Workup (HSC Apheresis, HSC Bone Marrow, MNC Apheresis)

Workup Process

After the workup request form is received, it is checked for completeness and correctness. The following information must be provided by the transplant center at the time of a formal request for a stem cell donation:

• Patient ID
• Patient HLA typing results: Minimum HLA-A, -B, -C, -DRB1 high resolution DNA typing
• Patient’s name
• Patient’s sex
• Patient’s date of birth
• Patient’s diagnosis
• Patient’s weight
• Patient’s blood group and rhesus factor
• Transplant Center name
• GRID of the requested donor
• Product preference
• Required date of clearance
• Duration of the conditioning
• Pre-collection samples requirement
• (Pre-collection samples shipping address)
• Prescription for HSC collection, detailing desired cell dose, additives, and anticoagulants
• Collection day samples requirement
• Transport temperature
• HLA verification typing results (DNA-based typing results for HLA-A, -B, -C, -DRB1 and -DQB1) from the requested donor.

If the workup request form contains all necessary information, it is assigned to a case manager. The case manager will then contact the donor as soon as possible to discuss all details and coordinate the collection.

The following details will be discussed with the donors during the workup procedure:

• Different methods of blood stem cell donation and the transplant center’s preferred stem cell product type
• Information about the risks and side effects of the donation
• Willingness of the donor to proceed with the donation
• Availability of the donor for the requested dates and donation method as well as time commitment
• Time frame of medical examination and donation
• Location of the collection center
• The physical examination procedure incl. the requirement of further tests and blood samples before donation
• Anonymity of the donor and patient and confidentiality of personal data
• Whether the donation is part of a clinical trial for the patient
• The donor’s right to withdraw consent and consequences of withdrawal after patient conditioning has begun
• Possibility of request for subsequent donation of hematopoietic stem cells or blood products
• Reimbursement and provision of expenses
• Insurance coverage

Maximum Number of Donations for DKMS Donors

If patients have a relapse or a graft failure, a subsequent donation of HSC from the same donor can become necessary. This happens in approximately 2-3 % of our cases. A donor can also be requested as best match for a different recipient (<1% of cases). To protect donors, the number of donations for HSC Apheresis or HSC Bone Marrow is limited to two collections per donor for each product type. There is no defined maximum number of donations for MNC Apheresis. However, when the donor is requested for MNC Apheresis the third time, a medical advisor will be contacted to evaluate the indication.

Subsequent Donation

• The transplant center must provide a written reason to justify the need for a subsequent donation and the WMDA F20 form (Previous Transplant History) or equivalent
• Subsequent donations of HSC for the same patient have to be approved by the medical advisor of DKMS. After a completed workup for the same patient, only a subsequent workup or MNC Apheresis request is accepted. HAC requests are not accepted in between.

Multi Donation

• Transplant centers will already be informed at the time of pre-workup request, if a donor has donated before, as the donor will only be available for the same stem cell product type one more time.

Interval between Donations

After an HSC donation the donor may suffer from side effects for some time. Therefore, there is a defined minimal interval between two donations.

• The interval between two PBSC donations should be at least 4 weeks as a graft failure cannot be diagnosed earlier.
• In urgent cases, e.g. poor mobilization, it might be possible to shorten the interval between donations, and switching the cell source (PBSC to BM / BM to PBSC) if not contraindicated.
• The interval between two BM donations should be at least 4 weeks. A PBSC donation should be considered for the second request, if possible.
• There is no defined minimal interval for MNC Apheresis. However, the donor blood count must be in normal range.
• A subsequent donation can only occur if the donor has fully recovered.
• All decisions have to be made after individual consideration.
• DKMS BMST Foundation India only provides PBSC products. DKMS BMST donors in India are not allowed to undergo any type of second donation (including MNC Apheresis) within 6 months after a peripheral stem cell harvest due to Indian law. Consequently, we recommend to request a higher cell count for the first donation, if possible, and to cryopreserve a part of the product for a potential subsequent transplant.

Cell Count Requests

We observe a huge range in requested CD34+ cell counts for HSC Apheresis from 1.5 x 106 / kg to 50 x 106 / kg body weight of the recipient. Generally, a CD34+ cell count of 5 x 106 / kg recipient body weight is considered sufficient. However, there are protocols in use that require higher numbers of CD34+ cells.

For HSC Bone Marrow, the requested TNC usually is within a range of 3-5 x 108 / kg body weight of the recipient. For children with rare diseases (e.g., SCID, other congenital disorders or metabolic diseases) as well as for patients with SAA, a higher cell count may be reasonable, as there is a higher possibility of graft failure.

• For HSC Apheresis, the transplant center must justify requests for CD34+ cell counts exceeding 5 x 106 / kg recipient body weight. Requests exceeding 5 x 106 / kg recipient body weight without a plausible explanation cannot be accepted.
• For HSC Bone Marrow the collection of TNC is limited, as only 20 ml bone marrow / kg body weight of the donor may be collected. Usually, a maximum volume of 1,500 ml is collected.
• Transplant centers should thus consider donor’s weight when requesting a BM product.
• If the HSC product is being cryopreserved, a higher number of cells might be approved provided that it is still feasible for the donor.

Simultaneous Confirmatory Typing and Workup

As nowadays HLA results from donor registry typing are very accurate, a transplant center can very often identify a match for a patient immediately on the search results list. Therefore, in urgent cases or in cases where the donor was already requested multiple times for CT, the HLA verification typing can be shifted to the workup process. In these cases, it is possible to request CT and workup at the same time. The transplant center has to consider that CT unavailability varies between 20-40% depending on the DKMS entity. For this reason, it is recommended that a Health and Availability Check (HAC) has been completed before a simultaneous CT and workup is requested to verify the donor’s availability and medically suitability. A HAC does not include IDM testing which will be performed only during workup in these cases.

• DKMS accepts workup requests without preceding CT request. The blood draw for HLA verification typing takes place at the time of physical examination and the transplant center has to confirm that HLA verification typing has been performed at the time of donor clearance. Results should be reported to DKMS before the donor receives G-CSF or is admitted for bone marrow harvest.
• Note: If the transplant center requires that the blood samples for HLA verification typing are drawn before physical examination, CT and workup must be requested separately.

Number of Donors Requested for one Patient at the same Time

At DKMS, the workup unavailability rate is approximately 15 % globally, including temporary reasons.

• DKMS accepts that a transplant center requests more than one donor for WU. However, the requesting transplant center / registry must inform DKMS which donor is the primary or backup donor. This also applies if one of these donors is not a DKMS donor but a donor from another donor registry.
• The primary donor will be contacted as usual and will not be informed that there is another donor requested for workup.
• If the DKMS donor is the backup donor, he/she will be contacted and informed that he/she is a backup donor and therefore might not be requested to donate, if the primary donor is able to proceed in the requested time frame. The information session will be performed with the backup donor to assess willingness and availability but no collection slots will be blocked in the collection center facilities.

If there is an increased risk that the primary donor will be unavailable, DKMS may, in exceptional, plan collection dates with both donors simultaneously. Further exceptions can be made in individual cases, e.g. if several donors have already failed for a patient and the urgency is given.

Replacement Donor Search at Workup

With a global DKMS donor pool of more than 11 million donors, many patients have more than one potential DKMS donor. In case a donor becomes unavailable for the patient during workup, DKMS starts a replacement donor search within all DKMS donors.

• As soon as we learn that a donor might be unavailable for the patient (e.g. donor is unavailable for the requested period or the stem cell source the transplant center is requesting), a replacement donor search is started.
• Transplant centers are informed about the outcome of the replacement donor search.
• In addition to the manually triggered replacement donor search, an automated replacement donor search is running at the start of the workup. If there are no other matching donors available, DKMS types potentially matching donors who are not fully typed at own costs.

Research Studies at Workup Level

Research studies for better treatment or outcome of the patients are important. DKMS therefore supports studies if they can result in a benefit for patient care or increase safety of donors and the additional burden on the donor is acceptable.

• All study requests have to be approved by DKMS.
• DKMS allows only one study per case.
• The study request has to be sent to DKMS with the workup request.
• Study requests received after physical examination of the donor cannot be accepted.
• For any research studies, transplant centers have to provide the full study synopsis, approval of the ethical review board, as well as translated information and consent form for donors (English or language of involved DKMS donor center).
• Any genetic testing must be approved by DKMS and thus specified in the study synopsis.
• Without approval for the study request, the transplant centers are not allowed to perform any tests with donor material (blood, BM, PBSC, MNC products or data) which are not standard requirement for either donor selection or transplantation.

Cryopreservation of Stem Cell Products

• Stem cell products from unrelated donors are normally transplanted fresh, once the product has arrived in the transplant center and the quality assessment at the transplant center has been performed. Under certain circumstances, a cryopreservation of the product can become necessary.DKMS has to approve any cryopreservation request. To be able to approve the request, DKMS needs a detailed justification for the cryopreservation request.
• DKMS wants to avoid cryopreservation of stem cell products. Therefore, a postponement of the transplant date before collection is generally preferred.
• Cryopreservation of bone marrow products is associated with higher cell losses. DKMS will approve such requests when excessive TNC counts are expected.
• The donor is contacted by the workup case manager and informed about the cryopreservation request. The donor has to agree to the cryopreservation of his/her product and give consent.
• A clear timeline for start of conditioning and date of transplantation must be communicated before cryopreservation can be approved.
• Infusion should be scheduled as soon as possible and pre-transplant conditioning should start immediately after safe arrival of the product or, in case of recipient related cryopreservation, once health status is appropriate.
• In addition, the transplant center must confirm with a formal cryopreservation request form to assess the feasibility of immediate transplantation prior to the beginning of the donation procedure (1st dose of G-CSF or hospital admission for BM collection).
  If the required information about the planned cryopreservation has not been provided before the start of the mobilization, the collection center, donor center or the donor may not proceed with the donation.
• DKMS will follow-up with the transplant center as long as the cells are cryopreserved and not infused. The transplant center needs to inform DKMS when they have infused the cells. If the cryopreserved product will not be used for the intended patient, the transplant center must also inform DKMS and explain why the product cannot be used.
• If the cells will definitely not be infused, some DKMS entities may ask transplant centers to keep unused PBSC products cryopreserved for the time being and / or initiate retrieval of those cells to be stored at DKMS Stem Cell Bank.
• As unrelated stem cell products are directed to a single patient, it is not allowed to use cells for another purpose, e.g. science, studies or validation processes without approval from DKMS and a specific donor consent.
• DKMS has to give final approval before cells are destroyed.
• Donors will always be kept updated about the infusion or non-infusion of their stem cells.

Partial Cryopreservation of Excess Cells of Stem Cell Products

If the stem cell product contains more cells than needed, the transplant center should cryopreserve residues of the HSCs or MNCs for a later use.

• Donors agree on the consent form, that portions of the stem cell product can be cryopreserved if the stem cell product contains more cells than needed. Excess cells can only be used as a subsequent transplant for the same patient.
• If remains of the stem cell product are no longer needed for the patient, the transplant center must discard the cells. A specific information to DKMS is not required.

It is not allowed to use the product for research or any other purposes without approval of DKMS and the donor.

Cryopreservation of MNCs

Donor MNC products usually are portioned and most parts are cryopreserved. One portion should be infused freshly.

• A transplant center needs to inform DKMS if they plan to cryopreserve the complete product and not infuse at least one fresh portion within 14 days. A reason and the plan for infusion should be communicated so that the donor can be informed correctly.
• If the transplant center wants to cryopreserve the lymphocytes for longer than 14 days before administering the first dose, the cryopreservation of MNC products is also subject to approval by DKMS and the donor.
• If an infusion seems very unlikely, the transplant center should consider postponing the MNC Apheresis.
• DKMS will follow-up with the transplant center some days after the planned date of the first infusion and inform the donor accordingly. Any changes of plans or delays should be communicated by the transplant center actively and in a timely manner.

Unavailability of a Donor for One Product Type

For recipient safety, transplant centers can request approval for cryopreservation of the stem cell product if a donor is only available for one stem cell source (HSC Apheresis or HSC Bone Marrow).

• HSC Apheresis: If the donor is only available for HSC Apheresis, the transplant center can request approval to cryopreserve the stem cell product in case the donor is a poor mobilizer and no sufficient cell count can be collected. If the donor does not give his/her consent to a cryopreservation, the transplant center will be informed accordingly.
• HSC Bone Marrow: If the donor is only available for HSC Bone Marrow, cryopreservation of the product can also be approved. However, the expected cell counts have to meet the minimum requirement of TNC cells by the Transplant Center.
• Even in these cases, the transplant center must request approval for cryopreservation from DKMS. A scheduled transplantation date is a prerequisite for approval.

DKMS recommends to infuse cells fresh wherever possible and to have a backup plan for each transplantation (e.g. other donor or therapeutic cell source).

Additional Testing Requests by the Transplant Center

In some countries, transplant centers have to perform additional tests, which are not relevant for donor clearance in the donor’s country.

• Transplant centers have to inform DKMS of any additionally required tests in good time before the donor’s physical examination. DKMS checks if it is possible to perform the tests in the laboratory of the collection center and informs the transplant center about the additional costs.
• The transplant center then decides if they want to perform the additional test themselves out of the pre-collection samples or if they want DKMS to perform the test and agree to pay the additional costs.
• If DKMS performs the test, results are communicated together with the donor final clearance.

Maximum Amount of Blood to be drawn at Physical Examination (Pre-Collection Samples)

Pre-collection samples of donors are often requested as part of the workup request. Transplant centers can perform specific tests required before transplantation.

• Pre-collection samples are drawn at the time of physical examination (PE).
• The maximum amount of blood for pre-collection samples to be drawn at PE is 50 ml.
• Exceptions can be taken into consideration on a case-by-case basis.
• For NMDP requests, 35 ml cannot be exceeded as additional blood tubes have to be drawn for FDA-approved infectious disease marker testing.

Transplant Center Acceptance of Formally Ineligible Donors

If the physical examination reveals that donation bears no increased risk for the donor but the potential transmission of a condition or disease to the recipient as specified in the respective official guidelines of the donor’s country, such a donor may only be cleared after written acceptance by the transplant center.

Examples: travel history, sexual high-risk behavior, enzyme deficiency (G6PDH).

Donor Reservation after Donation

As subsequent donations for the same patient occur in about 10% of all our cases (HSC Apheresis or Bone Marrow: 2.8% and MNC Apheresis: 7.8%), donors are reserved for the patient for whom they donated.

• All DKMS donors are reserved for the patient for whom they have donated for a period of two years (starting from the first day of collection).
• Transplant centers can ask for a prolonged reservation in case they may consider a subsequent donation from the same donor in the near future.
• DKMS informs the transplant center within 5 years after the first transplantation if the donor will be no longer available for subsequent donations.