14-Unrelated Stem Cell Donation- Ensuring Product Quality and Donor Safety_Dr. Veena Shenoy.pdf

Unrelated stem cell donation

1. Unrelated stem cell donation:
Ensuring product quality
and donor safety
Dr Veena Shenoy
Additional professor
Transfusion medicine
Amrita Institute of medical sciences Kochi
11.07.24

2. Overview
Unrelated stem cell donor apheresis
•Need
•Process of stem cell collection
Strategies to ensure
•Donor safety & satisfaction
•Steps to enhance Product Quality
•Logistic & ethical concerns

3. Introduction
•Hematopoietic stem cell transplantation (HSCT) is a curative therapy for many
malignant and nonmalignant hematological disorders
•In India, over 19000 transplants have been performed for various indications by
more than 95 centers
•Cytokine-mobilized PBSC collection preferred over Bone marrow for obtaining
allogeneic hematopoietic cell grafts
•For successful HSCT, the donor and recipient should have optimal HLA matching

4. Need for unrelated stem cell donors
•HLA matched sibling donor available20 –30%
•Matched close relatives5-10%
•Fully matched related family donor
not available60-70%

5. History

1974
•Anthony Nolan Bone Marrow Registry,1974
•First registry in the world
1979
•(NMDP)/Be The Match(National Marrow
Donor Program)
•Currently 6200 transplants per year
1988
•Bone marrow donors worldwide (BMDW),
Netherlands
•30 million donors and over 720,000 cord
blood units
Anthony Nolan, who suffered from Wiskott-Aldrich Syndrome
with Mother Shirley Nolan.

6. Global number of available unrelated donors
Report on 2020 unrelated hematopoietic stem cell transplants, WMDA

7. Global number of HSC products provided
Report on 2020 unrelated hematopoietic stem cell transplants, WMDA

8. Indian scenario
•Donors in Indian registries were only 33,678 in 2014
•Probability of finding an HLA match for an Indian patient
•from global registry: 16%
•from Indian registries 0.008%
•Presently Available unrelated donors : 0.35 million
•Large patient population & ethnic diversity cause difficulty in
finding an HLA-matched donor in India
A.K. Tiwari, et al., Probability of finding marrow unrelated donor (MUD) for an Indian patient in a multi-national human leukocyte antigen (HLA) Registry, IndianJ. Hematol. Blood Transf. 31 (2) (2015) 186–195
Tiwari AK, Mishra VC, Tiwari A, Dorwal P, Gupta K, Chandra D, Raina V. Matched unrelated donor hematopoietic progenitor cell transplantation: a report based on a single registry in India. Leukemia Research Reports. 2019 Jan
1;11:17-20.

9. Indian registries with WMDA membership
Organization Type
1 Datri blood stem cell donors
registry,Chennai,2009
DONOR
REGISTRY
2 DKMS BMST Foundation India“
3 Gene bandhu New delhi “
4 Marrow donor registry
Mumbai
“
5 The Arjan Vir foundation “
6 Stemcyte India Therapeutics
Pvt Ltd
Cord
blood
bank
7 Jeevan stem cell foundation,
Chennai
CBB

10. Unrelated donor program
Donor
registries
Donor
Transplant
centres
Apheresis
centres

11. Donor recruitment
•Awareness campaign at various institutions
•Recruitment drives at various institutions
•Sample collection
•Donors typed using high-resolution typing for HLA-A, B, and C; DRB1; & DQB1
•The HLA typing results uploaded to the software

12. Pretransplant matching request from transplant physician
Patient's HLA type entered in software to initiate a “Donor search.”
Best matched donor (10/10 HLA match )
Transplant physician informed
Registry counsels the donor
MUD DONOR SEARCH REQUEST PROCESS

13. Process of unrelated stem cell collection
Donor
counselling
Medical
examination
Sample
testing
HLA,IDM,NAT
Final
clearance
Counselling
& informed
consent for
procedure
Mobilization
& stem cell
apheresis
Donor follow
up

14. Donor counselling –
Safety Aspects
•Anonymity of the donor and patient
•Donation not being remunerated
•Requirement for further blood samples before donation
•Implications of transmission of infectious
from donor to patient
•Procedure and risks of donation
•Possible loss of time from normal activities
•Location of the collection
•Right to withdraw and consequences of this for the
patient
•Possible subsequent donations of
hematopoietic stem cells (HSC) or blood
products
•Alternative collection methods
•Insurance coverage: Expenses, disability,death
benefits
•Appropriately documented and retained

15. Medical examination &Investigations
•Investigations
CBC P.Smea
r
FerritinLFT,RFT LDH Uric AcidHb
electroph
oresis
Na,K,
Calcium
Vit D, Vit
B12
HbsAgIgM Hb
Core
Anti HCV
Antibodies
HIV 1 & 2
Antibodies
NAT
HIV,HBV,
HCV
RPR
Syphilis
Malaria
Antigen
HTLV I & II
Antibodies
CMV
IgG&IgM
ECG ECHOTMT USG
abdomen
Chest
Xray
PT/INR,
APTT
Medical examination by Apheresis centre physician,Cardiac , ENT evaluation, Pregnancy test

16. Objectives of a successful unrelated donor
program
•Improving the safety & Satisfaction of volunteer Unrelated donors during
donation
•Maintaining high standards for HPC product
Product
quality
Donor
safety
Donor
satisfaction
Standards of the World Marrow Donor Association (WMDA) 2020

17. Donor safety
Mobilization : GCSF 5-10 µg/Kg for 5 days
Donors to be advised to look for adverse effects of GCSF

19. Adverse effects of Mobilization
Pulsipher etal.Blood 2009

20. Hematological parameters in donors
•After mobilization
•WBC Increase: Neutrophils (8.28 x baseline) ,lymphocytes
(2.28 x baseline) & monocytes (10.08 x baseline)
•Platelet counts & hemoglobin levels ↓
•By 1 month, mean WBC, platelets, and hemoglobin recovered
to near-normal levels

21. Ensuring donor safety in
leukapheresis

22. Donor safety : Rate of central venous catheter placement
•CVC placed if blood flow from standard peripheral venous line is not adequate
NMDP data,Minneapolis,Minnesota
Rate of line placement: Females 18-24% ;Males 2-
5%
One day : Internal jugular= femoral (M & F)
Two day collection : internal jugular and subclavian vein
more than FC
Anatomic location of central lines Frequency of male & female donors receiving Central lines

23. Steps to donor comfort & satisfaction:
(Institutional experience)
•Steps taken to reduce femoral venous catheter Insertions
•Introduced mini midline catheter in difficult peripheral veins
•16-18G Mini midline catheter(15 cm) put under ultrasound guidance

24. Advantages of mini midline catheter usage
Femoral CatheterisationMini Midline catheter Remarks
More absence from
work/studies
Less absence from
work/studies
3 days admission vs One day
Outpatient procedure
.Hospital could save 60 bed
days
More Hospital stay Less Hospital stay
Expensive cheaper
Movement restricted Better comfort/Mobility of
arm during procedure
More Risk associated with
procedure
Less Risk

25. Short term side effects of leukapheresis
HOLIG et al, BLOOD, 2009

Females experiencing more apheresis related AEs
(20% vs 7%, P < .001)

26. Strategies : Safety & Satisfaction
Leukapheresis
•Comfortable & clean premises
•Entertainment: Music/TV
•Light refreshments during long procedure
•Calcium supplementation to prevent hypocalcaemia due to citrate
toxicity
•Restricting procedure duration to 4 hrs / 2-3 TBV to process
•Less donor exhaustion
•Volume to be processed adjusted based on Pre CD34 count & mid
procedure Product CBC
•Post procedure instructions: avoid risk for abdominal trauma
during GCSF Inj & for 1 week

27. Vitamin D /Calcium supplementation prior to
procedure
•Vitamin D, Calcium levels are checked and supplemented ,if
necessary.
•Vitamin D levels was low in donors with low peripheral CD34(+)
count (<20 cells/ μL) [13.5 μg/L vs 17 μg/L; p = 0.035]
•Vitamin D replacement before mobilization will be an easy, safe
approach to improve mobilization success.
THE IMPACT OF VITAMIN D LEVELS ON PERIPHERAL STEM CELL MOBILIZATION IN ALLOGENEIC HEMATOPOIETIC STEM CELL DONORS
Hocaoğlu, E.
1
; Yegin, Z. A.
2
; Can, F.
2
; Özkurt, Z. N.
2
; Yağcı, M.
2
,Gazi University School of Medicine, Ankara, Turkey

28. Long term complications

29. •Incidence of cancers(1.07%) Vs expected rates: No evidence of increased
cancer risk in the donor cohort.
•No cases of acute myelogenous leukemia or myelodysplasia were reported
•Median follow-up, 49 months in 2408 Unrelated donors
Reported malignancies in unrelated donors (1999-2004)NMDP
Pulsipher etal.Blood 2009

30. Is there increased risk of hematological
malignancy in mobilized donors
•0.3% (n=12) unrelated donors developed malignant diseases
•Hematologic malignancies (2 Hodgkin disease, 1 CLL, and 1 AML): 4
•No significant difference compared with age-adjusted populations. (HOLIG
et al ,Blood 2009)
•NMDP: Follow-up data of 4015 donors for >1 (9785 donor-years) with no
cases of leukemia or lymphoma.

31. Donor follow up
•Post procedure follow up
•After first week of donation, at 1-month post donation (or until resolution of
all symptoms ), at 1 year and thereafter annually for up to 10 years
•Policy for recognition & action plans for severe adverse events

32. Product quality

33. Enhancing the quality of processes
•Setting Key performance indicators
•Rate of donor adverse reactions during leukapheresis
•Rate of femoral catheterisation
•Product yield
•Collection efficiency
•Evaluation of KPIs
•If shortfalls are identified, Corrective action taken
•Audits of donor collections
•Equipment maintenance

34. C. D. Bolan et al. Donation Activities and Product Integrity in Unrelated Donor Allogeneic
Hematopoietic Transplantation:Experience of the National Marrow Donor Program, Biology
of Blood and Marrow Transplantation 2008
Parameters StandardsFrequency (in
26,878 products)
Observation
1Microbiological culture Sterile 145 BM + 29
PBSC
Staphylococcus,
propionobacteria,diphtheroi
ds, coryne bacteria etc
2Product clotting Nil 5 PBSC +5
BM
Clots in bag
3Compromised product
bags
Nil 3 PBSC+4
BM
Bag leak, breakage
4Nonstandard product
transport
Temperature
2-6 degrees
& Avoid
airport Xray
10 PBSC +4
BM
Incorrect transport
Product quality

35. Trained personnel
•Sufficient number of trained personnel
•Staff should maintain anonymity of the donors and transplant patients

36. Accreditation
•WMDA accreditation programme based on the WMDA International
Standards for Unrelated Hematopoietic StemCell Donor Registries.
•Compliance ensures
•high stem cell product quality
•high standards for safety and satisfaction of voluntary unrelated
stem cell donors

37. Subsequent donations
•Two donations (whether to same or different recipient)
•Third or subsequent donation : As per policy of registry on an individual
basis.
•After first donation, donor unavailable for other recipients for 1-2 yrs
•Later,2 or more donations for second recipient can be done
•Interval between HPC donations : 4 weeks
DL Confer et al, WMDA guidelines for subsequent donations following initial BM or PBSCs, Bone Marrow Transplantation
(2011)

38. Subsequent donations
•Only one Lymphocyte donation for a recipient
•Second Lymphocyte donation to the same recipient
•Dependent on individual registry policy
•At the discretion of the Medical Director
•Minimum interval between two Lymphocyte donation is 1-3 months
•Registries should encourage transplant centres to cryopreserve aliquots of the
surplus cells
DL Confer et al, Bone Marrow Transplantation (2011)

39. Concerns of Matched Unrelated Donor
Transplant
•More expensive
•Longer TATs: Preliminary search, formal search ,harvest, and infusion.
•Various stakeholders involved :Transplant centre, registry, and
apheresis centre
•Volunteer donor may not be immediately available for harvest.
•Donor attrition

40. Challenges
•Donor centers :
•Unrelated donor eligibility issues
•Unusual transplant centre requests
•Complications during the stem cell collection process.
•Donor registries :
•60% potential donors back out after finding a match
•Donor & Family should be counselled about the whole process

41. Donor concerns
C. D. Bolan et al. Biology of Blood and Marrow Transplantation 14:23-28 (2008)
Donor activityFrequency Reason
Requirement for
multiple donations
3.4% (More than
one donation)
82% for DLI
Relapse/Graft failure
Product collected ,
not infused
0.5% Worsening of clinical condition of the
patient
GCSF Injection
received ,but
product not
collected
0.7% Worsening of clinical condition of the
patient

42. Ethical concerns
•Cryopreserved product received at transplant centre before conditioning
•Cryopreservation for All Is No Option in Unrelated Stem Cell Transplantation.
•DKMS Registry : 71% cryopreserved in 2020 Vs 4.7% in 2019
•Cryopreservation for all will increase non transfusion
•Non transfusion of cryopreserved product :ethical concern from donor perspective
A.H. Schmidt et al. / Biol Blood Marrow Transplant 26 (2020)

43. Spread Awareness about stem cell donation
•To raise awareness on
importance of registering as
stem cell donor
•To raise awareness on impact
of stem cell transplantation
in patient’s life
•To honour voluntary stem
cell donors
September 21

44. Conclusion and summary
•Availability of unrelated donors have increased over years
•It is essential to ensure donor safety and improve donor satisfaction for
successful unrelated donor program
•Donors should be well informed about processes & risks so as to assist
them with their choice to become a donor.
•Key performance indicators to be monitored, audits of donor centres to be
done to enhance quality of processes

45. REFERENCES
•C. D. Bolan et al. Donation Activities and Product Integrity in Unrelated Donor Allogeneic Hematopoietic
Transplantation:Experience of the National Marrow Donor Program, Biology of Blood and Marrow Transplantation 14:23-
28 (2008)
•Dholaria B, Al Malki MM, Artz A, Savani BN. Securing the graft during pandemic: are we ready for cryopreservation for all?.
Biology of Blood and Marrow Transplantation. 2020 Jul 1;26(7):e145-6.
•Weber M, Sacchi N, Haun S, Tistl I, Thompson S, Sengomona H, Ahmed SM, Kürsteiner O, Schwarz C, Wuchter J. Audit of
donor centre: guidelines by the World Marrow Donor Association Quality and Regulation Working Group. Bone Marrow
Transplantation. 2022 Mar;57(3):466-72.
•Pulsipher MA, Chitphakdithai P, Logan BR, Shaw BE, Wingard JR, Lazarus HM, Waller EK, Seftel M, Stroncek DF, Lopez AM,
Maharaj D. Acute toxicities of unrelated bone marrow versus peripheral blood stem cell donation: results of a prospective
trial from the National Marrow Donor Program. Blood, The Journal of the American Society of Hematology. 2013 Jan
3;121(1):197-206.
•WORLD MARROW DONOR ASSOCIATION international standards unrelated hematopoietic stem cell donor registries,2020
•A.K. Tiwari, et al., Probability of finding marrow unrelated donor (MUD) for an Indian patient in a multi-national human
leukocyte antigen (HLA) Registry, IndianJ. Hematol. Blood Transf. 31 (2) (2015) 186–195
•Tiwari AK, Mishra VC, Tiwari A, Dorwal P, Gupta K, Chandra D, Raina V. Matched unrelated donor hematopoietic progenitor
cell transplantation: a report based on a single registry in India. Leukemia Research Reports. 2019 Jan 1;11:17-20.

46. Thank you