ESH-EBMT Training CourSE on Blood and Marrow TranSplanTaTion

BSBMT NEWS
British Society of Blood and Marrow Transplantation
Issue Number 11 - May 2012
ESH-EBMT Training Course
on Blood and Marrow
Transplantation
Alexander Nevsky Cathedral, Sofia.
Left to right - Marcus Frew, Ida Taisbak, Mohammed
Mohty, Tony Pagliuca, Victor Noriega, Shani Solanki, Justin
Loake, Cliff Chaplin, Vishnu Banumukala, Vikram Singh,
Anjum Khan, Adeel Saleem and (front) Dobrin
INSIDE...
Successful allogeneic transplantation depends upon recruitment of a pool
of donors and the knowledge to use those donors wisely. We applaud the
students in the UK who are making a huge commitment to donor recruitment
via the charity MARROW. In addition John Harvey, John Moppett and
Bronwen Shaw explore the limits of HLA tissue matching while a new series,
Nolan Notes, highlights a milestone in cord banking. Clinical delivery of
transplantation depends upon skilled up-to-date clinical teams and we have
reports from the recent EBMT ESH training course as well as the EBMT
Nurses Study Day. Ongoing progress in our speciality is founded on the
basic science emerging from academic centres of excellence and we focus
on the work of Heather Jorgensen and
Tessa Holyoake. Graham Jackson
discusses future developments for the
BSBMT community in his regular column
while Andy Chantry shares some extracurricular experiences.
Maria H Gilleece
Maria.Gilleece@leedsth.nhs.uk
In April 2012, the 16th annual ESHEBMT Training Course on Blood and
Marrow Transplantation was held in
Sofia, Bulgaria, organised by
Dr. Dobrin Konstantinov of the city’s
Childrens’ Onco-haematology Hospital
(SCOH). The programme addressed
a broad range of topics relevant to
the modern practice of bone marrow
transplantation, particularly the
principles underlying transplantation
and the range of potential
complications. It was a great course
for a trainee and was well attended
with over 100 delegates, providing lots
of opportunities to discuss practice
across Europe.
Details of future courses will be available
on the EBMT and ESH websites.
Vishnu Banumukala
Vishnu.Banumukala@leedsth.nhs.uk
Resolution matters
High resolution HLA matching in bone marrow transplantation for paediatric ALL.
John Harvey, Histocompatibility and Immunogenetics Laboratory, NHS Blood and Transplant, Filton, Bristol
and John Moppett, Paediatric Bone Marrow Transplant Unit, Bristol Royal Hospital for Children, Bristol.
Strong evidence for significantly improved transplant
outcome in unrelated donor haemopoietic progenitor
cell transplants by matching for Human Leukocyte
Antigens (HLA) using high resolution typing between
patient and donor has been published over recent
years (1-8). From these retrospective studies the
National Marrow Donor Program (NMDP, USA) issued
HLA matching guidelines of best practice for matched
unrelated donor (MUD) progenitor cell transplants in
adults (9;10). The core component of the NMDP
guidelines for optimal transplant outcome requires a
high resolution HLA-A, B, C and DRB1 loci matched
unrelated donor to be used where a HLA matched
sibling is not available. The NMDP did not offer donor
selection guidelines for paediatrics.
Figure 1. There was an approximately 25% improvement in survival
for matched unrelated transplants performed after 2002 following
the introduction of high resolution typing at class I and II.
In a recent publication,(11) we presented the first detailed
prospective study analysing overall survival (OS) in bone
marrow transplantation for paediatric ALL after the
introduction of high resolution HLA matching. The
transplants were analysed over five HLA typing epochs
delineated by changes in HLA typing methodology. 356
consecutive paediatric ALL stem cell transplants performed
between 1988 and 2007 were reviewed; 79 of these
transplants were performed after the introduction of high
resolution (HR) HLA class I and class II matching to the
transplant programme in January 2002.
Comparisons of matched unrelated donor (MUD) transplant
outcomes before and after this period were made. The
study shows (Figure 1) matching at the HR level for HLA-A,B,-C,-DRB1 and -DQB1 correlates with a greater than 25%
improvement in two and five year OS in paediatric ALL
patients transplanted with matched unrelated donors.
Comparisons with contemporaneous HLA matched sibling,
HLA mismatched unrelated donor found the HR-MUD
transplants had comparable five year OS (Figure 2) (88.2%)
to the HLA matched sibling transplants (86.7%).
Univariate and multivariate analysis was performed to look
for other factors that might explain these changes.
BSBMT NEWS Issue Number 11 - May 2012
Figure 2. Unlike the improvement seen in matched unrelated donor
BMT, the outcome for the mismatched unrelated donors has not
improved with the introduction of high resolution typing.
Continued on page 3
page 2
Continued from page 2
High risk leukaemias have a much higher relapse rate post
transplant. No change in the percentage of high risk cases
was observed for the differing epochs. However, some
reduction in relapse rates was observed across the whole
cohort, with a relapse rate of 16% since 2002 compared to
32% prior to that (Table 1). This explains the improved
survival observed in the matched sibling donor transplants
and contributes to the improvement seen in the unrelated
donor transplants.
Incidence of relapse categorised by epoch and
HLA match group
1988-2001
2002-2007
MSD
17/54 (31%)
4/26 (15%)
MUD
47/134 (35%)
5/33 (15%)
MMUD
22/75 (29%)
3/16 (20%)
Overall
86/263 (32%)
12/75 (16%)
Table 1. The reduction in relapse rate is due to better pre-transplant
chemotherapy. The relapse rate of 15% that we see is very similar to
that found in those patients who reach transplant from the recently
published UK relapse study R3 and is not unique to our institution.
However, competing risk analysis also showed a statistically
significant reduction in non-relapse mortality in the HRMUD transplants from an historical level of near 20% to 6%
(Figure 3) (11). There was no corresponding reduction in
NRM in the sibling or mismatched unrelated donor transplants.
In conclusion, we believe that our clinical experience of
using high resolution class I and II typing since 2002
References:
1. Petersdorf EW. HLA matching in allogeneic
stem cell transplantation. Curr.Opin.Hematol.
2004;11(6):386-91.
2. Petersdorf EW, Anasetti C, Martin PJ, Gooley
T, Radich J, Malkki M et al. Limits of HLA
mismatching in unrelated hematopoietic cell
transplantation. Blood 2004;104(9):2976-80.
3. Flomenberg N, Baxter-Lowe LA, Confer D,
Fernandez-Vina M, Filipovich A, Horowitz M
et al. Impact of HLA class I and class II
high-resolution matching on outcomes of
unrelated donor bone marrow transplantation:
HLA-C mismatching is associated with a strong
adverse effect on transplantation outcome.
Blood 2004;104(7):1923-30.
4. Lee SJ, Klein J, Haagenson M, Baxter-Lowe
LA, Confer DL, Eapen M et al. High-resolution
donor-recipient HLA matching contributes to
the success of unrelated donor marrow
transplantation. Blood 2007;110(13):4576-83.
Figure 3. The change in percentage of non-relapse mortality
observed is significantly reduced after 2002 for the HLA matched
unrelated transplants.
concurs with the NMDP retrospective data and does result
in significantly improved survival for high resolution fully
matched unrelated donor transplants. No improvement
were seen in less than fully matched transplants. The
outcome and clinical course of high resolution HLA
matched unrelated donor transplants is identical to
matched sibling transplants.
Class I and II high resolution typing is a cost-effective
intervention and should be routine for unrelated donor
transplants in the 21st century.
John Harvey John.Harvey@nhsbt.nhs.uk
John Moppett John.Moppett@UHBristol.nhs.uk
5. Petersdorf EW, Gooley T, Malkki M,
Horowitz M. Clinical significance of donorrecipient HLA matching on survival after
myeloablative hematopoietic cell
transplantation from unrelated donors.
Tissue Antigens 2007;69 Suppl 1:25-30.
9. Hurley CK, Baxter Lowe LA, Logan B,
Karanes C, Anasetti C, Weisdorf D et al.
National Marrow Donor Program HLAmatching guidelines for unrelated marrow
transplants. Biol.Blood Marrow Transplant.
2003;9(10):610-5.
6. Petersdorf E, Bardy P, Cambon-Thomsen A,
Goulmy E, Hansen J, Schwarer A et al.
14thInternational HLA and Immunogenetics
Workshop: report on hematopoietic cell
transplantation. Tissue Antigens 2007;69
Suppl 1:17-24.
10. Bray RA, Hurley CK, Kamani NR, Woolfrey A,
Muller C, Spellman S et al. National marrow
donor program HLA matching guidelines for
unrelated adult donor hematopoietic cell
transplants. Biol.Blood Marrow Transplant.
2008;14(9 Suppl):45-53.
7. Petersdorf EW. Optimal HLA matching in
hematopoietic cell transplantation. Curr.Opin.
Immunol. 2008;20(5):588-93.
11. Harvey J, Green A, Cornish J, Steward CG,
Cummins M, Keen L et al. Improved survival in
matched unrelated donor transplant for
childhood ALL since the introduction of
high-resolution matching at HLA class I and II.
Bone Marrow Transplant. 2012
(Transplantation advance online
publication, 20 February 2012;
doi:10.1038/bmt.2012.8.).
8. Macmillan ML, Davies SM, Nelson GO,
Chitphakdithai P, Confer DL, King RJ et al.
Twenty years of unrelated donor bone marrow
transplantation for pediatric acute leukemia
facilitated by the National Marrow Donor
Program. Biol.Blood Marrow Transplant.
2008;14(9 Suppl):16-22.
BSBMT NEWS Issue Number 11 - May 2012
page 3
Tessa L Holyoake
LAB
FOCUS
Heather G Jørgensen
Tessa L Holyoake
Born and educated in Scotland
PhD at the University of Glasgow
Post-doc position in Terry Fox
Laboratories, Vancouver, Canada
Group leader in Academic
Transfusion Medicine Unit,
Glasgow
Chair of Experimental
Haematology at University of
Glasgow since 2004
As a Centre, we are interested in
normal versus leukaemic stem
cells, specifically the mechanisms
that regulate the stem cell fate
decisions as well as how stem cells
evade cytotoxic chemotherapies
thus precluding disease cure.
Our research is truly translational
informing several clinical trial
designs over the years. We do not
exist in isolation but have strong
collaborative links locally and
worldwide with specialist
laboratories including University
of Manchester, City of Hope
University of California Los Angeles,
and Terry Fox Laboratories in
Vancouver. Our studies have been
made possible by research council
funding, industry support, national
leukaemia charity funding, local
patient trust funds as well as
on-going input from the Friends
of Paul O’Gorman Leukaemia
Research Centre in Glasgow.
Heather G Jørgensen:
Born and educated in Scotland
PhD at the University of
Strathclyde
Post-doc positions in Centre for
Cell Engineering and Academic
Transfusion Medicine Unit,
Glasgow
Research manager, deputy
group leader since 2005
With her medical training, Tessa has
always been interested in translational
research leading to improved patient
care. She pursued her interest in the
science behind medicine by completing
her PhD at the Beatson Institute for
Cancer Research in Glasgow. This
was the springboard to developing her
research group in haemato-oncology
at University of Glasgow.
BSBMT NEWS Issue Number 11 - May 2012
More or less simultaneously at
the time Tessa was returning to
Glasgow from two years postdoctoral research at the British
Columbia Cancer Centre in
Vancouver under the tutelage of
Prof Connie Eaves, the molecularly
targeted tyrosine kinase inhibitor,
imatinib was coming through
clinical trial. Tessa was lead clinician
for STI571 (as it was known then)
clinical trials in chronic myeloid
leukaemia (CML) in Scotland
alongside growing her reputation
for solid scientific research into
leukaemic stem cells (LSC).
It seems incredible looking back,
but it wasn’t a globally accepted
view that such ‘wonder drugs’
wouldn’t be so wonderful in terms
of cure unless they were targeted to
the right cell population, that is LSC
which formulate new and inventive
ways to subvert therapies designed
to kill them. So, for the last decade
or so, Tessa has headed her
interdisciplinary group using a
Systems Biology approach to
uncover novel targets for therapy
based on genes and pathways
critical for stem cell survival and
quiescence.
Continued on page 5
page 4
Continued from page 4
Heather has worked with Tessa
since 1999 on iterations of that
precise research focus
characterising quiescent LSC
and testing pipeline and clinical trial
investigational medicinal products
for efficacy against this key disease
sustaining cell population. With her
background in pharmaceutical
science, Heather has brought a
new dimension to the basic stem
cell research of the group, instigating
the subtheme of nanobiology
developing drug delivery methods
targeted at stem cells.
In 2001, following a citywide
laboratory review, it was decided
that oncology services should be
centralised at a new Beatson West
of Scotland Cancer Centre sited at
Gartnavel General Hospital in
Glasgow. Tessa had the vision to
begin planning for a purpose built
leukaemia research centre at
Gartnavel; it took many years of
fundraising until eventually the Paul
O’Gorman Leukaemia Research
Centre was opened by Dr Richard
Rockefeller in May 2008. The
Centre will soon have six research
groups investigating normal versus
leukaemic stem cells to understand
mechanisms that subvert normal
haemopoiesis and promote
leukaemia development as well as
ways in which to target LSC to
achieve disease eradication.
Programs currently underway
include research into:
•the control of cell division, self-
renewal and maintenance of
quiescence (Dr Mhairi Copland)
•using a Systems Biology
approach to uncover novel
targets for therapy based on
genes and pathways critical for
stem cell survival and quiescence
(Prof Tessa Holyoake)
•the transcriptional mechanisms
orchestrating normal and
leukaemic stem cell fate decisions
in vivo (Dr Kamil Kranc)
•the cellular and molecular
mechanisms that control normal
lymphoid and leukaemic cell
development (Dr Alison Michie)
•transcriptional and proteomic
changes involved in blood cell
commitment and how they are
altered by leukaemic oncogenes
(Dr Helen Wheadon)
The current active research projects in
Holyoake / Jørgensen lab are asking
multiple questions including are there
significant differences in the regulation
of survival for CML versus normal
haemopoietic stem cells (HSC) and
can these differences be exploited for
therapy? Our approach here is to
perform mRNA, microRNA and
proteomics profiling and a genome
wide epigenetic screen. We next will
ask what is the mechanism underlying
CML stem cell resistance to tyrosine
BSBMT NEWS Issue Number 11 - May 2012
kinase inhibitors (TKI)? We aim to
use our profiling data to identify
early and late factors or pathways
that mediate survival of LSC when
exposed to TKIs. When proliferating
versus quiescent stem cells were
compared, we found chemokine
ligands to be upregulated in
association with quiescence; so
we are now asking if chemokines
have a role in HSC quiescence?
Here, we are using knock-down
and chemical inhibitor as well as
over-expression approaches to
modulate chemokine expression to
examine the effect on cell-cycle in
vitro on human quiescent HSC.
We are investigating autophagy
induction by TKI as a survival
pathway and more importantly its
potential for inhibition in CML to
potentiate TKI-induced cell death.
We are proud to be a truly
international Centre with students
and staff hailing from as far flung
places as India and Iceland with
France, Spain, Germany, Italy,
Poland, Argentina and Canada
represented in between!
Continued on page 6
page 5
Continued from page 5
It’s not all work and no play; we’re
more than a laboratory, more like a
community sharing leisure time as
well as work time together.
Annually we enter a team into the
Cycle Glasgow challenge raising
money for our Centre (just some of
the Paul O’Gorman Pedallers are in
the picture, right); we have enjoyed
a fundraising Ladies’ Lunch (with
one or two men) hosted by Elaine
C Smith and her co-stars of the
stage production as well as the real
life characters who inspired the
phenomenon that is the Calendar
Girls (our ladies line-up in the
photo), to name but a few of our
group activities.
Heather Jørgensen
heather.jorgensen@glasgow.ac.uk
Tessa Holyoake
Tessa.Holyoake@glasgow.ac.uk
Some recent publications:
1. EK Allan, TL Holyoake, AR Craig and HG
Jørgensen (2011): Omacetaxine may have
a role in Chronic Myeloid Leukaemia
eradication through down-regulation of
Mcl-1 and induction of apoptosis in stem/
progenitor cells. Leukemia 25(6):985-94
2. F Pellicano, P Simara, A Sinclair,
GV Helgason, M Copland, S Grant,
TL Holyoake (2011): The MEK inhibitor
PD184352 enhances BMS-214662induced apoptosis in CD34+ CML stem/
progenitor cells. Leukemia. 25(7):
1159-67.
3. T Schmidt, B Kharabi Masouleh, S Loges,
S Cauwenberghs, P Fraisl, C Maes,
B Jonckx, K De Keersmaecker, M Kleppe,
M Tjwa, T Schenk, S Vinckier, R Fragoso,
M De Mol, K Beel, S Dias, C Verfaillie,
RE Clark, TH Brümmendorf ,
P Vandenberghe, S Rafii, T Holyoake,
A Hochhaus, J Cools, M Karin, G
Carmeliet, M Dewerchin, P Carmeliet
(2011): Loss or inhibition of stromal-derived
PlGF prolongs survival of mice with
imatinib-resistant Bcr-Abl1(+) leukemia.
Cancer Cell. 19(6):740-53.
4. S Balabanov, A Gontarewicz, G Keller,
L Raddrizzani, M Braig, R Bosotti, J Moll,
E Jost, C Barett, I Rohe, C Bokemeyer,
TL Holyoake, TH Brümmendorf (2011):
ABCG2 overexpression represents a novel
mechanism for acquired resistance to the
multi-kinase inhibitor danusertib in BCR-ABLpositive cells in vitro. PLoS One 6(4):e19164.
5. A Hamilton, GV Helgason, M Schemionek,
B Zhang, S Myssina, EK Allan, FE Nicolini,
C Müller-Tidow, R Bhatia, VG Brunton, S
Koschmieder and TL Holyoake (2011): Chronic
myeloid leukemia stem cells are not dependent
on Bcr-Abl kinase activity for their survival. Blood.
E-pub ahead of print
6. P Zhou, S Hatziieremia, MA Elliott, L Scobie,
C Crossan, AM Michie, TL Holyoake, GW
Halbert and HG Jørgensen (2010): Uptake of
Synthetic Low Density Lipoprotein by leukemic
stem cells – a potential stem cell targeted drug
delivery strategy. J Control Release 148(3):380-7.
7. F Pellicano, M Copland, HG Jørgensen,
J Mountford, B Leber and TL Holyoake (2009):
BMS-214662 induces mitochondrial apoptosis in
CML stem/progenitor cells, including CD34+38cells, through activation of protein kinase Cβ.
Blood 114(19):4186-4196.
8. C Bellodi, MR Lidonnici, A Hamilton,
GV Helgason, AR Soliera, M Ronchetti, S
Galavotti, KW Young, T Selmi, R Yacobi, RA Van
Etten, N Donato, A Hunter, D Dinsdale, E Tirrò,
P Vigneri, P Nicotera, MJ Dyer, T Holyoake,
P Salomoni, B Calabretta (2009): Targeting
autophagy potentiates tyrosine kinase inhibitor-
BSBMT NEWS Issue Number 11 - May 2012
induced cell death in Philadelphia
chromosome-positive cells, including primary
CML stem cells. J Clin Invest. 119(5):
1109-23.
9. MW Drummond, N Heaney, J Kaeda,
FE Nicolini, RE Clark, G Wilson, P Shepherd,
J Tighe, L McLintock, T Hughes, TL
Holyoake (2009): A pilot study of continuous
imatinib vs pulsed imatinib with or without
G-CSF in CML patients who have achieved a
complete cytogenetic response. Leukemia
23(6):1199-201.
10. HG Jørgensen, EK Allan, NE Jordanides,
JC Mountford, TL Holyoake (2007): Nilotinib
exerts equipotent antiproliferative effects to
imatinib and does not induce apoptosis in
CD34+ CML cells. Blood 109(9):4016-9.
11. HG Jørgensen, E.K. Allan, S.M. Graham,
J. Godden, L. Richmond, M.A. Elliott,
J.C. Mountford, C.J. Eaves, and T.L.
Holyoake (2005): Lonafarnib reduces the
resistance of primitive quiescent CML cells to
imatinib mesylate in vitro. Leukemia 19:
1184-1191.
12. S Graham, HG Jørgensen, E. Allan,
C Pearson, M Alcorn, L Richmond,
T Holyoake (2002): Primitive, quiescent,
Philadelphia-positive stem cells from patients
with chronic myeloid leukemia are insensitive
to STI571 in vitro. Blood 99(1): 319-325.
page 6
Permission to mismatch
Effect of T-cell-epitope matching at HLA-DPB1 in recipients of unrelateddonor haemopoietic-cell transplantation: a retrospective study.
The current gold standard
unrelated donor is one matched
at high resolution for HLA-A,-B,-C,DRB1 (+/- -DQB1) (10/10). HLADPB1 is at least as polymorphic as
HLA-DQB1 and has been shown in
numerous studies to result in
allogenicity in much the same way
as other HLA molecules. Despite
this, DPB1 has not been routinely
included in donor selection
algorithms due, in part, to the
difficultly in matching for this
locus. In addition, most clinical
results are based on the impact of
allele level matching, showing no
increase in overall survival except
in specific subgroups of patients.
In this recent study, published in the
Lancet Oncology, Shaw and
Fleischhauer et al, have considered
the impact of HLA-DPB1 matching
between patient and donor in a novel
way – taking both allele-level and
epitope-level matching into account in
the same analysis. Their results show
a survival detriment for patients with
donors with a non-permissive
mismatch, compared to those with a
permissive mismatch or an allele level
match. Since approximately only 30%
of donors will have non-permissive
mismatches, it is possible to avoid
these, while in 70% of patients adding
a survival advantage over and above
the use of a 10/10 matched donor.
This study used a novel model for
grouping HLA-DPB1 alleles based on
functional studies previously published
by Fleischhauer et al. In brief, in a
laboratory system, T cells alloreactive
to the donor’s HLA-DPB1*09:01 were
isolated from a patient who rejected
their 9/10 matched transplant and
tested for crossreactivity against the
most common HLA-DPB1 alleles.
On the basis of these functional
experiments, DPB1 alleles could be
classified into three groups predicted
to have a high, intermediate, or low
immunogenic potential at a T cell
epitope (TCE) level. Those with low
immunogenicity are predicted to be
‘permissive’ mismatches i.e. resulting
in no adverse clinical outcome, while
those with intermediate or high
immunogenicity are predicted to be
‘non - permissive’ mismatches i.e.
resulting in an adverse clinical
outcome.
The study set consisted of 8539 UD
transplants submitted to the
International Histocompatibility
Working Group in HCT (a large
collaborative project). Recipients and
UDs were classified as HLA-DPB1matched (20.1%), HLA-DPB1mismatched and TCE-mismatched
(non-permissive; 31.3%), or HLADPB1-mismatched but TCE-matched
(permissive; 48.6%).
In HLA 10/10-matched transplants
(n=5428), non-permissive HLA-DPB1
mismatches were associated with
statistically significantly increased
hazards of overall mortality (HR 1·15;
95% CI 1·05-1·25; p=0.002), nonrelapse mortality (HR 1·28; 95% CI
1·15-1·43; p<0.001) and severe acute
graft-versus-host-disease (OR 1·31;
95% CI 1·11-1·54; p=0.001),
compared to permissive mismatches.
There were no differences in survival
between those with permissive
mismatches and those who were
HLA-DPB1 allele matched.
BSBMT NEWS Issue Number 11 - May 2012
The significantly increased relapse risk
which was previously reported to be
associated with DPB1 allele level
matching, was also noted here (HR
1·34; 95% CI 1·17-1·54; p<0.001).
Interestingly, there was no significant
difference between the permissive
and non-permissive TCE mismatched
pairs in relapse risk (HR=0·89; 95%
0·77-1·02; p=0·10).
In many cases no 10/10 matched
donor can be found and transplant
physicians are often faced with a
choice of several 9/10 matched
donors. The authors were interested
in testing their model in this setting,
in order to understand if survival could
be improved in the 9/10 matched
setting too. Once again they were able
to show a survival advantage in
avoiding non-permissive mismatches
(OS: HR 1·10; 95% CI 1·00-1·22;
p=0.06; NRM: HR 1·19; 95% CI
1·05-1·36; p=0.007 and severe
aGvHD: OR 1·37; 95% CI 1·13-1·66;
p=0.002).
In conclusion, the authors suggest that
pre-transplant HLA-DPB1 typing may
be useful for patients and donors
where there is a choice between more
than one equally HLA matched donor.
In 70% of cases either an allele match
or DPB1 permissive mismatch can be
selected, thus improving the outcome
for patients.
Bronwen Shaw
bshaw@doctors.org.uk
Fleischhauer K et al. Effect of T-cell-epitope
matching at HLA-DPB1 in recipients of unrelateddonor haemopoietic-cell transplantation: a
retrospective study. Lancet Oncology 2012
page 7
anthony NOLAN NOTES
Cord blood bank gives
first lifeline
Jess Ridout, Ellen Marshall and Guy Parkes
In March 2012, Anthony Nolan announced that it
had issued its first two units from its cord blood
bank, with three more reserved for patients in the
UK and the USA – proof that the blood cancer
charity’s investment in cord blood is starting to
pay off.
Mary and Ivan donated baby Nancy’s cord blood at King’s
College Hospital in 2011 (Photograph: Alex Griffiths)
Guy Parkes, head of the cord blood project at Anthony
Nolan, says, “Although the scheme has been running
since 2008, we always knew that we would have to
reach a critical mass of units banked before we started
seeing the benefits. We’ve now banked nearly 1,000
cords for clinical use, and we’ve finally reached the
stage where transplant centres are choosing our cord
blood units for transplant. The fact that five of our cords
have been issued or reserved in the last few weeks is
also validation of our policy to only bank the highest
quality cord blood units.”
On 23rd February, Anthony Nolan co-hosted the
‘Symposium on Alternative Donor Transplantation:
The State of the Art’ which covered significant areas of
interest in unrelated, cord and haploidentical transplant
(more details with speaker slides on the BSBMT
website). The data that were presented both by UK
and international speakers reinforced Anthony Nolan’s
policy of pursuing quality as a central theme in their
cord blood banking. The symposium also confirmed
the importance of cord blood transplants in the
treatment of blood cancer and other blood disorders,
particularly in children.
Jo, 41, cord transplant recipient (Photograph: Alex Griffiths)
BSBMT NEWS Issue Number 11 - May 2012
Anthony Nolan’s cord blood strategy focuses on
building a supply of cord blood units to match the
unmet need from the UK and overseas. The charity
aims to reduce the UK’s reliance on cord blood units
imported from overseas and, in the process, reduce
costs to the NHS.
Continued on page 9
page 8
Continued from page 8
Their approach to cord blood banking is based on
four criteria:
Security
•Extensive range IDM virology assays including NAT
testing on HBV, HCV, HIV and HTLV
•Bacteriology assays for aerobic and anaerobic
bacteria and fungi presence to ensure sterility
•Haemoglobinopathy screening
•Strict donor eligibility criteria and screening
Identity
•High resolution HLA Typing on HLA-A,-B,-C, -DRB3,
-DRB4, -DRB5 and -DQB1 loci and allelic level
typing on DRB1
•Confirmatory typing from an attached segment from
CBU and maternal haplotype matching with CBU.
Cord tissue sample also available for DNA testing.
Purity
•The pre-processing threshold for clinically suitable
units is increasing to 1400 x 106 Total Nucleated
Cells (TNC)*
•The threshold for CD34
pre-processing for
clinically suitable units is increasing to 3.2 x 106 *
+
Potency
•Colony Forming Unit assay to confirm CD34
+
potency, ClonE > 10% prior to cryopreservation
Austin, 4, cord transplant recipient (Photograph: Alex Griffiths)
•Viability protocols 7AAD and Annexin V
*current thresholds TNC 1200 x 106 & 1.9 x 106 CD34+
will increase with effect from June 2012
Anthony Nolan is continuing to expand its cord blood
scheme by opening a new collection centre at
Birmingham Women’s Hospital in May. This will be the
fifth collection centre run by Anthony Nolan, with others
at King’s College Hospital, Leicester Infirmary, Leicester
General and the Royal Free in Hampstead, which was
opened by Health Minister Anne Milton on 23rd
January 2012.
BSBMT NEWS Issue Number 11 - May 2012
page 9
EBMT Nurses Group & EBMT
Swiss Nurses Working
Group Study day
Beverly Horne
Who would have thought that
presenting a poster at the EBMT
(UK) Nursing & Allied Professionals
group 40th meeting in June last
year would have meant that I got to
visit Zurich in November? Well that
is exactly what happened and
here’s how ……..
I am a research nurse working for
Leeds University and we are running a
research study called ALLINEX
(ALLograft INformation EXchange),
funded by Macmillan Cancer Support
and working in collaboration with the
Blood and Marrow Transplant Service
at St. James’s University Hospital, Leeds.
Our aim is to evaluate an intervention
for follow up of survivors of allogeneic
Haemopoietic Stem Cell Transplant
(HSCT): using the internet as an
information exchange between
patients, carers and their clinical team.
In early 2011 we had analysed the
results from the first phase of the study
which looked at the patient’s
psychological issues and which
services they had accessed such as
social work, psychology, occupational
therapy etc. A poster abstract was
submitted and accepted and I duly
registered for the conference.
The conference itself was attended by
25 nurses and allied professionals
within the transplant speciality from
across the UK. It was not my first
EBMT conference and I have always
found them very friendly, well
organised and interesting and this was
no exception. Presentations covered
such topics as the future of unrelated
HSCT, GvHD, survivorship and using
patient feedback to improve practice.
The content was absorbing and
discussion afterwards was thought
provoking. My poster was well
received and was awarded the Poster
Prize of £100.
University Hospital, Zurich
A month after the conference, I was
even more amazed to receive an
e-mail from one of the EBMT (UK)
NAP committee to say that because of
my work on the poster they had
thought of me when approached by
the EBMT National Nurses Groups to
nominate a nurse to attend their study
day in Zurich in November 2011.
BSBMT NEWS Issue Number 11 - May 2012
So feeling like I had won the lottery
I headed off to Zurich to attend the
EBMT Nurses Group & EBMT Swiss
Nurses Working Group Study day.
There were about 180 international
delegates including nurses and
doctors. Presentations included:
•Update on treatment and
outcomes for CML by Professor
Olavarria, Spain, explaining that
CML is now mostly treated by oral
medication (Tyrosine Kinase
Inhibitors) and that BMT numbers
are falling but as a therapy it is still
used in certain circumstances.
•Adherence to oral tumour therapies
by S. Degen, nurse specialist from
Switzerland, who quoted from a
study performed in 2009 that only
1 in 7 patients are perfectly
compliant to their therapy.
•The role of stem cell transplantation
in the lymphomas by Professor
Schmitz, Germany who informed
us that the role of radiotherapy in
the treatment of lymphomas is
decreasing and that survival is
improving and close to 90%.
Antibody treatments have caused
improvements in survival and,
similar to CML, are causing the
numbers of transplants needed for
this group of patients to fall. HSCT
is still needed, however, for
relapsed patients where they will
get approximately 40% survival.
Continued on page 11
page 10
Continued from page 10
•HSCT for severe autoimmune
diseases by Professor Saccardi,
Italy and Professor Martin,
Switzerland. HSCT may result in
high risk of late effects which can
be exacerbated by problems from
original disease.
•
Study on ambulatory care reported
by Arnold Mank from the
Netherlands which looked at early
discharge in the aplastic phase
until bone marrow recovery.
Patients were very positive about
the ambulatory care but as can be
expected the psychological burden
on the carers was high. No life
threatening situation occurred but
60% needed re-admission for a
period of time, usually due to fever.
They are going to continue to look
at this, concentrating on fevers and
infections and also whether home
visits should be included in the
package of care.
•New trends in HSCT by Professor
Passweg, Switzerland who
informed the conference that
Germany, Holland and Belgium
perform the most HSCTs. Looking
at the EBMT activity survey in 2010
there were 238,026 allografts
performed between 1990 and
2010, with survival at 45% which
was influenced by co-morbidities.
Cord blood transplant is increasing
in Europe with France and Spain
doing the most cord blood
transplants. Professor Passweg
stated that cellular therapy, using
natural killer (NK) cells was the
future for HSCTs with less GvHD.
•Objective and practice of (not)
getting to know each other – a
panel debate about whether the
patient and donor should be
allowed to be in touch and the pros
and cons of allowing this.
•Late effects by K. Davis and J.
Brennan from London on the set
up of the Late Effects clinic and
how each of the body systems are
assessed with the patients being
followed up for life.
•A patient’s story by a patient from
the Netherlands. He told his story
about his 2 HSCTs and 2 relapses,
plus the fact that he has also had
skin cancer. He felt it was
important to accept being unwell;
to have goals and to participate in
sport which he found was a
therapy for his body and mind.
Exercise helped him to deal with
his treatment and psychological
therapy was also important and put
the balance back in his life. He did
feel that the psychological care of
the patients warranted more
attention than it presently got.
After the study day had finished we
were given a tour of the transplant
ward at the University Hospital, Zurich.
A patient’s isolation room at the University
Hospital, Zurich
They have 8 beds and perform 89
transplants per year with strict
isolation; the rooms were split by a
plastic screen with the anteroom being
for the clinical staff to perform their
routines, the visitors to sit etc. The
patient occupied the rest of the room
where they spent the isolation period.
As few people as possible entered the
patient’s side of the room and there
was no en-suite; the commode was at
the end of the bed with the nurses
emptying it from the anteroom and the
BSBMT NEWS Issue Number 11 - May 2012
patient performed personal cares from
a wash bowl. Anecdotal reports from
the nurse showing us round were that
there was less GvHD with this method
of care. It was an amazing day where I
learnt a lot and saw a different way to
care for transplant patients.
As far as our research study goes we
have now developed our intervention
– a website for the HSCT patients and
their carers, called ALLINEX. The
website includes information about
blood and marrow transplants and
what the potential problems might be
in the short and long term. ALLINEX
also contains information and advice
on social and psychological issues
and local support within their own
region, both at the hospital and in the
community. There is an end of life
section, with practical advice on
considerations before and after death
and where to obtain support at this
very difficult time in their lives. The
website has the facility to e-mail the
clinical team directly and the patients
have a forum where they are able to
post messages to each other.
Feedback from the patients and
clinical team has been excellent and
our first GP to comment has said that
she thinks the site will be useful to GPs
as well. We are about to enter phase
3 of the research study where we are
to formally evaluate the website as an
intervention and we are going to do a
randomised study with half the
patients receiving standard care and
the other half standard care plus
access to the website. Our aspirations
are for the website to be rolled out
nationwide with each region having
their own section, so keep your eyes
and ears open!
page 11
PLURIPOTENT HAEMATOLOGISTS:
Grace notes
Andy Chantry
At school, I had no idea whatsoever
that I would become a doctor but I
did want to be a rock star!
My family was and still is very religious
and has been plagued by priests or,
to be more specific, Anglican clergy –
father, both grandfathers, brother,
sister-in-law, even my aunt! So I dutifully
went off to Lancaster University in
1983 to read Religious Studies and
Archaeology. This was actually more
subversive than it sounds given that it
comprised roughly equal coverage of
all world religions, most of which my
father used to refer to as ‘rank
idolatory’. He wanted me to become
an Anglican priest like him and would
have preferred me to read straight
Theology. However, I don’t think he
realised quite what Religious Studies
was, and, hey, it was close enough.
It was during that time, I was in two
fantastic bands - a rootsy blues rock
outfit and a quirky indie band heavily
influenced by bands of the era such
as The Smiths, Echo and the
Bunnymen and The Cure.
I left University hoping that the indie
band would make it big and I’d be off
round the world on tour releasing
platinum selling albums. We did
produce an album and I loved it and
still listen to it. Some bits are still
fantastic and only a few bits make me
cringe! So imagine my excitement
when a letter from EMI arrived shortly
after release. Unfortunately, it wasn’t a
contract. The review described the
songs as ‘awash with reverb’ and our
promo shot featured us ‘modelling
overcoats!’.
The band fizzled out and I wasn’t that
disappointed. By that time I was
working at a Day Centre for unemployed
people and with those dealing with
addiction to drugs and alcohol.
This became increasingly medicalised
as I moved from a rehab unit to a
Health Authority Psychology
Department to a Mental Health Unit.
BSBMT NEWS Issue Number 11 - May 2012
I realised that I needed to re-train
and the two options I entertained
were psychotherapy and medicine.
I was advised in no uncertain terms,
by a Consultant Psychiatrist, not to
do psychotherapy and, actually,
what I really fancied was medicine.
Continued on page 13
page 12
Continued from page 12
So, at the age of 28, I was accepted
by Sheffield University Medical School
via the Pre-Med course to read
medicine. I loved it, being a student
again, actually feeling vocational about
what I was studying and being in two
new fantastic bands. This was now the
90’s and both outfits were distinctly
acid-jazz flavoured. I no longer
hankered after being a rock star but
was frequently gigging and we were
having a lot of fun.
I married aged 23 and was supported
through Med School by my wife.
My son was born during my Obs and
Gynae attachment and after a long
procession of my fellow med students
visiting the newborn, his arrival was
cited by over half the year as one of
their requisite witnessed births!
I qualified and was on a post take
ward round as a House Officer when
I got the call from my wife saying she
was in labour again. I cycled home
and delivered my daughter myself
shortly afterwards on the back seat
of our car.
I settled on Haematology as the most
interesting and exciting specialty and
became a Haematology SpR
continuing to really enjoy my work.
Getting on in age, a bit, I thought I’d
better get on and qualify. But, instead
I sidestepped and launched into a
research career commencing a PhD
in Myeloma Bone Disease. I quickly
learnt that the practice of scientific
research is very different from the
practice of clinical medicine. I duly
experienced the manic highs and lows
as a researcher ranging from the
frustration of failed experiments and
rejected papers to the elation of
experiments that yield really interesting
results, papers accepted in good
journals and the thrill and fun of
international conferences.
Meanwhile, the music was getting
jazzy and I found myself playing on the
same bill as Courtney Pine, Snake
Davis and the Pasadena Roof
Orchestra, as well as other less well
known but truly excellent musicians
on over a hundred professional
engagements. This was a thrill, but I
must say I was feeling out of my depth
and stretched as I tried to balance the
demands of home life, research work,
clinical and on-call duties with gigging
all over the country, travelling home
late at night. I gig far less often these
days but am quite content and actually
enjoy it more!
Getting the balance right, of course
remains a challenge, but I can’t
imagine stopping any of my activities
– I’d be miserable! My latest project is
a punk/new wave project with a bunch
of mates and is an absolute gas!
I recently completed my PhD thesis
with great joy and relief as well as
becoming a Fellow of the Royal
College of Pathologists and was
honoured to receive the 2010 Royal
College of Pathology Research Medal
Award for Haematology, a reflection of
the support I have had from a superb
research team and Leukaemia and
Lymphoma Research. I was recently
appointed as Senior Clinical Lecturer
and Honorary Consultant in
Haematology, here in Sheffield
cementing my dual role as a clinician
and a researcher – a very exciting
prospect…and I was offered two
gigs this morning!
Andy Chantry
a.d.chantry@sheffield.ac.uk
Recent BMT related publications include:
1. A.D. Chantry, D. Heath, A.W. Mulivor,
S. Pearsall, M. Baud’huin, L. Coulton,
H. Evans, N. Abdul, E.D. Werner,
M.L. Bouxsein, M.L. Key, J. Seehra,
T.R. Arnett, K. Vanderkerken,
P.I. Croucher. ‘Inhibiting Activin-A
Signalling Stimulates Bone Formation and
Prevents Cancer induced Bone Destruction
In Vivo’. Journal of Bone and Mineral
Research 2010; 25(12);2357-237
2. A.D. Chantry, D. Heath, C. Buckle,
L. Coulton, J.D. Shaughnessy, H. Evans,
J.A. Snowden, D.R. Stover, K.
Vanderkerken, P.I. Croucher. ‘Inhibiting
Dickkopf-1 (Dkk1) Prevents the
Development of Osteolytic Bone Disease in
Multiple Myeloma.’ Journal of Bone and
Mineral Research, 2009 (24)3;425-436
3. A.D. Chantry, J.A. Snowden,
C. Craddock, K. Peggs, C. Roddie,
J. Craig, K. Orchard, K. Towlson,
R.M. Pearce, D.I. Marks. ‘Long term
outcomes of myeloablation and autologous
transplantation of relapsed acute myeloid
leukaemia in second remission: a British
Society of Blood and Marrow
Transplantation Registry Study’.
Biology of Blood and Marrow
Transplantation 2006; 12(12);1310-1317
BSBMT NEWS Issue Number 11 - May 2012
page 13
Hammaad Khalil
Marrow is a nationwide student led organisation that
works in collaboration with Anthony Nolan. Marrow
aims to raise awareness of blood cancers, the need for
more donors as well as the importance of fundraising
for Anthony Nolan to help them keep saving lives.
Lancaster University Campus Alexandra Square
It costs Anthony Nolan £125 to sign one person onto
the bone marrow register. Every 23 minutes somebody
is diagnosed with a blood cancer and for every one
that Anthony Nolan can save, one isn’t. This is largely
because of the lack of donors on the bone marrow register.
At Marrow Lancaster we aim to recruit as many people
to the Anthony Nolan register as possible, and fundraise lots
of money while we’re doing it. We train up volunteers so we
can run recruitment events in and around Lancaster to get
people on to the register. We deliver recruitment training
sessions after which you’re ready to become a Marrow
recruiter and help us out at our next recruitment event.
Since December 2010 Lancaster Marrow have signed up
over 350 people onto the bone marrow register and our
aim is to double this by the end of 2012. To help us do this
we need many volunteers to help us on our mission.
If you would like to get involved in any way, or are just
interested in putting yourself on to the bone marrow
register then please contact the Anthony Nolan team
(http://www.anthonynolan.org/Home/Contact-Us.aspx).
Tish Atherton –
Fundraising
Coordinator
Marrow Team on National Marrow Day 2012 on Lancs Campus
Please show your support to this great cause and get
involved with your local Marrow group to help us save more
lives of those taken with blood cancer.
Thank you
Hammaad Khalil
Lancaster Marrow President
lancastermarrow@gmail.com
BSBMT NEWS Issue Number 11 - May 2012
page 14
The President’s column
Firstly I must advertise that EBMT
2013 will be held in London on
7-10th April at the Excel
Conference centre, London. It is
clearly a very important date for
your diary but it is also a chance
for the UK to produce a top class
meeting. Jane Apperley is
President and together with
Francesco Dazzi, David Marks and
Tuula Rintala is responsible for
organising the meeting. I know
that we at the BSBMT are keen to
help and that Jane and her team
are keen to hear from anyone who
has ideas and who wants to help.
Let’s help to make it the best
EBMT yet.
We do know how to produce good meetings here
in the UK. The symposium on ‘Alternative Donor
Transplantation: The State of the Art’ held on the
23rd February was excellent thanks to the coorganisers Alejandro Madrigal, Charles Craddock
and Derwood Pamphilon who put together an
outstanding meeting and there was a great audience
to enjoy some really good talks. It was nice that the
Department of Health also supported this important
meeting. I am hoping we will continue to repeat this
meeting on a bi-annual basis. It also represented an
exciting collaboration between the Anthony Nolan,
BSBMT and the BBMR. Please remember our
Education day on the 3rd October.
It has been a difficult time for the BSBMT over the
last 6 months. Our finances are a constant cause for
concern and we were told this year that we had to
produce a business case to justify our registry
funding which is key to producing the excellent data,
publications and studies we produce. We were
successful this year and thanks go to Keiren, Jenny
Charles and Gordon who helped to produce a really
well written and well argued case.
It is clear that we remain under
intense scrutiny and that we have
to have a dialogue with Purchasers
together with other transplant
stakeholders. We therefore held a
round table meeting on 24th
February and we had some full
and frank discussions around
transplantation in the future.
The future is of course uncertain
particularly as government reforms
filter slowly through. It is great that
Tony Pagluica has the opportunity
to chair the committee overseeing
the future of commissioning for
stem cell transplantation.
It was nice to see both Tony and
Gordon gain their Chairs in the
last 12 months as both have been such hard working
supporters of the BSBMT.
Another change that has been controversial is the
SABTO recommendations suggesting that the
universal leukodepletion has obviated the need to
select CMV negative blood products for CMV negative
recipients. Clearly this is a major change and I am sure
all of us feel nervous about this. We will be developing
an audit with the CTC to monitor the impact of this
change. We are of course very keen to hear about any
CMV negative patients who develop CMV viraemia or
illness during their transplant and will be prospectively
collecting data and auditing the impact of these changes.
We have a great organisation and there are so many
people who work tirelessly to promote our
organisation particularly our dedicated hard working
committee, staff and members of the CTC. I would like
to thank everyone who gives their expertise and time
so freely to the BSBMT.
Graham Jackson
President of BSBMT
graham.jackson@ncl.ac.uk
BSBMT NEWS Issue Number 11 - May 2012
page 15