Determining Donor Eligibility for Donor Lymphocyte Infusions Aliquoted from a Product Intended for Transplantation
By Patrick J. Hanley, PhD
Chair, FACT Education Committee
Chief & Director, Cellular Therapy Program
Associate Professor of Pediatrics
Center for Cancer and Immunology Research
Children’s National Hospital & The George Washington University
Haploidentical hematopoietic progenitor cell (HPC) transplantation has increased drastically over the past five years. One reason for this increase is the introduction of T cell Receptor (TCR) α/β and CD19 depletion. In this manufacturing process, the α/β T cells and CD19 B cells are depleted, leaving γ/δ T cells, CD34+ stem cells, and other immune cells that are infused into the patient. The hypothesis is that the γ/δ T cells will provide an anti-tumor effect (in the case of malignancies) and anti-viral immunity, while the lack of α/β T cells will reduce the incidence of graft versus host disease (GVHD). However, the very limited CD3+ alpha beta T cell dose (often less than 1×105 CD3+ α/β /kg) may leave the recipient more susceptible to viral infections, or even engraftment failure. Therefore, clinicians often request that the cell processing facility cryopreserve aliquots of the α/β T cell-containing fraction to be used as a potential donor lymphocyte infusion (DLI).
Donor eligibility gurus may already see the conundrum: the TCR α/β/CD19-depleted cellular therapy product is an HPC product, for which donor infectious disease testing is allowed by the U.S. Food and Drug Administration (FDA) up to 30 days prior to collection; DLI is considered a therapeutic, leukocyte-rich tissue and therefore requires infectious disease testing to be done before or after seven days from collection. Programs can be conservative and simply draw samples for testing within seven days to cover both HPC products and therapeutic products. However, this may not align with the existing process for work-up of the donor in preparation for donation. In some cases, it may require an additional blood draw, which is not in the best interest of the donor.
Based on previous clarification from the FDA (which was confirmed by the FACT office in August 2021), the most straightforward way to address this issue is to recognize that separate eligibility determination is NOT required for the T cell product used as DLI if the lymphocytes were collected as a part of the HPC collection. When the donor of the HPC product is screened and tested in accordance with regulations and determined to be eligible for donation, the donor eligibility determination also applies to the remaining portion of the same product that is used for subsequent therapy.
The following example was presented during a FACT webinar by Safa Karandish, MT(ASCP) from the FDA in 2015 as part of a presentation titled, “FDA presents: Using Donor Screening and Testing to Determine Donor Eligibility,” which can be found on the FACT website at: http://www.factweb.org/forms/store/ProductFormPublic/fda-presents-using-donor-screening-and-testing-to-determine-donor-eligibility.As most of us can attest, with a number of nuances and exceptions to the regulations, donor eligibility determination can be complicated. It’s a relief to hear that in the case of labeling products for DLI from a product collected for an HPC transplant, the regulations are straightforward and the DLI product does not require separate donor eligibility determination.
World Marrow Donor Day (WMDD) is a global celebration of donors that takes place on the third Saturday of September, or September 18th in 2021. Donors will be celebrated on all continents of the world through both social and conventional media.
The World Marrow Donor Association (WMDA), which believes that all patients deserve a chance to receive a stem cell transplant, founded WMDD in 2014 to thank blood stem cell donors and to raise awareness about the importance of registering as a potential donor.
How will you celebrate WMDD? Whether a short message or a big event, the WMDA encourages you to be creative and find a way to acknowledge donors on September 18th. Looking for ideas? Enjoy browsing through the 2020 events for inspiration!
A 24-hour livestream on September 18th will share WMDD events for all to see! Submit your event by July 23rd for consideration.
In the meantime, take a moment to read uplifting stories about donors that are posted on the WMDD website. FACT thanks all blood stem cell donors for their lifesaving gifts!
On September 15, 2020, the American Society for Apheresis (ASFA) celebrated Apheresis Awareness Day. The purpose for this observance is to raise awareness of apheresis medicine, including apheresis practitioners and the donors and patients they save every day using evidence-based practice.
The awareness day included an official hashtag (#ApheresisDay2020), online games including Jeopardy and Apheresis Word Scramble, and a Question of the Day.
We at FACT extend our heartfelt appreciation to apheresis professionals around the world, including physicians, nurses, technicians, scientists, quality managers, and more who work as an important team performing life-saving work every day. We acknowledge the extensive role they play both in providing standard of care therapy and cutting edge research. Apheresis professionals are in high demand because the work they do is so important. Thank you for all that you do!
World Marrow Donor Day 2020 will be on Saturday, September 19, 2020. More than 50 countries around the world will participate to publicly thank donors, and to reach a large audience to recruit more.
On its fifth anniversary, the theme this year will be to “Join the virtual global donor drive: register online, save a life!” Despite millions of registered donors, 40% of patients are not able to find a matched donor. This is especially true for patients with mixed race or from ethnic minorities.
Please consider expressing your gratitude to donors and posting information on how to become a donor on websites, social media, or newsletters. The World Marrow Donor Association (WMDA) provides an online tool for potential donors to find active donor registries in their countries and determine eligibility.
Thank you to all the past, current, and registered donors who selflessly chose to become a donor for someone in need.
The interorganizational Donor History Questionnaire materials have been updated to reflect recommendations made by the FDA’s Guidance for Industry: “Revised Recommendations for Determining Eligibility of Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products Who Have Received Human-Derived Clotting Factor Concentrates,” published in November 2016.
The Donor History Questionnaire (DHQ) materials were developed to screen allogeneic HPC donors for communicable disease risk factors in accordance with requirements of the Food and Drug Administration (FDA), AABB, FACT, and the National Marrow Donor Program (NMDP).
The FDA does not mandate use of any particular tool to fulfill donor screening requirements for communicable disease risks and has determined that “official” recognition of DHQ materials in a guidance document is not warranted. The task force believes the DHQ materials, which are harmonized with applicable regulations and guidance documents, will optimize donor comprehension of the questions and provide donor historians with the tools needed to evaluate donor responses. Facilities should read the “User Instructions” carefully before adopting the materials for use.
When a facility implements a new version of these DHQ materials, it should follow its established change control process for the incorporation of the new DHQ materials. The change control process should address validation of the use of the new version with other existing processes and appropriate staff training.
Several organizations collaborate to create a standardized tool to screen allogeneic hematopoietic progenitor cell (HPC) donors and cord blood donors for communicable disease risk factors in accordance with the requirements of the Food and Drug Administration (FDA), FACT, AABB, and the National Marrow Donor Program (NMDP). Both the HPC and cord blood questionnaires were recently revised to include recommendations made by the FDA’s Guidance for Industry: “Donor Screening Recommendations to Reduce the Risk of Transmission of Zika Virus by Human Cells, Tissues, and Cellular and Tissue-Based Products.
When implementing the revised questionnaire and related materials, comply with established change control processes, including document control and personnel training. Changes made to the materials are listed in accompanying charts.
Throughout the past few months, the FDA has released numerous final and draft guidances that are pertinent to cellular therapy. The following are summaries of recent documents.
Final Guidance on Testing for Treponema pallidum (Syphilis)
The FDA published updated recommendations concerning donor testing for evidence of Treponema pallidum (T. pallidum) infection, the etiologic agent of syphilis. As required under 21 CFR 1271.80(a) and (c) (§ 1271.80(a) and (c)), testing must be performed using appropriate FDA-licensed, approved, or cleared donor screening tests, in accordance with the manufacturer’s instructions, unless an exception to this requirement applies under 21 CFR 1271.90. This guidance clarifies that the FDA does not consider cleared or approved diagnostic tests or pre-amendment devices (which have not been licensed, approved, or cleared) to be adequate for use in donor testing for T. pallidum infection under the criteria specified in § 1271.80(c).
Draft Guidance on Testing for West Nile Virus
The FDA also announced the availability of a draft document entitled “Use of Nucleic Acid Tests to Reduce the Risk of Transmission of West Nile Virus from Living Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps); Draft Guidance for Industry.”
The FDA recommends the use of an FDA-licensed nucleic acid test (NAT) to test living donors of HCT/Ps for evidence of infection with West Nile Virus (WNV) to reduce the risk of transmission to recipients.
Draft Guidance on Deviation Reporting
The Food and Drug Administration announced the availability of a draft document entitled “Deviation Reporting for Human Cells, Tissues, and Cellular and Tissue-Based Products Regulated Solely Under Section 361 of the Public Health Service Act and 21 CFR part 1271; Draft Guidance for Industry.”
The draft guidance document provides certain establishments that manufacture non-reproductive human cells, tissues, and cellular and tissue-based products (HCT/Ps), regulated solely under the Public Health Service Act (PHS Act) and under FDA regulations, with recommendations and relevant examples for complying with the requirements to report HCT/P deviations.
Final Guidance on Investigating and Reporting Adverse Reactions
The FDA published finalized guidance entitled, “Investigating and Reporting Adverse Reactions Related to Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) Regulated Solely Under Section 361 of the Public Health Service Act and 21 CFR part 1271; Guidance for Industry.” The guidance document provides establishments that manufacture HCT/Ps for which no premarket submissions are required with recommendations for complying with the requirements for investigating and reporting adverse reactions involving communicable disease in recipients of these HCT/Ps. The guidance also provides updated information specific to reporting adverse reactions related to HCT/Ps to supplement the general instructions accompanying the MedWatch mandatory reporting form, Form FDA 3500A.
Draft Guidance regarding Homologous Use of HCT/Ps
The FDA announced the availability of, “Homologous Use of Human Cells, Tissues, and Cellular and Tissue-Based Products; Draft Guidance for Industry and FDA Staff.” The draft guidance document provides human cells, tissues, and cellular and tissue-based product (HCT/P) manufacturers, health care providers, and FDA staff with recommendations for applying the criterion of “homologous use” as it applies to HCT/Ps. Comments must be submitted by September 27, 2016.
Draft Guidances Reopened for Public Comment
The FDA is again accepting comments for the following draft guidance documents. Comments must be submitted by September 27, 2106.
- Human Cells, Tissues, and Cellular and Tissue-Based Products From Adipose Tissue: Regulatory Considerations; Draft Guidance for Industry
- Minimal Manipulation of Human Cells, Tissues, and Cellular and Tissue-Based Products; Draft Guidance for Industry and Food and Drug Administration Staff
- Same Surgical Procedure Exception: Questions and Answers Regarding the Scope of the Exception; Draft Guidance for Industry