ESSENTIAL
THROMBOCYTOSIS (ET) THERAPIES:
·
Conventional
therapy in ET:
-
Observation: Since survival is good in ET, with some increase
in acute leukemia and MF in second
and third decade, physicians usually just observe patients. Major
problem is thrombosis, occurring in 20% of ET patients.
- Hydroxyurea: Used in U.S. in patients at high
risk for thrombosis.
- Pipobroman: Used in UK in patients at high
risk for thrombosis.
· New
agents with therapeutic activity in ET:
- Platelet lowering agents
* Anagrelide
* alpha-IFN
- Both agents lower reduce platelet counts,
but their real benefit has not been clearly
defined.
·
Ongoing trials in ET:
- MRC study in UK
* Anagrelide vs. hydroxyurea
- Will help to define the natural history of
ET.
* Microarray analysis planned.
·
Trials needed in ET:
- Perform: 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
patients should await the results
of the MRC study. (High risk = age > 60 and/or history of thrombosis)
-
Postpone: Clinical trial in pregnant ET patients.
* 30-40% of pregnant ET patients
miscarry during their first trimester.
* However, thrombosis and hemorrhaging
generally not a problem during pregnancy
(as shown in multi-center analysis of 43 pregnancies in last 25
years)
* Is it feasible to do a platelet
reduction agent vs. observation trial in pregnant ET patients
to determine if the agent increases the chance of an uneventful
first trimester?
· No. We do not even
know how to treat ET in non-pregnant women with ET.
· No. Before we tackle
extremely complicated scenario of pregnancy, at least first
undertake clinical trial of women with ET of childbearing age
who have high
platelet counts.
* Question: If a woman randomized to placebo
has a miscarriage, are we in deep ethical
trouble? (Dr. Silver)
· Response: No. Little
evidence exists that platelet-lowering agents affect miscarriage
rate. The only data are from study of > 30 pregnant women on
anagrelide who made it through
their first trimester successfully.
·
Low risk versus high risk ET:
- Risk definitions in ET present a real ethical dilemma.
* Many participants, including Drs. Steven
Fruchtman, Silver and Spivak, expressed
deep concern about the dilemma faced by practitioners making treatment
decisions based on definitions of low and high risk.
* Clinicians experience great unease when
the platelet count goes above 1 million.
They are not sure what to do at this point.
* We have no idea how to differentiate
those low-risk patients who have converted to
high-risk at time of thrombosis. Automatically classifying them
as high-risk due to thrombosis
development is not right.
* Also worrying to clinicians is the risk
of litigation resulting from not administering platelet-reducing
agents to low-risk patients with platelet counts of 2 million,
for example, or even 700,000.
These otherwise low-risk patients may develop Bud-Chiari
Syndrome, retinal thrombosis, etc.
- Dr. Spivak pointed out that a well-done Italian
trial did show no differences in rate of
thrombosis between treated and untreated ET patients < 60 years
old.
- Recommendations:
* There was agreement that a randomized
Cooperative Group trial would help resolve
the dilemma by providing informed consent and formal sanction
of treatment based on risk
definitions.
* We also need basic science component
in conjunction with a clinical trial to determine
which few patients will fare poorly and need therapy most. This
scientific study could help
resolve the dilemma of treating 100 patients to prevent
adverse outcomes in 2 patients. (Dr. Fruchtman)
POLYCYTHEMIA
VERA (PV) THERAPIES:
·
Conventional therapy in PV:
- Low-risk patients: Phlebotomy
- High-risk patients: hydroxyurea (U.S.) or pipobroman
(Europe) + phlebotomy
- (Risk stratification for PV is similar to that for
ET.)
·
New agents with therapeutic activity in PV:
- alpha-IFN
- Anagrelide
·
Ongoing trials/studies in PV:
- Randomized trials
* European Collaboration on Low-dose Aspirin
in Polycythemia (ECLAP) study = Low-dose
aspirin vs. placebo
- Uncontrolled studies
* Dr. Silver's ongoing study (now 15 years)
of alpha-IFN.
* Anagrelide has shown some beneficial
effects.
·
Trials needed in PV:
- Perform: Hydroxyurea vs. IFN vs. anagrelide in low-risk
patients with thrombocytosis. This study
is long overdue.
* Trial should address following questions:
· What is the role
of anagrelide and IFN as compared to hydroxyurea.
· Does anagrelide cause
anemia and is therefore a good agent for PV? (25% of patients
on anagrelide have 3 gram % drop in hemoglobin.)
· Does IFN retard the
transformation into MF?
- Design of PV trials must consider the following:
* Clinical and age heterogeneity of PV
patients
· e.g., young women
with hyperproliferative disease and big spleen vs. older patients
whose diseases may be more indolent
· Appropriate stratification.
* Endpoints:
· Survival.
· Thrombosis.
· Acute leukemic transformation/blast
transformation as endpoint.
· Quality of Life.
·
e.g., IFN and hydroxyurea have very different impact on QOL
·
Side effects of agents (e.g., long-term IFN in older patients)
· MF is not necessarily
an adverse outcome. If used at all, it should be used as one
of many other endpoints.
* Ability to yield clinically applicable findings
on best treatment.
* Follow up. There was some agreement that long-term
studies (10-15 years) are acceptable;
although agreement on this hinged on age of patient.
- Should myelofibrosis serve as an intermediate endpoint
in PV therapy trials?
* The consensus was not to use MF as an
important intermediate endpoint in PV trials.
* Case against MF as endpoint:
· MF does not indicate
progression or transformation of the disease.
· It is usually difficult
to detect reactive increase in reticulin resulting from acellular
marrow/MF.
· Dr. Thiele reminded
participants MF is morphologically heterogeneous, exhibiting
at least three patterns: reticulin, mixture of reticulin and collagen,
and collagen
fibrosis (gross MF). Different agents likely target different
types/degrees
of MF probably - e.g., hydrea may resolve reticulin MF, while
IFN does
not.
* Case for MF as endpoint.
· MF can be used if
it is one of many endpoints.
· Transfusion-dependent
MF spent-phase PV is definitely an issue for younger patients
worried they will develop spen phase or leukemia in the next ten
years.
·
Participants also debated the true estimate of median age in PV
patients, especially in context what it implies for length of
trial follow-up. Median ages mentioned were 58 in Europe, 66,
and "50 to 60, but most often 50" in the U.S. (40% of
PV patients in U.S. are < age of 50).
MYELOFIBROSIS (MF) AND MYELOFIBROSIS WITH MYELOID METAPLASIA
(MMM) THERAPIES:
·
Conventional therapies in MF/MMM:
-
There is no standard therapy in MF, unlike in PV and ET.
- Treatment is supportive.
- Androgens and steroids are generally used.
- Additional treatments:
* Hydroxyurea in patients with big
spleen
* Splenectomy if hydroxyurea does
not work.
* Erythropoietin in anemic patients.
* Transplant is an option.
·
New agents/therapies with therapeutic activity in MF/MMM:
-
Therapies found to be of some efficacy:
* Thalidomide
* Etanercept (reduced anemia in
15% of patients)
* Transplant
- Therapies found to be ineffective:
* STI (Gleevec)
· Results published
in Blood either April 2002 or May 2002
· Yet there persist
to be studies about to open using STI in MF patients.
* Pirfanidone
* IFN
* Anagrelide
* Suramin
·
Ongoing trials in MF/MMM:
-
Thalidomide plus steroids (prednisone)
* This combination is probably best
therapy yet for palliating anemia.
* Works best early on, when some
degree of residual hemaotpoiesis persists.
* Study just completed with low-dose
thalidomide + prednisone in 22 patients
* Engenders splenic response.
* Will not work with extensive MF
or osteosclerosis of the marrow.
- Low-dose thalidomide
* Dr. Barosi's trial of low-dose
thalidomide in > 55 year old patients with MF, is completed.
· Thalidomide
at 50 mg/day results less side effect and confers same benefit
as
standard dose - alleviation of anemia in 20% of patients.
· Response is
not on spleen size or MF.
· Dr. Zeldis
pointed out that responses to low-dose thalidomide is not surprising,
since it works nicely in inflammatory disease, and MF probably
has a strong
inflammatory component.
* Patients have trouble tolerating
thalidomide at over 50 mg/day.
* Thalidomide at standard 100-200
mg/day dosage results in 80% drop-out rate due
to toxicity.
- IMiDs and salsids:
* Two thalidomide successor compounds,
the ImiDs(Immunomodulary drugs) and Selcids(Selective
Cytokine Inhibitory drugs), now in two separate MDS trials, will
be taken into MMM trials within
the next year.
* Celgene currently is undertaking a big
study of the mechanism of action of the IMiDs.
- R115777 (FTI)
- PET
* PET trial about to open.
* Combines thalidmode, prednisone, and
etanercept.
·
Trials needed in MF/MMM:
-
Transplant vs. drug
- Novel agents
- Overall recommendations, summarized by Dr. Tefferi:
* We are not ready to move on to phase
III studies in MF/MMM.
* Continue to try to find to find better
therapy/novel agents in the phase I and II setting,
supported by CTEP. Otherwise, we'd be short-changing the potential
benefit that patients may
derive from small molecule treatment.
* Cooperative Group and CTEP support should
extend to innovative phase II studies
in MF therapy much the same as it would to phase III studies.
* Continue to look at transplant outcomes,
from conventional and reduced intensity
transplantation.
* Incorporate new genomic analytical techniques
and studies in search for novel agents.
- Undertake randomized trial testing thalidomide +
low-dose IFN vs. thalidomide + steroids
in patients without significant osteosclerosis of the bone marrow.
* Rationale for recommendations:
· Low-dose IFN + thalidomide
has been shown to engender substantial synergistic
effect in 25-30% of patients without significant osteosclerosis
of the bone
marrow - these are usually younger patients (50s and 60s).
· Response is rise
in hemoglobin and platelet counts and splenic response.
· Hb response is real:
Transfusion-dependent patients became completely transfusion-independent
(e.g., Hb of 7 gms% raised to 13 gms %).
- Future thalidomide protocols should include scans
to guard against exuberant response in
hematopoietic tissue. Proliferation of extramedullary hematopoiesis
has been seen in some thalidomide patients
to such an extent that a cardiac tamponade
developed.
- Studies determining predictive factors of response
should be performed, followed by clinical
trials capitalizing on their findings.
* 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.
* e.g., High circulating CD34 count and
post-polycythemic/ post-thrombocythemic myelometaplasia
have been shown to predict an undesired increase in platelet count
and thalidomide-induced myeloproliferative reactions.
* Dr. Valent urged that clinical response
should also be correlated with bone marrow
pathology.
·
Dr. Tefferi requested from participants specific proposals
for treatment trials in MF (long pause).
-
Scott: Without knowing what the real abnormality is in this disease,
we cannot give advice on novel agents.
- Dr. Silver: thalidomide + prednisone vs. thalidomide
+ IFN +/- Enbril
- Dr. Fruchtman: A novel agent vs. transplant trial.
A transplant arm would be appropriate
for patients with poor prognosis (transfusion-dependent, with
certain cytogenetic abnormalities).
- Dr. Spivak: If purpose is to optimize response,
undertake the combinations or additive-type
trials. If the purpose is to obtain regulatory approval, isolate
the contribution of each agent.
- Dr. Murphy: Results of phase I and II studies do
not justify a long-term phase III trial.
Observed responses to thalidomide and steroids are likely not
better than splenectomy.
Debate on response to thalidomide in MF/MMM patients
· We
do not know how thalidomide works in MF, nor has anyone looked
systematically into its mechanism of action.
· Response
to thalidomide is not due to angiogenesis, as determined with
CD34, which is a good marker for angiogenesis.
· Thalidomide
is not impressive as a single agent (activity in only 15-20% of
patients) ; but it shows promise in combination
with other agents.
· Dr.
Tefferi suggested that microarray analysis before and after treatment
would help in developing solid hypotheses for predicting
response sensitivity.
- Dr. Dunbar strongly disagreed, saying that array
analysis would be useless unless a very
highly separated populations of cells were examined. Otherwise,
you may not be looking at the cells in
which the response is elicited. It would be unjustifiably
expensive to do array analysis on just any cell type. Before looking
for agents, you have to at least determine
if MMF granulocytes, for example, are different
from normals.
· Dr.
Silver agreed with Dr. Dunbar.
· Dr.
Silver reminded participants that observed responses to thalidomide
combinations are so far quantitative, not qualitative.
Marrows are still abnormal, and changes in PB counts
not near the level seen in acute leukemia remission or in CML
with Gleevec.
CD34 banking
in MF/MMM
·
If a randomized, multi-center trial were conducted in MF/MMM
CD34s should be isolated prospectively and banked
for current or anticipated studies related to the trial.
- Small amounts of PB drawn pre- and post-treatment
would yield enough for storing, full immunophenotyping,
and following therapy and response.
- The median necessary concentration would be 95/microliter,
with range of 0 to 9,900/uL as CD34, not
white count.
- Dr. Tefferi observed that everything can and should
be banked - CD34, granulocytes, etc. Although
fully aware of potential pitfalls of any cells, he emphatically
urged isolating the granulocytes, due to their easy accessibility.
- Other observations on CD34 banking:
* CD34 cells have been stored in the European
low-dose thalidomide study (Germany,
France, Italy) for mechanism-of-action biological studies. Results
are not available yet, though.
(Dr. Barosi)
* Question: Due to CD34 cell heterogeneity,
would not separating out the different types
result in very small numbers for microarray analysis? (Dr. Valent)
· Response: The CD34 cells
are less heterogenous than may be thought, and have
specific phenotype. Most are not Lin-negative.
Prognostic
factors in MF/MMM
·
Current prognostic factors should be refined further on the
molecular level. It would be nice to apply microarray
analysis to this end.
·
Prognosis is difficult at level of individual patient: high-risk
patients can live for 20 years, whereas low-risk patients
can go into leukemia.
· Clinical prognostic variables will likely not improve
further.
Transplantation
in MF/MMM
·
General comments on transplantation in MF/MMM
-
Transplant / allogeneic cell therapy is the only current therapy
that can potentially cure MF/MMM and that
promises long-term survival, if successful.
- In the absence of a known mechanism of disease,
phase I and II novel agents solely afford
palliation at this point, as well as some reassurance to young
patients.
- If transplantation is to be used systematically,
it must be accepted that there will always
be some percentage of mortality in transplant patients who may
have otherwise lived without the transplantation.
·
Reduced intensity transplant is a new, improved transplant method.
-
Does not have the upfront morbidity and mortality associated with
classic allogeneic transplantation.
- May be used in patients > 60 years of age.
- Has expanded pool of eligible transplant candidates
to older patients, who form the majority
of MF/MMM patients and who have traditionally not been candidates
for allogeneic cell therapy.
- "Mini-transplant" and "non-myeloablative
transplant" are misnomers for reduced intensity
transplant, since it still ablates the bone marrow, though not
necessarily through the conditioning regimen.
·
Two primary goals in transplantation today:
-
Make it safer.
- Determine how to identify patients who should receive
transplantation.
* Prognostic criteria must be applied
or developed to prioritize who gets transplanted
(e.g., do not transplant MF patient likely to be asymptomatic
for 20 years; instead transplant
the patient who will otherwise die wthin two years).
* Risk stratification strategies for transplant
exist that can identify high-risk patients.
* Unfortunately, transplanted high-risk
MPD patients tend to do poorly.
·
Recommendations regarding transplantation in MF/MMM:
-
Establish a Myeloproliferative Disorders Study Group whose role
would be to:
* Organize a tissue bank.
* Organize studies of non-transplant therapies
and prognostic factors, enrolling patients
on these innovative therapy studies.
* Refer patients not responding to innovative
therapies in these studies to the Transplant
Clinical Trials Network, which would undertake transplant trials
specifically focusing on the
MPDs.
SYSTEMIC
MAST CELL DISEASE (SMCD) / MASTOCYTOSIS THERAPIES:
Note: Please
see the "Therapeutic options in systemic mastocytosis"
section of these minutes for the discussion of therapies in mastocytosis
that occurred earlier in the morning.
SMCD in adults
is not always indolent - it ranges from tolerable, intolerable,
and, at times, fatal.
·
Conventional therapies in SMCD:
-
interferon (IFN)
- steroids (prednisone)
- Dr. Valent objected, saying clinical trials are
needed to document that IFN-alpha with
or without prednisolone is indeed a standard therapy in SMCD;
especially considering the heterogeneity
of this disease. Otherwise, IFN and steroids cannot be
said to be standard therapy.
·
Ongoing trials in SMCD:
-
Cladribine
* Not a formal trial, but a compassionate
use protocol.
* Five SMCD patients treated so far.
· Two patients with
associated hematologic disorders have done extremely poorly
(bad cytopenias). So, people with MDS or MPD with mast cells do
not respond
very well to cladribine.
· Two patients with excellent
response patients did not have associated hematologic
disorders.
- STI571 (imatinib mesylate, Gleevec)
* Biological study of patients with hypereosinophilic
sydrome and mast cell disease.
* Eosinophilia as predictive factor for
response to STI571:
· Every non-CML patient
responding to STI571 has eosinophilia, with and without
5 ;12 translocations or other types of chromosomal translocations,
including
cryptic rearrangements.
* Lack of D816Y mutation as predictive
factor for response to STI:
· One SMCD patient
without the D816Y mutation dramatically responded to STI571.
· Dr. Metcalf mentioned
that in vitro experiments on the HMC1 cell line bear out this
observation of STI efficacy in absence of D816Y mutation:
·
STI571 inhibits growth of cells carrying only the juxtamembrane
mutation but not
the tyrosine kinase mutation, but not of cells with the tyrosine
kinase domain
mutation.
·
Same finding in in vitro phosphorylation studies of c-kit on those
cell lines.
·
No preferential killing of mast cells by STI571 has been seen
in short-term bone
marrow primary cell cultures of patients with mastocytosis.
· However, most mastocytosis
patients have the D816Y mutation.
· D816Y mutation is
difficult to find early on, since SMCD is a clonal disorder.
- Responses observed in these ongoing trials include:
* Allevation of symptoms such as severe
bone pain.
* Eradication of skin lesions cosmetically
unacceptable to patients.
* Reduction of serum tryptase and other
mast cell product.
* Reduction of mast cell concentration
in the bone marrow (from over 20% to almost
0%).
·
Trials needed in SMCD:
-
Transplant
- Novel agents
- Other inhibitors originally screened for Abelson
or PDGF beta receptor activity should
be tested for their effect on D816Y. These include those about
agents to go into clinical trials. (Dr.
Gilliland)
* Rationale for recommendation:
· FLIT-3 inhibitors
were originally derived as PDGF beta receptor inhibitors.
· Many PDGF receptor
inhibitors exist that could potentially be active.
* Yes, that type of screening is being performed
now by testing these various inhibitors
on marrow mast cells in mastocytosis patients known to have the
D816Y mutation. The screening is
in its earliest phase; too early to yield any conclusions.
- Positive results from STI and cladribine studies
would warrant a prospective study in SMCD,
perhaps in those who are IFN-resistant or IFN-intolerant.
·
Few mast cell lines exist:
-
The HMC1 cell line, developed at Mayo. Two forms - one with juxtamembrane
mutation, one with 8-16 mutation (and
one that has both).
- The newly developed SCF-dependent mast cell line.
NOTE ON
SENSITIVITY TO STI IN CLASSIC, CHRONIC EOSINOPHILIC SYNDROME/HYPEREOSINOPHILIC
SYNDROME (HES)
·
Evidence of eosinophilia's role as predictive factor for STI efficacy
in HES:
-
Six patients on STI have gone into complete remission or dramatically
responded:
* One from M.D. Anderson study, in press,
Leukemia Research (Ph+, overexpressed
c-kit, no other specific mutations)
* One from Rochester study (Ph+, overexpressed
c-kit, no other specific mutations)
* Four patients to be reported on in Lancet(
May, 2002) without apparent molecular
abnormalities, pending a Southern blot for PDGF R-B.
- Recommendation :
* Further investigate the interesting
observation that eosinophilia predicts response
sensitivity to STI in MPD patients.
CHRONIC
MYELOMONOCYTIC LEUKEMIA (CMML) THERAPIES
·
A broad study of STI in CMML of STI is justified, with correlative
genetic analysis for tyrosine kinases of all varieties.
-
We should not pre-judge whether STI is going to be effective or
not in CMML patients. (Dr. Gilliland)
- Look for evidence of PDGF receptor activating mutations.
* Although CMML does not have a high incidence
of 5 ;12 translocations (these justify
the main rationale for using STI), it may have other activating
mutations.
* Although most known PDGF receptor rearrangements
that are not cryptic cytogenetically,
some rearrangements may be.
- Perform complete sequencing for loss-of-function
mutations not just of PDGF beta receptor,
but also of alpha, kit, and the SH3 domain of Abelson.
·
Eosinophilia as predictive factor for response to STI571:
-
STI was successful in targeting PDGF beta receptor, commonly associated
with eosinophilia, in one CMML patient
with eosinophilia of the bone marrow (not peripherally).
(Dr. Dunbar's group)
·
Splenic ruptures/hyperproliferative reaction in CMML patients
on STI571.
-
Anecdotal.
- Two of two CMML patients treated with STI experienced
splenic rupture in a CMML STI study. Study
was stopped because:
* Other STI trials in CMML were not showing
encouraging results.
* Another splenic rupture occurred in
an MF patient, albeit 1 of 23 patients who was
also off treatment for five months.
· Case was described
by Dr. Barosi: Fever, abrupt enlargement of spleen, and thrombocytosis,
with recovery after STI571 stopped and high-dose hydroxyurea
administered.
- Pathology and possible mechanism of splenic rupture
in STI trials.
* Pathology was mostly extramedullary
hematopoiesis congestion, with nothing to suggest
blastic transformation.
* Rupture is similar to response seen
in relapsed blast crisis patients and may be due
to development of resistance to STI571. (Dr. Gilliland)
* Patients were on no concurrent treatments,
and had been off treatment for at least
two weeks (at least one was off treatment for five months).
* Patients were not on erythropoietin
when they experienced splenic rupture.
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