The MDS/MPD category includes myeloid disorders that have both dysplastic
and proliferative features at the time of initial presentation and that
are difficult to assign to either the myelodysplastic or myeloproliferative
group of diseases. The WHO classification provides a less restrictive view
of these diseases than do previous classification schemes that arbitrarily
assigned them to either the MDS
or MPD
categoryref1,
ref2.
For individual patients, the clinician may view the patient in the context
of whether proliferative or dysplastic manifestations predominate and treat
accordingly. For cooperative groups and clinical investigators, the WHO
category of MDS/MPD may allow for more focused clinical and scientific
investigation of these entities that overlap 2 major disease categories.
The criteria for the recognition of these disorders are detailed in the
WHO monograph, but some aspects of CMML and aCML are particularly problematic
and warrant some comment here. The molecular pathogenesis of MPD/MDS is
poorly understood, but a subset of patients presents with translocations
that disrupt and constitutively activate protein tyrosine kinases, most
commonly the platelet-derived growth factor receptor or the fibroblast
growth factor receptor 1 (FGFR1)ref1,
ref2,
ref3,
ref4,
ref5,
ref6,
ref7,
ref8.
chronic myelomonocytic
leukemia (CMML) with eosinophilia : CMML has generated considerable
controversy among a number of investigators as to whether it is primarily
a MPD or MDS disease or bothref1,
ref2.
The French-American-British group initially included CMML in its classification
of MDSref.
Later, there was an attempt to classify CMML into either the MPD category
if the total WBC count was > 13,000 x 109/L, or the MDS category
if it was < 13,000 x 109/Lref
. The FAB group recommended that patients who meet the criteria for the
diagnosis of CMML be subdivided into CMML, MDS-like or CMML, MPD-like,
depending on the degree of leukocytosisref.
Clinical studies that divided patients according to the FAB suggestions,
however, concluded that the magnitude of the white blood cell count does
not identify subgroups that have major biologic or prognostic differencesref1,
ref2.
To date, no specific cytogenetic or molecular differences between patients
with predominantly MDS or MPD characteristics have been reported. Furthermore,
some patients who initially manifest as having "nonproliferative" CMML,
with low white blood cell counts and minimal if any splenomegaly, may eventually
become quite "proliferative," with markedly elevated white blood cell countsref.
For these reasons, the WHO committees chose not to divide CMML into these
2 subtypes. To emphasize the nosologic issues, CMML is placed in a separate
category of diseases, the name of which clearly states the problem. The
WHO classification does not make any significant changes in the criteria
for the diagnosis of CMML. Despite the controversy over the disease category
to which CMML belongs, there is one issue about which all investigators
agree: the higher the blast count in CMML, the more unfavorable the prognosisref1,
ref2,
ref3,
ref4,
ref5.
As a result, the WHO divides CMML into 2 prognostic categories, CMML-1
and CMML-2, based on the number of blasts in the blood and bone marrow.
Epidemiology : CMML is a highly heterogeneous
disorder that predominantly presents in the elderlyref
(Seymour JF, Cortes JE. Chronic myelomonocytic leukemia. In: Talpaz M,
Kantajarian HM, eds. Medical Management of Chronic Myelogenous Leukemia.
New York, NY: Marcel Dekker; 1998:43)
Pathogenesis : tyrosine kinase fusion
genes :
ETV6 (TEL)-PDGFRB t(5;12)(q33;p13)
HIP1-PDGFRB t(5;7)(q33;q11)
H4-PDGFRB t(5;10)(q33;q21)
RAB5-PDGFRB t(5;17)(q33;p13)
Concurrent with the heterogeneous clinical presentation and course of CMML
patients, no consistent genetic abnormality has yet been linked with CMML
pathogenesis, although it is clearly a clonal hematopoietic disorder. Karyotypic
abnormalities can be demonstrated in a significant number of patients,
but most of the abnormalities are also routinely observed in patients with
other MDS category diseases. RAS gene mutations are observed in a significant
proportion of patients (up to 40%) either at presentation or at some stage
during the course of their diseaseref.
The incidence of RAS mutations in CMML may be higher than in other MDS
subtypes. A very small subset of CMML patients have a specific translocation,
t(5;12)(q33;p13). This translocation fuses TEL, a member of the Ets family
of transcription factors, to the PDGFßR, leading to constitutive
activation of the tyrosine kinase domain of the PDGFRref.
Multiple signaling pathways appear to be activated by TEL/PDGFßRref1,
ref2,
ref3,
ref4.
Complete delineation of the relative contribution of these pathways to
the pathogenesis of CMML will require further investigation, including
the use of mouse modelsref1,
ref2.
In addition to the activating RAS point mutations and the TEL/PDGFßR
gene fusion, a number of studies have investigated the role of specific
cytokines in the in vitro growth of CMML progenitors. TNF, GM-CSF,
IL-3, IL-4, IL-6, and IL-10 have all been implicated as playing potential
roles in the pathogenetic hyperproliferative growth pattern of CMML cells
in vitro or in vivo in patientsref1,
ref2,
ref3,
ref4,
ref5,
ref6 Symptoms & signs : splenomegaly,
monocytosis with granulocytosis, and thrombocytopenia.
Diagnostic criteria :
< 20% blasts (include myeloblasts, monoblasts, and promonocytes) in
the blood or bone marrow
dysplasia in one or more myeloid lineages. If myelodysplasia is absent
or minimal, the diagnosis of CMML may still be made if the other requirements
are present and:
an acquired, clonal cytogenetic abnormality is present in the marrow cells,
or
the monocytosis has been persistent for at least 3 months and all other
causes of monocytosis have been excluded
diagnose CMML-1 when blasts < 5% in blood and < 10% in bone
marrow
diagnose CMML-2 when blasts 5-19% in blood, or 10-19% in marrow,
or if Auer rods are present and blasts < 20% in blood or marrow
diagnose CMML-1 or CMML-2 with eosinophilia when the criteria above
are present and when the eosinophil count in the peripheral blood is >
1.5 × 109/L
Prognosis : sometimes it progresses to its
acute counterpart (M4
AML)
Therapy : for the small subset of patients
who demonstrate translocations in their leukemia cells involving PDGFßR,
imatinib mesylate (STI571) has been recently reported to produce dramatic
and durable responsesref.
As most CMML patients are elderly at the time of diagnosis, myeloablative
stem cell transplantation is not a viable option for the majority. For
those patients who do have a donor and are young enough to tolerate the
toxicities, myeloablative stem cell transplantation should be seriously
considered, as this remains the only proven curative option for this disease.
Nonmyeloablative
allogeneic HSCT
strategies are rapidly emerging and may ultimately prove to be a less toxic
but effective alternative to myeloablative transplantation. Otherwise,
cytokine therapy and low- and high-dose chemotherapeutic options have been
attempted, but with limited success. Part of the problem in interpreting
many previous trials is that CMML patients have been treated, evaluated,
and reported together with all other MDS subtypes, making specific evaluation
of the response in CMML problematic. Responses to erythropoietin therapy
can be observed in 15-20% of patientsref.
CMML patients can also respond temporarily in terms of increases in peripheral
blood neutrophil counts to G-CSF
or GM-CSF,
but
because CMML progenitor cells can also respond to these cytokines, there
is a concern for a potentially higher transformation rate to AMLref.
Given the toxicities of high-dose chemotherapy in this elderly patient
population, chemotherapeutic trials have generally not produced sufficient
response rates to justify routine use of high-dose chemotherapy. Because
CMML pathogenesis has been linked to dysregulated signal transduction involving
the Ras pathway and to one or more cytokines such as GM-CSF, more targeted
therapeutic approaches are now beginning to emerge. The farnesyltransferase
inhibitors (FTIs)
were developed as specific compounds to block Ras signal transduction by
inhibiting Ras binding to the inner plasma membraneref.
Whether this is their true or primary mechanism of action is a matter of
ongoing debate, but mounting evidence suggests that response of malignancies
to FTIs is independent of RAS mutational statusref1,
ref2,
ref3.
Investigators from Stanford have recently reported preliminary results
of the use of one FTI, R115777, in a Phase I/II study of MPD patients,
including 2 CMML patients (Gotlib J, Dugan K, Katamneni U, et al. Phase
I/II study of farnesyltransferase inhibitor R115777 (Zarnestra) in patients
with myeloproliferative disorders (MPDs): preliminary results [abstract].
ASCO Proceed. 2002;21:4a). Further results from this and similar trials
will be of interest. Blocking the dysregulated cytokine signal transduction
operative in CMML, such as by blocking GM-CSF at the cell surface, is also
a potentially viable approach to targeted therapy. 2 compounds discussed
below, E21R and DT388-GM-CSF, are entering trials in adults and children
for various myeloid malignancies and may prove efficacious in CMML. Imatinib
mesylate is also being investigated in CMML, but with discouraging early
results.
atypical chronic myeloid
leukemia (aCML) is not an ideal name for any disease, because it implies
that the associated disorder is merely an atypical variant of chronic
myelogenous leukemia (CML).
Instead, aCML lacks the Philadelphia (Ph) chromosome and BCR/ABL fusion
gene that are the hallmarks of classic CML. In addition, aCML is associated
with marked granulocytic and often multilineage dysplasia, which is not
observed during the chronic phase of CML. The few clinical studies published
to date indicate that aCML is clinically a very aggressive disease, with
reported median survival times of only 11 to 18 monthsref1,
ref2.
Although the WHO committees struggled for a better name for aCML to avoid
the possibility of confusion with CML, none could be agreed upon. However,
the placement of aCML in a different disease category does serve to set
it apart from CML. Atypical CML affects a truly heterogeneous group of
patients, and the exact incidence is not known. Reports of small numbers
of these patients indicate that they often have other cytogenetic abnormalities
and suffer from short median survival times. Because of the paucity of
these patients and their vast clinical heterogeneity, little can be said
regarding pathogenesis. Preliminary findings indicate that these patients
generally do not respond to imatinib mesylate. Other potential treatment
options to consider are a clinical trial, if available, stem cell transplantation,
or low-dose chemotherapy such as hydroxyurea
juvenile myelomonocytic
leukemia (JMML) is a clonal hematopoietic disorder characterized by
proliferation principally of the neutrophil and monocytic lineages. It
lacks the Ph chromosome and BCR/ABL fusion gene and manifests as a leukemic
disorder in infants and young children, although adolescents may occasionally
be affected as well. The criteria utilized in the WHO classification for
JMML follow the guidelines established by the European Working Group of
MDS in Childhoodref.
This entity incorporates those leukemias of childhood previously referred
to as juvenile chronic myeloid leukemia and chronic
myelomonocytic leukemiaref.
Cases previously referred to as the infantile monosomy 7 syndrome
are also included in this categoryref.
Epidemiology : afflicts infants and young
children, with the vast majority of cases presenting when children are
<= 5 years of age
Pathogenesis : much more is known about
the pathogenesis of JMML than about that of CMML and aCML. JMML is a clonal
disorder arising from the pluripotent stem cellref1,
ref2.
More so than any other leukemia or myeloproliferative disorder, JMML cells
in vitro nearly uniformly show spontaneous colony formation without
addition of exogenous growth factors. This in vitro growth characteristic
and the subsequent pathogenesis of JMML have been definitively linked to
dysregulated growth factor signal transduction through the Ras pathwayref1,
ref2,
ref3,
ref4,
ref5,
ref6,
ref7,
ref8.
This Ras dysregulation results in JMML cells demonstrating a selective
hypersensitivity to GM-CSFref.
Either activating RAS point mutations or inactivating NF1 mutations can
lead to constitutive signaling of the Ras pathway. JMML patients demonstrate
RAS and NF1 gene abnormalities in their hematopoietic cells at estimated
rates of 20% and 30%, respectively, and these subsets remain mutually exclusiveref1,
ref2,
ref3.
Murine hematopoietic cells that are homozygously deleted of Nf1 (Nf1-/-)
are also hypersensitive to GM-CSF and, if these cells are transplanted
into irradiated recipient mice, they are capable of inducing an MPD reminiscent
of JMMLref1,
ref2.
Nf1 mutant murine hematopoietic cells demonstrate hyperactivation to numerous
cytokines, including GM-CSF, SCF, and IL-3ref.
However, studies by Birnbaum and colleagues with Gmcsf-Nf1 doubly mutant
cells have shown that GM-CSF plays a central role in the aberrant growth
of Nf1 mutant cellsref,
thus providing a compelling rationale for pursuing therapeutic strategies
that target the GM-CSF signal transduction pathway in JMML patients.
Symptoms & signs : marked hepatosplenomegaly
Laboratory examinations : leukocytosis
with monocytosis, anemia and thrombocytopenia, and elevated fetal hemoglobin
in most patients (even when corrected for age)ref.
Most patients (> 80%) have a normal karyotype and are, by definition, Philadelphia
chromosome negative and BCR/ABL- Therapy : there is no known, consistently
effective therapy for JMML. Single- and multiagent chemotherapy regimens
in limited numbers of patients report widely varying response rates but
provide little evidence that such therapy improves ultimate outcome. Only
allogeneic stem cell transplantation (SCT) has resulted in extended survivalref1,
ref2,
ref3.
Unfortunately, the relapse rate from allogeneic SCT is inordinately high
in JMML, ranging from 28-55% in several studies, with 5-year disease-free
survival rates ranging from only 25-40%. Although 13-cis retinoic
acid can produce a 40-50% overall response rate, complete remissions sustained
off therapy are rare. Given the knowledge of JMML pathogenesis, mechanism-based
molecularly targeted approaches such as that used for imatinib mesylate
in BCR/ABL+ CML now seem justifiable for JMML. However, given
that SCT can result in long-term survival, it seemed inappropriate to completely
abandon this treatment approach. Therefore, a Phase II window/Phase III
trial design for JMML was activated by the Children’s Oncology Group in
2001.
There are 3 appealing aspects to this protocol design. First, it permits
the rigorous evaluation of the efficacy of a single molecularly targeted
agent in untreated JMML patients who have not yet developed drug resistance.
Second, if one phase II agent fails, the protocol is designed to allow
for the substitution of a different agent for Phase II testing without
disrupting the rest of the study. Finally, the fact that participation
in the Phase II window is not required allows patients and their parents
who are skeptical regarding experimental agents an opportunity to still
enroll in the remainder of the protocol. The first agent to be tested in
this format for JMML is the FTI R115777, the same agent being tested in
adults with MPD (Gotlib J, Dugan K, Katamneni U, et al. Phase I/II study
of farnesyltransferase inhibitor R115777 (Zarnestra) in patients with myeloproliferative
disorders (MPDs): preliminary results [abstract]. ASCO Proceed. 2002;21:4a).
A multitude of other agents capable of targeting the GM-CSF/Ras pathway
(albeit with varying degrees of specificity) are now emerging as potential
capable agents that can substitute into the Phase II window of this protocol
once R115777 has completed testing.
peptidomimetics : E21R was created by a single amino acid substitution
in the GM-CSF molecule at position 21. This substitution allows E21R to
function as a GM-CSF antagonist by binding to the -subunit of the GM-CSF
receptor but preventing its association with the ß-subunit, which
is critical for downstream signal transduction. At concentrations of 1
µg/mL and 10 µg/mL, E21R induced apoptosis in AML and CML cellsref,
and in JMML cellsref,
respectively. In a JMML-SCID/NOD mouse modelref,
E21R prevented dissemination of leukemic cells and induced remission in
animals that had developed JMML-like MPD after injection of human JMML
cells. E21R is in Phase II studies in adult AML and CMML in England and
Australia. A Phase I trial in relapsed pediatric myeloid malignancies is
in the planning stages in the USA
GM-CSF fused to toxins : 2 groups have reported the successful development
of a GM-CSF molecule/diphtheria toxin fusion constructref1,
ref2.
This fusion product has shown some effectiveness in toxicity to acute leukemia
cells and JMML cellsref.
A Phase I trial of this agent has been conducted in relapsed adult AML.
other signaling inhibitors : a DNA enzyme that targets Raf-1 gene expression
has shown effectiveness at JMML cell growth inhibition in vitro and in
a JMML NOD-SCID mouse modelref.
The Nf1 JMML mouse model provides a useful system for testing targeted
therapeutics such as the MEK inhibitor PD184352ref.
These ongoing studies demonstrate the utility of both the Nf1 and NOD/SCID
JMML mouse models to not only help elucidate pathogenetic mechanisms but
also to test molecularly targeted therapeutics.
If future studies provide more definitive evidence that CMML, atypical
CML, or JMML are more accurately classified as purely myelodysplastic or
myeloproliferative processes, appropriate changes in their classification
will be warranted.
or MPD
