Taming The beasT - British Society of Blood and Marrow

Transcription

BSBMT NEWS
British Society of Blood and Marrow Transplantation
Issue Number 16- December 2014
Taming
the beast:
Delivering
a clinical trial
in SCT
On being approached to write a piece on “How to run a clinical trial in
stem cell transplantation” I began to reflect on quite what I could
contribute that might be of any practical use to the readership.
I realized pretty quickly that much of what I had learnt through my own
misguided meanderings through this particular minefield might be more properly
classified as “How to avoid the mistakes I have made whilst …”, providing more of
a roadmap to highlight some of the more obvious traps (well, more obvious with
the benefit of hindsight perhaps), rather than a roadmap to success per se.
My treatise is more of a list of personal suggestions for ‘dos’ and ‘don’ts’ – take
what you can, discard what you will. I’m mindful of the fact that the ‘unknown
unknowns’ remain, understandably, unknown.
And remember:
all characters
appearing in this work
are fictitious; any
resemblance to real
persons, living or
dead, is purely
coincidental.
INSIDE...
As the musical ‘ping!’ of your e-mail client
announces the arrival of another BSBMT
newsletter, you may take pause to
consider that this heralds the passing
of yet another six months of time.
Ah well, sic transit gloria mundi. Before
melancholy thoughts of your own
impermanence overwhelm you, allow me
to distract you with a bumper Christmas
edition of BSBMT news.
The stem cell transplant world is often
much criticised by its chemotherapeutic
brethren for its lack of trial data. There is,
perhaps, a certain amount of resentment
from the transplant world that it’s often
the same chemotherapeutic brethren
who impede the progress of any such
trials, telling us that ‘it can’t be done!’ In
truth such trials are very difficult to do, but
one man stands out as having done the
very difficult more than once. Karl Peggs’
experience in getting trials in transplant
completed is of great value to the UK
transplant community and I’m very
grateful to him for sharing it with us here.
Elsewhere inside we continue our series
on the future of autologous SCT as
Jaimal Kothari and Graham Collins talk
us through transplantation for Hodgkin
lymphoma. The departmental spotlight
falls on Southampton where Amy
Publicover and Kim Orchard conduct
the guided tour. Kim also invites you to
consider training as a JACIE inspector see the notice on page 11. Michelle
Kenyon brings us up to speed with
what’s afoot in the BSBMT nursing group
and Steven Marsh tells us about the
advent of Next Generation Sequencing at
the Anthony Nolan.
After that Laura Machin wants your help
in collecting data about perceptions of
quality in cord blood transplantation.
For those of you who couldn’t make it to
the annual Education Day I provide a
précis of the proceedings, before Rob
Wosley lets rip with part 3 of his guide to
quality management and Gordon Cook
signs off with his valedictory President’s
column.
Continued on page 2
I wish you all a Merry Christmas and a
Happy New Year.
Patrick Medd
patrick.medd@nhs.net
A human lymphocyte
Dr. Triche. National Cancer Institute, Sep 20 1976 via Wikimedia Commons
Continued from page 1
The “DO” list: Do…
•Make sure you know your target •Whilst on the subject of costs,
population inside out -- how
many patients will be potentially
eligible, have I accidentally
excluded any subpopulation of
these, what are the treatment
pathways for these patients in your
trial sites -- e.g. will they be seen by
the right team at the right time to
approach them for the study? You
will be endlessly surprised by
differences in clinical practice
throughout the UK, and how these
might impact on your recruitment if
you have been too restrictive in
terms of inclusion criteria. For
example, you might decide it’s a
great idea to try to recruit patients
after one line of salvage, but if the
patients are still under the care of
satellite units or other teams (eg.
oncology) at that time you may
miss the opportunity to recruit
them.
•Ensure you understand the
implications of any mandatory
investigations you outline in the
trial -- both in terms of cost and
practical delivery. You might feel
that a particular investigation is
standard of care in your institution,
but is that true elsewhere? Do you
understand, for example, the issues
surrounding quality assurance and
quality control of such
investigations and how these will
be delivered in the context of a
clinical trial; do you require GLP
(good laboratory practice) and if so
is this readily available in all sites? Is
the investigation you take for
granted not available locally to
others, and what are the
implications for patients on study,
for example, availability of static
versus mobile imaging facilities.
do make sure you address these
early in the process; the email
telling you that site X can’t proceed
because someone has flagged up
an excess treatment cost that isn’t
met are hugely frustrating.
Likewise, make sure you know how
much you need to raise to cover
costs of trial management –- are
you expected to cover costs for
statistical input, what is the
expectation of your chosen clinical
trials centre?
•Try your best to define current
and predict future competing
studies, both nationally and
equally significantly locally – the
latter will often hit you far harder
than national studies if one of your
best recruiting sites suddenly
opens a study which will become
the preferred default study. This
might extend to trials of supportive
care therapies.
•Get firm commitments of
support from your peers in
writing/email -- this has become
critical for applications for funding
or protocol adoption, and it is far
better to know ‘now’ rather than get
a ‘that sounds good’ type of
response that you can’t
subsequently deliver on.
•Engage with other critical
players very early in the
planning phase – for example
clinical trial centres, nuclear
medicine, MRD monitoring,
funding bodies, donor registries.
Again, you might feel that
approaching an unrelated donor to
participate (and this includes cases
where you will not be asking them
to do anything in addition to the
BSBMT NEWS Issue Number 16 - December 2014
routine stem cell donation)
shouldn’t be problematic, but the
registries may disagree. Their
internal approval processes can
take a long time. They may ask for
additional funding. Some collection
centres may refuse to be involved
with particular studies. Some
donors will say ‘no’ – and you need
to account for this. Note also that if
you only have approval from some
registries your potential recruitment
pool is reduced. Be aware also that
whilst you might be working
comfortably towards a deadline to
submit for funding, some of your
key support teams might require a
fully finalized and costed version of
your application up to 2 weeks
before this!
•Respond rapidly to unpredicted
changes in practice that will
impact on your study -- for
example, the introduction of new
agents used in salvage might
suddenly exclude potential patients
if your inclusion criteria are
inflexible; if this is the case you
need to be aware of the change
and act quickly to amend you
protocol if necessary
•Respond rapidly and politely to
requests from funders, clinical
study groups (CSGs), clinical trial
centres -- regarding clarifications,
updates etc.
•Retain a sense of good will and
humor -- let’s be honest, you’re
volunteering yourself to be the fall
guy for everyone else’s disparaging
remarks about the UK transplant
community and our inability to
deliver prospective studies; take it
all with good humor, then show
them they’re wrong!
page 2
The “DOn’t” list: Don’t…
•Try to do it all on your own
•Be too rigid in your thinking in
•Assume that your practice is
•Think you have to incorporate
either reflected or can be easily
recapitulated elsewhere -- as
previously noted, you’ll be amazed
at how differently care is provided
in different centres, right the way
through from arrangements for
pre-transplant consults, which
physicians see the patients and
drive the decisions, to posttransplant care -- decide what bits
matter and what bits don’t
•Be overly restrictive on points
•Try to deliver the undeliverable
the early stages -- you need input
from as many knowledgeable
colleagues as possible, but don’t
everyone’s wishes -- this is a
balance, but if you are too
permissive the intent of the trial may
be diluted too much for it to deliver
a useful outcome
that don’t matter so much -eg. think hard about entry criteria
-- whilst it is nice to make it neat and
homogeneous how much can you
control salvage; supportive care
protocols may differ between units
and trying to align others from their
standard to yours in the context of a
minority of patients on a trial is
probably not worthwhile in most
cases -- you’ll inevitably just end up
with a raft of protocol violations
•Avoid talking to those you might
think will be obstructive -- you are
likely to need their support in the
longer term, but conversely don’t
•Devote too much time and
attention to the active resistors
-- concentrate your efforts on those
who are enthusiastic and motivated,
as loss of their interest will be far
more damaging to you
-- just because a trial is a good idea
clinically doesn’t mean you will be
able to deliver -- if your focus is on
very rare indications then most
centres will not feel it worth the
effort to open a study to try to
recruit one patient in 12-18 months;
even if your transplant colleague is
eager it doesn’t mean his clinical
trials team will be willing to devote
resource; best case scenario in a
large stand-alone multi-centre study
is that you will recruit 20-25%% of
the number you first had in your
head; if you feel you have to
overestimate recruitment potential
just to secure support or funding
you’re saving up a whole world of
pain for later down the line
•Underestimate the complexity in
complicated than it needs to be
dealing with Advanced Therapy
Investigational Medicinal
Products (ATIMPs) – from
regulatory approvals through to
pharmacy oversight
•Design a study that will provide
•Stick your head in the sand if its
•Make anything more
elegant proof of concept but
can’t possible be translated
into routine clinical practice
there-after
he did actually like you. What may
be the most important thing in the
world to you may not register so
highly with others.
I hope that these thoughts are of at
least some use to some of the people
who might wish to step forward to do
battle in this arena. And please don’t
be put off. In a world where we face
increasing scrutiny over clinical activity
decisions, the provision of a
meaningful evidence base becomes
ever more important to allow us all to
provide the options we believe are
correct. And if we’re wrong, we need
to know!
Karl S Peggs
Reader in Stem Cell Transplantation
and Cellular Immunotherapy
UCL Cancer Institute and UCLH NHS
Foundation Trust, London
all going a bit pear-shaped
•Take it personally. Remember,
Dr X would probably have put no
more patients on your study even if
page 3
Stem Cell Transplantation
in Relapsed classical
Hodgkin Lymphoma
Dr Jaimal Kothari, Consultant Haematologist. Dr Graham P Collins, Consultant Haematologist.
Oxford Cancer and Haematology Centre, Churchill Hospital, Oxford OX3 7EJ
Autologous stem cell
transplantation
carmustine for
Bendamustine (BeEAM),
and a Thiotepa based
regimen has also looked
efficacious. However,
there is no randomised
trial data that shows
superiority of a particular
regimen, and the
emphasis should be on
units using regimens
with which they are
familiar.
High dose chemotherapy with
autologous stem cell transplantation
(ASCT) following salvage
chemotherapy is currently the gold
standard treatment for relapsed
Classical Hodgkin Lymphoma (cHL).1
This approach has been validated by
two randomised clinical trials.
The first, reported by the British
National Lymphoma Investigation
(BNLI) group, randomised patients
between BEAM chemotherapy followed
by ASCT, or up to 3 cycles of miniBEAM only. Only 40 patients were
randomised and there was no
statistically significant difference in
overall survival. However, 3 year event
free survival was 53% for the BEAM
group and 10% for the mini-BEAM
cohort. The second study was larger
with a slightly different design. All
patients received 2 courses of DexaBEAM chemotherapy. Those
randomised to high dose therapy
underwent this procedure if they were
responding after the 2 cycles of
salvage. For those randomised to
standard chemotherapy, they received
2 further cycles of dexa-BEAM. Again,
no overall survival difference was
demonstrated, but the 3-year freedom
from treatment failure was 55% for the
transplant group versus 35% for the
chemotherapy group. In both trials, a
lack of overall survival benefit may
Survival after autologous stem cell transplantation for Hodgkin
lymphoma from Pasquini MC, Wang Z. Current use and outcome
of hematopoietic stem cell transplantation: CIBMTR Summary
Slides, 2013. Available at: http://www.cibmtr.org
have been due to patients failing on the
chemotherapy arm then progressing to
high dose therapy anyway.
Key questions remain with regards to
optimising ASCT, including the best
conditioning regimen, whether tandem
ASCT has a role, and also whether
novel agents may be able to prevent
relapse in high-risk patients post ASCT.
There is no standard conditioning
regimen used prior to ASCT. In view of
the BNLI study, BEAM has been one
of the most commonly used regimens
in the United Kingdom. Other regimens
worldwide use various combinations
based around other drugs including
Lomustine, Etoposide, Busulfan and
Cyclophosphamide. There has also
been interest in modifying the BEAM
regimen by substituting the
The use of tandem
ASCTs in high risk
patients has been
investigated in the
German H96 study.2 For the purposes
of this study, high risk was defined as
time to relapse of < 12 months, stage
III or IV relapse and relapse within a
previously irradiated site. Conditioning
for the 2 transplants was different,
with the 2nd occurring between
45-90 days after the first in those
patients who were not showing signs
of progression.
The 5 year freedom from 2nd
treatment failure and overall survival
were 46% and 57% respectively,
which for such a high risk group are
encouraging results. However a
randomised trial is required to confirm
superiority of this very intensive
approach.
Continued on page 5
page 4
The significance of pre-ASCT FDGPET status has also been confirmed
by other studies.
PET-CT in Hodgkin lymphoma. By Hg6996, courtesy of courtesy of “Südwestdeutsches PET-Zentrum
Stuttgart am Diakonie-Klinikum” via Wikimedia commons
The importance of PET
status prior to
Transplantation
An important aim of second line
treatment is to achieve a complete
remission by FDG-PET scan. This has
been highlighted by a number of
studies, especially by the group from
Memorial Sloan-Kettering. A seminal
paper by this group reported on
consecutive patients from 1994 to
2003 treated with ICE based second
line treatment. The exact second line
treatment did vary according to era of
treatment, with earlier patients treated
with standard ICE, whereas later
patients received a risk-based
approach where higher risk patients
received at least 1 cycle of augmented
ICE. The pathway was also slightly
unusual in that patients received IFRT
to all sites of residual or relapsed nodal
based disease prior to stem cell
transplantation. In addition the
conditioning used was not that
normally used in the UK, consisting of
high dose cyclophosphamide and
etoposide for radiation-naïve and CBV
(cyclophosphamide, BCNU and
etoposide) for those previously
irradiated. Patients received functional
imaging (initially gallium scanning but
more latterly FDG-PET scanning) prior
to second line treatment, and preASCT. The overall 5 year EFS and OS
for the group were 63% and 71%
respectively. Importantly, on
multivariate analysis the only factor
predictive of outcome was disease
status pre-ASCT as determined by
functional imaging. The 5y EFS for
functional imaging positive and
negative patients was 31% and 75%
respectively, with no difference seen
between type of functional imaging.
A natural question following from
these finding is ‘what should be done
if the PET scan remains positive after
first salvage treatment?’ This was
addressed in a prospective, riskadapted study where patients with
relapsed Hodgkin lymphoma received
2 cycles of ICE or augmented ICE
(depending on clinical risk factors).3 If
PET-negative after 2 cycles, patients
went on to receive ASCT. If positive,
patients received 4 cycles of biweekly
gemcitabine, vinorelbine and
liposomal doxorubicin (GVD). A further
PET scan was performed and all
patients with responsive disease
(irrespective of PET status) proceed to
ASCT. The key message from this trial
is that the event free-survival curves for
those patients who obtained a
negative PET scan after either only
ICE / aICE or GVD were
superimposable. Those who were PET
positive after GVD had much worse
outcomes. The message seems to be
that achieving PET negativity with
salvage chemotherapy prior to ASCT,
should be a high priority.
The Role of Brentuximab
as a Bridge to Autologous
Transplantation
The ability to obtain PET negativity with
additional agents, when traditional
salvage regimens have not
succeeded, is a clear area of
therapeutic need if patients are able to
proceed to high-dose therapy.
Brentuximab Vedotin (BV) has been
used in this setting, and is an ideal
candidate as a bridging agent, as it
has a toxicity profile that does not
overlap with either salvage or
conditioning regimens, and it can lead
to PET negativity in refractory patients4.
Continued on page 6
page 5
Whether the outcomes from ASCT
after achieving a CMR with
brentuximab are as good as those
obtained after gemcitabine-based
chemotherapy is unknown. Perhaps
the more pertinent question is whether
BV should be incorporated into (or
used alongside) salvage regimens
earlier, to increase the proportion of
patients attaining complete metabolic
responses prior to high-dose therapy.
A Phase II study is currently
addressing this question, and
preliminary results have indicated a
very high proportion of patients
obtaining complete remissions
(27/28) with either BV alone or used
before/after augmented ICE therapy.
With a short follow-up to date (median
9.5 months), 26 patients are still in
remission post ASCT. Another
important question is whether BV is
able to prevent relapse in high-risk
patients post ASCT, and efficacy data
from a Phase III study that has
addressed this question is due to be
presented this December at ASH. Data
released early from the sponsor,
Seattle Genetics, states that the
primary endpoint of the study was
met, with brentuximab vedotin
maintenance resulting in a 75%
improvement in progression-free
survival compared to maintenance
using placebo infusions. No overall
survival benefit has so far been
demonstrated.
The anti-PD1 agents nivolumab and
pembrolizumab also appear highly
effective in relapsed and refractory
classical Hodgkin Lymphoma and
have a favourable safety profile.
According to abstracts being
presented at this year’s ASH meeting,
response rates are high and appear
durable, enabling several patients to
progress to allogeneic stem cell
transplantation. Follow up is short
however and it will be interesting to
see how the role of these exciting new
agents is defined by future studies.
Survival after autologous stem cell transplantation for Hodgkin lymphoma from Pasquini MC, Wang Z.
Current use and outcome of hematopoietic stem cell transplantation: CIBMTR Summary Slides, 2013.
Available at: http://www.cibmtr.org
The role of allogeneic
stem cell transplantation
The role of allogeneic stem cell
transplantation in relapsed Hodgkin
lymphoma is controversial. However,
there are reasonable data supporting
its use in those relapsing after
autologous stem cell transplantation.
Data from registries and larger series
suggest a long-term progression-free
survival of between 20-40% although
the non-relapse mortality of up to 20%
does offset this benefit to a degree. A
few reports suggest that those who
progress to allogeneic stem cell
transplantation do, in fact, have
superior outcome than those who do
not, providing indirect evidence in
support of this approach5. Recently a
risk-adapted strategy has been trialled
in which allogeneic stem cell
transplants are performed in high-risk
patients at first relapse, where high-risk
is defined as failure to achieve a
metabolic complete remission after
first-line salvage therapy.
The original report showed a 3 year
PFS of 68% with the interesting
observation that some relapsing
patients could be brought back into a
PET negative remission by the use of
donor lymphocyte infusions. This
strategy has recently been tested in a
multi-centre trial, although results are
awaited.
Allogeneic stem cell transplantation is
only feasible if a suitable donor can be
found. For those without a sibling
match or a suitable unrelated donor,
alternative donor strategies including
cord transplantation and
haploidentical transplantation have
been used in Hodgkins. A recent
report from the Fred Hutchinson
Cancer Research Centre reported on
their outcomes in 90 heavily pretreated patients (median number of
prior therapies was 5).
Continued on page 7
page 6
Suggested schema for the management
of relapsed Hodgkin lymphoma in
transplant-eligible patients
Key references
Relapsed cHL
1. Collins GP, Parker AN, Pocock C, et al.
Guideline on the management of primary
resistant and relapsed classical Hodgkin
lymphoma. Br. J. Haematol. 2013.
n
ASCT
e
tiv
a
eg
PET-CT
positive
PET-CT
relapse
Brentuximab
PD-1 inhibitor?
PET-CT
PR
or C
R
allo-SCT
The outcome from patients using a
haploidentical donor (n=28) were
perhaps better than expected with a
2 year OS of 58%, PFS of 51% and
relapse rate of 40%6. These compared
favourably with results from the
HLA-matched donors. Favourable
results have also been reported by
other groups, but all such reports
involve relatively small numbers of
patients, have inherent biases and
contain differing conditioning
regimens. Although a randomised
study would not be feasible in this
setting, collaborative multi-centre,
prospective studies would help to
define the risk and potential outcome
of such approaches.
2nd line salvage
possible alternative if PET-positive
possible alternative if PET-positive
Salvage
Allogeneic stem cell transplantation is
considered by many to be standard for
those relapsing after autologous stem
cell transplantation and may have a
role earlier in the treatment pathway.
The impact of novel agents, such as
brentuximab vedotin and possibly the
anti-PD1 agents nivolumab and
pembrolizumab is yet to be defined
but appears to improve remission in
high risk patient, enabling stem cell
transplantation to occur.
2. Morschhauser F, Brice P, Fermé C, et al.
Risk-Adapted Salvage Treatment With Single
or Tandem Autologous Stem-Cell
Transplantation for First Relapse/Refractory
Hodgkin’s Lymphoma: Results of the
Prospective Multicenter H96 Trial by the
GELA/SFGM Study Group. Journal of Clinical
Oncology. 2008;26(36):5980–5987.
3. Moskowitz CH, Matasar MJ, Zelenetz AD,
et al. Normalization of pre-ASCT, FDG-PET
imaging with second-line, non-cross-resistant,
chemotherapy programs improves event-free
survival in patients with Hodgkin lymphoma.
Blood. 2012;119(7):1665–1670.
4. Moskowitz A, Schoder H, Gerecitano J et al.
FDG-PET Adapted Sequential Therapy With
Brentuximab Vedotin and Augmented ICE
Followed By Autologous Stem Cell Transplant
For Relapsed and Refractory Hodgkin
Lymphoma. ASH annual meeting Abstracts
2013. Blood 2013: 122 (suppl 21)
5. Thomson KJ, Peggs KS, Smith P, et al.
Superiority of reduced-intensity allogeneic
transplantation over conventional treatment
for relapse of Hodgkin’s lymphoma following
autologous stem cell transplantation. Bone
Marrow Transplant. 2008;41(9):765–770.
6. Burroughs LM, O’Donnell PV, Sandmaier
BM et al. Comparison of outcomes of
HLA-matched related, unrelated, or
HLA-haploidentical related hematopoietic cell
transplantation following nonmyeloablative
conditioning for relapsed or refractory
Hodgkin lymphoma. Biol Blood Marrow
Transplant. 2008 Nov;14(11):1279-87.
Conclusions
Autologous stem cell transplantation
remains the standard of care for
patients with relapsed or refractory
classical Hodgkin lymphoma who
respond to salvage treatment. The
achievement of a complete metabolic
response to salvage treatment
appears important and the
investigation of novel strategies is
warranted for those who respond
inadequately.
Dr Graham P Collins, Consultant Haematologist
Dr Jaimal Kothari, Consultant Haematologist
page 7
departmental SPOTLIGHT
Wessex Blood and Marrow
Transplantation Unit
Background
Southampton (University Hospital
Southampton NHS Foundation
Trust) has been delivering
autologous transplants since the
mid 1980s, initially treating patients
with lymphoma under the
Oncologists (Prof Whitehead and
Dr Mead) and then for patients with
myeloma (initially under Andrew
Duncombe and Alistair Smith).
Historically, allogeneic stem cell
transplants were performed in
three centres in the region – Poole,
Bournemouth and Southampton,
with small numbers of patients at
each site. The allogeneic service
was rationalised in the late 1990s
and moved to Southampton with
the appointment of Kim Orchard as
Director of the Wessex Blood and
Marrow Transplantation Unit in
2001. The department relocated
from the Royal South Hampshire
Hospital to its current location in
University Hospital Southampton in
December 2001 and both the
Haematology and Transplantation
services have continued to expand
since then. The unit initially served
the referring hospitals in
Basingstoke, Bournemouth, Poole,
Portsmouth, Salisbury, Winchester
and the Isle of Wight, later expanding
to include Chichester, Dorchester and
the Channel Islands. Some of the
more exotic locations we have treated
patients from include St Helena and
the Falkland Islands. While becoming
established, the unit performed 15-20
sibling transplants a year, expanding to
volunteer unrelated donors in 2004
and now performs 65-70 autologous
and 60-65 allogeneic transplants
annually.
The Team
The team consists of two allogeneic
transplant Consultants, Dr Kim
Orchard and Dr Debbie Richardson,
with autologous transplantation for
Myeloma by Kim and Dr Matthew
Jenner, and for Lymphoma by Prof
Peter Johnson and Dr Andy Davies.
We have one Associate Specialist,
Dr Kate Hill and four specialist
nurses, Nikki McKeag (Lead Nurse
for BMT), Joan Newman (BMT
CNS), Sara Main (Allogeneic
Transplant Co-ordinator) and Jane
Lamb (Autologous Transplant
Co-ordinator). The lead nurse for
apheresis is David Hutchins. Our
Quality Manager, Carol Hurlock and
Data Manager, Lynn Jarvis support
the clinical service. In recent years a
Transplant Fellow has been added
to the team, which also benefits
from the input of a range of allied
health professionals.
Continued on page 9
page 8
Steph Churchill, our ward manager,
with the other ward sisters, leads a
team of extremely dedicated
nurses. Stem cell processing is
performed on site in the Steve Mills
laboratory run by Dr Claire Wiggins
and tissue typing is performed by
Tooting NHSBT.
We maintain close links with our
referring centres, including weekly
e-mailed updates from Joan on the
progress of the patients
undergoing allogeneic
transplantation. Nikki and Joan
established a weekly nurse-led
clinic, enabling newly discharged
allograft patients to be reviewed
twice weekly, as well as an
emergency nurse led drop-in clinic.
Once a year we hold a regional
transplant meeting, presenting
outcome data for all the regional
autologous transplantation centres
in addition to our own. The meeting
also includes a ‘business meeting’,
allowing all the referring centres to
raise concerns and suggestions they
have, and an educational content,
usually involving an invited speaker.
Seeing the need to specifically
manage patients in the longer term,
in 2010 a late effects clinic was
established, run by Kate and Nikki,
which allows for focus on the longer
term sequelae of transplantation, away
from the main post-transplant clinic
setting. Kate is an active member of
the EBMT Complications and Quality
of Life Working Party.
New Developments
In 2002 the original transplant unit
was integral within a newly created
Haematology ward with six HEPA
filtered rooms. In 2006 we were
successful in obtaining a £5 million
grant from the Department of
Health that allowed us to build a
BMT extension with nine new
HEPA filtered in-patient rooms,
which opened in 2009. The unit
has also benefited from recent
developments funded by the ‘Red
and White Appeal’. Actively
supported by patients and staff, as
well as businesses and trusts, the
appeal raised >£1.5 million pounds
over six years. Patients, staff,
friends and families took part in a
wide range of fundraising activities
– possibly the most committed was
the climb of Kilimanjaro!
Continued on page 10
Ward nurses
page 9
The appeal part funded our new
Haematology Day Case unit, which
opened last year. It serves all
haematology patients requiring day
case treatment and includes a
three bedded apheresis bay and
space for giving donor lymphocyte
infusions. The unit is also used to
provide the ECP service, which has
now been running for five years.
David Hutchins has also taken on
the role of Day Unit Manager.
Co-located with the Haematology
in- and out-patient facilities, is a new
Teenage and Young Adult Unit,
funded by the Teenage Cancer
Trust. With six in-patient beds, a day
case bay and a social space the
unit feels as little like a hospital as is
possible. Patients aged 16 to 25
years are able to benefit from the
social support provided for them, in
addition to practical features such
as a second bed to allow a parent
or friend to stay overnight.
The unit first received JACIE
accreditation in 2009 and was
re-accredited in 2013. Both Kim
and Debbie are accredited JACIE
inspectors, and Kim is the UK’s
JACIE representative. With this
strong involvement with the JACIE
system the Quality Management
Programme in Southampton has a
high profile and underpins the
whole of the service, with regular
quality meetings. Documentation
for the programme is managed
using the ‘QPulse’ system, which
has made management of the
increasing number of SOPs far easier.
Research
We have participated in several
multi-centre trials, including CMVIMPACT, ProT4 and LenaRIC. Local
research interests include targeted
radiotherapy for transplant conditioning
in a range of indications, particularly
myeloma (autologous and allogeneic
transplants) and acute leukaemia and
pre-conditioning in the allograft setting.
The Future
With the ever-growing pressure on
space and the opportunities provided
by our new day unit, one of our next
aims is to develop an ambulatory care
unit so that conditioning for autologous
and allogeneic transplantation can be
delivered as an outpatient where
appropriate. We have also developed
a hub and spoke with Salisbury,
with patients receiving conditioning
chemotherapy and autologous
stem cell return in Southampton
and then returning to Salisbury for
their neutropenic phase, which we
are actively considering for other
referring hospitals in our region.
Our outcomes are good compared
with the BSBMT benchmarking
exercise but our aim is to
continually improve our service for
patients. Finally, we are developing
the role of the Advanced Nurse
Practitioner, to support medical
staff on the ward.
Amy Publicover,
Transplant Fellow
Kim Orchard,
Consultant Haematologist and
Transplant Programme Director
University Hospital Southampton
Kim Orchard
page 10
JACIE Inspector Training Course
Manchester, UK 2-3 July 2015
This course is designed to train JACIE inspectors.
Anyone working in the transplant setting who is
interested in JACIE but is not interested or is not
qualified to become an inspector can also attend.
Note that priority will be given to inspector
candidates.
Cost
The course is free and includes catering and materials.
Efforts are being made to secure funding to cover - at
least partially - accommodation and travel. More details
will follow in due course.
Programme
Message from Prof. John Snowden (Sheffield), JACIE
Medical Director, and Dr. Kim Orchard (Southampton),
UK JACIE National Representative:
To help address the relatively limited pool of active
UK-based JACIE inspectors in all sections i.e. clinical
(adults and paeds), collection and processing, and the
increasing dependency on overseas based inspectors,
we are organising UK-based training course to be
delivered by JACIE staff and other experts. We would be
grateful if you could encourage your appropriately
experienced clinical, nursing apheresis and scientific
processing colleagues to take part in the training
(perhaps by identifying one potential individual from each
of the clinical, apheresis/collection and processing
sections of your programme). Note that JACIE inspector
criteria permits ‘retired experts’ who would like remain
part of the BMT community to participate for up to 5
years from their retirement date.
The programme will be uploaded here in early 2015.
Count on 2 days of training.
Language
English
Register
To register for the course, go to ebmt.stagehq.com/
events/3198 and click on the ‘Register’ button on the
top-right of this page
Documentation required from
inspector candidates
Following completion of the information online, the next
step is to send the following documents by email to the
JACIE Office (@ eoin.mcgrath@ebmt.org):
Download the files by (1) click on the links below and
when open, (2) click on ‘File’ in top left-hand corner and
select ‘Download’.
•Concise copy of your CV, in English (download the
Criteria for inspector candidates
suggested template)
Inspector registration form (download this form here)
In order to be admitted to the course as an inspector
candidate, participants must meet the criteria to be an
inspector described here. If you have any doubts or
questions about the criteria, please contact the JACIE
Office at eoin.mcgrath@ebmt.org.
•Evidence of qualifications e.g. medical degree,
Note: Registration via this web page does not guarantee
a place on the course. JACIE reserves the right of
admission to the course. You may not be admitted to the
course if you do not satisfy JACIE that your training and
experience are sufficient. JACIE may request advice
from national contacts when deciding whether to admit
a candidate to the course.
Accommodation & Travel
registration as specialist. Candidates who are listed
as members of an EBMT member centres will not be
required to provide this documentation. Check
membership at www.ebmt.org.
Venue: Chancellors Hotel, Chancellors Way,
Moseley Road, Fallowfield Manchester M14 6ZT
United Kingdom. Web: www.chancellorshotel.co.uk
The Manchester venue has been chosen to be centrally
located, and easily accessible by plane, rail and road
with free parking.
page 11
History
The EBMT (UK) NAP Group stands for the European
Bone Marrow Transplant (United Kingdom) Nurses and
Allied Professions Group – now you can understand
why we have an abbreviation!
Thirty years ago, in 1984, the first meeting of the EBMT
Nurses Group (EBMT-NG) was held in Bad Hofgastein,
Austria. This meeting ran in parallel to the physicians’
meeting, aiming to provide a platform for nurse
education and sharing experiences within the field of
HSCT. At this time, HSCT was actually just BMT and
very much an experimental treatment, with very few
hospitals offering it. Therefore it was critical for nurses
throughout Europe to have an annual meeting to share
their knowledge.
Over the last 17 years, much has been achieved:
•Commitment to provide regular educational meetings
at affordable cost to the participants.
•Travel scholarships
•A national directory of BMT units to include contact
details of staff to be used as a resource
•Website development and improved communication
•Solutions to improve sibling donor care follow up
•Joint meetings with the National Quality Managers
Forum to promote JACIE accreditation
•A patient and carers day in line with the main EBMT
annual conference
Meetings
As the EBMT-NG became increasingly successful at
organising their annual conferences, it was important to
strengthen the links with the European countries. The
Netherlands and United Kingdom led the way forming
national groups that were affiliated to the EBMT-NG.
The UK group wanted to provide 3 educational
meetings per year, make the meetings affordable
nurses at all levels and to include allied professionals
that were working within the field of BMT. A committee
was formed, sponsorship was obtained from six
companies and the first meeting was held in
Birmingham in 1997.
Our most recent meeting, now an annual event, took
place in Bristol on Friday 14th November. We are
delighted to have a fantastic agenda focusing on the
very topical ‘transplantation in the younger adult’ and
have attracted leaders in the field to present on this
topic: Professor David Marks, Dr Fiona Dignan and
Dr Jacqui Stringer.
Initial meetings aimed to share experiences and
synchronise transplant-nursing practices through the
development of guidelines on various topics:
Membership
•Central line access
•Isolation issues
•Day case Management
•BMT Coordination
•Symptom control
•Staff recruitment
The meeting also provides an opportunity for our two
EBMT (UK) NAP scholarship winners to present the
work they undertook for the main EBMT meeting in
Milan earlier this year.
HSCT nursing is at a very exciting evolutionary stage.
Over the last two decades, with the support of medical
colleagues, BMT nursing has grown rapidly and has
acknowledged the care needs of the patients, their
families and donors. Nurses have been taking a leading
role in the care of patients, providing holistic care; HSCT
nurses are involved in the decision-making process
about treatment options for their patients, and they
evidently contribute to an enhancement in their patients’
quality of life. More and more, HSCT nurses are
conducting research on topics based on clinical
practice, and are creating their own research agenda.
page 12
Forums for exchanging knowledge and experience are
increasingly needed.
Individual Membership of EBMT (UK) NAP is open to
all healthcare professionals actively involved in the care
of stem cell transplant patients. Membership is FREE
to all approved members. In order to register for
membership of the group and the website, just
complete the registration from the home page of the
site (http://ebmt.co.uk/). Once your registration is
approved, you will receive a unique user name and
password. You will then be able to use your log in
details to use all areas of the site.
Membership entitles you:
•Build an individual profile
•Access and amend details of your institution
•View details of other institutions through the directory
•Network with other members
•Set up and contribute to forums
•View and register for forthcoming national meetings
•Rights to vote at our AGM
•Apply for our scholarships and educational grants
Membership will give you the opportunity to share
ideas, successes and opportunities with colleagues
across the country interested in promoting quality care
in stem cell transplantation.
EBMT (UK) NAP is part of the wider
EBMT group.
Currently the Nurses Group has over 500 members
from 50 different countries throughout Europe and a
few members in Australia, Asia and North America. The
main EBMT nurses group is open to all healthcare
professionals involved in the care of stem cell transplant
patients. Please click here to visit the main site and
register for the 2015 European meeting in Istanbul.
New developments - G-CSF education
project (http://ebmt.co.uk/gcsf-e-learning/)
The GCSF project was inspired by the need for nurses
to have documented evidence of continuing
professional development and education as part of
JACIE. The 5th edition stipulates that nurses shall be
trained and experienced in the management of patients
receiving cellular therapy: ‘Administration of blood
products, growth factors, cellular therapy products, and
other supportive therapies’ (Section B3.6.3.3). Training
on growth factors is often in-house and therefore not
supported by robust standardised documentation. The
primary aim of the e-learning project was to provide an
online resource that could be studied in your own time
and at your own pace with valuable information about
the variety of growth factors available. The document
also includes the use of plerixafor. All the pharmaceutical
companies involved gave permission for their product
literature to be displayed within the tool and links to their
websites are embedded.
There is a short 11-question quiz at the end of the tool
that requires a score of 8 or more to ‘pass’. A certificate
can then be printed to confirm completion the e-learning.
The next aim is to obtain formal accreditation for the tool.
Scholarships and educational grants
The main EBMT annual meeting occurs each March/
April in a different European country. The EBMT (UK)
NAP offers the opportunity for an individual to attend this
meeting via a travel scholarship. As a committee we also
offer other travel and educational opportunities for each
year. We have established 3 types of travel/educational
grants for our members:
•Exchange Visit Scholarship
•Educational Travel Scholarship
•EBMT Conference Travel Scholarship
Please see the website to be able to take advantage of
these, for details of how to apply and deadlines for
applications. Historically, these funds often attract few
applicants and so offer a high chance of success for
those that do apply!
Michelle Kenyon
ELF post-BMT Clinical Nurse
Specialist
King’s College Hospital,
London
page 13
anthony NOLAN NOTES
INVESTMENT IN THIRD
GENERATION SEQUENCING
Professor Steven GE Marsh, Director of Bioinformatics & Deputy Director of Research, Anthony Nolan Research Institute
After a period of considerable research, Anthony Nolan
made the decision earlier this year to purchase two
Pacific Biosciences® RS II DNA sequencers. We are
the first stem cell registry in the world to invest in this
particular technology, which enables Single Molecule,
Real-Time (SMRT) DNA Sequencing of full-length
HLA genes.
I believe this technology will provide the most significant
breakthrough in tissue typing for 15 years.
It is fitting that we made the investment this year,
40 years since Shirley Nolan set up the appeal to create
the world’s first bone marrow registry. Since that time,
Anthony Nolan has always been a scientifically
pioneering organisation. The purchase of RS II is a
significant investment for the charity and reflects our
continued commitment to scientific knowledge, which
underpins the improvements we make to the service
we offer to transplant centres and other customers. The
introduction of this technology means we will be able to
offer unparalleled detail and accuracy across out entire
tissue typing service.
Advances in technology have an impact on every
aspect of our lives and tissue typing is no
exception. While significant progress has been
made in tissue typing and stem cell provision over
the last few years, Third Generation Sequencing
(TGS) – technology which allows allele-level typing
as standard – provides
a major opportunity to improve the speed and
accuracy of gene sequencing.
The Pacific Biosciences RS II System was selected
because it is currently the only system available that
can sequence full-length HLA genes due to its industryleading read lengths and consensus accuracy. By
providing the highest resolution typing available, we will
be able to unambiguously phase HLA alleles with the
goal of making Haematopoietic progenitor cell
transplants more successful.
Anthony Nolan intends to use this new technology to
comprehensively HLA type new and existing donors as
well as to improve and extend services to our current
customer base.
page 14
Furthermore, using the RS II will allow us to type many
more donors than before and by providing allele level
typing up front, we will also contribute to reducing the
time to transplant.
As well as investing in the purchase of the technology,
we are simultaneously investing in a research
programme around the new technology. My colleague,
Dr Neema Mayor, was awarded the ASHI International
Scholar Award 2014, for her abstract on TGS:
Generation of 252 HLA Class I Genomic Sequences in
a Single Sequencing Reaction Using DNA Barcodes
and Single Molecule Real-Time (SMRT®) DNA
Sequencing Technology.
Dr Neema Mayor receives the ASHI International Scholar
Award 2014
Allied with this, Anthony Nolan’s strategy seeks to offer
services to new customers requiring full HLA typing for
first-time donors, re-typing existing donors, confirmatory
typing when donor/patient matches have been found,
and typing for HLA-related disease association and
drug hypersensitivity.
Anthony Nolan staff and users of our HLA typing
services will gain extra confidence that they have the
most comprehensive data available as we strive toward
ultimately improving transplant outcomes for patients in
the future.
We expect that there will be an increased survival rate
for patients thanks to better matching as a result of the
improvement in accuracy of typing. Of course,
improved matching reduces the incidence of post
transplant complications, such as graft versus host
disease, and will help improve overall survival rates.
Neema also presented work on TGS at the International
Donor Registry Conference in London in May, the
European Federation for Immunogenetics (EFI)
Conference in Stockholm in June and at the British
Society for Histocompatibility and Immunogenetics
(BSHI) conference in Manchester in September.
We are currently in a testing phase with the new
equipment, which has been installed at our laboratories
at the Royal Free site in Hampstead, London.
We expect the machines will be fully operational during
2015. We will continue to conduct research throughout
this time, and beyond, so that scientific knowledge
underpins all the work we undertake with RS II.
Until we have completed the necessary testing phase,
it is difficult to provide an exact cost of the new services
we can offer using the new technology. However, we
already know that RS II will increase our economic
efficiency and will result in highly-competitive pricing.
Early indications are that RS II will allow us to carry out
automated allele-level typing a price that is at least
comparable to typing at a high-to-medium level
resolution.
I’m very excited by this new phase in Anthony Nolan’s
research programme and the associated services we
can offer. We will provide an update next year once we
have completed the testing phase and are preparing to
launch the new technology.
Francisco Boix-Giner, Clinical Scientist at the Anthony Nolan
laboratories, starts RS II on its first test run
page 15
Exploring Perceptions of Quality
Cord Blood in Stem Cell Treatments
Cord blood banking and
treatments are relatively novel in
the UK and Japan compared to
other countries, such as Spain and
America, hence much of the policy
and practices are still being
developed. Exploring perceptions
of ‘quality’ cord blood is an
important field of study for
Japanese and UK policy makers,
cord blood collectors, donors and
bankers, haematologists and
oncologists given these current
policy and practice developments
taking place.
A review of the scientific, clinical and
social literature suggests there are
agreed factors thought to influence the
‘quality’ of cord blood when used in
treatments, such as the cell counts,
and the HLA type and typing
techniques. More recently, the length
of storage and the age of the cord
blood unit have been considered as
factors affecting the ‘quality’ of the unit.
Controversially, elements of the
banking and collection systems have
been raised as possible indicators of
‘quality’ cord blood units, for example
how the cord blood is stored (inclusive
of red blood cells, the bag used),
whether the cord blood bank is
accredited, the methods used to
measure cell counts, and what is or is
not included in the cell count report
received by those working in
transplant centres. As discussed
above, it can be inferred from policy
discussions that clinical expertise may
now also factor in the ‘quality’ of cord
blood units.
However, what is currently unknown is
how those working in Japanese and
UK transplant centres perceive ‘quality’
in cord blood and what factors
influence those perceptions. In
particular, do those working in
transplant centres deem the collection
and banking processes as influencing
the ‘quality’ of cord blood units? What
policies and practices do those
working in transplant centres consider
as facilitating a ‘quality’ cord blood
collection?
How do those in transplant centres
decide which banks to import a cord
blood unit from? Finally, does the notion
of ‘quality’ in cord blood collection,
banking and transplant differ across
countries like Japan and the UK?
The Great Britain Sasakawa Foundation
is funding Dr Laura Machin, a Lecturer
at Lancaster Medical School, and
Dr Tak Matsushige, a Senior Research
Fellow at the National Institute of Public
Health in Japan, to explore these
questions. They plan to do this through
qualitative interviews and an online
survey. Those associated with cord
blood treatments including
haematologists, immunologists,
scientists, donor co-ordinators,
oncologists, are invited to complete
the survey:
http://www.lancaster.ac.uk/shm/
research/projects/cord-blood-quality/
or agree to be interviewed. Ethics
approval has been granted from
Lancaster University and the NHS.
Further details of the project can be
found on the project website: http://
www.lancaster.ac.uk/shm/research/
projects/cord-blood-quality/about/
Or contacting Dr Laura Machin at:
l.machin@lancaster.ac.uk
01524 594 973
Results of voting for BSBMT Executive positions
President:
Charles Crawley, Cambridge
President Elect: Jenny Byrne, Nottingham (previously BSBMT Secretary)
Past President: Gordon Cook, Leeds
Secretary:
John Snowden, Sheffield
We say farewell and thanks to:
Executive:
Stephen Robinson, Bristol
Graham Jackson, Past President
Executive:
Kavita Raj, King’s London
Emma Morris
Executive:
Maria Gilleece, Leeds
Grant McQuaker
page 16
Brunei gallery - By An Siarach, via Wikimedia Commons
8
Octo1b4er
20
BSBMT
Education Day
This year’s BSBMT education day once again found itself in the Brunei
gallery at The School of Oriental and African Studies. The day itself is a
very valuable opportunity to hear speakers of an international reputation
give an update on the state of the art in the field of stem cell
transplantation and the BSBMT committee are to be congratulated on
putting together a rewarding and varied programme. For those of you
who couldn’t make it this year, here’s what you missed:
Post-transplant
lymphoproliferative
disorder
Christopher Fox, Nottingham
University Hospitals NHS Trust
Many centres monitor Epstein Barr
Virus (EBV) viral load following
allo-SCT, but the optimal viral load
threshold and indications for
treatment remain unclear. Dr Fox
guided us through EBV and its
potential consequence - posttransplant lymphoproliferative
disorder (PTLD). EBV is a human γ
herpes virus which has powerful in
vitro growth transforming
properties (it is used to immortalise
B cells in cell culture) and which is
found as a latent infection in 95%
of the adult human population.
EBV has several states of latency
and each is characterised by the
expression of differing sets of viral
proteins and micro-RNAs. Each
latency programme is associated
with different phenotypes of
EBV-related malignancy. Latency III,
associated with blastoid
transformation on infection of naïve
B cells, is the pattern associated
with PTLD.
Donor derived B cell malignancies
(‘immunoblastic sarcomas’) were first
described following allo-SCT in the
1970s and 80s, the reported mortality
rate was high (~90%). While there is
an overlap between EBV DNA-aemia
(the detection of EBV by PCR of
peripheral blood) and probable and
proven EBV disease (where EBV in
blood or tissue respectively is
associated with lymphadenopathy or
end-organ disease) there is by no
means an absolute correlation
between the two.
EBV DNA-aemia after allo-SCT is more
frequent where T-cell depletion has
been used, and is less frequent in
Epstein Barr Virus
EBV author Liza Gross 2005 Virus Proteins Prevent
Cell Suicide Long Enough to Establish Latent
Infection. PLoS Biol 3(12): e430 DOI: 10.1371/
journal.pbio.0030430 http://biology.plosjournals.
org/perlserv?request=get-document&doi=10.1371/
journal.pbio.0030430
patients previously exposed to
Rituximab in the months prior to
allo-SCT. The modal time to EBV
reactivation is at 8-12 weeks
post-transplant and time to peak
EBV load 12-16 weeks. However,
significant numbers of reactivations
are recorded later than 1 year
post-transplant. In a retrospective
survey of 15 UK transplant centres–
looking at transplants performed
between 2001 and 2010 – 69
cases of PTLD were identified (Fox
et al., Bone Marrow Transplantation,
2014). Seven cases presented with
features of aggressive end-organ
disease or multi-organ failure and
these were generally associated
with very high levels of EBV
viraemia (105–107 copies/ml).
The remaining 62 cases presented
with features of aggressive
lymphoma. The median time to
presentation of these cases was
day 120 post-transplant, 81% had B
symptoms and 63% were ECOG
performance status 2–4 at
presentation. Extra-nodal disease
was present in 62%, the liver and GI
tract being to most frequent extranodal sites. The majority of patients
had stage IV disease at presentation.
page 17
There was a significant variation in
EBV viral load recorded at
presentation – between 101 and
108 copies/ml. Of note 23% and
45% of cases had <10,000 and
<40,000 copies/ml.
demonstrated a benefit for a CMV
positive donor in this situation in the
setting of myeloablative conditioned
transplantation, but not in the setting
of reduced intensity conditioning
(irrespective of T-cell depletion).
Following onset of PTLD, OS
was approximately 50% at 2 years.
Patients with lymphadenopathy
had significantly better survival
than those without. Rituximab
monotherapy was effective
treatment for PTLD in approximately
70% of patients. For those patients
failing monotherapy subsequent
combination chemotherapy is
ineffective, but cellular therapy
with DLI can salvage the situation.
A series of cases reported in
Blood (Doubrovina et al. 2012)
demonstrated equivalent efficacy
for unselected DLI, ex-vivo
expanded EBV-specific cytotoxic
T-lymphocytes (CTL) and third
party EBV specific CTL.
The good news in the world of CMV
is that several new drugs are getting
nearer and nearer to the clinic and
offer the promise of simplifying the
management of this problem.
Maribavir has reached a phase III
stage of trials, where it was not
shown to be effective as prophylaxis.
However, this result needs to be
viewed in the light of the fact that the
primary endpoint of this trial was
CMV disease (rather than
reactivation) and the rate of this was
only 6% in the placebo arm. It would
therefore be difficult to demonstrate
a significant reduction in this outcome
and further data on this drug are
needed. Letermovir is a pure CMV
antiviral with specific activity for the
CMV terminase enzyme. It has
demonstrated efficacy as CMV
prophylaxis in phase II clinical trials
and importantly it does not appear
to have significant haematopoietic or
renal toxicity. Phase III trials are
currently in progress.
This is the largest published series
looking at PTLD following allo-SCT
and adds significantly to our
understanding of the nature of this
disease.
Infectious
complications of SCT
Brincidofovir By Ed (Edgar181),
via Wikimedia Commons
Third in the trinity of new and exciting
agents for the CMV problem is
Brincidofovir. Unlike Letermovir, this is
a multi-specific anti-viral agent and
we are likely to be hearing more
about it in a wider context, as one of
its targets seems to be the Ebola
virus. It is a lipid conjugate of Cidofovir
which is released intracellularly and
is orally bioavailable.
Its targets include CMV, BK virus,
adenoviruses, herpes simplex and
variola (smallpox). In phase II trials as
CMV prophylaxis in HSCT recipients,
haematologic and renal toxicity was
not observed, although diarrhoea
(always welcome in the SCT patient!)
was a dose-limiting toxicity.
CMV remains one of the most
persistent and tricky management
problems after allo-SCT, any
expansion of the armoury we can
deploy against it is very welcome.
Per Ljungman, Karolinska Institutet,
Stockholm
Prof Ljungman began by
reminding us that CMV remains an
on-going challenge in allo-SCT.
Any patient/donor combination
where CMV is present is
associated with an impaired
transplant outcome; because of
this a CMV-negative patient should
have a CMV-negative donor if at all
possible. The situation is less clear
in the CMV positive patient – an
EBMT retrospective study has
CMV retinitis - http://www.nei.nih.gov/photo/eyedis/index.asp via Wikimedia Commons
page 18
Veno-occlusive disease
Grant Prentice, Hg Consulting Ltd.
Prof Prentice highlighted the salient
features of veno-occlusive disease
(VOD, aka sinusoidal obstruction
syndrome – SOS). The hepatic
sinusoids contain a mixture of
oxygenated and deoxygenated
blood from the portal and arterial
systems. In VOD, endothelial
damage to the sinusoids releases
tissue factor, leading to thrombosis
within these vessels. The clinical
picture is one of rapid weight gain,
(often tender) hepatomegaly and
jaundice. The onset is usually
within 2-4 weeks of full intensity
allograft but tends to occur later
after reduced intensity conditioning.
Diagnosis should be made on
clinical grounds and the use of liver
biopsy in this situation carries risks.
Cyclophosphamide appears to be
particularly implicated in the
pathophysiology of the disease.
Hepatic glutathione is involved in
the metabolism of the active
metabolite of Cyclophosphamide
and Busulfan downregulates
glutathione expression, possibly
explaining why Busulfan is
associated with an increased
incidence of VOD. The therapy of
VOD remains based on principles of
supportive care. Defibrotide remains
the drug of choice but it is fair to say
that the evidence base behind it is
mixed. As Gordon points out in his
editorial to this issue, we are expecting
a commissioned policy on the use of
this drug soon.
Dendritic Cells
Matthew Collin, Freeman Hospital,
Newcastle
Prof Collin opened with a brief history
of the dendritic cell (DC), reminding
us that for some time after Ralph
Steinman first described them, many
immunologists believed them to be
merely macrophages by another
name. Few probably subscribe to that
view now and the relationship
between monocyte, macrophage
and dendritic cell proves to be more
complex than at first it seemed. Unlike
macrophages, DCs can migrate to the
draining lymph node where they act
as the professional antigen-presenting
cell par excellence. One of the
pursuits of modern day immunology
is the identification of functional
subsets of DCs that express different
Cellular architecture of the liver Zorn, A.M., Liver development (October 31, 2008), StemBook, ed. The
Stem Cell Research Community, StemBook, doi/10.3824/stembook.1.25.1, http://www.stembook.org.
receptors for pathogens (toll-like
receptors), secrete different
cytokines and stimulate the
proliferation of specific T cell
subsets. DCs are principally
divided into plasmacytoid and
myeloid subsets, the latter further
split into CD1c positive, CD141
positive cells. A tissue DC previously
identified as CD14 positive now
appears, by gene expression
analysis, to be a monocyte-derived
macrophage relative.
The answer to the question as to
whether DCs and macrophages
are both derived from circulating
monocytes is ‘probably not, at least
in the steady state’. Part of the
answer to that question comes
from a condition characterised by
DC deficiency, monocytopenia,
severe mycobacterial and viral
infections and alveolar proteinosis.
Variously known as DCML deficiency
or MonoMAC it is caused by
heterozygous germ line mutation
of the GATA2 transcription factor.
In this condition there is severe loss
of DCs and monocytes but the
patients still have Langerhans cells
and tissue macrophages.
There is evidence to suggest that
Langerhans cells and tissue
macrophages are laid down in
utero from embryonic or foetal liver
precursors and are either selfrenewing (LCs) or very stable
(macrophages). The DCML
phenotype can be corrected by
HSCT and cases of GvHD have
been reported following these
transplants. As there are no
recipient monocytes or DCs in this
situation, then the priming of donor
T cells to alloreactivity must be by
other routes, either by long-lived
Langerhans cells and
macrophages or by donor derived
DCs.
page 19
BSBMT open meeting
At this point, dear reader, the
meeting paused; first to allow the
Society to conduct its business in
the annual open meeting and
secondly for lunch. In the spirit of an
accurate representation of the day’s
activities therefore, this article will
now also pause to allow you to
obtain a fresh cup of coffee/glass of
sancerre/bowl of hemlock
according to preference. Ready?
Good, then we shall proceed.
Autografts: The
Cinderella of Transplants
Graham Jackson, Freeman Hospital,
Newcastle
You have to feel sorry for autograft,
the workhorse of the SCT world.
While we’re all spending time and
energy creating human
immunological chimeras and
battling GvHD and CMV, autologous
stem cell transplants (or cis-plants as
they could be called) are getting on
with the work; curing diseases and
prolonging survival with low rates of
TRM and complications.
Although monocytes do not give
rise to DCs in the steady state,
GVHD and other inflammatory
states are different and here
recruited monocytes probably
differentiate into short-lived DCs
and macrophages, a process that
can be modeled by culturing
monocytes in vitro.
Studying skin in cases of GvHD
demonstrates a decrease in
steady-state DC compartments
and an increase in inflammatory
monocyte-derived DCs. Thus an
alternative peripheral model of GvHD
pathogenesis begins to emerge. In this
model conditioning chemo/
radiotherapy causes activation of
resident tissue macrophages (which
are not monocyte derived). These
prime donor memory T cells that enter
the tissues directly. These activated
T cells then recruit donor monocyte
derived DCs, amplifying the process.
This talk emphasised the fact that
when someone works effectively on
both basic biology and clinicpathology at the same time the results
can be far-reaching.
Prof Jackson guided us through
some of the figures that support this
view. There are still far more
autologous procedures than
allogeneic performed. Use of ASCT
over the age of 60 is increasing and
the TRM remains low in multiple
myeloma and Hodgkin lymphoma.
For chemosensitive diffuse large B
cell lymphoma the OS at 5 years is
greater than 60%. In mantle cell
lymphoma the survival curve for
ASCT does no cross that for allo-SCT
until beyond 6 years and the Nordic
MCL2 data have changed practice in
this disease, with reported 10 year
OS of 65% and PFS of 40%. ASCT
also remains very effective in follicular
lymphoma although its use here is
decreasing.
page 20
Reviewing BSBMT data for 14,000
ASCT, non-relapse mortality
(NRM) was 2% and 4% at 100
days and 1 year respectively.
Between 2006 and 2011, 2285
myeloma ASCT procedures in
patients over the age of 60 were
registered. NRM was 2% and 5
year OS 56%. There was no effect
of centre size on these outcomes.
In a meta-analysis of outcomes of
ASCT for myeloma Koreth and
colleagues demonstrated that
ASCT was always associated with
an advantage in PFS although not
always in OS. Whichever induction
regimen is used ASCT always
improves response rate. When
Palumbo and co-workers
compared ASCT with MPR
maintenance, ASCT outperformed
maintenance and, importantly,
only 63% of MPR maintenance
patients were subsequently able
to proceed to ASCT. ASCT may
be the Cinderella of
transplantation, but with outcomes
like these it can make allo-SCT
look like one of the ugly sisters.
The assessment and
staging of GvHD
Paul Carpenter, Fred Hutchinson
Cancer Research Centre, Seattle
This talk was a master class in GvHD
from someone who devotes his
working life to the topic. GvHD can be
difficult to definitively diagnose and
Prof Carpenter began by stressing
that temporal associations are always
important in making the diagnosis;
thus rash, anorexia, nausea or
diarrhoea associated in time with a
precipitant event (engraftment,
tapering immunosuppression, DLI)
is likely to be acute GvHD. In the case
of hepatic GvHD he recommended
watching closely for a transaminitis
following a precipitant event and
intervening early. A biopsy is, of
course, still recommended where
possible. The ongoing biomarker
studies in GvHD mean that one day
we may have blood tests that can help
expedite the diagnosis.
The optimal dose of prednisolone to
use as first line treatment probably still
hasn’t been defined. Prospective trials
Numbers of autologous and allogeneic SCT performed per year in the USA, from Pasquini MC,
Wang Z. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR Summary
Slides, 2013. Available at: http://www.cibmtr.org
have never shown a benefit for a
dose of >2mg/Kg and doses of
1mg/Kg are associated with less
toxicity. At the FHCRC there is a
large emphasis on the use of topical
steroids, both for cutaneous and
gastrointestinal GvHD, where
budensonide has a significant role
to play. Two randomized controlled
trials assessing whether adding
mycophenolate to corticosteroids in
the upfront treatment of GvHD have
failed to demonstrate any benefit
from the addition of mycophenolate.
The talk then turned to chronic
GvHD. The median onset time for
chronic GvHD is 6 months following
allo-SCT and 10% of chronic GvHD
occurs more than 1 year posttransplant. Once on immunosuppression for GvHD treatment, the
median duration of treatment is long
– for cord transplants 1 year, marrow
transplants 1.8 years and for PBSC
transplants 3.3 years. Prof Carpenter
then described a screening
approach for the detection and
assessment of chronic GvHD, which
can be found at http://www.
bloodjournal.org content/118/10/
2679 and which summarises the
approach in much more detail than
there is space for here.
The day concluded with
presentations from Emma DasGupta and Ram Malladi on two
forthcoming UK studies in GvHD.
The first of these, POSTAGE, is a
data collection study on the
outcome of varying second line
treatments for steroid refractory
GvHD. The second, AZTEC, will
examine whether azacitidine may
have a role to play in steroid
refractory or dependent GvHD. It is
encouraging to see BSBMT centres
leading on research of this nature
and was an uplifting end to the day.
page 21
I Fought the Law,
and the HTA Won
Regulation, Standards and Codes of Practice from the Human Tissue Authority
The business of transplantation
is a closely regulated thing,
understandably, as the processes
and outcomes involved can cause
massive changes to the recipient
and also have significant impact
upon the donor. The top brass
at hospitals often seem to Clash
with our aspirations for a worldclass transplant unit and more
beds, day case space, medics,
nurses, scientists, etc., thinking
that ‘those pesky Haematologists
only have to worry about FACTJACIE standards’, but they would
be wrong. This article is a quick
overview of Human Tissue
regulation.
The Human Tissue Authority is the
recognised Competent Authority in
the United Kingdom charged with
regulating our activities. They do this
by conducting audits to assure
compliance with regulations and
standards, and issue licences to
organisations (‘corporate bodies’)
that meet their requirements.
They also monitor what we do through
a programme of annual activity
reporting and through notification of
Serious Adverse Events and Reactions
(SAERs).
The regulations are predominantly
Statutory Instrument (SI) 2007:1523,
the Human Tissue (Quality and Safety
for Human Application) Regulations
2007. Parts of SI 2004:0030, The
By Redreg (travail personnel/œuvre dérivée) [Public domain], via Wikimedia Commons
Rob Wosley
2.The storage of tissues and/or cells
for human application.
The licence may be shared with other
hospital departments; for instance, in
our trust bone-banking is performed
by the orthopaedics department
under the same license.
The licence is bestowed on the
Trust as a Corporate Body; the
hierarchy of mandated positions is as
follows; Licence Holder > Designated
Individual (DI) > Person Designated
(PD).
Contemplating fighting the law? –
Don’t, they’ll win
Human Tissue Act, also apply, and so
does SI 2006:1659 The Human
Tissue Act 2004 (Persons who Lack
Capacity to Consent and Transplants)
Regulations 2006. These regulations
are a direct result of the 2004 EU
Directive ‘on setting standards of
quality and safety for the donation,
procurement, testing, processing,
preservation, storage and distribution
of human tissues and cells’ (and
*breathe*) and the two subsequent
technical directives from 2006.
Thus an SCT centre will hold a
licence for:
1.The procurement, testing and/or
distribution of tissues and/or cells
intended for human application.
The Licence Holder is the
representative of the organisation,
with a raft of responsibilities including
(but not limited to) ensuring third
party agreements are in place,
data protection and confidentiality,
distribution and recall and serious
adverse event and reaction reporting.
The Designated Individual is the
person who drives the licence on a
day-to-day basis. They’re the Head
Honcho with a hotline to the HTA.
The DI has a statutory duty to ensure
that only suitable persons participate
in licensed activity and that suitable
practices are employed, (both on site
and at third party premises), licence
conditions are complied with and
regulations for information and
confidentiality are complied with.
page 22
Other roles of the DI include:
•Ensuring that the Quality and
Safety Regulations are complied
with
•Submission of an annual activity
report
•Notifying the HTA of serious
adverse events and reactions
(SAERs) within 24 hours of
discovery
•Ensuring a functional Quality
Management System is in place
•Ensuring donor selection and
evaluation complies with the
Regulations
•Ensuing acceptance or rejection or
tissues and cells complies with the
Regulations
•Ensuring third party agreements
are in place and maintained for all
licensable activities
•Ensuring HTA Directions, regulatory
alerts and other communications
from the HTA are provided to
relevant third parties
•Supervising the system for
verification of tissues and cells prior
to release
•Approving documented risk
assessments
•Determining fate of tissues and cells
•Ensuring, in conjunction with the
LH, that imports and exports of
tissues and cells from non-EEA
states meet the standards required
here.
The role looks scary, but it’s
predominantly common sense, guided
by regulation.
The Person(s) Designated doesn’t
have a legal duty comparable with the
DI, but they do have the ability to direct
others in relation to the Human Tissue
Act and Regulations. Their primary
function is to assist the DI in
developing and implementing those
procedures that ensure the
requirements of the Regulations are
met. This means that other persons
working under the direction of the PD,
which includes clinicians and nurses,
are advised about how and why they
need to follow the procedures and
systems in place.
The trust’s Licence Holder is usually
the Medical Director, the DI usually a
consultant in one of the specialities
carrying out the licensed activities. The
PD for SCT is likely to be the Service’s
Governance & Quality Manager. This
might seem odd to some, but it
releases the Clinical Program Director
to focus on being a Doctor, and the
knowledge of regulatory and
accreditation requirements the QM
has makes them ideally suited to the
role. They provide the DI with all the
SOPs relevant to licensed activity for
their approval prior to final sign-off and
distribution, copies of reviewed SLAs,
and the Quality Manual.
At our trust the DI holds quarterly
Licence meetings with the Persons
Designated, the Programme Directors,
and other relevant team members
(matrons, transplant coordinators, lead
apheresis nurses, etc.) to ensure both
systems are working in accordance to
the regulations, and to discuss activity,
SAERs, relevant accreditation activity
and any regulatory updates or
Directions that have occurred. In the
six months leading to a two-yearly
Licence Audit, these Licence
meetings become monthly and focus
on preparation, the intention being that
resources are pooled to facilitate a
cohesive inspection process. Selfassessments are completed against
the HTA Guidance and Standards,
and these allow gap analysis to be
conducted if necessary.
The Guidance I’ve referred to is the
Guide to Quality and Safety Assurance
for Tissues and Cells for Patient
Treatment, which is every DI & PD’s
bible. It’s on the HTA website and can
be downloaded for free as a PDF. Its
62 packed pages make it a more
essential read than the Victor Book for
Boys Summer Special used to be (but
the pictures aren’t as good).
Yes, I did also mention Standards.
The HTA have standards, which are
derived from the regulations, and they
expect organisations to comply with
them. The standards are available on
their website, and are grouped into the
following sections:
•Consent
•Governance and Quality
•Premises, Facilities and Equipment
•Disposal
Because they have their roots in the
Regulations and the EU Directives,
most of the standards require things
that compliance to FACT-JACIE
requires too.
The standards also reference the
HTA’s Codes of Practice, which again
are freely available from the HTA
website as PDF documents, and
which have been given a refresh this
year. The Codes we need to concern
ourselves with are:
•Consent
•Disposal of human tissue
•Donation of allogeneic bone
marrow and PBSC for
transplantation
•Import and export of human
bodies, body parts and tissue
•Research
page 23
The HTA expect to see a robust
training programme for Consent
based on the Code – there’s a handy
presentation available from them,
which you can modify and add
questions to the end of – a great tool
to add to mandatory e-learning for your
medics. Keeping accurate and current
records that the Doctors have
completed the training successfully is
guaranteed to score points with the
regulator. Training should also be
given in the other Codes, and it’s a
good idea to ensure that the whole
team have some knowledge of the
Regulations, the Codes, the Guidance
and the Standards. It’s possible to get
it all into a one-hour presentation, but
remember to keep it engaging or your
audience may suffer information
overload.
As an audit experience, the HTA
approach is subtle, engaging,
informative and supportive. The HTA
have embraced the principle that audit
is a tool to assess compliance, not a
weapon with which to detect nonconformity. They want the process to
be as stress-free as possible and for
the exchange of information to be
open, honest and transparent. There’s
the usual formal opening meeting (the
Licence Holder should attend, along
with the DI and PD, Clinical
Programme Director(s), Quality
Manager(s), senior managers and
senior nurses), a tour of the facilities,
document and records review, and
interviews with key personnel (always
the DI and PD, Quality Manager(s),
and core personnel if necessary,
which will be notified in advance when
the HTA send a timetable for approval).
There will be no surprises in the
closing meeting; you will have
constant feedback all day about how
things are performing. This gives you
the opportunity to put things right
before the audit closes, or to explain
why you do things the way you do if
there’s a query. The auditors will also
praise good practice and will want to
share it with other centres – and will
bring other people’s ideas to you.
Don’t think they’re a soft touch,
though. Failing to meet a standard will
result in a documented shortfall –
these can be minor or major,
dependant on severity. The auditors
can also issue ‘advice’ where they see
practices that aren’t non-compliant,
but could be tighter. The audit report is
usually published on the HTA website
70 days after the report is issued to
the centre – and that means the world
can see it, shortfalls and all. The report
will contain a CAPA plan if one is
required, this is also sent separately,
and it makes sense to get the team
together to complete and return it.
Remember, plan what your actions
are, do them, check them, and act on
anything that didn’t go to plan, and
then send the evidence to the HTA as
soon as you can.
A robust Service will have a strong
Quality Management System and this
will ensure the HTA process runs
smoothly, after all, there’s no point
fighting the law, because they’ll win…
Rob Wosley
Quality Manager, South West
Peninsula Transplant Service
Code of practice 6
Donation of allogeneic bone marrow
and peripheral blood stem cells for
transplantation
Version 14.0
Updated: July 2014
Scheduled review date: July 2016
www.hta.gov.uk
page 24
The President’s column
This is my second column of 2014, and
my last as the sitting President. I would
like to formally thank Graham Jackson,
outgoing Past-president for his support,
guidance and counsel – helping me to
be a better president over these past two
years. I leave the Society at least no
worse than I took it over from him and
have every confidence that the incoming
president, Charles Crawley, will drive the
Society forward. Good luck Charles!
I would like to thank Emma Morris and
Grant McQuaker, both of whom leave the
Executive, for the efforts and support
over these past 6 years. Finally, I wish to
congratulate Jenny Byrne on becoming
the Society’s President-elect, whom
I know will support Charles and the
Society over the next couple of years
before taking the helm. The Society is
definitely in good hands from now on!
Professor Cook presents
Professor Marks with the
BSBMT long-service award at
the BSBMT autumn meeting
Over the last 18 months, the provision of specialist services
in England has been dramatically altered with the creation
of NHS England. Whilst everyone knew it would be a
learning curve for both clinicians and commissioners alike,
I guess we didn’t realise how steep a curve it has been,
especially with the constraints of the public finances. In the
context of BMT, the commissioners have been supported
through the CRG, driven by the excellent chairmanship of
Tony Pagliuca. There has been the evolution of
performance matrix, quality improvement schemes and
initiatives, but perhaps the most pressing issue is the
commissioning of clinical practice elements fundamental to
the provision of a robust and comprehensive clinical
transplant service. Several issues have been tackled
already, from a commissioning perspective, such as
Plerixafor usage and umbilical cord blood grafts in
allogeneic transplantation in adults, with a commissioned
policy on Defibrotide usage expected shortly. However,
there is a very pressing area that needs to be agreed,
representing a clear area of clinical unmet need. That is,
second allogeneic stem cell transplantation (AlloSCT2) for
relapsed disease. We already have a commissioned
position for AlloSCT2 for graft failure, but for adults with
relapsing disease, there is currently no national uniform
recourse to funding, and patients are being denied this
form of therapy. I have spent considerable time on
preparing an evidence-based review and position paper,
currently being circulated for consultation within the CRG
before going to the NHS England commissioning board,
that sets out the parameters for the usage of AlloSCT2.
The evidence-base in this setting is
relatively sparse, though is augmented by
a key retrospective analysis by the EBMT
and by a BSBMT CTC study, both being
submitted for publication imminently. Not
surprisingly, not all patients benefit from
an AlloSCT2 in the relapse setting, with
analysis delineating which clinical features
delineate both those that will and those
that are unlikely to benefit from an
AlloSCT2. There is thus a clear need to
formulate a commissioned policy in this
regard and I am hopeful we can agree
this soon with the commissioners to
prevent further clinical decision-making
from being denied.
Once again, the BSBMT team produced
an excellent and professional Annual
Commissioning report, the 5th in fact, and
I would like to thank them for all their hard
work and devotion. Furthermore, I would to thank all
transplant centre directors and data managers for helping
us complete this task. This document demonstrates the
clear delivery of a publically funded healthcare system
specialist service of the highest quality, something all of us
should be proud of.
This year, I thought it was important to recognise individuals
who have served the Society, devoting timeless commitment
over an extended period. I was immensely proud to present
Professor Graham Jackson and Professor David Marks with
a BSBMT Long-service award at our autumn meeting. This
small token represents our acknowledgement of their
service to the Society spanning over 10 years, for which the
Society is very much the better. Thank you both.
Finally, thanks to Patrick Medd for taking over the running of
the newsletter, revamped and reinvigorated by Maria
Gilleece. This professionally produced snapshot of the
Society and members’ activities serves to highlight the high
standards of professionalism exhibited by the UK transplant
community and I have been immensely proud to serve them
these past 2 years. I’m sure Charles will provide better
columns (and on-time I’m sure…. sorry Patrick for my ‘11th
hour’ approach!)
No apology needed Gordon, I’d say your approach was
‘7th hour’ at worst! - Ed.
Thank you all for enduring my ramblings and I wish you all
the very best for 2015.
Best wishes, Gordon.
“The reward for work well done is the opportunity to do more”
Jonas Salk (1914-1995)
page 25

Taming The beasT - British Society of Blood and Marrow

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