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 8 - February 12, 2007 in Keystone, Colorado.
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:
| TBI | Total Body Irradiation |
| DLI | Donor Leukocyte Infusion |
| TRM | Transplant Related Mortality |
| DFS | Disease Free Survival |
| EFS | Event Free Survival |
| OS | Overall Survival |
Unlike previous Tandem meeting, I had a lot of meetings to go to,
e.g. the CIBMTR executive and advisory meeting and I did not get to
attend as many of the scientific sessions as I usually do.
FRIDAY - FEBRUARY 9
10:30 am, Oral Abstracts -- Allogeneic Transplants
I have included links to the original abstracts below.
Corey Culter
Sirolimus was initially developed as an anti-fungal, but not
particularily effective. It is part of the standard of care for
immunosuppression in kidney and liver transplants. Condition of
Cytoxan and TBI (14 Gy!). No G-CSF before day 12 (because of
anticipated early engraftment because of not using MTX). 53 patients
with Matched Related donors and 30 URD. Most patients had AML and CML
and few others. Engraftment to 500 ANC was at day 14. Platelet count
to 100K was about 17 days. Discharge was at 19 days (median). 80 of
81 patients survived until initial discharge. No cases of steriod resistant
acute GVHD. Toxicity was lower then many other series. 2 deaths
related to GVHD, 13 deaths due to relapse. 66% relapse free survival
at 2 years.
Conclusions: Sirolimus and Tacrolimus without MTX results in early
engraftment and low transplant related toxicity with excellent GVHD
control. The related and unrelated donor had similar survival. The
control of Acute GVHD was good, however the incidence of chronic GVHD
was still higher then desired (50%).
There is a randomized trial (BMT CTN 0402) comparing sirolimus
(rapamycin) and Tacrolimus versus Tacrolimus and MTX.
Rafael Durate
CD4+CD25hi T-cells (T-regs) may effect the outcome of
HSCT in humans. 86 patients with an matched unrelated donor had a T-cell depleted transplant
(71 patients were T cell depleted). The level of T-regs did not have any effect on
acute GVHD or transplant related mortality, however the incidence of chronic
GVHD was higher as was the rate of relapse.
Vikas Gupta
Previous reports suggest auto transplants are useful in HIV+ patients
with lymphoma. The objective was to evaluate the outcomes of HIV+
patients undergoing allo-HSCT. All confirmed HIV+ patients who
underwent AlloHSCT in the CIBMTR database, from 1987-2003 (8 after
1996, the rest before), 30 patients, 22 with maliginant disease, 8
with non-malignant disease. Median age was 34. 5 of the
non-malignant patients were transplanted for primary HIV disease.
Median days to engraftment was 15 days. 45% mortality at 100%.
Survival of 20% at 2 years. Of 8 patients transplanted after 1996, 4
survive, compared to 2 of 22 transplanted before 1996, probably due to
better supportive care and better HIV treatments. 3 patients died of
relapse, the rest primiarily from infection and organ toxicity.
Vikram Matthews
There are 10000 children diagnosed with Beta-Thalassemia major,
annually. HSCT is only known cure. 190 patients under HLA matched
related transplants at their center. Patients can be stratified based
on risk factors into Lucarelli Class I, II and III patients. Class I
and II patients had much better survivial then Class III patients.
Unfortunatley some what more then 50% patients are Class III. When
Class III patients were stratified according to age over 7 and liver
size (bigger then 5cm), those patients had a very poor outcome.
Patients who were in Class III who were 7 and younger and a liver size
less then 5cm had an outcome almost as good as Class II patients.
Vikram Matthews
(Same cohort of patients as above). Pre-transplant Splectomy in Class
III patients, 27 patients had splectomy, 73 did not havea splectomy.
ANC engratment was faster in the patients splectomy (15.4 days) versus
non (17.5 median days). Significantly fewers packed red cells
transfusion were done in spectomy group and somewhat fewer platelet
transfusions. However the overall survival of the splectomy group was
signficantly worse as was the EFS. This might be because the patients
who had a splectomy had other risk factors. In conclusion, no
significant benefit from splectomy and should be used only based on
transfusion guidelines and not routinely used prior to transplant.
Frederico Moscardo
Cord blood units have a low number of stem cells and result in long
time to engraftment and high rate of graft failure. Hypothesis that
an early mixed chimerism after UCB transplant predicts poor
engraftment. 49 patients who underwent UCB transplant and had a bone
marrow sample early (14-19 days post transplant). 90% of patients had
successful engraftment (median of 19 days). 95% engrafted by day 60.
All 4 patients that had less then 60% donor chimerism at early bone
marrow failed to engraft.
12:15 Donor Health and Safety Working Committee
Presented data on the 41000+ donors listed in the CIBMTR database,
their ages ranged from <1 to 96!. Discussed a paper, The Burden
of the Volunteer Unrelated Hematopoietic Cell Donor: Results of a
Prospective NMDP Trial Assessing Toxicities Associated with PBSC
Collections, 1999-2005, that looked at side effect experience by
donors who donate peripheral stem cells. Most (80%) appeared to have
few adverse effect, although most experience
some bone pain. About 10% experience severe bone pain.
A similar study of marrow donors, showed that about 3% experience
severe side effects, with about 1.35% have severe side effects as
determined by a panel of 5 doctors.
The data on safety is limited. What is available is largely in
younger adult donors. There is little safety data in donors over 60
and almost none in pediatric donors (who only donate for
relatives).
RDSafe is a study to look at complications in related donors. The
plan is to get data on about 2700 donors at 30 large volume donor
centers. Trying to find rare side effects possibly related to the use
of G-CSF. Also will use 6400 donors from NMDP. The donor centers
will fill out a couple of initial forms and the follow up will by
phone from the CIBMTR.
Paul O'Donnell present a proposal to do a survey of CIBMTR centers, to
see if related donors are cared for by different doctors then the
patient -- is this seen as a conflict of interest. (NMDP has a policy
that requires the donor to be cared for by a different doctor then the
patient).
4:30 pm Designing Clinical Trials in HCT: Case Studies
Mary Horowitz, Shelly Carter, DSc; Brent Logan, PhD; Gerard Socie,
MD, PhD; Marcie R. Tomblyn, MD, MS<
Marcie Tomblyn gave an overview of clinical trials: A Clincal Trial is
a prospective evaluation of a treatment or intervention. Conduncted
in an organized fashion to answer a particular question. For HSCT,
define utility for a disease, define appropriate stem cell source
(URD, UCB, etc.), conditioning regimens (NSCT, fully ablative),
prophylaixs, supportive care, relapse.
Determine the hypothesis, primary and secondary endpoints, study
schema, inclusion and exclusion criteria -- define accural issues,
statistical approach, informed consent.
Elements of a research question, is it feasible, interesting, ethical.
Are there enough patients?
Endpoints, event that occurs and is used to answer study question. --
Used to determine sample size (big enough to have statisical
significant).
HSCT endpoints, OS, DFS, PFS, disese control, TRM, engraftment,
toxicities, infections, GVHD.
Study Structure, Phase I-III. Control Group, -- Historical,
concurrent comparative group
Phase I -- Toxicity screening and deterimination of maximum tolerated
doses. PHase IA - healthy subjects, IB - disesased subjects. Small
Studies - < 10 per dose
Phase II -- Deterimination if treatment has any biological activity.
Single well describe treatment regimen. Small sample size, <40 -
50 Used to select treatment for Phase II trils
Phase III -- Usually Randomized Clinical Trial. Goal: Comparision of
two or more treatment regimens. Large sample sizes, possibly
heterogeneous population.
Phase IV -- long term survellience.
Statistical Design -- What number of patients do you need to answer
the question. Stopping guidelines -- stop if treatment is not safe.
SATURDAY - FEBRUARY 10
CIBMTR Stem Cell Outcomes Database Data Advisory Meeting
This session was an overview and discussion on the new Stem Cell
Outcomes Database. The new legislationg (C.W. Bill Young Cell
Transplantation Program) requires all transplants in the U.S. to be
reported to the CIBMTR. The discussion include what information would
be collected on cord blood units, how patients would be uniquely
identified (even if they changed centers, e.g. after an auto and then
used another center for an allo transplant, or began a search and one
center but then were transplanted at another), want kind of data would
be collected, in particular what kind of quality of life data would be
collected.
7:30 pm ASBMT President's Dinner
Usually there is not much of interest happening at the ASBMT dinner.
However Dr Yoshihisa Kodera of the Japanese Red Cross Nagoya
First Hospital sat next to me and we had some fascinating
conversation. The story of his that I liked the best (I hope I have
this accurately, it was a bit difficult to understand him, mostly
because he did not talk loudly and the room was fairly loud). He had
a patient with leukemia. She had a transplant when she was in her
50s. Now she is over 80! and in good health. That is
the kind of story I like to hear.
Sunday - FEBRUARY 11
Consumer Advocacy Committee (CAC) meeting
We had an interesting discussion on how to disseminate the recently
released guidelines for patients on long term screening that survivors
(of both autologous and allogeneic) transplants should undergo. Some
folks, including me felt that it had take a very long time (a year or
so) to finish these, however others who are more familiar with similar
projects thought it was done rather quickly. We also discussed
several relatively recent publications from the CIBMTR (listed below)
that we could try to translate into lay language. Three of the papers
are not yet published, although the paper by Bishop et.al. should be
published shortly. The papers we considered (and have been published
or accepted for publication are):
Bishop MM, Beaumont JL, Hahn EA, Cella D, Andrykowski MA, Brady MJ,
Horowitz MM, Sobocinski KA, Rizzo JD, Wingard JR. The late effects of
cancer and hematopoietic cell transplantation on spouses/partners
compared to HCT survivors and survivor-matched controls. J Clin
Oncol
Laughlin MJ, Eapen M, Rubinstein P, Wagner JE, Zhang MJ, Champlin RE,
Stevens C, Barker JN, Gale RP, Lazarus HM, Marks DI, van Rood JJ, A
Scaradavou, Horowitz MM. Outcomes after transplantation of cord blood
or bone marrow from unrelated donors in adults with leukemia. N Engl J
Med 351:2265-2275, 2004
Arthur Flatau
flataua@acm.org
Austin, Texas
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