they were used for staging.
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d. adverse events

Please see section **6.1.1** Adverse Event Recording E. Tumor response and measurements x Restaging studies performed at protocol specified time points and as clinically indicated.  
x Any physical exam findings will be collected as Adverse Events and labs results. x Years 5-15 follow-up is only for survival.
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f. 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
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13.3 appendix c guidelines for

Infusions of CAR T cells are often complicated by significant acute toxicities in the first 2 to 3 weeks after the infusion. In many cases the toxicities correlate with serum inflammatory cytokine levels.4 The toxicities most often experienced by patients receiving infusions of anti-BCMA CAR T cells include, but are not limited to, tumor lysis syndrome, fever, fatigue, hypotension, tachycardia, acute renal failure, and neurological toxicities such as aphasia, ataxia, headache, somnolence, and coma. Fever is usually the first toxicity to occur. CARs targeting different antigens than BCMA might have different toxicities. Suggested Guidelines for common acute CAR T-cell toxicities Note these are guidelines that might require modification based on clinical circumstances of each patient, and failure to exactly follow these guidelines is not a protocol deviation.  
Administration of corticosteroids should be avoided if at all possible to avoid killing or impairing the function of the CAR T cells.  
1. All patients with significant malignancy burdens and without a contradiction such as allergy should be started on allopurinol at the time of the start of the chemotherapy conditioning regimen or 1 day before the CAR T cell infusion. The suggested allopurinol dose is 200 to 300 mg/day with a possible loading dose of 300 to 400 mg.  
2. Vital signs should be checked a minimum of every 4 hours during hospitalization.  
Increasing the time interval between vital sign checks for patient convenience or other reasons should be avoided.
3. Strict ins and outs should be recorded on all patients. 4. Fevers should be treated with acetaminophen and comfort measures. NSAIDs and corticosteroids should be avoided.  
5. Administer fresh frozen plasma (FFP) for a PTT 1.5-fold or more above the upper limit of normal.  
6. For patients with an increased PTT, check the fibrinogen level and keep the fibrinogen level above 100 mg/dL with cryoprecipitate.  
7. Patients with a heart rate persistently higher than 115/minute and fever should have vital signs checked every 2 hours.  
8. Patients who are neutropenic and febrile should be receiving broad-spectrum antibiotics.  
9. Patients at risk of syncope
Patients on this protocol will be placed on strict fall precautions including instructions to get out of bed only with assistance under the following conditions:  
1. Any history of syncope or near-syncope within 1 month before Anti BCMA CAR T-cell infusion or any time after CAR T-cell infusion.  
2. Any blood pressure reading of less than 90 mm Hg systolic blood pressure after antiBCMA CAR T-cell infusion.  
3. Heart rate greater than 100 beats per minute.
Any patient with syncope, near-syncope, or light-headedness will have orthostatic blood pressure and heart rate checked and receive intravenous fluids as appropriate. These patients will also receive an ECG.  
Hypotension is a common toxicity requiring intensive care unit (ICU) admission. In general patients should be kept well-hydrated. Maintenance I.V. fluids (normal saline (NS) should be started on most patients with high fevers especially if oral intake is poor or the patient has tachycardia. I.V. fluids are not necessary for patients with good oral intake and mild fevers. For patients who are not having hypotension or tumor lysis syndrome, a generally even fluid balance should be strived for after allowing for insensible fluid losses in patients with high fevers. The baseline systolic blood pressure is defined for this protocol as the average of all systolic blood pressure readings obtained during the 24 hours prior to the CAR T-cell infusion. The first treatment for hypotension is administration of IV NS boluses.  
x Patients with a systolic blood pressure that is 80% or less of their baseline blood pressure and less than 100 mm Hg should receive a 1 L NS bolus.  
x Patients with a systolic blood pressure less than 85 mm Hg should receive a 1 L NS
bolus regardless of baseline blood pressure.
These I.V. fluid management suggestions may need to be modified based on the clinical characteristics of individual patients such as pulmonary status, cardiac function, edema and other factors.  
10. Patients receiving fluid boluses for hypotension should have a stat EKG and troponin, and a cardiac echocardiogram within 24 hours.  
11. Patients should be transferred to the ICU under these circumstances. Patients not meeting these criteria could also require ICU admission at the discretion of the clinical team caring for the patient.  
x Systolic blood pressure 75% or less than the patient's baseline blood pressure and less than 100 mm Hg after administration of a 1L NS bolus.  
x Anytime the systolic blood pressure is less than 85 mm Hg after a 1L NS bolus.  
x Continuous tachycardia with a heart rate higher than 125 beats per minute on 2 occasions separated by at least 4 hours.  
x Oxygen requirement of more than a 4L standard nasal cannula x Greater than grade 2 neurological toxicity
12. All patients transferred to the ICU for hypotension or tachycardia should have a stat EKG
and a cardiac echocardiogram at the time of transfer.  
13. Patients with hypotension not responding to IV fluid resuscitation should be started on norepinephrine at doses called for by standard ICU guidelines.  
14. Patients should have a cardiac echocardiogram and an EKG within 24 hours of starting norepinephrine.  
15. Patients in the ICU should get twice-daily labs (CBC with differential, acute care panel, mineral panel, hepatic panel, uric acid, LDH. Patients in the ICU should also get a daily troponin level).  
16. Anecdotal evidence suggests that the IL-6 receptor blocker tocilizumab can be an effective treatment for cytokine-release syndrome toxicities after CAR T-cell infusions. Tocilizumab should be administered under the following circumstances if the listed disorders are thought to be due to cytokine release from CAR T cells. Tocilizumab is administered at a dose 8 mg/kg infused IV over 1 hour (dose should not exceed 800 mg).  
x Left ventricular ejection fraction 40% or less by echocardiogram x Creatinine greater than 2.5-fold higher than the most recent level prior to CAR Tcell infusion x Norepinephrine requirement of 3 Pg/min or more for 36 hours since the first administration of norepinephrine even if norepinephrine administration was not continuous.  
x Systolic blood pressure of 90 mm Hg cannot be maintained with norepinephrine. x Oxygen requirement 55% or greater fraction of inspired oxygen (FIO2) for more than 2 continuous hours.  
x Dyspnea that is severe enough to potentially require mechanical ventilation.  
x PTT or INR>2x upper limit of normal x Clinically-significant bleeding x Creatine kinase greater than 5x upper limit of normal for greater than 2 days 17. THERE IS NO EVIDENCE THAT TOCILIZUMAB HELPS NEUROLOGICAL
TOXICITY, SO IT SHOULD NOT BE ADMINISTERED FOR THIS PURPOSE.  
18. If no improvement in hypotension or tachycardia occurs within 6 hours of tocilizumab infusion, consider other agents such as methylprednisolone 1 mg/kg every 12 hours or etanercept.  
19. Avoid meperidine due to seizure risk. 20. In the setting of cytokine-release syndrome, patients with a left ventricular ejection fraction of 30% or less and patients who in the opinion of an ICU physician is at significant risk of needing intubation in the next 4 hours should be given methylprednisolone 100 mg every 6 hours.  
21. Some patients may experience decreases in serum immunoglobulins. Replacement of serum IgG with intravenous IgG is recommended for serum IgG levels below 400 mg/dL.
22. In general, follow standard vaccination practices including an annual influenza vaccination in the absence of data to suggest otherwise.  
23. All patients with grade 2 or greater neurological toxicities should get a neurology consult. 24. The following patients should receive dexamethasone 10 mg intravenously every 6 hours until the toxicities improve to Grade 1 or resolve or until at least 8 doses of dexamethasone have been given.  
1. Patients with Grade 3 or 4 neurological toxicities except that dexamethasone is not recommended for isolated Grade 3.  
2. Any generalized seizure
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13.4 appendix d infusion instructions

Primary IV tubing (2) Secondary IV tubing (1) NS (sodium chloride 0.9%) 250cc bags (2) IV infusion pump Gloves  
| Steps:                                                                                                                                                                                                                                                                                                                                                                | Key Points:   |                                                                       |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|-----------------------------------------------------------------------|
| 1. On the morning of infusion the primary  RN will be notified of the approximate  time TIL cells will be ready (usually  between 11AM and noon).                                                                                                                                                                                                                     | x             | Premeds are acetaminophen 650 mg  PO and diphenhydramine 12.5 mg  IV. |
| 2. Verify the physician orders: - to administer the cells - for the date of administration - for premedication orders  - protocol number 3. Verify that the protocol consent and  DPA are signed. 4. Ensure that emergency and monitoring equipment are available in the patient's  room: - oxygen - suction - vital sign monitor with pulse oximeter and thermometer |               |                                                                       |  
| Version Date: September 21, 2017 5. Provide patient education covering  infusion procedure, potential complications  and associated symptoms to report.  7. Measure and record baseline vital signs,  respiratory and circulatory assessments. 8. Verify the patency of the patient's IV   | A central venous access device such as a                                                                                                                                                                                                                                                    |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| access.                                                                                                                                                                                                                                                                                    | non-valved PICC line should be used.                                                                                                                                                                                                                                                        |
| 9.                                                                                                                                                                                                                                                                                         | Hang a primary line of 250cc NS at a                                                                                                                                                                                                                                                        |
| kvo rate - NEW bag and NEW tubing.                                                                                                                                                                                                                                                         | This will be the dedicated NS line for  infusing the cells. Under no circumstances  are any other substances to be infused into  the line.  Cell death occurs quickly - the infusion  must be initiated immediately.                                                                        |
| This MUST be ready and infusing prior to  the cells being delivered to the unit. The patient's primary IV hydration can  infuse via a separate lumen while the cells  are infusing, but NO MEDs should be administered during this time.                                                   | Do not infuse medication during the cell  infusion. If emergency meds must be  administered, use the hydration or  emergency NS IV line.                                                                                                                                                    |
| Have a second bag of 250cc NS and tubing  ready as an emergency line.                                                                                                                                                                                                                      | This will be the emergency IV solution  and can be used for medication administration. Do not use an inline filter for cells.                                                                                                                                                               |
| 10.                                                                                                                                                                                                                                                                                        | The primary RN will be notified                                                                                                                                                                                                                                                             |
| approximately 10 minutes before the cells  arrive on the unit. The cells will be hand  delivered to the bedside.                                                                                                                                                                           | It is critical to be at the bedside awaiting  the arrival of the cells for infusion; have  baseline VS, assessment, and IV lines  hooked up when the cells arrive. Cell  death occurs as soon as the cells are  removed from the laboratory. Initiate the  infusion as quickly as possible. |
| It is critical to be at the bedside awaiting  the arrival of the cells for infusion.  12. Prior to spiking the cell bag, two RNs  will perform the identification procedure.                                                                                                               |                                                                                                                                                                                                                                                                                             |  
| Version Date: September 21, 2017 Both RNs must sign the tag on the cell bag. 13. Infuse the cells by infusion pump over  20 minutes. a. Piggyback the cells into the  dedicated NS line; use the backflush  technique to prime the line. b. While the cells are infusing, gently agitate the bag of cells every few  minutes to prevent clumping in the  bag. When the cell bag is empty,  backflush NS to rinse the bag and  infuse this at the same rate as the cells;  rinse bag until NS runs clear. Note, when very small cell doses are  given, the cells will arrive at the  bedside in a syringe. In these cases,  the cells should be manually infused over 20 minutes via the syringe. 14. Measure and record VS before and  after the cell infusion, q1h x 4and then q4h  after completion of the infusion.  a. Assess and document the  patient's respiratory and circulatory  status post cell infusion. 15. Documentation: a. After the cells have infused, remove  the adhesive backed "cell therapy  product" tag from the cell bag and  place it on a progress note in the  patient's chart.  b. Document the cell infusion in  CRIS using the appropriate screens.   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|