By Arthur Flatau (flataua@acm.org)
Table of Contents
Introduction
The combined annual meetings of the American Society for Blood and
Marrow Transplantation (ASBMT) and the Center for International Blood
and Marrow Transplant Research (CIBMTR), -- aka the Tandem BMT meeting
-- were held February 9 - February 14, 2004 in Keystone, Colorado.
I was supposed to arrive Thursday evening, but my flights were messed
up so I arrived Friday morning and therefore missed the sessions
Friday morning. The CIBMTR advisory committee met during this meeting
so I was able to attend some of the other sessions. Below is a summary
of the talks and presentations that I attended. Since I am not a
medical doctor or researcher in the field, it is possible; in fact
quite likely that I have misunderstood or misinterpreted some of what
was said. In addition, this is based on my notes at the time and I may
not have been able to read them or remember correctly what was said.
I try to attend sessions that focused on clinical aspects of
transplants. I did not see much talk of mice, which is good because I
generally stop understanding at that point and often tend to fall
asleep. There are some sessions or talks below where I have not
reported much or anything. This usually meant that I did not
understand enough of the important points of the talk to say anything
useful. Please send me an e-mail (flataua@acm.org) if you have
questions, comments, notice a typo or just think that this was useful
to you.
As in any field that is undergoing a lot of changes the terminology
that was used was sometimes inconsistent. I will try to use consistent
terminology and acronyms throughout this report. I will use NST
to refer to non-myeloablative stem cell transplants and
reduced intensity conditioning (RIC) refers to transplants
where the preparative regimen was not as intense as the usual regimen,
but was still sufficiently intense enough that it would not be given
with out a transplant. A true non-myeloablative regimen could be
given without a transplant. The preparative regimen in a RIC
transplant still has significant anti-cancer effects, but can be
tolerated by older and less stable/sicker patients.
I use HSCT to stand for Hematopoetic Stem Cell
Transplant as a generic name to refer to some kind of stem cell
transplant, where the source of stem cells might be bone marrow,
peripheral blood, or cord blood. I will use URD for
unrelated donor to mean a transplant with a Matched
Unrelated Donor (MUD) or a mismatched Unrelated
Donor (which also would be abbreviated MUD, I guess). Of course,
GVHD stands for Graft versus Host Disease. Some other
acronyms that are used:
| Bu | Busulfan |
| Cy | Cytoxan also called Cyclophosphamide |
| PBSCT | Peripheral Blood Stem Cell
Transplant |
| TBI | Total Body Irradiation |
| DLI | Donor Leukocyte Infusion |
| CR1 | First Complete Remission |
| CR2 | Second Complete Remission |
| TRM | Transplant Related Mortality |
| DFS | Disease Free Survival |
| EFS | Event Free Survival |
| OS | Overall Survival |
Summary
At this meeting, I did not see anything that I thought was really
novel and exciting. Patients with CML are still being treated
overwhelming with Gleevec, although some get transplants after Gleevec
appears to stop working or they can not tolerate Gleevec (this is good
news). More and more "mini" transplants (non-myeloablative
transplants and reduced intensity transplants) are being done.
Because of this more and more patients are getting transplants,
including some patients in their seventies. Whenever I attend the
Tandem BMT meeting, I always alternate between thinking that this is
the same old thing and seeing exciting, novel therapies that could
cure many patients. This meeting was more of the former, I did not
see many new and exciting treatments.
Friday, February 11, 2005
New Directions in Hematopoietic Stem Cell
Transplantation: Overcoming Redundancy of the Immune System
Luncheon Satellite Symposium
12:00 PM - 1:30 PM
Chair: Andrea Bacigalupo, MD;
Supported by an unrestricted educational grant from Genzyme
Corporation.
Allogeneic Marrow or PBSC for Myelodysplasia and Myeloproliferative
Disorders -- H. Joachim Deeg;
The optimal life expectency for Low Risk Myelodysplasia (according to
IPPS scores) is to wait to transplant until the patient starts
progressing to AML [1]. High-risk patients
should be transplanted as soon as possible. The probability of
relpase is higher however for high risk patients after transplant.
There is no significant different for patients who have a transplant
from a HLA identical sibling and a matched URD (with matching done
with high resolution typing). It appears that Peripheral Blood (PB)
is more effective then bone marrow (BM) at least for high risk
patients. Adding ATG to the prepartive regimen reduces the likelihood
of GVHD (both acute and chronic), but survival is no better and may
actually be worse.
An open question is whether there is any benefit to pre-transplant
induction chemotherapy. A French study showed patients who got
induction and achieve a remission do not relapse as often. However it
is not clear whether this just indicates who is still responding to
chemo. A retrospective study from Seattle showed no difference in
survival between patients who recieved induction therapy and those who
did not.
Myeloproliferative Disorders (MPD)
There are two major risks factors for patients with MPD according to
the Lille Score. Anemia (Hgb < 10) or a high (> 30,000) or low White
blood count (< 4,000). Barosi [2] identified
another risk factor, patients with fewer CD34+ -- less then
300 x 106 did better.
The Addition of Rabbit Anti-thymocyte Globulin to a
Non-Myeloablative Conditioning Regimen to Reduce Graft vs. Host and
Host vs. Graft Reactions -- Scott Rowley, MD;
Background and rationale for study. Allogeneic transplants using a
conditioning regimen of low-dose TBI alone resulted in a significant
risk of graft failure. Fludarbine was added to the prepartive regimen
to reduce graft failure. However the known higher incidence graft
failure and acute GVHD suggest that additional immunosuppresion would
be beneficial if it were not too toxic (additional TBI was deemed to
toxic).
Patients were eligible for the study if the were older then 50 or if
they were at high-risk for regimen related toxicity if they were 50 or
younger. They needed to have a matched or 1 antigen mismatched
donor. There Karnofsky score (a measure of their overall health) had
to be at least 50, compared to a Karnofsky score of at least 70
required for a fully ablative regimen.
22 patients were transplanted (one got two transplants) for a variety
of hematological cancers. The median age was 56 and the oldest was 72
(the 72 year old is now 74.5 years old and in remission). 8 patients
had had a previous transplant. No patients had CMV disease. The
incidence of acute GVHD was 40% and chronic GVHD was 80%, however
there were no deaths due to GVHD. 7 patients remain alive and in
remission 11 to more then 28 months post transplants.
Imatinib Mesylate/Bu/Flu/Thymo for Allogeneic CML
Transplantation -- Richard E. Champlin, MD.
Transplants are the only know curative therapy for CML. However
almost all patients are now treated initially with Gleevec (Imatinib
Mesylate) as it has very low toxicity and almost all patients respond
to it. With the use of Gleevec and DLI after a transplant, there are
multiple chances for curing the patients. Gleevec has been used
successfully to treat relapses after transplants as well as DLIs
11 patients have been treated with a NST (using Gleevec, Busulfan,
Fludarabine and ATG as a prepartive regimen). All are alive in
cytogentic remission, although about half are recieving Gleevec
post-transplant as they had evidence of Minimal Residual Disease
(MRD).
Gleevec is the preferred initial treatment for CML for most patients.
If there is a good response, it should be continued. For younger
patients and those who do not respond well to Gleevec, transplants
should be done.
CIBMTR Solid Tumors Working Committee Meeting
2:30 PM - 4:00 PM
Chairs: P Stiff, MD, R Childs, MD, D Blaise, MD;
Scientific Director: M Arora, MD, MS;
Statisticians: K Sobocinski, MS, B Logan, PhD.
There were many studies of different tumors in progress.
Some transplants were tried in melanoma, but survival has been poor
and no one is doing further studies.
Allogeneic transplant for Breast Cancer. There are 30 cases in the
registry from the U.S. and 37 from Europe. The question is whether
there is a graft versus tumor effect, is a reduced intensity
conditioning (RIC) transplant useful. Some data from the registry
indicates that there might be some graft-versus-tumor effect, although
the numbers are very small.
A study of renal cell carcinoma is looking at about 100 transplants
between 1998 and 2002 and what predicts survival or a good response.
This study is still collecting more data on patients, in particular
what other therapies they had undergone. There are more then 300 such
transplants reported to the CIBMTR.
There was a presentation on a study on autologous transplants for
testicular cancer, although I found it confusing. Some patients have
undergone tandem transplants which have a higher earlier chance of
death from treatment but a lower risk of relapse yields equivalent
long term survival.
Another study is looking at transplants for adults with Ewing's
Sarcoma. There are 137 patients less then 50 years old who were
transplantetd between 1989 and 200. The Disease Free Survival (DFS)
is 31% at 3 years and Overall Survival (OS) of 38% at 3 years.
Patients with poor performance status did much worse as patients with
metastatic disease or who had relapsed did poorer.
There are studies that are in progress or planned to look at
autologous transplants for soft tissue sarcoma (there are about 120
transplants reported to the registry for soft tissue sarcoma between
1999 and 2000). Another potential study is looking at allogeneic
transplant for colon cancer, there are only about 35 patients reported
from 1999 and 2004.
WORKSHOP 2: Non-myeloablative Allotransplants
4:00 PM - 5:30 PM
Co-Chairs: Sergio Giralt, MD, MD Anderson Cancer Center;
Dietger Neiderwieser, MD
The workshop attempted to address the question of what constitutes a
Non-myeloablative Transplant (NST) conditioning regimen and the
applicability of NST to a particular disease.
According to the Champlin critieria a reduced intensity
conditioning (RIC) regimen (this is more usually used to describe
NSTs):
- Reversible Myelosuppresion without stem cell support
- Limited non-hemotological toxicity
- Associated with mixed chimerism at engraftment
It is not understood into which category many regimens that are used
for NSTs and RIC transplant fit. Cytoxan at less then 200 mg/kg and
TBI and less then 500 cGy are generally considered non-myeloablative.
However the dose of Busulfan that is that is non-myeloablative is not
as well establiched, 9 mg/kg is generally thought of as a RIC.
Melaphalan has been given at 140 mg/m2 without stem cell
support.
There is a lock of data regarding does of conventional alkaylating
agents that can be used without stem cell support. There is a lack of
data regarding the toxicity of conditioning regimens used in NSTs.
There are no good surrogate markers for tissue damage.
Older patients are getting more transplants (RIC and NST) even using
unrelated donors. Patients are not required to be in remission even
with RIC transplants.
The session ended with talk about what to do with CML patients, this
had little to do with the topic, other then what kind of transplant
they should have if they fail Gleevec. The consensus was that they
should not rely on "super-Gleevec" drugs that are not being tried
experimentally. There is too little data on them, only about 8 months
of follow-up. Gleevec is not a cure, if it is stopped even in
patients with a molecular response, the patients will relapse.
Patients on Gleevec should be monitored at the molecular level.
Anti-Infective Strategies in the Management of
Hematologic Stem Cell Transplantation
Dinner Satellite Symposium
7:00 PM - 8:30 PM
Chair: John R. Wingard, MD;
Supported by an unrestricted educational grant from Pfizer Inc.
"Managing MRSA Infections in HSCT Recipients" -- Jan
E. Patterson, MD, University of Texas Health Science Center at San
Antonio, Texas;
Dr. Patterson gave an overview on how to prevent and treat
Methicillin-Resistant Stphhylococcus aureus (MRSA). MRSA appears to
be getting resistant to more drugs and the number of infections that
are resistant is increasing. 60% of S. aureaus infections are
resistant now versus 30% in 1989 according to a recent survey of 300
hospitals.
Hand washing is the most important measure to prevent
MRSA.
Some strains exhibit "intermediate": resistance to vancomycin. The
vancomycin resitant organisms have thicker cell walls. The good news
is that resistance to vancomycin is not that common.
There are many drugs that can be used to treat MRSA. Vancomycin
works, but must be monitored in the blood. Linezolid (Zyvox ™)
also has efficacy. In a randomized trial with vancomycin the overal
results were similar. Minocycline can be used orally or IV and is the
most active tetracycline in treating MRSA.
Evaluating the Risks of Blood Transfusions in HSCT Recipients
-- Edward L. Snyder, MD, Yale University School of Medicine, New
Haven, Connecticut;
Dr. Synder gave an overview of the potential risks of blood
transfusions. Patients can have a variety of reactions to blood
productions (hemolytic, allergic, immunologic) and blood can transmit
various infections.
The use of Leukocyte Reduction filters (filters that remove white
blood cells from red blood or platelets in the blood banks) have
reduced the incidence of allergic reactions to red blood cell
transfusions by about 30% and almost eliminated the risk of allergic
reactions to platelets.
Many viruses can be transmitted by blood and bone marrow or peripheral
stem cells. This include Hepatitis (A, B and C), HIV and CMV. Blood
is screend for Hepatitis B and C (not Hepatitis A, because if the
donor can transmit the disease he or she will be sick and will be
screened out from donating).
Bone marrow and peripheral blood stem cells can be contaminated with
bacteria. However this is not a contraindication to transplanting
these cells, patients do not appear to do worse.
Strategies for the Management of Pulmonary Fungal Infections --
John R. Wingard, MD.
Dr. Wingard gave an overview of diagnosing and treating fungal
infections in the lungs. Unfortunately by this time I was too tired
to be able to absorb much of what he talked about.
Saturday, February 12, 2005
Immune-Mediated Marrow Failure Syndromes: Issues
in Effective Transplantation
Breakfast Satellite Symposium
6:30 AM - 8:15 AM
Chair: H. Joachim Deeg, MD;
Supported by an unrestricted educational grant from Pfizer Inc.
Cord Blood Therapy and Conditioning Regimens -- Nelson J. Chao, MD;
Dr. Chao talked about cord blood transplants in adults. Cord blood
may provide an alternative source of stem cells for adults who do not
have a matched sibling donor and can not find a match in bone marrow
registries. Cord blood has disadvantages and advantages. Advantages
include naive T Cells, so it does not have to match as well as bone
marrow or PBSC and allows a more rapid recovery of Natural Killer (NK)
cells. However it provides a limited cell dose and engraftment is
slower. It only provides an option for a single transplant, there is
no opportunity for a DLI.
The Japanese have transplants a relatively large number of adults and
overall patients who recieve cord blood appear to have the same
survival as those who recieved bone marrow. They found a lower risk
of acute GVHD, but a higher rate of chronic GVHD compared to
transplants with bone marrow from unrelated donors (other studies,
however have shown a lower risk of chronic GVHD). There was a lower
risk of transplanted related mortality (TRM). Overall cord blood appeared
to be as good as a 1 antigen mismatched related donor, but not quite
as good as a well matched unrelated donor. Another study have shown
that the Japanese have a lower risk of acute GVHD from bone marrow
transplants as compared to caucasian Americans.
One way to reduce the TRM because of long engraftment times is to use
a Non-myeloablative UCBT (umbilical cord blood transplant). At study
at Duke (and at University of Minnesota or another similar study
there) is using a conditioning regimen of Fludarbine, Cytoxan and
ATG. Only a few patients have been transplanted, but it seems that
the time of neutropenia is short and that usually the donor cell
engraft and lead to full donor chimerism.
In conclusion, cord blood transplants in adults are feasible and the
overall results look encouraging.
Aplastic Anemia and Other Immune-Mediated Marrow Failure
Syndromes--When to Transplant -- Neal S. Young, MD.
Aplastic Anemia (AA) and Myelodysplasia (MDS) are related syndroms and
are often hard to distinguish. The immune system is the culprit in
almost all cases of AA (i.e. it is an auto-immune disease).
PLENARY SESSION 3: GvHD/Histocompatibility
8:30 AM - 10:00 AM
Chair: Olle Ringdén, MD, PhD, Karolinska Hospital;
Overview of Graft-versus-Host Disease in Allogeneic Stem Cell
Transplantation -- Olle Ringdén, MD, PhD, Karolinska Hospital;
Cell injury from chemo, radiatoin and infections leads to over
production of cytokines, which in turn leads to GVHD. Risk factors
for acute GVHD include:
- Histocompability i.e. patients with donors that are not as well
matched are more likely to have GVHD.
- Immunosuppresive therapy
- A Female donor into a Male Recipient
- Age
- Full donor chimerism
Adding methotrexate (MTX) to Cyclosporine (CsA) reduced GVHD compared
to CsA alone. In Seattle they believe that Tacrolimus (FK-406 or
Prograf) is equivalent to CsA in the short term but allows earlier
reduction of immuno-suppresions and leads to better outcomes. ATG
given to patients who are undergoing a MUD transplant reduces TRM and
improves survival. 6-8 mg/kg appears to be the optimal dose.
The role of the microenvironment. Patients in LAF rooms have a
decreased risk of GVHD. Home care patients have a decreased risk of
acute GVHD but chronic GVHD was similar and relapse was similar. Long
term survival was better with home care.
Ethnic role of GVHD. More homogenous populations (e.g. Japan)
have a lower risk of GVHD. Faster engraftment (full donor chimerism)
is associated with a greater risk of GVHD. The use of G-CSF
(Neupogen) is also associated with a higher risk of GVHD.
Treatment of GVHD. Drugs used to treat GVHD include steroids,
ATG and OKT-3, Thalidomide and PUVA. For Grade III and IV GVHD
neither ATG or steroids work well. Mesenchymal Stem Cells (MSE) look
promising for treating Grade III-IV GVHD - can be taken from another
donor -- e.g. a parent.
Chronic GVHD Risk factors include:
- Age
- Acute GVHD
- Splenctomy
- Peripheral Blood appears to cause more chronic GVHD then Bone
Marrow.
Treatment -- mostly with the same agents as acute GVHD, although
another option is Rapamune. Chronic GVHD has a bigger anti-leukemic
effect compared to Acute GVHD. There still appears to be a graft
versus leukemia effect without GVHD as teh relapse rate for allogeneic
transplants is lower then for twins or for autologous transplants. In
Renal Cell Carcinoma, good survival is seen in patients who get
chronic GVHD and recieve DLI.
Pathophysiology of Graft-versus-Host Disease -- George Sale,
MD, Fred Hutchinson Cancer Research Center;
Some day I may understand pathology and pathophysiology, but now is
not the time. Dr. Sale talked aobut the targets of GVHD, which
appear to be sites where there are more epithelal stem cells.
Histocompatibility and Graft-versus-Host Disease -- John
Hansen, MD, Fred Hutchinson Cancer Research Center
Dr. Hansen talked about allo-reactivity and GVHD in HSCT patients. A
patient who had a transplant with a mismatched URD will generally have
a worse outcome if there is a mismatch in class I and class II alleles.
Petersdorf [3] found that HLA-C mismatches are
more important than was thought in the early and mid 1990's.
Flomenberg [4] found that patients whose had an
HLA mismatch in A, B, C or DR had a poorer outcome, however mismatches
in DQ and DP are OK.
For patients with CML transplants within 1 year of diagnosis, or
between 1 and 2 years of diagnosis did about equally well and did
better then those transplanted later.
The effect of HLA mismatches may be disease specific, mismatches in
AML patients do not appear to be as important as other diseases.
All allele mismatches are not the same. PBSC patients appear to to
take longer to get off all immunosuppresive therapy , but there is no
difference in survival. With HLA mismatched patients, there is a
longer time to get off immunosuppresive therapy and survival is
poorer.
We do not know if a particular therapy for GVHD will work. There is
no good way to predict who will benefit from a particular therapy.
Consumer Advisory Committee Meeting
10:30-12:00
The CIBMTR would like to get input from consumers (i.e. patients,
family members of patients and donors) on research that CIBMTR
conducts and how it effects consumers. This meeting was another step
towards this goal. The attendees included:
Mary Horowitz, M.D., Scientific Director-CIBMTR
Jeffrey Chell, M.D., CEO-CIBMTR and NMDP CEO
Robert Baitty, Head of the Bone Marrow Transplant Division of HRSA and
a transplant survivor
Shelley Tims, HRSA
Robyn Ashton, HRSA
Doug Rizzo, M.D., CIBMTR and Scientific Director for the Late Effects committee
Stephanie Lee, M.D., Dana Farber Cancer Institute and co-chair of the
Health Services and Psyhosocial commitee
Seira Kurian, M.D., CIBMTR
Pamela Weisdorf, former head of Office of Patient Advocacy of NMDP
Arthur Flatau, patient rep., that's me
Cyndi Newman, Gift of Life Bone
Marrow Registry
Andrea Feldmar, patient family rep., member NMDP board
Melanie Goldish, patient family rep., SuperSibs!, member
NMDP board
Myra Jacobs, Executive Director, National Bone Marrow Transplant Link
Mary Halet, donor rep., NMDP
Rebecca Drexler, CIBMTR
Paula Watry, CIBMTR
Participants who called in:
Sue Stewart, patient rep., BMT InfoNet
Joana Ramos, patient rep.
This was a good discussion of how to include consumers in the
activities of the CIBMTR. In particular it is felt that consumers can
make a significant contribution to the Health Services and
Psychosocial Issues Working Group, the Late Effects Working Group and
the Donor Health and Safety Working Group. My feeling is that there
probably are contributions that can be made to the other committees as
well, however it would probably be most valuable to have patients
attend some of the meeting to report on what is going on. Some
activities that a Consumer Advisory Comittee could help with are
disseminating the research done by CIBMTR to patients. There are
several ways this could be done, Sue Stewart from BMT Infonet reported
that they have more then 15,000 subscribers and that regular
communication with patients is important. A specific project that
could be undertaken in the relatively short-term is the dissemination
of the consensus paper from the late effects committee (see below). It is important to get this paper to not
only patients currently being released back to their referring
physician, but also to patients who were treated years ago and are
being followed by their referring physicians.
CIBMTR Late Effects and
Quality of Life Working Committee Meeting
12:30 PM - 2:00 PM
Chairs: G Socie, MD,PhD, J Wingard, MD, B Bolwell, MD;
Scientific Director: JD Rizzo, MD;
Statisticians: H Tang, MS, J Klein, PhD.
Doug Rizzo (CIBMTR) and other including Stephanie Lee (Dana Farber),
Stella Davies (Cincinnati Children's Hospital Medical Center) and John
Wingard (University of Florida) have written a paper that gives
recommendations for long term follow-up care for HSCT patients. This
is intended as a guide giving expert consensus of long term follow-up
for HSCT patients. This is not evidence based as there is not a great
deal of evidence on what to do. John Wingard said that it should be
distributed to patients when they are released from the transplant
center back to their referring physician. This paper is intended for
referring doctors. The hope is that this will be updated every 2-3
years. [I hope that we can get it to patients and their doctors who
have already been referred back to their transplant center, perhaps
years ago.]
Another study is looking at the effectiveness of DLI in treating
Post-Transplant Lymphoproliferative Disorder (PTLD). There are
currently too few patients in the registry who had PTLD and were
treated with DLI to do a study. It would probably be better to look
at all patients who were diagnosed with PTLD and see how they were
treated and what the outcome was.
A recently published study [5] found that
patients who had chronic GVHD were at increased risk of getting
squamous cell carcinoma (skin cancer). Another study is looking at
the risk fo other solid tumors post-transplant.
Studies were proposed to look at the incidence of Bronchoilitis
Obliterans (BO) are reduced-intensity stem cell transplants and causes
of secondary cancers post-transplant.
CIBMTR Health Policy Working Committee Meeting
2:30 PM - 4:00 PM
Chairs: S Lee, MD, G Switzer, MD;
Scientific Director: JD Rizzo, MD;
Statisticians: S Kurian,MD,MS,MPH, J Klein, PhD.
There is a study in progress that is looking at the effect of
different ethnicity on the outcome of HSCT. Another study is looking
at the effect of different income levels on outcomes.
Proposed studoies include one by some economists proposes to try and
figure out whether centers that do more transplants (and have better
outcomes) do so because they have learned more or for other reasons.
Another would look at access to unrelated transplant. A third would
attempt to compare the costs of different graft sources, e.g. cord
blood versus unrelated donors.
Best Abstracts (AB04)
4:00 PM - 5:30 PM
The
abstracts for the talks are available on the web site of the Biology of Blood and Marrow
Transplantation web page. However as of today (March, 2005), they
are only available to paid subscribers. At some point they may be
available for free.
Allogeneic stem cell transplantation (allo SCT) in adult ALL: Does
prophylactic donor lymphocyte infusion (DLI) improve survival?
-- R. Arnold, Univerity Hospital Charité, Berlin, Germany
Dr. Arnold gave a presentation on the use of DLI for patients who had
a transplant for ALL, but had not (yet?) relapsed. The rationale is
that there are a significant number of relapses after allo-transplants
for ALL and DLI is not very effective at treating relapsed ALL.
Plan: For patients who had no history of Grade III or IV GVHD
and no active GVHD and no evidence of disease at day +60. Increasing
doses of T-cells are given, at day +60, +88 and +116, stopping when
GVHD occurs. The median time of the first DLI was day +112 (I am not
sure how this occured given the plan).
The disease free survival at 3 years was 68% and overall survival was
70%. 79 patients were transplanted without DLI 32% are alive in
complete remission at 3 years and overall survival is 34%. More then
50% of the deaths in the later group were due to relapse.
Patients who were transplanted beyond first complete remission who
recieved prophylactic DLI had much better survival then those who did
not recieve DLI. For this transplanted in first remission survival
was equivalent. Patients who had no chronic GVHD, particularily
patients who did not recieve a DLI had poorer survival.
Adult transplant outcomes, single versus pooled cord blood
transplants -- J.D. Wofford, St. Louis Cord Blood Bank
Some centers are doing transplants on adult patients using two units
of cord blood. Dr. Wofford's talk was comparing patients who recieved
a single unit versus those who recieved two units.
In every dual transplants, the number of cells infused at least
2x107 cells/kg which is greater then the median dose
infused with single units. There were no early deaths due to
infections in the first 100 days post transplants in patients who
recieved two units, but there were several deaths in the patients who
recieved only one unit. Overall Survival is better in patients who
recieve two cord units, better then would be expected based only on
the cell dose.
Results of the Cord Blood Transplantation Study (COBLT): Clinical
outcomes of 193 unrelated donor umbilical cord blood transplantation
in pediatric patients with malignant conditions --
J. Kurtzberg, Duke University.
Dr. Kurtzberg talked about the experience with the COBLT study. They
created 3 cord blood banks, at Duke, UCLA and National Children's
Hospital/Georgetown University.
Their transplant experience between 2000 and 2003 included 191
patients not including patients with ALL in relapsed or CML in blast
crisis. All patients did not have a matched sibling donor. A
standard ablative regiment was used.
HLA matching did improve survival. About 20% of patients had chronic
GVHD (30% of those had extensive cGVHD). Better matching lead to less
chronic GVHD.
20% of patients relapsed and there were 95 deaths out of the 191
patients. 40% of the deaths were due to relapse. The overall
survival was 67% at 180days (which was the primary endpoint of the
study). Patients who engrafted early had better survival.
Sunday, February 13, 2005
CIBMTR Executive Committee
7:00 AM - 8:30 AM
Although it is interesting to be on the executive committee, much of
the meeting was not very exciting. We discussed things like how much
money CIBMTR was making from the conference (this is their largest
source of funds, and they did a little better then expected this year)
and where to hold the conference the next two years. Next year is in
Hawaii (that was already settled) and in 2007 it will be back in
Keystone.
PLENARY SESSION 4: Autologous Transplant Innovations
8:30 AM - 10:00 AM
Chair: Stephen Forman, MD, City of Hope Comprehensive Cancer Center;
Current Status of Autologous Transplantation: Limitations and
Potential Solutions -- Stephen Forman, MD, City of Hope
Comprehensive Cancer Center;
The executive committee meeting ran late and I missed most of Forman's
talk.
T-Cell Immunotherapy Following Autologous Hematopoietic Cell
Transplantation -- Michael Jensen, MD, City of Hope Comprehensive
Cancer Center;
Dr. Jensen's talk was on T-cell graft engineering. Most of the
relapses in auto-HSCT are due to minimal residual disease. The idea
is to engineer T-cells to recognize tumor cells.
The protocol to treat high risk lymphoma patients (recurrent
disease):
- Harvest stem cells
- Chemotherapy (for cytoreduction)
- engineer T-cells
- Auto transplant
- At day +28, plus 2 later times infuse engineered T-cells to
clean up an residual disease
They have treated 5 patients so far. However in only 2 of the 5
patients were they able to generate the proper clones of the T-cells
to do the engineering. (This is in contrast to healthy donors where
they can get the proper clones). Unfortunately even in the 2 patients
who get the engineered cells, it did not seem to have much effect. So
they are trying to figure out different ways of targeting tumor cells.
Innovations in Regimen Development for Autologous Stem Cell
Transplanation -- Frederick Appelbaum, MD, Fred Hutchinson Cancer
Research Center
Commonly used regimens are not very different from those in use 20
years ago. Vose [6] showed that patients with
diffuse NHL who received an autologous transplant in first remission
or second remission had a long term survival of about 40%. This means
that 60% or so patients did not have their disease cured by the regimen.
We would like to improve upon these results, but there is a lock of
randomized data comparing regimens and a lack of compelling Phase II
(non-randomized) data of different regimens.
Radioactive Immunotherapy (RIT), give an antibody attached to a
radioactive isotope. This has an advantage over TBI, because you can
not escalate the dose of TBI becuase of toxicity. RIT should deliver
radiation to the tumor but not to healthy cells, or at least not as
much to healthy cells. Cytoreduction with chemotherapy is still
necessary since large tumors do not get enough radiation from RIT to
kill them. A non-randomized study has shown better results with I-131
antibody then with conventional radiation and an autologous
transplant. It is also possible to combine Cytoxan, VP-16 and the
same dose of RIT. This results in better survival compared to
standard auto transplant (although again there has not been a
randomized study). Using RIT in patients with mantle cell lymphoma
who had failed previous therapy, the use of RIT and autologous
transplants results in 60% survival at 2 years.
In patients with AML a CD-45 antibody attached to a radioactive
isotype can deliver more radiation (2-3 times as much) to the bone
marrow in 90% of cases than conventional TBI. It is still desired to
increase targeting as much as possible as the radioactive antibodies
are in the blood and the radiation the circulating antibodies give off
is not specific. One way to do this is to remove by pherisis
circulating radioactive antibodies after giving them to be absorbed
into the cancerous cells in the bone marrow. A second strategy,
called pre-targetting gives antibodies not attached to a
radioactive isotope. The antibodies attach to the tumor. Then a
radioactive substance is given which quickly attaches to the antibody
or is quickly excreted in the urine. This approach is still
experimental and there are not any long term results.
CIBMTR
Graft Sources and Manipulation Working Committee Meeting
12:30 PM - 2:00 PM
Chairs: J Wagner, MD, H Johnsen, MD, A Gee, PhD;
Scientific Director: M Eapen, MD;
Statisticians: H Tang, MS, M-J Zhang, PhD.
CIBMTR GvHD Working Committee Meeting
2:30 PM - 4:00 PM
Chairs: AJ Barrett, MD, O Ringdén, MD,PhD, C Anasetti, MD, S Pavletic, MD;
Scientific Director: MM Horowitz, MD, MS;
Statisticians: S Gandham, MS, J Klein, PhD.
Studies in progress
Risk factors for AGvHD
Dr. McCarthy gave an update about this study. There were some
surprising finding, although they are still preliminary. For instance
that analysis showed higher risk of GvHD in CML patients and no higher
risk for older patients.
Factors determining leukemia relapse in patients with CGvHD
Dr.Pavletic described the intention of this study, which is still at a
very preliminary stage.
Risk factors for development of AGvHD in adults receiving URD
BMT
Dr. McCarthy presented this study for Dr. Chao. This is similar to
the above study but using URD instead of matched siblings.
Future/proposed studies
There were a number of proposed studies. One proposed examining at
the how the grade and duration of Acute GVHD correlates with the
relapse rate. Another is trying to develop a prognostic model of
chronic GVHD in children. Finally another study is looking at DLI
after NSCT to see how effective it is, however there are still too few
patients who have undergone NSCT and then had a DLI in the registry.
CIBMTR Advisory Committee
6:00 PM - 8:00 PM
This was the first full meeting of the CIBMTR advissory committee. As
it is a transistional advisory committee, the committee is quite
large, containing people who were on the IBMTR/ABMTR advisory committee
as well as the NMDP Research and Publications committee. There were
discussions on forming an international committee to facilitate
research between international organizations, in particular into
developing countries which often have different issues then centers in
the developed world (for instance access to some drugs). There was
also an overview of how the CIBMTR has functioned the first 8 or so
months of it existence.
References
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decision analysis of allogeneic bone marrow transplantation for
the myelodysplastic syndromes: delayed transplantation for
low-risk myelodysplasia is associated with improved outcome,
Corey S. Cutler, Stephanie J. Lee, Peter Greenberg, H. Joachim
Deeg, Waleska S. Pérez, Claudio Anasetti, Brian J. Bolwell,
Mitchell S. Cairo, Robert Peter Gale, John P. Klein, Hillard
M. Lazarus, Jane L. Liesveld, Philip L. McCarthy, Gustavo
A. Milone, J. Douglas Rizzo, Kirk R. Schultz, Michael E. Trigg,
Armand Keating, Daniel J. Weisdorf, Joseph H. Antin, and Mary
M. Horowitz Blood
2004 104: 579-585.
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Diagnostic and clinical relevance of the number of circulating
CD34(+) cells in myelofibrosis with myeloid metaplasia,
Barosi G, Viarengo G, Pecci A, et al, Blood. 2001;98:
3249-3255.
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Limits of HLA mismatching in unrelated hematopoietic cell
transplantation, Petersdorf, Effie, et. al. Blood. 2004; 104:
2976-2980.
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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, Flomenberg, Neal, et. al. Blood. 2004; 104:
1923-1930.
-
Impact of chronic GvHD therapy on the development of squamous
cell cancers after hematopoietic stem cell transplantation: an
international case-control study, Curtis, R. et. al., Blood. 2005,
prepublished online February 1, 2005; DOI
10.1182/blood-2004-09-3411.
-
Autologous transplantation for diffuse aggressive Non-Hodgkin
lymphoma in first relapse or second remission, Vose,
J. M. et. al., Biology of Blood
and Marrow Transplantation, February 2004, Volume 10, Number
2.
I would like to thank the National
Marrow Donor Program (NMDP) and the Bone Marrow Transplantation
Branch of the Deparment of
Transplantation of the Office
of Special Programs of the United
States Department of Health Resources and Services Administration
(HRSA) for paying for my travel and conference registration. The
views expressed in this article are my own and do not necessarily
reflect the views of NMDP or HRSA
Arthur Flatau
flataua@acm.org
Austin, Texas
GrannyBarb and Art's Leukemia Links Site
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