untitled h1
7.5 nihrequired data and safety

The clinical research team will meet on a regular (i.e., weekly) basis when patients are being actively treated on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if applicable will be made based on the toxicity data from prior patients. All data will be collected in a timely manner and reviewed by the principal investigator. Events meeting requirements for expedited reporting as described in section **7.2.1** will be submitted within the appropriate timelines. The principal investigator will review adverse event and response data on each patient to ensure safety and data accuracy. The principal investigator will personally conduct or supervise the investigation and provide appropriate delegation of responsibilities to other members of the research staff.  
7.5.2 Safety Monitoring Committee (SMC)
This protocol will be periodically reviewed by an intramural Safety Monitoring Committee. Initial review will occur as soon as possible after the annual 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 based on the risks presented in the study. For initial and subsequent reviews, protocols will not be reviewed if there is no accrual within the review period. The SMC review will focus on unexpected protocol-specific safety issues that are identified during the conduct of the clinical trial. 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
8 sponsor safety reporting 8.1

Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product (ICH E6 (R2))
8.1.2 Serious Adverse Event (SAE)
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:
- Death, - A life-threatening adverse event (see section 8.1.3) - Inpatient hospitalization or prolongation of existing hospitalization  
o A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery arranged prior to the start of the study), a planned hospitalization for pre-existing condition, or a procedure required by the protocol, without a serious deterioration in health, is not considered a serious adverse event.  
o A hospitalization/admission that is solely driven by non-medical reasons (e.g.,
hospitalization for patient convenience) is not considered a serious adverse event.  
o Emergency room visits or stays in observation units that do not result in admission to the hospital would not be considered a serious adverse event. The reason for seeking medical care should be evaluated for meeting one of the other serious criteria.  
- Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions
- 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.  
8.1.3 Life-threatening An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have caused death. (21CFR312.32)
8.1.4 Severity The severity of each Adverse Event will be assessed utilizing the CTCAE version 4.0.  
8.1.5 Relationship to Study Product All AEs will have their relationship to study product assessed using the terms: related or not related.  
- Related - There is a reasonable possibility that the study product caused the adverse event. Reasonable possibility means that there is evidence to suggest a causal relationship between the study product and the adverse event.  
- Not Related - There is not a reasonable possibility that the administration of the study product caused the event.
untitled h1
8.2 assessment of safety events

AE information collected will include event description, date of onset, assessment of severity and relationship to study product and alternate etiology (if not related to study product), date of resolution of the event, seriousness and outcome. The assessment of severity and relationship to the study product will be done only by those with the training and authority to make a diagnosis and listed on the Form FDA 1572 as the site principal investigator or sub-investigator. AEs occurring during the collection and reporting period will be documented appropriately regardless of relationship. AEs will be followed through resolution. SAEs will be:
- Assessed for severity and relationship to study product and alternate etiology (if not related to study product) by a licensed study physician listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  
- Recorded on the appropriate SAE report form, the medical record and captured in the clinical database.  
- Followed through resolution by a licensed study physician listed on the Form FDA 1572 as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section 6.1 All serious adverse events recorded from the time of first investigational product administration must be reported to the sponsor with the exception of any listed in section 8.4
untitled h1
8.3 reporting of serious adverse

Any AE that meets a protocol-defined serious criterion or meets the definition of Adverse Event of Special Interest that require expedited reporting must be submitted immediately (within 24 hours of awareness) to OSRO Safety using the CCR SAE report form. Any exceptions to the expedited reporting requirements are found in section 8.4. All SAE reporting must include the elements described in section **8.2.**
SAE reports will be submitted to the Center for Cancer Research (CCR) at: OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. CCR SAE report form and instructions can be found at: https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=157942842 Following the assessment of the SAE by OSRO, other supporting documentation of the event may be requested by the OSRO Safety and should be provided as soon as possible.
untitled h1
8.4 reporting pregnancy 8.4.1 maternal

If a patient becomes pregnant during the study, the study treatment should be discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later than 24 hours of when the outcome of the Pregnancy becomes known, Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects and spontaneous miscarriages that meet serious criteria (section 8.1.2) should be reported as SAEs. The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) should be followed up and documented.  
8.4.2 Paternal exposure Male patients should refrain from fathering a child or donating sperm during the study and for 4 months after the last dose of receiving protocol treatment. Pregnancy of the patient's partner is not considered to be an AE. However, the outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) occurring from the date of the first dose until (*120 days)* after the last dose should, if possible, be followed up and documented.
untitled h1
8.5 regulatory reporting for studies

Following notification from the investigator, CCR, the IND sponsor, will report any suspected adverse reaction that is both serious and unexpected. CCR will report an AE as a suspected adverse reaction only if there is evidence to suggest a causal relationship between the study product and the adverse event. CCR will notify FDA and all participating investigators (i.e., all investigators to whom the sponsor is providing drug under its INDs or under any investigator's IND) in an IND safety report of potential serious risks from clinical trials or any other source, as soon as possible, in accordance to 21 CFR Part 312.32. All serious events will be reported to the FDA at least annually in a summary format.
untitled h1
9 clinical monitoring

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 and secondary study endpoints; adherence to the protocol, regulations, ICH E6, 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. This trial will be monitored by personnel employed by a CCR 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 conduct.
untitled h1
10 statistical considerations

Note: Cohort 2 (Patients who have had an HLA-matched sibling or an 8/8-matched unrelated donor transplant): Per amendment B this cohort has been closed to Accrual until further notice.  
The primary endpoint of this trial is to determine the safety of administering CAR-expressing T cells to patients with relapsed or persistent B-cell malignancies. Secondary objectives of this trial are to measure any anti-malignancy effect that might occur, to assess the feasibility of administering CAR-expressing T cells, to assess repeated CAR T-cell treatments, and to measure persistence and function of CAR-expressing T cells. The study will be conducted using a standard 3+3 approach as defined in section 3.1.  
Patients will be enrolled on a 2 different cohorts: **Cohort 1**: Patients who have not had an allogeneic hematopoietic stem cell transplant (alloHSCT) and **Cohort 2** (closed as of amendment B): Patients who have had an HLA-matched sibling or a 8/8-matched unrelated donor transplant. Each cohort will have a separate but identical dose-escalation scheme. The dose escalation schemes are separate because of the possibility of greater toxicity in the patients who have undergone prior alloHSCT. DLTs occurring on one cohort's dose escalation will not affect dose escalation of the other cohort. Both cohorts can undergo repeat treatments following an identical re-treatment plan.  
The trial will be conducted as 2 different dose escalation schemes, one for Cohort 1 (nonalloHSCT) and Cohort 2 (alloHSCT recipients). For each cohort, a dose escalation scheme with up to 4 doses and up to 6 patients per dose level will be carried out. In addition, up to 8 additional patients can be treated at the MTD for each cohort to establish additional safety and toxicity data at that level. Thus, up to 64 patients may be enrolled onto the trial.  
The fraction of post-allogeneic transplant patients experiencing Grade 3 or 4 toxicities will be compared to the fraction of patients who never had an allogeneic transplant experiencing Grade 3 or 4 toxicities by using a Fisher's exact test. The degree of persistence of anti-CD19-CAR-transduced T cells will be evaluated by a quantitative measure (flow cytometry or quantitative PCR) in all patients. Anti-malignancy effects will be measured by clinical response and categorized according to Section 6.2. The clinical responses will be interpreted cautiously in the context of a pilot study which may be used to guide parameters for study in future protocols if warranted. All other evaluations of secondary objectives will be performed using exploratory techniques. No formal adjustment for multiple comparisons will be used since the evaluations are being done to generate hypotheses. As of approval of Amendment C, we will treat a maximum of 14 more patients on this protocol (6 on Dose Level 3 plus an expansion cohort of 14 patients). Despite 2/6 patients experiencing strictly-defined DLTs on dose level 2 of the study, the second DLT on this dose level was actually not definitively related to CAR T cells and likely unrelated to dose, so the dose escalation is allowed to proceed to dose level 3 starting with the 13th patient to receive CAR T cells on this trial. If more than 1 of the first 3 patients experience a DLT on dose level 3, enrollment will continue on dose level 2. In other words, if more than 1 of the first 3 patients treated on dose level 3 has a DLT, Dose Level 2 will be declared the MTD despite the fact that 2 DLTs have occurred on Dose Level 2. If Dose Level 2 is declared the MTD, an 8 patient expansion cohort will be treated at this dose level. If 1 of the first 3 patients on dose level 3 experiences a DLT, 3 more patients will be enrolled on dose level 3.
untitled h1
11 collaborative agreements

There is a Collaborative Research and Development Agreement (CRADA\# 03019) in place between Kite Pharma, Inc. and the National Cancer Institute for this protocol.
untitled h1
12 human subjects protections 12.1

The patients to be entered in this protocol have advanced B-cell malignancies that are almost always incurable diseases. 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.
untitled h1
12.2 participation/selection rationale

- The eligibility criteria for this protocol only allow enrollment of patients with advanced B-cell malignancies that are usually incurable despite recent advances in standard therapies.  
- Patients with treatment options with proven efficacy and limited toxicity will not be enrolled.  
- Improving the treatment of advanced B-cell malignancies is an important area of clinical research.  
- In previous studies, anti-CD19 CAR T cells have demonstrated dramatic activity against B-cell lymphoma and B-cell leukemia. Many patients have obtained remissions lasting more than 2 years on multiple clinical trials of anti-CD19 CAR T cells. Some of these studies were clinical trials conducted by the Principal Investigator of this trial, and some patients treated on the Principal Investigator's prior trials have been in complete remission for over 3 years. Despite these impressive results, improvements in anti-CD19 CAR T cells to increase efficacy and to decrease toxicity are still needed. This trial aims to improve upon prior results by evaluating several important changes in the administered CAR T cells including: use of a fully-human CAR, use of a new lentiviral vector, use of a new CAR design, and use of planned second and third CAR T-cell treatments.  
- Because patients on previous trials of CAR T cells have experienced hypotension, tachycardia, prolonged fevers, neurological toxicities, and depressed myocardial function, participation in this trial clearly carries significant risk. In many patients on prior CAR trials, toxicities were severe enough to require intensive care unit admission. We will limit enrollment to patients 73 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.
untitled h1
12.3 participation of children

Children will not be enrolled on this study, 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.
untitled h1
12.4 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 **12.4**), all subjects ≥ age 18 will be offered the opportunity to fill 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 NIH HRPP SOP 14E 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.
untitled h1
12.5 evaluation of benefits and

The experimental treatment has a chance to provide clinical benefit although it is quite possible that patients will obtain no clinical benefit. 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, specifically CAR T cells. The risks of the study fall into 5 general categories (see section 13 for details). 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 cytokine-release type toxicities such as high fevers, hypotension, and fever. A third area of toxicity is neurological toxicity such as delirium, obtundation, myoclonus, seizures, headache, and transient focal neurological toxicities including aphasia and focal paresis. Cytokine-release-type toxicities and neurological toxicities have appeared in other clinical trials of CAR T cells during the first 2 weeks after CAR T cells were infused.72,115 The 4th main category of toxicity is direct damage to normal tissues by the CAR T cells. This could happen because of unexpected cross-reactivity of the anti-CD19 CAR with proteins other than CD19 in vivo. A 5th possible toxicity is hypogammaglobulinemia. Hypogammaglobulinemia has been a complication of many patients on clinical trials of anti-CD19 CAR-expressing T cells.72,73 Hypogammaglobulinemia in these patients was routinely treated with infusions of intravenous immunoglobulins.72 The lentiviral 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 or lentiviral vectors.75-77 The risks associated with biopsies are pain and bleeding at the biopsy site. In order to minimize pain, local anesthesia will be used. Rarely, there is a risk of infection at the sampling site. The success of this clinical trial cannot be predicted at this time. Because all patients in this protocol have advanced B-cell malignancies 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.  
12.5.1 Risks of exposure to Ionizing Radiation The procedures for performing the CT scans will follow clinical policies, no special procedures apply to these additional assessments for research purposes. In summary, subjects may receive additional radiation exposure from up to seven (7) CT neck +CAP, three (3) CT-Guided biopsies and seven (7)18FDG-PET/CT scans in the first year of the study. The total additional radiation dose for research purposes will be approximately 19.9 rem in the first year of the study. This amount is more than would be expected from everyday background radiation. Being exposed to too much radiation can cause harmful side effects such as an increase in the risk of cancer. The risk of getting cancer from the radiation exposure in this study is 2.0 out of 100 (2.0%) and of getting a fatal cancer is 1.0 out of 100 (1.0%).
untitled h1
12.5.2 risks of scans and

If contrast dye is used, there is a small chance of developing an allergic reaction from the contrast material, which may cause symptoms ranging from mild itching or a rash to severe difficulty breathing, shock or rarely, death. The contrast material may also cause kidney problems. Common reactions include pain in the vein where the contrast was given, a metallic or bitter taste in the mouth, headache, nausea and a warm or flushing feeling that lasts from 1-3 minutes. An IV line may need to be inserted for administration of the contrast agent or anesthetic, which may cause pain at the site where the IV is placed and there is a small risk of bruising or infection 12.5.3 Risks of blood Sampling Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting.  
12.5.4 Risks of Bone marrow aspiration and biopsy Side effect of bone marrow aspiration and biopsy may feel a pressure sensation when the needle is being inserted and a pulling sensation and brief pain as the marrow is withdrawn. Potential complications of this procedure are local bleeding, pain at the site, and infection. Both of these are very rare. Bleeding can be stopped by applying local pressure and an infection can be treated with antibiotics.  
12.5.5 Risks of Intravenous Catheter Side effect of placing some catheters include pain, bleeding, infection and rarely, collapsed lung. The long- term risks of the catheter rarely include infection and clotting of veins.  
12.5.6 Risks of Lumbar Puncture Side effect of lumbar puncture may cause pain at the site where the needle goes in and the spinal fluid is taken. There is a small risk of infection or bleeding. A third or fewer patients may experience some headache while the body replaces the fluid that is removed.
untitled h1
12.5.7 risks of apheresis

The risks of apheresis are similar to whole blood donation and include pain and bruising at the needle insertion site in the arms, lightheadedness, dizziness, nausea, and rarely fainting due to a rare reflex reaction to needle placement and to the temporary decrease in blood volume during apheresis. It may also feel tingling around your mouth or in your fingers caused by a blood thinner given during the procedure. The tingling may reduce by giving calcium containing chewable antacid. All the symptoms usually go away within a few minutes of stopping the procedure.
untitled h1
12.6 consent process and documentation

The informed consent document will be provided to the participant or consent designee(s) (e.g., legally authorized representative [LAR] if participant is an adult unable to consent) for review prior to consenting. A designated study investigator will carefully explain the procedures and tests involved in this study, and the associated risks, discomforts and benefits. In order to minimize potential coercion, as much time as is needed to review the document will be given, including an opportunity to discuss it with friends, family members and/or other advisors, and to ask questions of any designated study investigator. A signed informed consent document will be obtained prior to entry onto the study. The initial consent process as well as re-consent, when required, may take place in person or remotely (e.g., via telephone or other NIH approved remote platforms) per discretion of the designated study investigator and with the agreement of the participant/consent designee(s). Whether in person or remote, the privacy of the subject will be maintained. Consenting investigators (and participant/consent designee, when in person) will be located in a private area (e.g., clinic consult room). When consent is conducted remotely, the participant/consent designee will be informed of the private nature of the discussion and will be encouraged to relocate to a more private setting if needed. Consent for the optional biopsies performed on this study will be obtained at the time of the procedure. If the patient refuses the optional biopsy at that time, the refusal will be documented in the medical record and in the research record..
untitled h1
13 pharmaceutical information

Note: The commercial drugs used in this study will not alter labelling of the FDA approved drugs and nor does the investigation involve a route of administration or dosage level in use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product.
untitled h1
13.1 lentiviralvector containing the anti-cd19cargene

The lentiviral vector (LSIN-47G4-CD828Z) encoding a chimeric antigen receptor (CAR) directed against CD19 was prepared and preserved following cGMP conditions in the Indiana University Vector Production Facility. This self-inactivating 3rd generation lentiviral vector includes the murine stem cell virus promoter, and a truncated version of the woodchuck post-transcriptional regulatory element (WPRE) designated oPRE122. The anti-CD19 CAR protein encoded by this vector contains a signal peptide from human CD8-alpha, 47G4 fully-human antibody light chain variable region (47G4 VL), linker peptide, 47G4 fully-human antibody heavy chain variable region (47G4 VH), human CD8-alpha (hinge and transmembrane), CD28 (cytoplasmic region),
and the CD3-zeta (cytoplasmic region) T-cell activation domain.  
The vector will be stored at –80° C in the Dept. of Transfusion Medicine, NIH. Both storage facilities are equipped with around-the-clock temperature monitoring. Vector will be used in in vitro transductions of T cells. There will be no re-use of the same unit of supernatant for different patients. Handling of the vector should follow the guidelines of Biosafety Level-2 (BSL2). The specific guidelines for Biosafety Level-2 (BSL-2) can be viewed at http://bmbl.od.nih.gov/sect3bsl2.htm
untitled h1
13.2 commercial agents

Please refer to the US approved package insert for the full prescribing information here:
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails 13.2.1 Cyclophosphamide 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.  
13.2.1.2 Administration procedures The cyclophosphamide used in this regimen will be given as Intravenous infusion over 60 minutes.
untitled h1
13.2.2 fludarabine 13.2.2.1 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.  
13.2.2.2 Administration procedures Fludarabine is administered as an IV infusion in 100 ml 0.9% sodium chloride, USP over 15 to 30 minutes. The doses will be based on body surface area (BSA).
untitled h1
14 references

1. Gattinoni L, Finkelstein SE, Klebanoff CA, et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+
T cells. *Journal of Experimental Medicine.* 2005;202(7):907-912.  
2. North RJ. Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells. Journal of Experimental Medicine. 1982;155(4):1063-1074.  
3. 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.  
4. American Cancer Society. Cancer Facts and Figures 2007. 5. Wierda WG, O'Brien SM. Initial therapy for patients with chronic lymphocytic leukemia.  
Seminars in Oncology. 2006;33(2):202-209.
6. Byrd JC, Jones JJ, Woyach JA, Johnson AJ, Flynn JM. Entering the era of targeted therapy for chronic lymphocytic leukemia: Impact on the practicing clinician. Journal of Clinical Oncology. 2014;32(27):3039-3047.  
7. Jares P, Colomer D, Campo E. Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics. *Nature Reviews Cancer.*
2007;7(10):750-762.  
8. Campo E, Rule S. Mantle cell lymphoma: Evolving management strategies. *Blood.*
2015;125(1):48-55.  
9. Gribben JG. How I treat indolent lymphoma. *Blood.* 2007;109(11):4617-4626.  
10. Schouten HC, Qian W, Kvaloy S, et al. High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin's lymphoma: results from the randomized European CUP trial.[see comment]. *Journal of Clinical Oncology.*
2003;21(21):3918-3927.  
11. Montoto S, Davies AJ, Matthews J, et al. Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma. *Journal of Clinical Oncology.*
2007;25(17):2426-2433.  
12. Van Oers MHJ, Kersten MJ. Treatment strategies in advanced stage follicular lymphoma.  
Best Practice and Research: Clinical Haematology. 2011;24(2):187-201.  
13. Armitage JO. How I treat patients with diffuse large B-cell lymphoma. *Blood.*
2007;110(1):29-36.  
14. Van Den Neste E, Gisslbrecht, Christian, Schmitz, N. et al. Diffuse Large B-cell Lymphoma (DLBCL) Patients Failing Second-Line R-DHAP of R-ICE Chemotherapy Included in the Coral Study. *American Society of Hematology* Annual Meeting Abstracts. 2013.  
15. Friedberg JW. Relapsed/refractory diffuse large B-cell lymphoma. *Hematology / the* Education Program of the American Society of Hematology. American Society of Hematology. Education Program. 2011;2011:498-505.  
16. Martelli M, Ferreri AJM, Agostinelli C, Di Rocco A, Pfreundschuh M, Pileri SA. Diffuse large B-cell lymphoma. *Critical Reviews in Oncology/Hematology.* 2013;87(2):146-171.  
17. Seshadri T, Stakiw J, Pintilie M, Keating A, Crump M, Kuruvilla J. Utility of subsequent conventional dose chemotherapy in relapsed/refractory transplant-eligible patients with diffuse large B-cell lymphoma failing platinum-based salvage chemotherapy.  
Hematology. 2008;13(5):261-266.  
18. Elstrom RL, Martin P, Ostrow K, et al. Response to second-line therapy defines the potential for cure in patients with recurrent diffuse large B-cell lymphoma: Implications for the development of novel therapeutic strategies. Clinical Lymphoma, Myeloma and Leukemia. 2010;10(3):192-196.  
19. Van Besien K. The evolving role of autologous and allogeneic stem cell transplantation in follicular lymphoma. *Blood Reviews.* 2006;20(5):235-244.  
20. Dreger P, Brand R, Milligan D, et al. Reduced-intensity conditioning lowers treatmentrelated mortality of allogeneic stem cell transplantation for chronic lymphocytic leukemia: a population-matched analysis. *Leukemia.* 2005;19(6):1029-1033.  
21. Khouri IF, Lee M-S, Saliba RM, et al. Nonablative allogeneic stem-cell transplantation for advanced/recurrent mantle-cell lymphoma. *Journal of Clinical Oncology.* 2003;21(23):4407-4412.  
22. Khouri IF, McLaughlin P, Saliba RM, et al. Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab.[see comment]. *Blood.* 2008;111(12):5530-5536.  
23. Grigg A, Ritchie D. Graft-versus-lymphoma effects: clinical review, policy proposals, and immunobiology. *Biology of Blood & Marrow Transplantation.* 2004;10(9):579-590.  
24. Sorror ML, Maris MB, Sandmaier BM, et al. Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia. *Journal of* Clinical Oncology. 2005;23(16):3819-3829.  
25. Stein A, Forman SJ. Allogeneic transplantation for ALL in adults. *Bone Marrow* Transplantation. 2008;41(5):439-446.  
26. Rezvani AR, Storer B, Maris M, et al. Nonmyeloablative allogeneic hematopoietic cell transplantation in relapsed, refractory, and transformed indolent non-Hodgkin's lymphoma. *Journal of Clinical Oncology.* 2008;26(2):211-217.  
27. Dreger P, Corradini P, Kimby E, et al. Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus. *Leukemia.* 2007;21(1):12-17.  
28. Maris MB, Sandmaier BM, Storer BE, et al. Allogeneic hematopoietic cell transplantation after fludarabine and 2 Gy total body irradiation for relapsed and refractory mantle cell lymphoma. *Blood.* 2004;104(12):3535-3542.  
29. Morris E, Thomson K, Craddock C, et al. Outcomes after alemtuzumab-containing reduced-intensity allogeneic transplantation regimen for relapsed and refractory nonHodgkin lymphoma. *Blood.* 2004;104(13):3865-3871.  
30. Schetelig J, Thiede C, Bornhauser M, et al. Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stemcell transplantation: the Cooperative German Transplant Study Group. Journal of Clinical Oncology. 2003;21(14):2747-2753.  
31. Marks DI, Lush R, Cavenagh J, et al. The toxicity and efficacy of donor lymphocyte infusions given after reduced-intensity conditioning allogeneic stem cell transplantation. Blood. 2002;100(9):3108-3114.  
32. Bishop MR, Dean RM, Steinberg SM, et al. Clinical evidence of a graft-versuslymphoma effect against relapsed diffuse large B-cell lymphoma after allogeneic hematopoietic stem-cell transplantation. *Annals of Oncology.* 2008;19(11):1935-1940.  
33. Kolb H-J. Graft-versus-leukemia effects of transplantation and donor lymphocytes.  
Blood. 2008;112(12):4371-4383.  
34. Kolb HJ, Schattenberg A, Goldman JM, et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients.[see comment]. *Blood.* 1995;86(5):2041-2050.  
35. Collins RH, Jr., Shpilberg O, Drobyski WR, et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation.[see comment]. *Journal of Clinical Oncology.* 1997;15(2):433-444.  
36. Mandigers CMPW, Verdonck LF, Meijerink JPP, Dekker AW, Schattenberg AVMB,
Raemaekers JMM. Graft-versus-lymphoma effect of donor lymphocyte infusion in indolent lymphomas relapsed after allogeneic stem cell transplantation. Bone Marrow Transplantation. 2003;32(12):1159-1163.  
37. Porter DL, Levine BL, Bunin N, et al. A phase 1 trial of donor lymphocyte infusions expanded and activated ex vivo via CD3/CD28 costimulation. *Blood.* 2006;107(4):13251331.  
38. Bethge WA, Hegenbart U, Stuart MJ, et al. Adoptive immunotherapy with donor lymphocyte infusions after allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning.[see comment]. *Blood.* 2004;103(3):790-795.  
39. Bloor AJC, Thomson K, Chowdhry N, et al. High response rate to donor lymphocyte infusion after allogeneic stem cell transplantation for indolent non-Hodgkin lymphoma. Biology of Blood & Marrow Transplantation. 2008;14(1):50-58.  
40. Porter D, Levine JE. Graft-Versus-Host Disease and Graft-Versus-Leukemia After Donor Leukocyte Infusion. *Seminars in Hematology.* 2006;43(1):53-61.  
41. Collins RH, Jr., Goldstein S, Giralt S, et al. Donor leukocyte infusions in acute lymphocytic leukemia. *Bone Marrow Transplantation.* 2000;26(5):511-516.  
42. Guglielmi C, Arcese W, Dazzi F, et al. Donor lymphocyte infusion for relapsed chronic myelogenous leukemia: prognostic relevance of the initial cell dose. *Blood.*
2002;100(2):397-405.  
43. Mackinnon S, Papadopoulos EB, Carabasi MH, et al. Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: separation of graft-versus-leukemia responses from graft-versus-host disease. *Blood.* 1995;86(4):1261-1268.  
44. Peggs KS, Thomson K, Hart DP, et al. Dose-escalated donor lymphocyte infusions following reduced intensity transplantation: toxicity, chimerism, and disease responses.[see comment]. *Blood.* 2004;103(4):1548-1556.  
45. Miller JS, Weisdorf DJ, Burns LJ, et al. Lymphodepletion followed by donor lymphocyte infusion (DLI) causes significantly more acute graft-versus-host disease than DLI alone. Blood. 2007;110(7):2761-2763.  
46. Levine JE, Braun T, Penza SL, et al. Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stemcell transplantation.[see comment]. *Journal of Clinical Oncology.* 2002;20(2):405-412.  
47. Kolb H-J, Schmid C, Barrett AJ, Schendel DJ. Graft-versus-leukemia reactions in allogeneic chimeras. *Blood.* 2004;103(3):767-776.  
48. Horowitz MM, Gale RP, Sondel PM, et al. Graft-versus-leukemia reactions after bone marrow transplantation. *Blood.* 1990;75(3):555-562.  
49. Weiden PL, Sullivan KM, Flournoy N, Storb R, Thomas ED. Antileukemic effect of chronic graft-versus-host disease: contribution to improved survival after allogeneic marrow transplantation. *New England Journal of Medicine.* 1981;304(25):1529-1533.  
50. Marmont AM, Horowitz MM, Gale RP, et al. T-cell depletion of HLA-identical transplants in leukemia. *Blood.* 1991;78(8):2120-2130.  
51. Bierman PJ, Sweetenham JW, Loberiza FR, Jr., et al. Syngeneic hematopoietic stem-cell transplantation for non-Hodgkin's lymphoma: a comparison with allogeneic and autologous transplantation--The Lymphoma Working Committee of the International Bone Marrow Transplant Registry and the European Group for Blood and Marrow Transplantation.[see comment]. *Journal of Clinical Oncology.* 2003;21(20):3744-3753.  
52. Bleakley M, Riddell SR. Molecules and mechanisms of the graft-versus-leukaemia effect.  
Nature Reviews. 2004;Cancer. 4(5):371-380.
53. Falkenburg JH, Wafelman AR, Joosten P, et al. Complete remission of accelerated phase chronic myeloid leukemia by treatment with leukemia-reactive cytotoxic T lymphocytes. Blood. 1999;94(4):1201-1208.  
54. Randolph SSB, Gooley TA, Warren EH, Appelbaum FR, Riddell SR. Female donors contribute to a selective graft-versus-leukemia effect in male recipients of HLA-matched, related hematopoietic stem cell transplants. *Blood.* 2004;103(1):347-352.  
55. Robinson SP, Goldstone AH, Mackinnon S, et al. Chemoresistant or aggressive lymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor cell transplantation: an analysis from the Lymphoma Working Party of the European Group for Blood and Bone Marrow Transplantation. *Blood.* 2002;100(13):4310-4316.  
56. Sullivan KM. Graft-vs.-Host Disease. In: Blume K, Forman SJ, Appelbaum FR, ed.  
Thomas' Hematopoietic Cell Transplantaion, Third Edition: Blackwell Publishing Ltd.;
2007:635-664.  
57. Filipovich AH, Weisdorf D, Pavletic S, 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. Biology of Blood & Marrow Transplantation. 2005;11(12):945-956.  
58. Przepiorka D. Grading and Management of Graft-vs-Host Disease. In: Laughlin, ed.  
Current Clinical Oncology: Allogeneic Stem Cell Transplantation. Totowa, NJ: Humana Press Inc.; 2003:237-260.  
59. Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD
Grading. *Bone Marrow Transplantation.* 1995;15(6):825-828.  
60. Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group Report. Biology of Blood and Marrow Transplantation. 2015;21(3):389-401.  
61. Restifo NP, Dudley ME, Rosenberg SA. Adoptive immunotherapy for cancer:
Harnessing the T cell response. *Nature Reviews Immunology.* 2012;12(4):269-281.  
62. Brenner MK, Heslop HE. Adoptive T cell therapy of cancer. *Current Opinion in* Immunology. 2010;22(2):251-257.  
63. Park TS, Rosenberg SA, Morgan RA. Treating cancer with genetically engineered T
cells. *Trends in Biotechnology.* 2011;29(11):550-557.  
64. Morgan RA, Dudley ME, Wunderlich JR, et al. Cancer regression in patients after transfer of genetically engineered lymphocytes.[see comment]. *Science.* 2006;314(5796):126-129.  
65. Rosenberg SA. Cell transfer immunotherapy for metastatic solid cancer-what clinicians need to know. *Nature Reviews Clinical Oncology.* 2011;8(10):577-585.  
66. Kershaw MH, Teng MWL, Smyth MJ, Darcy PK. Supernatural T cells: Genetic modification of T cells for cancer therapy. *Nature Reviews Immunology.* 2005;5(12):928940.  
67. Hoyos V, Savoldo B, Dotti G. Genetic modification of human T lymphocytes for the treatment of hematologic malignancies. *Haematologica.* 2012;97(11):1622-1631.  
68. Turtle CJ, Hudecek M, Jensen MC, Riddell SR. Engineered T cells for anti-cancer therapy. *Current Opinion in Immunology.* 2012;24(5):633-639.  
69. Brentjens RJ, Rivière I, Park JH, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory Bcell leukemias. *Blood.* 2011;118(18):4817-4828.  
70. Kalos M, Levine BL, Porter DL, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. *Science* Translational Medicine. 2011;3(95).  
71. Robbins PF, Morgan RA, Feldman SA, et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. *Journal of Clinical Oncology.* 2011;29(7):917924.  
72. Kochenderfer JN, Dudley ME, Feldman SA, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. *Blood.* 2012;119(12):2709-2720.  
73. Kochenderfer JN, Wilson WH, Janik JE, et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. *Blood.* 2010;116(20):4099-4102.  
74. Savoldo B, Ramos CA, Liu E, et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. *Journal* of Clinical Investigation. 2011;121(5):1822-1826.  
75. Scholler J, Brady TL, Binder-Scholl G, et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. *Science Translational Medicine.* 2012;4(132).  
76. Recchia A, Bonini C, Magnani Z, et al. Retroviral vector integration deregulates gene expression but has no consequence on the biology and function of transplanted T cells. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(5):1457-1462.  
77. Heslop HE, Slobod KS, Pule MA, et al. Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. *Blood.* 2010;115(5):925-935.  
78. Zhao Y, Wang QJ, Yang S, et al. A herceptin-based chimeric antigen receptor with modified signaling domains leads to enhanced survival of transduced T lymphocytes and antitumor activity. *Journal of Immunology.* 2009;183(9):5563-5574.  
79. Irving BA, Weiss A. The cytoplasmic domain of the T cell receptor zeta chain is sufficient to couple to receptor-associated signal transduction pathways.*Cell.* 1991;64(5):891-901.  
80. Eshhar Z, Waks T, Gross G, Schindler DG. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proceedings of the National Academy of Sciences of the United States of America. 1993;90(2):720-724.  
81. Louis CU, Savoldo B, Dotti G, et al. Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. *Blood.*
2011;118(23):6050-6056.  
82. Curran KJ, Pegram HJ, Brentjens RJ. Chimeric antigen receptors for T cell immunotherapy: Current understanding and future directions. *Journal of Gene Medicine.*
2012;14(6):405-415.  
83. Pule MA, Savoldo B, Myers GD, et al. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma.[see comment]. *Nature Medicine.* 2008;14(11):1264-1270.
84. Hwu P, Shafer GE, Treisman J, et al. Lysis of ovarian cancer cells by human lymphocytes redirected with a chimeric gene composed of an antibody variable region and the Fc receptor gamma chain. *Journal of Experimental Medicine.* 1993;178(1):361366.  
85. Hwu P, Yang JC, Cowherd R, et al. In vivo antitumor activity of T cells redirected with chimeric antibody/T-cell receptor genes. *Cancer Research.* 1995;55(15):3369-3373.  
86. Kershaw MH, Westwood JA, Parker LL, et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. *Clinical Cancer* Research. 2006;12(20 Pt 1):6106-6115.  
87. Kochenderfer JN, Feldman SA, Zhao Y, et al. Construction and preclinical evaluation of an anti-CD19 chimeric antigen receptor. *Journal of Immunotherapy.* 2009;32(7):689-702.  
88. Cheadle EJ, Gilham DE, Thistlethwaite FC, Radford JA, Hawkins RE. Killing of nonHodgkin lymphoma cells by autologous CD19 engineered T cells. *British Journal of* Haematology. 2005;129(3):322-332.
89. Brentjens RJ, Latouche JB, Santos E, et al. Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin15.[see comment]. *Nature Medicine.* 2003;9(3):279-286.  
90. Imai C, Mihara K, Andreansky M, et al. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. *Leukemia.* 2004;18(4):676-684.  
91. Milone MC, Fish JD, Carpenito C, et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. *Molecular Therapy: the Journal of the American Society of Gene* Therapy. 2009;17(8):1453-1464.  
92. Porter DL, BL; Kalos, M et al. Chimeric Antigen Receptor-Modified T Cells in Chronic Lymphoid Leukemia. *The New England Journal of Medicine.* 2011;365(8):725-733.  
93. Wang X, Naranjo A, Brown CE, et al. Phenotypic and functional attributes of lentivirusmodified CD19-specific Human CD8 + central memory T cells manufactured at clinical scale. *Journal of Immunotherapy.* 2012;35(9):689-701.  
94. Cooper LJ, Topp MS, Serrano LM, et al. T-cell clones can be rendered specific for CD19: toward the selective augmentation of the graft-versus-B-lineage leukemia effect.  
Blood. 2003;101(4):1637-1644.  
95. Kebriaei P, Huls H, Jena B, et al. Infusing CD19-directed T cells to augment disease control in patients undergoing autologous hematopoietic stem-cell transplantation for advanced B-lymphoid malignancies. *Human Gene Therapy.* 2012;23(5):444-450.  
96. Hollyman D, Stefanski J, Przybylowski M, et al. Manufacturing validation of biologically functional T cells targeted to CD19 antigen for autologous adoptive cell therapy. *Journal* of Immunotherapy. 2009;32(2):169-180.  
97. Song DG, Ye Q, Carpenito C, et al. In vivo persistence, tumor localization, and antitumor activity of CAR-engineered T cells is enhanced by costimulatory signaling through CD137 (4-1BB). *Cancer Research.* 2011;71(13):4617-4627.  
98. Maher J, Brentjens RJ, Gunset G, Rivière I, Sadelain M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ/CD28 receptor. Nature Biotechnology. 2002;20(1):70-75.  
99. Guest RD, Hawkins RE, Kirillova N, et al. The role of extracellular spacer regions in the optimal design of chimeric immune receptors: Evaluation of four different scFvs and antigens. *Journal of Immunotherapy.* 2005;28(3):203-211.  
100. Rossig C, Bar A, Pscherer S, et al. Target antigen expression on a professional antigenpresenting cell induces superior proliferative antitumor T-cell responses via chimeric Tcell receptors. *Journal of Immunotherapy.* 2006;29(1):21-31.  
101. Cheadle EJ, Hawkins RE, Batha H, O'Neill AL, Dovedi SJ, Gilham DE. Natural expression of the CD19 antigen impacts the long-term engraftment but not antitumor activity of CD19-specific engineered T cells. *Journal of Immunology.* 2010;184(4):18851896.  
102. Kochenderfer JN, Yu Z, Frasheri D, Restifo NP, Rosenberg SA. Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells. *Blood.* 2010;116(19):3875-3886.  
103. Brentjens RJ, Santos E, Nikhamin Y, et al. Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. *Clinical Cancer Research.* 2007;13(18 Pt 1):5426-5435.  
104. Kowolik CM, Topp MS, Gonzalez S, et al. CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells. *Cancer Research.* 2006;66(22):10995-11004.  
105. Nadler LM, Anderson KC, Marti G, et al. B4, a human B lymphocyte-associated antigen expressed on normal, mitogen-activated, and malignant B lymphocytes. Journal of Immunology. 1983;131(1):244-250.  
106. Scheuermann RH, Racila E. CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy. *Leukemia & Lymphoma.* 1995;18(5-6):385-397.  
107. Uckun FM, Jaszcz W, Ambrus JL, et al. Detailed studies on expression and function of CD19 surface determinant by using B43 monoclonal antibody and the clinical potential of anti-CD19 immunotoxins. *Blood.* 1988;71(1):13-29.  
108. Pontvert-Delucq S, Breton-Gorius J, Schmitt C, et al. Characterization and functional analysis of adult human bone marrow cell subsets in relation to B-lymphoid development. *Blood.* 1993;82(2):417-429.  
109. McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. *Journal of Clinical Oncology.* 1998;16(8):2825-2833.  
110. Rafailidis PI, Kakisi OK, Vardakas K, Falagas ME. Infectious complications of monoclonal antibodies used in cancer therapy: a systematic review of the evidence from randomized controlled trials. *Cancer.* 2007;109(11):2182-2189.  
111. Quinti I, Soresina A, Spadaro G, et al. Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency. Journal of Clinical Immunology. 2007;27(3):308-316.  
112. Porter CD, Collins MK, Tailor CS, et al. Comparison of efficiency of infection of human gene therapy target cells via four different retroviral receptors. *Human Gene Therapy.* 1996;7(8):913-919.  
113. Jensen MC, Popplewell L, Cooper LJ, et al. Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. *Biology of Blood and Marrow Transplantation.* 2010;16(9):1245-1256.  
114. Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: A phase 1 dose-escalation trial. *The Lancet.* 2014.  
115. Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Science Translational Medicine. 2013;5(177).  
116. Davila ML, Riviere I, Wang X, et al. Efficacy and Toxicity Management of 19-28z CAR
T Cell Therapy in B Cell Acute Lymphoblastic Leukemia. *Sci Transl Med.* 2014;6(224):224ra225.  
117. Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. *Journal of* Clinical Oncology. 2015;33(6):540-549.  
118. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. *New England Journal of Medicine.* 2014;371(16):1507-1517.  
119. Kochenderfer JN, Dudley ME, Carpenter RO, et al. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. *Blood.* 2013;122(25):4129-4139.  
120. Cruz CRY, Micklethwaite KP, Savoldo B, et al. Infusion of donor-derived CD19redirected virus-specific T cells for B-cell malignancies relapsed After allogeneic stem cell transplant: A phase 1 study. *Blood.* 2013;122(17):2956-2973.  
121. King DJ, Rao-Naik C, Pan C, Cardarelli J, Blanset D. Human antibodies that bind CD19 and uses thereof. *United States Patent Application US2010/0104509 A1.*Publication date 4-29-2010:Assignee: Medarex, Inc.  
122. Yang S, Dudley ME, Rosenberg SA, Morgan RA. A simplified method for the clinicalscale generation of central memory-like CD8+ T cells after transduction with lentiviral vectors encoding antitumor antigen T-cell receptors. *Journal of Immunotherapy.*
2010;33(6):648-658.  
123. 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.  
124. Carpenter RO, Evbuomwan MO, Pittaluga S, et al. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. *Clinical Cancer* Research. 2013;19(8):2048-2060.  
125. 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.  
126. 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.  
127. 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.  
128. Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. *Science.*
2002;298(5594):850-854.  
129. 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. 2008;26(32):5233-5239.  
130. 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.  
131. 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.  
132. 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.  
133. Li S, Yang J, Urban FA, et al. Genetically engineered T cells expressing a HER2-specific chimeric receptor mediate antigen-specific tumor regression. *Cancer Gene Therapy.*
2008;15(6):382-392.  
134. Deol A, Lum LG. Role of donor lymphocyte infusions in relapsed hematological malignancies after stem cell transplantation revisited. *Cancer Treatment Reviews.*
2010;36(7):528-538.  
135. Tomblyn M, Lazarus HM. Donor lymphocyte infusions: The long and winding road: how should it be traveled? *Bone Marrow Transplantation.* 2008;42(9):569-579.  
136. Berger C, Flowers ME, Warren EH, Riddell SR. Analysis of transgene-specific immune responses that limit the in vivo persistence of adoptively transferred HSV-TK-modified donor T cells after allogeneic hematopoietic cell transplantation. *Blood.*
2006;107(6):2294-2302.  
137. Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: A phase 1 dose-escalation trial. *The Lancet.* 2015;385(9967):517-528.  
138. Sallusto F, Lenig D, Förster R, Lipp M, Lanzavecchia A. Two subsets of memory T
lymphocytes with distinct homing potentials and effector functions. *Nature.* 1999;401(6754):708-712.  
139. Gattinoni L, Powell DJ, Jr., Rosenberg SA, Restifo NP. Adoptive immunotherapy for cancer: building on success. *Nature Reviews Immunology.* 2006;6(5):383-393.  
140. Cortelazzo S, Ponzoni M, Ferreri AJM, Dreyling M. Mantle cell lymphoma. *Critical* Reviews in Oncology/Hematology. 2012;82(1):78-101.  
141. Kochenderfer JN, Rosenberg SA. Treating B-cell cancer with T cells expressing antiCD19 chimeric antigen receptors. *Nature Reviews Clinical Oncology.* 2013;10(5):267276.  
142. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. *Journal of Clinical Oncology.* 2007;25(5):579-586.  
143. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of hodgkin and non-hodgkin lymphoma: The lugano classification. *Journal of Clinical Oncology.* 2014;32(27):3059-3067.  
144. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. *Blood.* 2008;111(12):5446-5456.
untitled h1
15 appendices 15.1 appendix a

| 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., Davis, |                                                                                                                                                                                       |  
* 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. 15.2 **APPENDIX B: DATA COLLECTION ELEMENTS REQUIRED BY PROTOCOL** All of the following elements will be recorded in the C3D database:
untitled h1
a. patient enrollment

- Date of birth, age, gender, race, ethnicity - Height - Weight - Performance Status - Date of original diagnosis - Stage at diagnosis - Tumor Histology and date of confirmation - CD19 expression by tumor type of tissue studied and date of confirmation
- Date of Informed Consent signature, consent version and date of registration - Baseline History/Physical - Baseline Symptoms - Number of prior lines of therapy
- Findings of consultations done at screening B. **Study Drug administration and response for each course of therapy given**
- Dates anti-CD19-CAR-transduced T cells given - Dose level, actual dose, schedule and route given - Height, weight, and body surface area at start of each course (a course is defined as chemotherapy followed by a CAR T-cell infusion)
- Response assessment for each restaging performed - Concomitant medications will not be collected in C3D
untitled h1
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 CT scan, PET scan results and bone marrow biopsy and peripheral blood flow cytometry results will be reported at the scheduled follow-up points at 1 months and 2 months after infusion; after 2 months only the overall malignancy status (CR, PR, stable disease, progression) will be reported.
untitled h1
d. adverse events

Please see section **6.1.1** Adverse Event Reporting E. Tumor response and measurements
- Restaging studies performed at protocol specified time points and as clinically indicated.  
- Any physical exam findings, will be collected as Adverse Events and labs results. - Years 5-15 follow-up is only for survival.  
F. Off study
- Date and reason for off study - Date and cause of death - Autopsy findings
untitled h1
15.3 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.72 The toxicities most often experienced by patients receiving infusions of 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. 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 or violation. 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. As a minimum, keep hemoglobin greater than 8.0 g/dL and platelets greater than 20K/microliter.  
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. Fevers should be treated with acetaminophen and comfort measures. NSAIDs and corticosteroids should be avoided.  
8. Patients with a heart rate persistently higher than 115/minute and fever should have vital signs checked every 2 hours.  
9. Patients who are neutropenic and febrile should be receiving broad-spectrum antibiotics. 10. 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 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 antiCD19 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.  
11. A CBC will be obtained twice daily while the patient is inpatient. If the absolute neutrophil count becomes less than 500/microliter, Filgrastim will be initiated at a dose of 300 micrograms daily for patients under 70 kg in weight and a dose of 480 micrograms daily for patients over 70 kg in weight only in patients with absolute neutrophil counts less than 500/microliter. Filgrastim will be discontinued as soon as the absolute neutrophil count recovers to 1500/microliter.  
12. 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.  
- Patients with a systolic blood pressure that is less than 80% of their baseline blood pressure and less than 100 mm Hg should receive a 1 L NS bolus.  
- **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.  
13. Patients receiving more than 1 fluid bolus for hypotension should have a stat EKG and troponin, and a cardiac echocardiogram within 24 hours of the second fluid bolus.  
14. 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.  
- Systolic blood pressure less than 75% the patient's baseline blood pressure and less than 100 mm Hg after administration of a 1L NS bolus.  
- Anytime the systolic blood pressure is less than 90 mm Hg after a 1L NS bolus if 90 mm Hg is less than the patient's baseline systolic blood pressure.  
- Continuous tachycardia with a heart rate higher than 125 beats per minute on at least 2 occasions separated by 4 hours.  
- Oxygen requirement of more than a 4L standard nasal cannula
- Greater than grade 2 neurological toxicity 15. All patients transferred to the ICU for hypotension or tachycardia should have a stat EKG
and a cardiac echocardiogram within 24 hours of the time of transfer.  
16. Patients with hypotension not responding to IV fluid resuscitation should be started on norepinephrine at doses called for by standard ICU guidelines.  
17. Patients should have a cardiac echocardiogram and an EKG within 12 hours of starting norepinephrine.  
18. 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).  
19. 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 of 4 mg/kg infused IV over 1 hour (dose should not exceed 800 mg).  
- Left ventricular ejection fraction less than 40% by echocardiogram - Creatinine greater than 2.5-fold higher than the most recent level prior to CAR T-cell infusion
- Norepinephrine requirement at a dose greater than 2 µg/minute for 48 hours since the first administration of norepinephrine even if norepinephrine administration was not continuous.  
- Systolic blood pressure of 90 mm Hg cannot be maintained with norepinephrine.  
- Oxygen requirement 55% or greater fraction of inspired oxygen (FIO2) for more than 2 continuous hours.  
- Dyspnea that is severe enough to potentially require mechanical ventilation. - PTT or INR>2x upper limit of normal
- Clinically-significant bleeding
- Creatine kinase greater than 5x upper limit of normal for greater than 2 days 20.THERE IS NO EVIDENCE THAT TOCILIZUMAB HELPS NEUROLOGICAL
TOXICITY, SO IT SHOULD NOT BE ADMINISTERED FOR THIS PURPOSE.
untitled h1
96 version dateseptember 17 2020

21.If no improvement in hypotension or tachycardia occurs within 6 hours of tocilizumab infusion, consider other agents such as methylprednisolone 1 to2 mg/kg every 12 hours or etanercept.  
22. Avoid meperidine due to seizure risk. 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. Note: for seizures administer standard seizure therapies in addition to dexamethasone.  
1. Patients with Grade 3 or 4 neurological toxicities except that dexamethasone is not recommended for isolated Grade 3 headaches.  
2. Any generalized seizure
untitled h1
15.4 appendix d clinical staging

| Stage   | Skin                                     | Liver                    | Gut                           |
|---------|------------------------------------------|--------------------------|-------------------------------|
| 1       | Rash < 25% BSAa                          | Total bilirubin 2.0-2.9  | Diarrhea >500- 1000ml/day, or |
| mg/dlb  | upper GI symptoms                        |                          |                               |
| 2       | Rash 25-50% BSA                          | Total bilirubin 3.0-6.0  | Diarrhea 1001-                |
| mg/dl   | 1500ml/day                               |                          |                               |
| 3       | Rash >50% BSA                            | Total bilirubin 6.1-15.0 | Diarrhea 1501 to              |
| mg/dl   | 2000 ml/d                                |                          |                               |
| 4       | Bullae                                   | Total bilirubin > 15.0   | Diarrhea >2000 mL             |
| mg/dl   | /day or severe  abdominal pain or  ileus |                          |                               |
untitled h1
clinical staging and treatment of

aBSA = body surface area; use "rule of nines" or burn chart to determine extent of rash.  
bRange given as total bilirubin.  
Note: Elevation of transaminase without elevation of bilirubin is not recognized as acute GVHD ( a note should say "GVHD transaminitis" and mention if biopsy proven or not.  
c Persistent nausea with histologic evidence of GVHD in the stomach or duodenum.  
The nominal stage is reduced by one if the organ is simultaneously and unequivocally affected by a complication other than GVHD.  
Gradee Skin Liver Gut  
0 (none) None None None I Stage 1-2 None None II Stage 3 Stage 1 Stage 1 III Stage 2-3 Stage 2-4  
IVd Stage 4e Stage 4 Stage 4  
eCriteria for grading given as minimum degree of organ involvement required to confer that grade.  
The highest single organ stage determines the overall grade.  
dPatients with Stage 4 gut GVHD are usually Grade IV. Stage 4 gut GVHD can only be a part of Grade III when it is not severe enough to cause a substantially impaired performance status. A substantially impaired performance status would be an ECOG performance status of 3 or 4.  
eDesignation of Grade III is appropriate for only scattered bullae.  
The NIH Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versushost Disease defines classic acute GVHD as maculopapular rash, nausea, vomiting, anorexia, profuse diarrhea, ileus, or cholestatic hepatitis occurring within 100 days after transplantation or Donor Cell Infusion (DCI) 57. We will define acute GVHD in the same manner for this trial.  
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. Failure to follow these guidelines is not a protocol deviation. Grade I GVHD: 1) Topical corticosteroids (usually 0.1% triamcinolone; 1% hydrocortisone to face) applied to rash BID.  
Grade II-IV GVHD: 1) Methylprednisolone (MP) 1 mg/kg per dose IV, BID for 4 consecutive days. 2) If no response after 4 days, continue until response (7-day maximum trial); the dose may be doubled (4 mg/kg/day).  
3) If response within 7 days, taper as follows:
a) 0.75 mg/kg per dose IV BID for 2 days. b) 0.5 mg/kg per dose IV BID for 2 days. c) 0.375 mg/kg per dose IV BID for 2 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 cyclosporine at therapeutic levels.  
4) If no response is observed within 7 days of MP treatment:
a) Increase Methylprednisolone to 10 mg/kg per dose IV, BID for 2 days. b) If there is no improvement, consideration will be given to using second-line immunosuppressive therapy, e.g., tacrolimus, mycophenolic acid, monoclonal antibodies, or studies of investigational agents for acute GVHD, if they are available.  
5) Antifungal prophylaxis with agents effective against mould 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 ≤ 70%).  
d) Progressive disease: Further progression of signs and symptoms of acute GVHD, and/or decline in performance status after the initiation of therapy.  
100 Version Date:September 17, 2020 15.5 APPENDIX E: INFUSION INSTRUCTIONS Equipment: Primary IV tubing (2) Secondary IV tubing (1) NS (sodium chloride 0.9%) 250cc bags (2) IV infusion pump Gloves  
| Steps:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Key Points:                                                                  |                                                                         |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------|-------------------------------------------------------------------------|
| 1.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | RN will be informed of the approximate  time of cell arrival at the bedside. | a. 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  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. |                                                                              |                                                                         |  
| Version Date:September 17, 2020 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.                                                                                                                                                  |
| This MUST be ready and infusing prior to  the cells being delivered to the unit.                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Cell death occurs quickly - the infusion  must be initiated immediately.                                                                                                                                                                                                                    |
| 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.  Both RNs must sign the tag on the cell bag. 13. Infuse the cells by infusion pump or  syringe over 20-30 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. When the cell bag is  empty, backflush NS to rinse the bag | This prevents the cells from clumping in the  bag.                                                                                                                                                                                                                                          |  
| and infuse this at the same rate as the  cells; rinse bag until NS runs clear.                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                                                                  |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------|
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | c. Note: in some cases cells will arrive  from DTM in a syringe. In this case  infuse the cells via syringe over 20 -30 minutes. |
| 14. Measure and record VS before and after  the cell infusion, q1h x 4, and 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. |                                                                                                                                  |