Foundation For The Accreditation Of Cellular Therapy Research Articles

Abstract 18 Leveraging the BMDI Cord Blood Bank to Create a GMP-Compliant Cord Blood (CB)–Derived Induced Pluripotent Stem Cell (iPSC) Master Cell Bank (MCB) for Potential Allogeneic Therapies

Abstract Introduction The BMDI Cord Blood Bank (CBB) in Melbourne is a public cord blood bank that operates under a Good Manufacturing Practice (GMP) cell-manufacturing licence from the Therapeutic Goods Administration (TGA) and is internationally accredited by the Foundation for the Accreditation of Cellular Therapy (FACT). An iPSC MCB derived from cord blood (CB) could form the basis of future cell-based therapies. Banked CB is an ideal source of starting material for the creation of iPSCs, with a host of advantages not afforded by other cell sources. Objectives We have previously described the technical aspects of creating “GMP-like” iPSCs from banked CB (https://www.frontiersin.org/articles/10.3389/fcell.2022.835321/full). Our objective is to leverage the CBB to transition our “GMP-like” protocols, developed in the research lab, into a fully GMP-compliant environment. Methods A small lab within the CBB was seconded for the purpose of establishing an Institutional Biosafety Committee (IBC) – approved PC2 laboratory to create GMP-compliant iPSC lines from banked cord blood. CB donors have been re-consented to use a portion of their banked HLA homozygous CB to create iPSC lines (https://doi.org/10.1093/stcltm/szac060). The CBB Quality Framework was replicated as a side module, mimicking all key components. Results * Established an IBC-approved PC2 laboratory within the GMP-compliant CBB facility. * Developed a Quality Systems framework in-line with the FACT Common Standards for Cellular Therapy, leveraging off that in place for the CBB. * Tested and validated the process in its entirety, including robustness of the Quality Systems, by the creation of new CB-derived “GMP-mock” iPSC lines. * Established collaborations for pre-clinical studies to use our CB-derived iPSC lines for therapies directed towards retinal and neurological repair, NK and CAR-NK immunotherapies. Discussion A PC2 GMP-compliant laboratory has been established. Challenges, and solutions, will be discussed. Quality systems have been developed that mimic those in place for the CBB. The robustness of the Quality framework and GMP manufacturing have been confirmed by a full mock-run to create new CB-derived iPSC lines. Lower grade reagents used for the mock-run have now been swapped out for more expensive, fully GMP-certified (CTS) reagents and creation of our first fully GMP CB-derived iPSC line is underway.

A robust quality infrastructure is key to safe and effective delivery of immune effector cells: how FACT-finding can help

AbstractImmune effector cells (IECs) include a broad range of immune cells capable of modulating several disease states, including malignant and nonmalignant conditions. The growth in the use of IECs as both investigational and commercially available products requires medical institutions to develop workflows/processes to safely implement and deliver transformative therapy. Adding to the complexity of this therapy are the variety of targets, diseases, sources, and unique toxicities that a patient experiences following IEC therapy. For over 25 years, the Foundation for the Accreditation of Cellular Therapy (FACT) has established a standard for the use of cellular therapy, initially with hematopoietic cell transplantation (HCT), and more recently, with the development of standards to encompass IEC products such as chimeric antigen receptor (CAR)-T cells. To date, IEC therapy has challenged the bandwidth and infrastructure of the institutions offering this therapy. To address these challenges, FACT has established a programmatic framework to improve the delivery of IEC therapy. In this study, we outline the current state of IEC program development, accreditation, and solutions to the challenges that programs face as they expand their application to novel IEC therapy.

Pre-transplant Medical Evaluation: A Multidisciplinary Approach

Conventional autologous and allogenic hematopoietic stem cell transplants (HSCT) are lifesaving or life extending medical procedures but associated with significant risk for non-infectious and infectious complications. The center for international blood and marrow transplant research estimates that worldwide about 100000 transplants are performed yearly. The frequency of transplantation is varied widely from country to country, with a close association of transplant rates with gross national income (GNI) per-capita. Appropriate indication for transplant is mandatory for these rigorous procedures. Hematological malignancies, bone marrow failure syndromes, inherited immune deficiencies, hemoglobinopathies and inherited metabolic disorders are usual indications for BMT. Sources of hematopoietic stem cells are crucial. Patient evaluation includes psychosocial and systems evaluation. Foundation for the Accreditation of cellular therapy (FACT) is required. General guidelines for patient eligibility are chemo sensitive, adequate performance status, adequate nonhematopoietic organ function, ability to provide informed consent and adequately matched available donor or adequate collection of autologous stem cells. Exclusion criteria include chemo refractory, life expectancy severely limited by other illness, inability to tolerate preparative regimen and pregnancy. Relative contraindications are major medical comorbidities, major psychiatric illness and lack of insurance/financial resources. Comorbidities are cardiac arrhythmia, EF d” 50%, body mass index e” 35 kg/m2, serum creatinine > 2 mg/dl and EFV1 d” 65%. Allogeneic donor evaluation is also vital and includes HLA typing for HLA-A, -B, -DRBI; screening of transmissible diseases, laboratories, consents and notifications. J Medicine 2023; Vol. 34, No. 2(1) Supplement: 212

Haploidentical Hematopoietic Stem Cell Transplantation: A New Transplantation Modality Implemented In a Recent Accredited FACT Institution In Latin America

IntroductionThe Foundation for the Accreditation of Cellular Therapy (FACT) has developed and implemented programs of voluntary inspection and accreditation for hematopoietic cellular therapy, and for cord blood banking. These programs are based on the standards of the clinical and laboratory professionals of the American Society of Blood and Marrow Transplantation (ASBMT), the International Society for Cellular Therapy (ISCT), and NETCORD. Our transplantation service was the first Hospital in Latin America to be accreditated by FACT in 2012. FACT accreditated hospitals might have a positive impact in Implementing new procedures and treatment protocols. Haploidentical SCT program was developed in our institution during FACT accreditation process. Since high complexity procedures challange transplantation units, we believe that conducting protocols after FACT accreditation helped the achievment of better standard of care that might be translated in results comparable with international transplantation centres. SCT from Haploidentical donor can be one therapeutic option specially for patients with no available MRD or MUD. In order to overcome HLA disparity, more intensive immunossupresion is usually used that can be associated to higher TRM. These difficulties demand a well stablished transplantation unit. Here we show the first 25 patients who recieved haploidentical SCT during FACT accreditation in a single institution in Brazil. Patients and methods: From april 2008 to july 2013, 25 patients were treated with haploidentical SCT. The median follow-up time was 3,3 months (range ). 8 (32%) patients had AML, 1 (4%) ALL, 1 (4%) JMML, 1(4%) LH, 1 (4%) MDS. 7 (28%) had adrenoleukodystrophy x-linked, 3(23%) had SAA and 2(28%) SCID. 8 (33%) patinets had refreactory disease. Median age at transplantation was 3.3 (range 1-72) years. 12 (48%) patients were in pediatric age range (1 to 18) years. 13 (54%) had donor/receptor ABO incompatibility. 10 (40%) patients were transplanted after myeloablative conditioning regimen (Bussulfan/Fludarabine or Busulfan/fludarabine/thiotepa) and 15(60%) after non-myeloablative conditioning regimen (Fludarabine/cyclophosphamide/TBI200cGy). 22 (88%) patients have received bone marrow as stem cell source and 3 (12%) peripheral blood stem cells. Median total nucleated cell x 108/Kg was 5.5 (range 3.0 to 10.34). Median CD34+x106/Kg 3.61 (range 1.48 to 7.06). Post transplant immunosuppression consisted of tacrolimus/MMF plus post transplant Cyclophosphamide in 22 (88%) patients, steroids plus CsA or tacrolimus in 2 (8%) and T cell depleted graf with no immunosupression in one SCID patient. All patients engrafted by day 28 after transplantation and 4 patients had secondary graft rejection. Only one (4%) patient developed synusoidal obstruction syndrome. 7 (28%) patients developed Acute graft-verus-host disease (3 grade I/II and 4 grade III/IV). 16 patients (64%) developed CMV reactivation. At the end of the follow-up 21 (84%) were alive. Four patients died from relapse at day 100 post transplant, 2 from infection and 1 from coronary heart disease. Sencondary graft failure had a negative impact in overal survival (HR: 14 (IC: 1,2-157), p= 0,033). Conclusion: The FACT accretidation process can promote improvement and progress in stem cell transplantation process, by controlling every aspect that impacts the quality of products and therapeutic care. In our center, there was a process developed in order to meet FACT standards that brought better patient care. We have shown the first 25 haploidentical patients who was treted after this accreditation, showing similar results when comparing to international centres and previous publications. We believe that these results could only be achieved in a transplant unit that meets specific quality control guided by FACT. Disclosures:No relevant conflicts of interest to declare.

Validation of a flow cytometry-based method to quantify viable lymphocyte subtypes in fresh and cryopreserved hematopoietic cellular products

Background aimsAdoptive cellular therapy with immune effector cells (IECs) has shown promising efficacy against some neoplastic diseases as well as potential in immune regulation. Both inherent variability in starting material and variations in cell composition produced by the manufacturing process must be thoroughly evaluated with a validated method established to quantify viable lymphocyte subtypes. Currently, commercialized immunophenotyping methods determine cell viability with significant errors in thawed products since they do not include any viability staining. We hereby report on the validation of a flow cytometry-based method for quantifying viable lymphocyte immunophenotypes in fresh and cryopreserved hematopoietic cellular products. MethodsUsing fresh or frozen cellular products and stabilized blood, we report on the validation parameters accuracy, uncertainty, precision, sensitivity, robustness and contamination between samples for quantification of viable CD3+, CD4+ T cells, CD8+ T cells, CD3–CD56+CD16+/– NK cells, CD19+ B cells and CD14+ monocytes of relevance to fresh and cryopreserved hematopoietic cellular products using the Cytomics FC500 cytometer (Beckman Coulter). ResultsThe acceptance criteria set in the validation plan were all met. The method is able to accommodate the variability in absolute numbers of cells in starting materials collected or cryopreserved from patients or healthy donors (uncertainty of ≤20% at three different concentrations), stability over time (compliance over 3 years during regular inter-laboratory comparisons) and confidence in meaningful changes during cell processing and manufacturing (intra-assay and intermediate precision of 10% coefficient of variation). Furthermore, the method can accurately report on the efficacy of cell depletion since the lower limit of quantification was established (CD3+, CD4+ and CD8+ cells at 9, 8 and 8 cells/µL, respectively). The method complies with Foundation for the Accreditation of Cellular Therapy (FACT) standards for IEC, FACT-Joint Accreditation Committee of ISCT-EBMT (JACIE) hematopoietic cell therapy standards, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Q2(R1) and International Organization for Standardization 15189 standards. Furthermore, it complies with Ligand Binding Assay Bioanalytical Focus Group/American Association of Pharmaceutical Scientists, International Council for Standardization of Hematology/International Clinical Cytometry Society and European Bioanalysis Forum recommendations for validating such methods. ConclusionsThe implications of this effort include standardization of viable cell immunophenotyping of starting material for cell manufacturing, cell selection and in-process quality controls or dosing of IECs. This method also complies with all relevant standards, particularly FACT-JACIE standards, in terms of enumerating and reporting on the viability of the “clinically relevant cell populations.”

Gap Analysis of the Australian cGMP and FACT Immune Effector Cell Standards

Background & Aim The Department of Cell and Molecular Therapies (CMT) adheres to the Australian Code of Good Manufacturing Practice (cGMP) for human blood and blood components, human tissues and human cellular therapy products. CMT is actively seeking accreditation for immune effector cells from the Foundation for the Accreditation of Cellular Therapy (FACT). In preparation for FACT accreditation a Gap Analysis was conducted to determine the differences between the two quality standards. Methods, Results & Conclusion Methods Gap Analysis was conducted to compare the FACT Immune Effector Cell Standards to the cGMP. This analysis compared Collection Activities (Part C2, Collection Facility Standards) and Processing Facility Standards (Part D) from the FACT Immune Effect Standards (Version 1.1) to the Australian cGMP (Version 1.0). For the purpose of this analysis, gaps were defined as those instances in which FACT Immune Effector Standards demonstrated a variance against cGMP standards. Results The cGMP focuses on manufacturers that undertake the collection, processing, testing storage, release for supply and quality assurance of products, whereas the FACT Immune Effector Cells Standards addresses all quality aspects of cellular therapy including collection, processing, administration and patient care. A total of 95 gaps were identified; with disparities noted in each FACT section. The majority of gaps were identified in the Quality Management, Coding and Labelling of Cellular Therapy Products, Process Controls and Cellular Therapy Product Transportation and Shipping. These results were used to implement changes in CMT in preparedness for FACT accreditation. Conclusions The summary format of this gap analysis tool is an effective method to clearly identify disparities between the cGMP standards and FACT Immune Effector Cells Standards. The gaps identified highlight potential areas for improvement within the department of CMT. This tool can be used by facilities in Australia to identify any gaps when seeking FACT or Therapeutics Goods Administration GMP accreditation

Data Manager in a Bone Marrow Transplant Team in Brazil: Training, Certifications, International Connections and Dissemination

Introduction Regular analysis of demographic, clinical and outcome data is indispensable for ensuring and maintaining quality in a hematopoietic stem cell transplant (HSCT) center. For this, data needs to be extracted accurately. Organization accreditations such as FACT (Foundation for the Accreditation of Cellular Therapy) require submission of data to the US (CIBMTR) or the European (EBMT) Registries correctly. Due to discrepancies found between medical charts data and the data submitted to CIBMTR in the first FACT accreditation cycle (2012), our HSCT center decided to hire a dedicated data manager. Objective We describe here the training and performance of the data manager in the process of collecting and transferring HSCT data to national and international registries. Methods The professional hired as data manager received internal and external training. Externally, she attended national and international congresses and visited the CIBMTR (2016). Internally, she first received training by the clinical team about the forms to be filled in. Together with the HSCT multi-professional team, they evaluated the data collection process and defined which data should appear in the medical records. Appropriate outcomes were defined for data analysis based on literature searches, the FACT requirements and the need of the clinical staff, and the data manager was trained in data analysis using R. The clinical team together with data manager developed templates appropriate for the clinical follow-up of patients, such as the Dentistry to collect data on mucositis. The quality nurse developed a regular internal auditing system. Results One of the results was the reduction of three hours in filling out the forms (TED 2400). From the structuring, organization and updating of the database, it was possible to obtain relevant indicators on survival and cumulative incidence of acute and chronic graft versus host disease, transplant-related mortality and disease relapse. These are used by the HSCT team in clinical rounds and in critical analyses of the program performance. In re-accreditations (2015 and 2018) after hiring and training, no non-compliance was identified in item B9, related to the insertion and submission of transplant data. In 2017, the clinical team designed, with the data manager, an ethically-approved multicenter study until 2027, about on transplant-related outcomes, currently with 19 centers in Brazil that sending data to CIBMTR. Conclusion Training of the data manager at our HSCT center (a profession not official in Brazil) allowed the development of strategies and tools that resulted in greater accuracy in data collection and analysis, and FACT-compliant.

Obtaining BMT Programmatic Feedback for Performance and Quality Improvements

Over the last year, the Medical City Dallas Blood and Marrow Transplant (BMT) Program quality management team implemented a formal process to solicit feedback from the processing facility, collection facility, and the clinical programs within the BMT Program. The information received is used to improve interactions and processes, as well as meeting and/or exceeding Foundation for the Accreditation of Cellular Therapy (FACT) requirements. <b>Background:</b> Feedback is one of the most powerful influences for learning and achieving process improvements, but its impact can be positive, negative, or neutral. The 7^th edition <i>FACT-JACIE International Standards</i> requires that the Quality Management Plan include, or summarize and reference, policies and procedures for obtaining feedback from associated Clinical, Collection and Processing Facilities. Figure 1, "Feedback Flow between Program Facilities", illustrates the flow of feedback between facilities. <b>Method:</b> To facilitate the collection of data, an electronic survey instrument was used to expedite survey completion. Over a 10-month period, the Quality Manager, assisted by the program's BMT Secretary, sent out bi-weekly feedback surveys and to each facility. If facility staff did not return surveys, reminders were sent again after 3 days and then again after 10 business days (refer to figure 2. "Survey Questions and # of Returns"). Returned surveys are then analyzed. Results and any concerns are presented during the program's quarterly quality meetings for review and endorsement of performance improvement plans. <b>Analysis:</b> To date, the responses have been approximately 90% positive; the other 10% suggested that professional communication could be improved (refer to Figure 3. "Example Feedback"). Some survey respondents remarked that fear of retaliation arising from negative comments prevented them from responding honestly and openly. <b>Results:</b> The survey process has been well received, providing actionable feedback. The evidence confirms that the type of feedback, and the way it is delivered, can be perceived as positive or negative. As one outcome of the survey process, documents are now placed on a shared drive folder so that staff who need them can access them directly. This has improved information flow and communication within the team. The Program is investigating opportunities to improve interpersonal communication approaches in order to improve "sense of team". From the perspective of this program, in addition to surpassing FACT requirements, this initiative provides ways in which feedback can be used to improve communications and streamline processes between facilities.

Multi-laboratory assay for harmonization of enumeration of viable CD34+ and CD45+ cells in frozen cord blood units

Background aimsIn 2016, specifications for both pre-cryopreserved and post-thawed cord blood were defined in the sixth edition of NetCord Foundation for the Accreditation of Cellular Therapy (FACT) Standards for Cord Blood Banks. However, for several experts, harmonization regarding flow cytometry analysis performed on post-thawed samples is still a concern. A multicenter study led by Héma-Québec aimed to provide scientific data to support the cord blood accreditation bodies such as NetCord FACT in the revision of standards. MethodsTwelve cord blood units were processed for plasma and red cell reduction following standard operating procedures. Cord blood unit aliquots were shipped to eight participating centers under cryogenic conditions for analysis before and after standardization of protocol. Repeatability of stem cell count, measured pre- and post-intervention with the centers, was estimated using multilevel linear regression models with a heterogeneous compound symmetry correlation structure among repeated measures. ResultsExcellent inter-center repeatability was reported by each participant regarding the viable CD34+ cells concentration, and a successful improvement effect of protocol standardization was also observed. However, we observed that better control over the critical parameters of the protocol did not have a significant effect on improving homogeneity in the enumeration of CD45+ cells. ConclusionsThe current practice in cord blood selection should now also consider relying on post-thaw CD34+ concentration, providing that all cord blood banks or outsourcing laboratories in charge of the analysis of post-thaw CB samples take into account the consensual recommendations provided in this work and adhere to a good-quality management system.

Sinusoidal Obstructive Syndrome Among Pediatric and Adolescent and Young Adult Patients: Analysis of Pediatric EBMT Diagnostic and Severity Criteria at MD Anderson

Background: Sinusoidal obstructive syndrome (SOS) is a potentially catastrophic complication of stem cell transplantation (SCT) which disproportionately affects younger patients. The incidence of SOS may vary widely depending on the diagnostic criteria (Baltimore versus Seattle), and delays in initiation of definitive treatment remains the most important predictor of outcome. Recently proposed pediatric diagnostic and severity grading criteria by the European Society of Blood and Marrow Transplantation (EBMT) may offer increased sensitivity and allow for more prompt diagnosis, but the extent to which these have been adopted and/or validated by centers in the United States is unclear. Methods: This is a retrospective analysis of all patients undergoing SCT on the Pediatric service at MD Anderson Cancer Center from 2009-2019. Patient records were reviewed for diagnosis of SOS. Among patients identified with SOS, application of Baltimore, Seattle and pediatric EBMT (pEBMT) criteria were compared. Descriptive statistics were used for data analysis where appropriate. Results: A total of 248 patients received 268 transplants during the study period. Patient characteristics are summarized in Table 1. When Baltimore criteria was used the incidence of SOS was 4.5% (n=12) as compared to 8.2% (n=22) when the Seattle or pEBMT criteria were applied. At diagnosis, the majority of these patients had moderate to very severe disease according to pEBMT criteria. The median time to diagnosis of SOS varied according to diagnostic criteria used, with a trend to earlier diagnosis with pEBMT criteria (13 days post-SCT with pEBMT versus 15 days with Seattle/Baltimore) as shown in Table II. Prior exposure to inotuzumab and gemtuzumab were associated with high rates of SOS (75% and 86% respectively). Anicteric SOS, refractory thrombocytopenia and rising bilirubin from a baseline value on 3 consecutive days or bilirubin ≥2 mg/dL within 72 hours were present in 63.6%, 77.3% and 91% of patients with SOS, when pEBMT criteria were applied. Late-onset SOS (diagnosed after 21 days post-SCT) was present in 22.7% of patients when Seattle or pEBMT criteria were applied (n=5) and could not be diagnosed per Baltimore criteria. Severe SOS was eventually observed in 95% of patients. Severe ascites requiring paracentesis (23%), impaired coagulation (77%), respiratory distress requiring supplemental oxygen and/or invasive pulmonary ventilation ( 55%), delirium (32%), acute kidney injury/KDIGO Stage 3/requiring renal replacement therapy (50%) were observed. Defibrotide treatment was initiated in 55% of patients with a median duration of treatment of 26 (3-74) days and complete resolution of SOS was observed in 42% of these patients. For patients who were initiated on defibrotide on the day of diagnosis (n=7) versus those who were not (range 1-11 days) the median time to complete resolution of SOS was 35 and 20 days respectively (p=0.2). Conclusions: To our knowledge, this is the first reported retrospective analysis of SOS among pediatric and adolescent young adult SCT patients in the United States using pEBMT SOS diagnostic and severity criteria. Our study was limited by small sample size associated with single center analyses. Use of the pEBMT criteria showed a trend to earlier time to diagnosis by a median of two days. This is a potentially clinically significant finding, as a delay in initiation of defibrotide among children with severe SOS, has been associated with statistically significant decreased rates of complete resolution. Inherent flaws of the Baltimore and Seattle criteria are the time restriction and reliance of hyperbilirubinemia for the diagnosis in children and adolescents and young adults. Our retrospective analysis suggests that pEBMT criteria for the diagnosis of SOS among children and young adults may be appropriate, especially given the rates of anicteric and late-onset SOS seen in this population. Disclosures Petropoulos: Foundation for the Accreditation of Cellular Therapy (FACT): Membership on an entity's Board of Directors or advisory committees, Other: Foundation for the Accreditation of Cellular Therapy (FACT). Kebriaei:Amgen: Research Funding; Jazz: Consultancy; Pfizer: Honoraria; Kite: Honoraria. Wierda:Xencor: Research Funding; Janssen: Research Funding; Loxo Oncology Inc.: Research Funding; KITE pharma: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma Inc: Research Funding; Pharmacyclics LLC: Research Funding; Genentech: Research Funding; GSK/Novartis: Research Funding; AbbVie: Research Funding; Cyclcel: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; Sunesis: Research Funding. Mahadeo:Recipient of unrestricted medical education grant from Jazz: Research Funding; PI for ATARA EBV CTL Trials: Other: Other .

Integration of Publicly Reported Center Outcomes into Standards and Accreditation: The FACT Model.

The rapid evolution of blood and marrow transplantation (BMT), coupled with diverse outcomes associated with heterogeneous groups of patients, led to the formation of 2 important organizations early in the development of the field: the Center for International Blood and Marrow Transplant Research (CIBMTR) and the Foundation for the Accreditation of Cellular Therapy (FACT). These organizations have addressed 2 of the 9 elements identified by the National Quality Strategy (NQS) for achieving better health care, more affordable care, and healthy people and communities: a registry that promotes improvement of care and accreditation based on quality standards. More recently, a federally mandated database in the United States addresses the third element of the NQS: public reporting of treatment results. Here we describe the current process by which FACT incorporates patient outcomes reported by the CIBMTR into standards for accreditation, the requirements for accredited programs with performance below expected outcomes to maintain accreditation, and preliminary findings of an assessment of corrective action plans intended to improve outcomes.

Clinical utilization of Chimeric Antigen Receptor T-cells (CAR-T) in B-cell acute lymphoblastic leukemia (ALL)–an expert opinion from the European Society for Blood and Marrow Transplantation (EBMT) and the American Society for Blood and Marrow Transplantation (ASBMT)

On August 30, 2017, the U.S. Food and Drug Administration (US-FDA) approved tisagenlecleucel (KYMRIAH, Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor-T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring and disease assessments. To address these issues, experts representing the American Society for Blood and Marrow Transplant (ASBMT), the European Group for Blood and Marrow Transplantation (EBMT), the International Society of Cell and Gene Therapy (ISCT), and the Foundation for the Accreditation of Cellular Therapy (FACT), formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved.

Integrating Immunotherapy and Bone Marrow Transplant Clinic Operations Policies for FACT Accreditation

Topic Significance & Study Purpose/Background/Rationale Our Blood and Marrow Transplant (BMT) center is part of an NCI-designated cancer center that performs nearly 500 transplants a year. Historically, it was a free-standing hospital/clinic and in 2001 became part of a larger clinical alliance. BMT Physicians manage clinical care and research. Standard Practice guidelines were established with physicians based on the need for standardized care and to educate rotating medical personnel. In the last 25 years BMT care has transferred from hospital to the Ambulatory Clinic. BMT Ambulatory Nurse Management recognized standardization of Operational Policy was essential. This work became the basis for creating the policies required for Foundation for the Accreditation of Cellular Therapy (FACT). Methods, Intervention, & Analysis The BMT clinic managed patient care and staff orientation when chimeric antigen receptor (CAR) T-cell therapy first began at our institution. The Immunotherapy (IMTX) Clinic is now separate from the BMT Clinic but many clinical care guidelines remain similar. It was determined that the IMTX clinic would fall under the BMT FACT accreditation standards, as our needs for accreditation are intertwined. BMT maintains Operations Standards for adult/pediatric inpatient/ambulatory care across three geographic sites of practice. IMTX operations guide adult inpatient/ambulatory care across two institutions in our alliance. Findings & Interpretation BMT and IMTX maintain Operations Standards by review through the Transplant & Immunotherapy Clinic Operations Team (TICOT). TICOT membership includes all departments providing services to BMT and/or IMTX patients and in each institution with patient care involvement. Policies each have designated owners and are distributed a month prior to the meeting when due for revision. At monthly cross-institutional meetings, policies are collaboratively reviewed and approved for the central policy data base. Discussion & Implications Changes in 2015 transferred policy management to the BMT Nursing Supervisor with BMT Medical Director oversight. The IMTX clinical staff is responsible for reviewing policy and addressing the differences to cover IMTX FACT requirements. BMT/IMTX designated CNS reviews policies to assure alignment with FACT standards. Nurse leaders most familiar with clinic operations are critical to the process of policy creation, implementation, revision and maintenance for the best standards of care and practice in BMT/IMTX cellular therapy care delivery.

Handling, processing and disposal of stem cell products in Europe: A survey by the cellular therapy and immunobiology working party of the European Society for Blood and Marrow Transplantation

BackgroundThere is considerable heterogeneity in processing of stem cells for hematopoietic stem cell transplantation across Europe. The Foundation for the Accreditation of Cellular Therapy (FACT)–Joint Accreditation Committee International Society for Cellular Therapy and European Society for Blood and Marrow Transplantation (EBMT) (JACIE) standards provide minimum guidelines that, however, leave room for significant variations in practices at the individual transplantation center (TC). MethodsTo better understand the extent of heterogeneity in storage conditions, quality controls (QCs), graft processing and disposal, a questionnaire was developed, reviewed by the Cellular Therapy and Immunobiology Working Party (CTIWP) and sent to all EBMT TCs. ResultsIn this study, 288 TCs from 46 countries (32 European, 14 associated) responded to the survey. Long-term storage is performed mainly either in liquid nitrogen or in the vapor phase of liquid nitrogen with 10% dimethyl sulfoxide (DMSO; 58% of centers). In case of microbiological contamination, most TCs make a case-by-case decision in collaboration with the clinicians. CD34+ counts are performed routinely either before and/or after thawing. Some centers perform additional QCs. DMSO is generally not removed (83%) and the graft is thawed at the bedside (68%) in a water bath (78%). There is heterogeneity between the centers regarding duration of storage and graft disposal. DiscussionOverall, this survey demonstrates that the majority of responding TCs uses standardized procedures (intracenter standardization). However, significant intercenter variations persist, which warrant further standardization and investigations on clinical and financial consequences. Additionally, efforts should be undertaken to provide more specific international guidelines on storage duration and graft disposal, which may also have an important impact on health care services worldwide.

Leveraging a software application to prepare for regulatory inspection within a hematopoietic cellular therapy program.

142 Background: The Sarah Cannon Blood Cancer Network (SCBCN) is comprised of seven Hematopoietic Cellular Therapy (HCT) programs. Regulations require that programs have a consistent and continuous process to identify and measure compliance to ensure standards are met. Every 3 years, programs undergo inspections by the Foundation for the Accreditation of Cellular Therapy (FACT). Historically, programs would prepare for inspections by utilizing paper documents that support and demonstrate compliance with standards. The goal of this project was to develop an electronic platform to manage the FACT inspection. COMAIBA (Compliance Management Actionable Intelligence Business Analytics) was selected as a development partner. Methods: Within our HCT programs, a thorough analysis was performed to determine the current processes by which inspections took place. The FACT assessment questionnaire was reviewed and each standard was evaluated. Quality coordinators within the programs highlighted the key documentation necessary to meet each standard. Results: In collaboration with COMAIBA, a regulatory compliance module was developed which allows the programs to electronically prepare for and manage FACT inspections. There are currently over 1600 questions within the application broken down into clinical, apheresis, marrow collection and processing facility subsections. Programs upload supporting documentation to demonstrate how they comply with each standard. From a programmatic level, administrators and key personnel can, at any time, view the preparation process via a dashboard and view the compliance measures electronically. Conclusions: This electronic solution allows quality teams to proactively prepare for inspections and keep information current and up to date on an ongoing basis. As standards evolve, the design of the COMAIBA application allows versatility in updating and maintaining compliance. COMAIBA is working to utilize this format for other regulatory and accrediting bodies i.e. CoC, UNOS. In addition, allowing the inspectors to view information electronically prior to coming onsite may enhance the inspection process and allow for a more comprehensive review.

Integrating cancer survivorship care into allogeneic BMT recovery.

39 Background: AlloBMT patients are at risk for chronic morbidity and late effects. Prior to 2015, the Stanford BMT program conducted group classes at three months post-transplant to prepare alloBMT patients and their families for the transition to survivorship, but no formal cancer survivorship program existed. Cancer survivorship care is required by the Foundation for the Accreditation of Cellular Therapy ( FACT). In order to fill this gap, we developed a standardized pathway to survivorship care for alloBMT survivors. Aim: To implement an initial cancer survivorship care consultation with comprehensive symptom assessment, late effects monitoring, and development of a survivorship care plan (SCP) three to six months after alloBMT. Methods: Standard work was implemented including patient introduction to survivorship by the BMT nurses and Advanced Practice Providers [APP] and during group ‘moving home’ class; responsibility for referral to survivorship; metric tracking, and administration of patient survey. The survivorship visit included an evaluation by the patient’s BMT social worker, introduction to post-BMT nurse coordinator and consult with cancer survivorship APP. Eligible patients were alloBMT recipients receiving care in the outpatient setting. Results: From July 28, 2015 to January 25, 2016, 90% (66/72) of eligible alloBMT patients were referred to cancer survivorship by day 100, 66% (42/66) of referred patient s were seen in survivorship clinic by day 180, 33% (22/66) deferred the visit or were unreachable, 1% (2/66) died. Of the 42 patients who received a cancer survivorship visit, 38% (13/42) responded to a post-visit survey. Responses indicated the patients believed their health goals and needs were addressed, and a SCP in the context of a comprehensive visit was valuable. Conclusions: Integrating standardized cancer survivorship care into the alloBMT recovery period is feasible, satisfactory to patients, and adds a structured approach for long-term effects monitoring and treatment. Early experience and patient surveys demonstrate value in an individual visits 3-6 months after alloBMT with a focus on returning to life and goal oriented post-transplant care.

A survey of infectious disease clinical practices among pediatric blood and marrow transplant programs in the United States.

We assessed clinical practice standards for infectious complications among pediatric blood and marrow transplant (PBMT) recipients. An anonymous online survey was sent to all 64 pediatric program directors (PD) of PBMT centers in the United States, which are accredited by the Foundation for the Accreditation of Cellular Therapy (FACT). The overall response rate was 56% (CI: 44-68%); variations in clinical practices were noted regarding (i) surveillance for late onset cytomegalovirus (CMV) infection and (ii) pharmacokinetic/therapeutic drug monitoring of antimicrobials. Prospective studies among PBMT recipients to address infectious complications among this population and variations in clinical practice may be required.

Access to Advanced Care and Survival in Multiple Myeloma

Background: There has been major improvement in the survival of patients with multiple myeloma (MM), mostly due to the availability of more effective drugs and increased use of autologous hematopoietic progenitor cell transplantation (AHPCT). Access to AHPCT has been linked to demographic, geographic and socioeconomic parameters. We hypothesize that the distance between the patient county of residence and a transplant center is an adequate surrogate of access to advanced care (comprising not only AHPCT, but also experimental therapies) and may affect survival of MM patients.Methods: We conducted an analysis of patients diagnosed with MM between 2002 and 2011 reported to the Surveillance Epidemiology and End Results program (SEER-18). Cases reported from death certificate or autopsy only, and cases with missing race or county of residence were excluded (1% of total). Patients were classified according to the distance between county of residence and the nearest program accredited by the Foundation for the Accreditation of Cellular Therapy (FACT): Cohort A (<20 miles), B (20-70 miles), C (70-200 miles) and D (>200 miles).Results: We included 45,079 patients with median follow up of survivors of 30 months. There were substantial differences between the cohorts, particularly in race-ethnicity, income and education (Table 1). Median survival was 34, 37, 31 and 30 months for cohorts A, B, C and D respectively (Figure 1). Using Cox proportional hazards, we built two different survival models. Model 1 included demographic parameters and distance to transplant center. Compared to cohort A, risk of death was lower in cohort B and higher in cohorts C and D (Table 2). Model 2 included all parameters of model 1 plus median household income and proportion of adults in the county of residence with at least bachelor degree. Income and education were strongly associated with survival and displaced distance to transplant center from the model (Table 2). Other factors associated with worse survival were age, earlier year of diagnosis, male sex, presentation with plasma cell leukemia, and race-ethnicity.Conclusion: Distance to transplant center, a surrogate for access to advanced care, is associated with survival in patients with MM, likely reflecting underlying differences in demographics, income and education. Abstract 858. Table 1 –Characteristics of the patientsTotalABCDN=45,079N=19,476N=15,614N=8,262N=1,727PFemale20,419 (45.3%)8,967 (46.0%)7,036 (45.1%)3,654 (44.2%)762 (44.1%)0.02Age68.468.468.868.368.20.005Race-ethnicity<0.001AIAN211 (0.5%)39(0.2%)36 (0.2%)36 (0.4%)100 (5.8%)API2282 (5.1%)1381(7.1%)751 (4.8%)124 (1.5%)26 (1.5%)Hispanic4557 (10.1%)2504 (12.9%)1,129 (7.2%)470 (5.7%)454 (26.3%)NHB8615 (19.1%)4708 (24.2%)2,236 (14.3%)1,600 (19.4%)71 (4.1%)NHW29,414 (65.2%)10,844 (55.7%)11,462 (73.4%)6,032 (73.0%)1,076 (62.3%)Year of diagnosis0.022002-200621,076 (46.8%)9,185 (47.2%)7,185 (46.0%)3,854 (46.6%)852 (49.3%)2007-201124,003 (53.2%)10,291 (52.8%)8,429 (54%)4,408 (53.4%)875 (50.7%)Household income$59.157$60,254$66,540$45,237$46,633<0.001Adults with at least bachelor degree29.7%32.8%31.6%19.7%24.3%<0.001Disease0.46Multiple Myeloma44,749 (99.3%)19,327 (99.3%)15,498 (99.3%)8,212 (99.2%)1,712 (99.1%)Plasma Cell Leukemia330 (0.7%)149 (0.7%)116 (0.7%)60 (0.8%)15 (0.9%)Table 2 –Multivariate analysis of factors associated with survival in MMFactorReferenceHR95% C.I.PModel 1Year of diagnosisPer year0.9630.959-0.968<0.001Age at diagnosisPer year1.0421.041-1.044<0.001FemaleMale0.900.89-0.93<0.001Plasma Cell LeukemiaMultiple Myeloma2.942.60-3.31<0.001Race-ethnicity<0.001AIANNHW1.040.87-1.260.65APINHW1.030.97-1.090.32HispanicNHW1.141.09-1.19<0.001NHBNHW1.111.07-1.15<0.001Distance to advanced care<0.00120 - 70 miles<20 miles0.960.93-0.990.00570-200 miles<20 miles1.101.06-1.14<0.001>200 miles<20 miles1.101.03-1.170.004Model 2Year of diagnosisPer year0.9630.959-0.968<0.001Age at diagnosisPer year1.0421.041-1.044<0.001FemaleMale0.910.89-0.93<0.001Plasma Cell LeukemiaMultiple Myeloma2.942.60-3.31<0.001Race-ethnicity<0.001AIANNHW1.040.86-1.250.68APINHW1.061.00-1.120.04HispanicNHW1.151.10-1.20<0.001NHBNHW1.081.05-1.12<0.001Household incomePer $10,0000.980.96-0.990.001% adults with bachelor degreePer % point0.9940.992-0.996<0.001 [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Can we assure quality without stifling innovation?

The emergence of regenerative medicine raises new questions about the best ways to ensure the safety and efficacy of stem cell therapies for patients. The Foundation for the Accreditation of Cellular Therapy (FACT) believes minimum requirements for cellular therapy for regenerative medicine will promote patient safety, protect the research environment, and aid in the swift advancement of regenerative therapies from bench to bedside. The standards development process has demonstrated that consensus on minimum requirements advances the field. FACT's accreditation process and newly established "Common Standards for Cellular Therapies" can help meet unmet needs in regenerative medicine that will drive commercialization of new cell therapies.

The impact of center accreditation on hematopoietic cell transplantation (HCT).

There are two voluntary center-accrediting organizations in the USA, the Foundation for the Accreditation of Cellular Therapy (FACT) and core Clinical Trial Network (CTN) certification, that are thought to improve and ensure hematopoietic cell transplantation (HCT) center quality care and certify clinical excellence. We sought to observe whether there are differences in outcomes between HLA-matched and -mismatched HCT by CTN and FACT status. Using the 2008-2010 Center for International Blood & Marrow Transplant Research data we created three center categories: non-FACT centers (24 centers), FACT-only certified centers (106 centers) and FACT and core clinical trial network (FACT/CTN) certified centers (32 centers). We identified patient characteristics within these centers and the relationship between FACT certification and survival. Our cohort consisted of 12 993 transplants conducted in 162 centers. After adjusting for patient and center characteristics we found that FACT/CTN centers had consistently superior results relative to non-FACT and FACT-only centers (P<0.05) especially for more complex HCT. However, non-FACT centers were comparable to FACT-only centers for matched related and unrelated patients. Although FACT status is an important standard of quality control that begins to define improved OS, our results indicate that FACT status alone is not an indicator for superior outcomes.