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Key Questions:
 What types
of studies should be funded by the NCI to address the myeloproliferative
disorders (MPDs) and mastocytosis?
Should trials
in MPD move out of individual institutions into the Cooperative Groups
directly or into an individual MPD study group?
What
potential molecular targets have been identified for development of novel
agents?
What are the
issues in transplantation in MPD patients?
Outcomes and Discussion Points:
Disorders
covered by meeting: SMCD, MF, ET, PV, CMML, JMML, HES
Etiology/Etiology/Molecular
Biology/Pathology (Breakout Session A)
Abnormal Signaling/
Cytokines (Breakout Session B)
Innovative
Therapeutics (Breakout Session C)
Intensive
Therapies (Breakout Session D)
Key Recommendations
General recommendations
Intensive
Therapies / Transplantation
Essential
Thrombocytosis (ET)
Systemic
Mast Cell Disease (SMCD) / Mastocytosis
Polycythemia
Vera (PV)
Hypereosinophilic
syndrome (HES)
Myelofibrosis
(MF) / Myelofibrosis with Myeloid Metaplasia (MMM)
Chronic
Myelomonocytic Leukemia (CMML)
Juvenile
Myelomonocytic Leukemia (JMML)
General
recommendations:
-
Establish a MPD Study Group building on the EORTC model.
- Encourage programs studying MPDs to make
their material widely available.
. - Develop standard diagnostic criteria for the MPDs,
including mastocytosis.
- Make histopathology/bone marrow biopsy
(e.g., WHO criteria) a part of the diagnosis
for any MPD trial. A syllabus for instructing pathologists and technicians
on histopathologic diagnostic
criteria should be developed, and a hematopathology committee
established to reproduce diagnoses.
- Develop clinical response criteria that
reflect Quality of Life (QOL) and clinically meaningful
endpoints.
- Incorporate a basic science component
in MPD clinical trials to develop prognostic markers.
- Make assays more specific. Undertake a
prospective study in the Cooperative Groups
using innovative microarray analysis to identify specific differences
within the MPD subtypes.
- Use pathology reference centers, to ensure
performance of appropriate molecular studies.
- Undertake studies of the epidemiology
of the MPDs.
- Emphasize to NCI the importance of simultaneously
studying MPD therapy and the
natural history. This might involve having control arms of studies that
consider best supportive care.
- For patients with MPDs set up banks of
samples that would be available for analysis
of molecular pathophysiology of disease by interested scientists following
approval by a designated review
committee.
- Current trials for any novel agents should
include banking, particularly for identifying
prognostic and predictive markers for MF.
- Look to COG's FTI trial in JMML as a paradigm
for how to approach research in the MPDs.
- Explore the possibility of a randomized
Cooperative Group trial that would clarify risk-based
therapy.
Intensive Therapies / Transplantation
- Develop and apply prognostic markers,
including molecular markers, to determine 1)
patient need for transplantation; 2) when transplantation is most appropriate;
3) if reduced intensity vs.
a conventional dose regimen is indicated; and 4) need for matched
sibling vs. mismatched or unrelated donor.
- Establish a non-transplant Myeloproliferative
Disorders Study Group to interact with
the Transplant Clinical Trials Network.
- Reduced-intensity transplantation is the
issue to address over the next few years.
- Fully integrate transplantation into studies
of novel agents; e.g., use novel agents to
debulk prior to transplant, and refer poor responders to transplantation
trials.
- Enhance clinician awareness of the potentials
(i.e., cure) of transplantation in the MPDs.
- Compare autologous transplantation with
allogeneic transplantation in poor-risk patients.
Essential Thrombocytosis (ET)
- Establish a specific hematopathology committee
to confirm the role of megakaryocyte
morphology in diagnosing ET, particularly distinguishing it from primary
fibrosis/IMF ("false ET"). Develop a syllabus on histopathologic
diagnostic criteria emphasizing
the importance of bone marrow biopsy in MPD diagnosis.
-
Bank cells from ET patients in conjunction with any clinical trial, even
in low-risk patients, making
banked material available to investigators interested in the molecular
pathogenesis of ET.
- As samples are banked, determine which
patients do and do not have clonal hematopoiesis.
- Ready for phase III: Perform a randomized
study of observation vs. platelet-lowering agent
in low-risk ET patients with extreme thrombocytosis (platelet count >
1 million)
- Postpone further randomized studies in
high-risk ET patients. These should await the
results of the MRC study in the U.K. (High risk = age > 60 and/or history
of thrombosis)
Systemic
Mast Cell Disease (SMCD) / Mastocytosis
- Mastocytosis should be considered one
of the myeloproliferative disorders.
- Bank material from any trial of STI571
in SMCD patients to determine if responders really
are those with the c-kit mutation outside the enzyme pocket.
- Screen other existing PDGF family member
inhibitors back into cell lines transfected
with the mastocytosis mutation to determine if they inhibit D816Y enzyme
pocket mutants. Also screen primary cell systems.
- Determine if a trial is justified for
establishing interferon-alpha +/- prednisolone as standard
therapy for mastocytosis.
- Conduct prospective studies of STI571
and cladribine in SMCD patients, perhaps in
those who are IFN-resistant or IFN-intolerant.
- Develop novel agents targeting other signaling
pathways in aggressive SMCD, in addition
to D816Y. This is important due to the clinical heterogeneity of SMCD.
- Focus mastocytosis studies in small centers
with a strong biology component.
- Ensure that intended responses to agents
targeting D816Y are clinically meaningful.
Polycythemia Vera (PV)
-
Per the German Society of Internal Medicine: Test all potential PV patients
for PRV1 overexpression.
- Bank samples with data on response, especially
in multi-center trials comparing therapies.
- Ready for phase III: Perform hydroxyurea
vs. IFN vs. anagrelide in low-risk patients with
thrombocytosis.
- Endpoints in PV trials should include
thrombosis, acute leukemic transformation/blast
transformation, survival, Quality of Life, and clinically meaningful
endpoints.
- Targeted therapy is impossible in PV until
molecular targets are identified.
Hypereosinophilic
syndrome (HES)
- Further investigate the interesting observation
that eosinophilia predicts response sensitivity
to STI571 in MPD patients. Determine molecular basis for this sensitivity.
- Bank samples from primary HES patients
and perform in-depth sequencing on samples.
- Determine if mutations exist in c-kit,
the PDGF receptor, the SH3 domain of Abelson,
and possibly ARG.
- Search for a novel kinase if sequencing
of existing kinases is negative, by following TK
signaling.
Myelofibrosis
(MF) / Myelofibrosis with Myeloid Metaplasia (MMM)
- Establish either an MF Study Group or MPD Study
Group with a subgroup studying
MF.
- Establish a registry as part of this Study
Group to facilitate specimen banking.
- Bank samples, tying them to clinical response
data from various phase I, II, and small
trials and making them accessible to investigators.
- Not ready for phase III. Phase I and II
findings on thalidomide and steroids do not justify
a long-term phase III trial. Continue therapeutic studies in the phase
I and II setting, supported
by CTEP.
- However, suggestions for future MF/MMM
randomized trials include 1) thalidomide +
low-dose IFN vs. thalidomide + steroids in patients without significant
osteosclerosis of the bone marrow;
2) novel agent vs. transplant trial; and 3) thalidomide
+ prednisone vs. thalidomide + IFN +/- Enbrel.
- Continue to look at transplantation outcomes
(see "Intensive Therapies / Transplantation",
above).
- Incorporate new genomic analytical techniques
into search for novel agents and prognostic
markers.
- Predictive factors: Single out a patient
subpopulation with highest response to a new
agent, then characterize them clinically and cytogenetically. This could
enable design of a trial benefiting
those most likely to respond, thus avoiding undue
toxicity.
- Correlate clinical response with bone
marrow pathology.
- Prospectively isolate and bank CD34s and
other cells (e.g., granulocytes) for current
or anticipated studies associated with a MF/MMM trial.
Chronic
Myelomonocytic Leukemia (CMML)
- Undertake a broad trial of STI571 in CMML, with
correlative genetic analysis for tyrosine
kinases of all varieties. The study should undertake complete sequencing
for loss-of-function mutations
not just of the PDGF beta receptor, but also of alpha, kit,
and the SH3 domain of Abelson. STI's efficacy or lack of efficacy in CMML
should not be pre-judged.
- Alternate approach: Screen samples from
CMML patients in vitro for sensitivity to STI,
putting patients with sensitive in vitro samples onto the STI571 trial.
Juvenile Myelomonocytic Leukemia (JMML)
- Establish mechanisms for correlative
studies, including study financing and specimen
banking. Although support exists for trials proper, it is lacking for
correlatives.
- Prioritize agents for targeting the ras/GM-CSF
pathway in JMML patients.
- Determine if patients with NF1 vs. ras
abnormalities respond differently to therapies.
- Look for clinical evidence linking GM-CSF
hypersensitivity in JMML to the ras signaling
pathway.
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