Strong consensus
supported the conclusions from the morning's breakout on intensive
therapies. Dr. Antin presented the conclusions from that session:
·
Allogeneic transplantation is the only cure for the MPDs,
as demonstrated in small series and isolated case
reports.
·
Autologous transplantation has demonstrated usefulness as palliative
therapy in at least one series.
·
Reduced-intensity transplantation is the issue to address over
the next few years.
- Reduced-intensity transplantation is of great
interest to the MPDs for two major reasons:
* MPD patients are usually older,
and reduced-intensity transplants are increasingly
applied in older patients. The technique has a capacity to sidestep
the comorbidities common
to older patients.
* Reduced intensity transplantations
are most effective in indolent or low-grade diseases
like the MPDs, where you do not have a highly proliferative, very
malignant phenotype.
Disease indolence gives the graft vs. abnormal hematopoiesis
phenomenon an opportunity to take place before blasts have proliferated.
·
The challenge is not only identifying patients that merit transplantation,
but finding them. It is likely there are a lot of
patients out there that are probably not getting through
to either transplant specialists or to groups studying the MPDs.
(as summarized by Dr. Barrett)
·
Diagnostically subclassifying MPD patients is not a real issue
in transplantation in the MPDs.
·
Limitations of hematopoietic stem cell transplantation
- The usual ones:
* Intrinsic toxicity of the procedure
* Graft vs. host disease
* Immunoincompetence
- Other limitations have been addressed:
* Donor availability - addressed
in part through the National Marrow Donor Program
and mismatched transplantation
* Age - addressed with reduced intensity
transplantation.
·
Recommendations:
- We need to apply prognostic markers, including
molecular markers, to determine the
following for a given patient:
* Need for transplantation at all.
* When transplantation is most appropriate.
* If reduced intensity vs. a conventional
dose regimen is indicated.
* Need for matched sibling vs. mismatched
or unrelated donor.
- An organized approach is essential to avoiding
a proliferation of small series and case
studies in determining prognostic factors in transplantation.
* To realize this organized approach,
develop a Myeloproliferative Disorders Study
Group to organize studies of non-transplant therapies and
interact with the recently
established a Bone Marrow Transplantation (BMT) Clinical Trials
Network (CTN)
* Patients enrolled on MPDs Study
Group trials would become collaborators with the
CTN, with those among them who are candidates for transplantation
subsequently enrolled
in CTN studies.
· The CTN is
a Cooperative Group developed with support from NCI and NHLBI.
· The CTN has
capacity to store samples and perform multi-center studies.
- As for recommendations for clinical practice,
a MPD consortium of some sort should
shoulder the burden for accessing, properly assessing, and identifying
MPD patients requiring transplants.
SLOWNESS OF PROTOCOL APPROVAL PROCESS ADDRESSED
·
Question for Dr. Cheson: by Dr. Tefferi: Single institutions
are finding it difficult to muster enthusiasm about
doing studies through the Cooperative Groups and NCI, because
the protocol approval process through these mechanisms is so slow
and bureaucratic, even for pilot and phase II studies.
Can you address this issue ?
- Response by Dr. Cheson:
* The system is unconscionably slow;
but this is not the sole fault of the NCI.
· It is a multi-factorial
issue, spanning from one end of the clinical trials program
to the other. (e.g., a drug company taking months to review the
protocol).
· Usually, the
wait is the fault of the Group and the investigator (e.g., a protocol
sent
to CTEP 18 months after CTEP has approved the LOI).
* NCI is in the process of trying
to streamline protocol development and is actively
working with several of the Cooperative Groups to do so.
* Dr. Tallman also mentioned that,
unfortunately, the system works in series, not in
parallel.
·
Question: Is it more efficient to do pilot studies within institutions,
with companies, rather than going through Cooperative
studies, and do the larger studies through the Cooperative
system? (Dr. Tefferi)
- Response by Dr. Tallman:
* Advantages of using the Cooperative
Group system must be considered:
· Ancillary laboratory
studies.
· Reproduced results.
· Faster accrual,
especially since certain institutions in the Groups have unique
niches,
for example in the MPDs.
· Provision of
the large numbers of patients frequently necessary to answer a
study
question.
· Question: Maybe we can bring a study initiated
by a single institution into the Cooperative Group
system? (Dr. Tefferi)
- Response by Dr. Cheson: Yes - that has happened
in a number of situations, primarily
in the solid tumors (e.g., the Philadelphia BMT Consortium, which
became a breast cancer transplant
trial through ECOG). Other examples of collaborative
mechanisms are multi-center consortia and international collaborations.
* Caveats:
· But initiating
a study within the Cooperative Groups system may be easier from
a bureaucratic standpoint, since Group bureaucratic protocols,
forms, paperwork,
etc., will already be in place.
· The study must
be of interest to the Group.
- Response by Dr. Larson: The Clinical Trials
Support Unit (CTSU) offers a potential
mechanism for doing multi-center phase III studies not sponsored
by the Cooperative Groups.
* CTSU allows investigators
to work through their cancer center as long as they have
appropriate biostatistical support.
* CTSU helps investigators manage
the trial and trial data.
PATIENT ADVOCATES SPEAK
Dr. Bennett
solicited comments from patient advocates Mala Hermon and Robert
Tollen.
·
Question from Mala Hermon (paraphrased): Has a study been
done or should a study be done in MPD patients over
age 60 with no associated risk factors for stroke/thrombotic
event besides high platelet counts, comparing just aspirin versus
aspirin and platelet-lowering therapy? Several patients
over age 60 wonder if aspirin suffices as a platelet-lowering
agent, or are more cytotoxic drugs necessary?
- Response from Dr. Tefferi:
* Your question is being actively
investigated in current trials.
* In every randomized study, patients
are stratified above and below age 60.
* Unfortunately, stratifying already
small numbers of patients means fewer patients
on which to base your conclusions, thus reducing the validity
of those conclusions.
* However, the randomized study
in England has over 500 high-risk patients, including
patients over age 60 without risk of thrombosis and patients under
60 with a history of
thrombosis. Similarly, the Italians are also addressing this question
in their study on aspirin in PV patients.
·
Comments from Mr. Tollen (paraphrased):
- There is very strong need to educate the general
hematologist to look for the different
MPDs, so that people with MPDs can get diagnosed.
- Up to 1,400 MPD patients have used his website, on which a survey has just been
completed (he offered to send the survey results to anyone interested).
- From a business perspective, it is clear that
the MPD experts assembled here are
used to giving orders, but would do well with a myeloproliferative
czar who would assign them studies
and provide oversight.
- The delay in protocol approval is very worrying,
and dangerous; the approval process
must be streamlined.
- There seems to be a great need for a uniformity
of awareness among the groups studying
the MPDs of what each group is doing. This lack of mutual understanding
could lead to redundancy of effort.
- This understanding and oversight could be
achieved via:
* Appointment of a myeloproliferative
czar.
* The computer, for example using
project management software.
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