Introduction
Both the UK and USA guidelines for cord blood selection recommend three and four mismatches as suitable options for patients with high-risk leukemia and for treatment-resistant types of blood cancer. Some of the WMDA member organisations have implemented to run a routine cord search with up to four mismatches as a default. Therefore, WMDA is implementing this option as well in Search & Match Service.
At the moment, the Search & Match Service (with the Hap-E matching algorithm) is providing an extensive list of potential cord blood units, when a three and/or four mismatch search is performed. For search coordinators it is difficult to select the best possible potential stem cell source, when they perform a three and/or four mismatch search in the Search & Match Service today.
The match list presents all possible options. In order to help search coordinators to select the best potential stem cell source, WMDA will be implementing additional features to assist search coordinators, you can read the details below.
How to perform a three and/or four mismatch search for cord blood?
Three and four mismatch searches have been implemented for cord blood searches in Search & Match Service. This is a resource intensive service, therefore you first perform a two mismatch cord blood search before you start a three mismatch cord blood search:
- Step 1: run a two mismatch cord blood search, before you can start a three mismatch search
- Step 2: run a three mismatch cord blood search before you can start a four mismatch cord blood search
What is important to know about three and/or four mismatch searches?
In the legacy version of Search & Match Service, no overall match probabilities calculations for cord blood were done. The sorting was performed within the match class (i.e. 5/8. 4/8) based on the Total Nucleated Cell (TNC) or CD34+ cell counts (depending on what a search coordinator prefers). This has been implemented in the same way in the new version of Search & Match Service operating using the Hap-E matching algorithm.
In the new version of Search & Match Service the number of search results can be bigger, as the Hap-E matching algorithm returns more potential matched cord blood units. If you experience a high number of potential cord blood options, you can for example filter on the minimum TNC, minimum CD34+ or by selecting certain registries or mismatch locations.
How is sorting done of three and/or four mismatch searches?
Three and/or four mismatch cord blood search results do not have any match probabilities calculated, the results are currently sorted within their match class (e.g. 5/8, 4/8) only by TNC or CD34+. The Hap-E matching algorithm returns more potential cord blood units than the legacy Search & Match Service. Many of these “extra” cord blood units tend to be low probability options to be selected for a patient in need of a transplant, because these cord blood units have low HLA resolution typing or missing allele typing.
This means that a poorly matched cord blood units with high cell dose are at the top of the match list and potentially better cord blood units with a high enough cell dose are lower. For a search coordinator, it is harder to identify the best possible cord blood, because of the increased number of valid potential matches.
In an effort to improve the search coordinator's experience when performing three and/or four mismatch cord blood searches, WMDA is currently developing several features that should improve the efficiency of finding suitable cord blood unit. These are:
- Filter for returning only donors/cord blood with typing at C (and/or DQB1). Scheduled for delivery December 2022.
- Filter on match class - a search coordinator can go directly to the 5/8 or 4/8 potential matches. Scheduled for delivery December 2022.
- "Score" based sorting for three and/or four mismatch cord blood results (find details below). Scheduled for delivery December 2022.
- Match probability calculation for three and/or four mismatches (find details below). Scheduled for delivery Q1 2023.
"Score" based sorting for three and/or four mismatch cord blood results (see option 3 in above paragraph) - interim solution
It is generally true that the better HLA-typed a stem cell source (donor/cord blood) is, the higher the probability of a potential match. As WMDA is currently not able to provide match probabilities on cord blood searches, WMDA will be implementing an interim score based approach. Find below the explanation:
- Assign a score based on the typed loci and the resolution of the cord blood unit
- Each locus can have one of the following “resolutions”
- High resolution typing (only one ARD)
- Low or intermediate typing
- No typing
- Each resolution class per locus has a “score”.
- High resolution typing = 20
- Low or intermediate typing = 17
- No typing = 0
- WMDA will sort cord blood units based on the sum of the score first and only then by TNC/CD34+
- n/6: sum of score at A, B, DRB1
- n/8: sum of score at A, B, C, DRB1
- n/10: sum of score at A, B, C, DRB1 and DQB1
- Sorting for 0, 1 and 2 mismatches remains unchanged
Because of the way the scores are assigned per locus, a cord blood unit with typing at C when doing an n/8 search will always be ranked higher than a cord blood unit with high resolution typing at 3 loci and no typing at C.
Below you can find some examples.
Match probability calculation for three and/or four mismatches (see in paragraph above option 4) - long-term solution
WMDA aims to implement calculation of actual match probabilities, because this would provide a better way of ranking than score-based ranking (described in the paragraph above). It will require a lot of work to develop this feature, as it will impact core elements of the Hap-E matching algorithm. This therefore needs to be done with great care and will be thoroughly tested in order to make sure no part of the Hap-E matching algorithm is accidentally broken as a result of the added functionality.