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A heterogeneous group of disorders characterized by abnormal hematopoietic
stem cells => increased apoptosis of precursor cells and trilineage defects
in hematopoiesis, including the erythrocytic, granulocytic, and mega-karyocytic
lineages => intramedullary accumulation abnormal localization of immature
precursors (ALIP) => "ineffective hematopoiesis" => progressive
pancytopenia (normocytic and normochromic
anemia
,
leukocytosis
with relative neutropenia,
and thrombocytopenia).
Splenomegaly,
hepatomegaly,
and lymphadenopathy
may not occur until the onset, often explosive, of acute
myelogenous leukemia.
The term "syndrome" is indicative of the wide clinical spectrum of MDS,
which includes patients with moderate anemia with normal neutrophil and
platelet counts, patients with hypocellular or markedly hypercellular bone
marrows, and others with frank leukemia; clinical courses can range from
a few months to many years. Indeed, it is clear that a number of biologically
distinct disorders are combined under this rubric, awaiting better molecular
characterization to allow better classification. An overview of current
understanding of the biology of MDS, the limitations of current treatments
and possible future approaches are available in the proceedings of an National
Cancer Institute (NCI)-sponsored "State of the Science" meetingref.
MDS may be the most common clonal neoplastic disease of hematopoietic origin
in adults, with a suggestion that the incidence is rising, in part because
of the aging of the population in the Western world. It is probably
underdiagnosed and may be the cause of some of the mild to moderate anemias
encountered in older people, often attributed to "anemia
of chronic disease".
MDS is a consequence of multiple mutations accumulating over time that
affect the HSC. It is notoriously resistant to chemotherapy with low complete
response rates as well as short durations of response. Drug resistance
is a feature of virtually all myeloid leukemias deriving from multipotent
stem cells, presumably due to further perfection by the neoplastic cells
of the multiple mechanisms that protect normal progenitors from damage
by exogenous toxins. In addition, there is often a prolonged period of
cytopenia due to delayed recovery of normal hematopoiesis following chemotherapy,
a particular problem in the elderly population of patients with MDS. Incomplete
marrow recovery can also preclude the delivery of postremission treatment
to some responding patients. This is in contrast to patients with de
novo acute leukemia, in whom there is a relatively reliable return
of normal blood counts following effective cytoreductive chemotherapy.
This may suggest a deficiency in either the quality or number of normal
stem cells in MDS patients. The mechanism(s) by which the development and
proliferation of a dysplastic clone suppresses the growth of residual normal
hematopoietic elements is not known. It is also unknown whether recovery
of peripheral blood counts following therapy for MDS is attributable to
the return of polyclonal hematopoiesis or reflects improved differentiation
capacity of the MDS clone. Although the MDS were initially considered by
many to be synonymous with "preleukemia," this notion has given
way to the realization that MDS is a heterogeneous spectrum of stem cell
malignancies, with the majority of patients succumbing to complications
of bone marrow failure rather than acute leukemia.
Epidemiology
: overall, MDS affects approximately 1 in 500 persons over 60 years of
age, making it the most common hematologic malignancy in this age groupref;
it may develop at any age, including childhood
Aetiology :
,
Fanconi
anemiaref,
and neurofibromatosis type
1ref_Glu785Lys
a novel SNP located within the cytoplasmic domain due to G to A transition
at position 2591 Screening a cohort of primary MDS patients, de novo
AML patients, as well as age- and sex-matched controls identified this
mutation as a rare SNP, which is associated with the development of high-risk
MDS. Functional analysis by retroviral transfer of G-CSF-R_785Lys into
myeloid progenitor cells of G-CSF-R–deficient (Gcsfr-/-) mice
revealed a significantly diminished colony-formation capacity after G-CSF
stimulation as compared with cells expressing the wild-type receptorref.,
alkylating
agents
or DNA topoisomerase II
inhibitorsref1,
ref2,
ref3,
ref4,
ref5,
ref6
in :
who received bone marrow transplants (15% at 5 yrsref1,
ref2,
to 18% at 5 and 6 yearsref,
19.8% at 10 yrsref).
At the time of autologous HSCT, the prevalence of polyclonal hematopoiesis
is 77% (80/104), of skewed X-inactivation pattern (XIP) was 20% (21/104),
and of clonal hematopoiesis was 3% (3/104). To determine the predictive
value of clonality for the development of t-MDS/AML, a subgroup of 78 patients
with at least 18 months follow-up was analyzed. As defined by the HUMARA
assay, 53 of 78 patients had persistent polyclonal hematopoiesis, 15 of
78 had skewed XIP, and 10 of 78 (13.5%) either had clonal hematopoiesis
at the time of ABMT or developed clonal hematopoiesis after ABMT. t-MDS/AML
developed in 2 of 53 patients with polyclonal hematopoiesis and in 4 of
10 with clonal hematopoiesisrefref
(DeCillis A, Wickerham D, Brown A, Fisher B: Acute myeloid leukemia (AML)
in NSABP B-25. Proc Am Soc Clin Oncol 14:A92, 1995)ref
(15-20%): point mutation
(5%) internal tandem duplication (ITD) and activating loop mutations (D835)
are found in 4% of t-AML
and 27% of de novo AMLsref.
33% of MDS patients acquire activating mutations of FLT3 or NRAS
gene during AML evolution and FLT3/ITD predicts a poor outcome in MDSref
(rare): mutation
(rare): mutation
(rare): mutation
(5-10%): mutation, deletion
(rare): mutation, deletion, promoter methylation
(rare): mutation
fusion : in contrast to AMLs harboring oncogenic transcription factor fusions,
hardly any oncogene activation has been assigned specifically to MDS and
AML with CCAs. One exception is the 11q23 region and its resident MLL gene,
which is amplified in a significant fraction of MDS and AML with karyotypic
complexity and an adverse prognosisref1,
ref2,
ref3,
ref4.
MLL has long been recognized as an important component of translocation-generated
fusion proteins. In contrast to other oncogenic fusion proteins, MLL participates
in translocations with > 40 different partner chromosomal loci. Homodimerization
of the chimeric proteins appears to underlie the promiscuity of MLL in
its ability to combine with many fusion partners, at least for a subset
of its productive fusionsref.
The new studies mentioned above suggested that amplification of MLL represents
a new mechanism of oncogenic activation of this gene. A recent study confirmed
the importance of MLL within the 11q23 amplicon by analysis of MLL target
genes like HOXA9 and MEIS1ref.
It has long been recognized that HOXA9 is one of the important target genes
of MLL and recent reports from several independent laboratories, including
ours, provide a comprehensive view of other HOX genes that may be inappropriately
activated in leukemias with MLL rearrangementsref1,
ref2.
Very recently, Hoxa7 and Hoxa9 were shown to be essential for MLL-dependent
leukemogenesis in vivoref.
Thus, aberrant MLL activation in MDS/AML and consequent dysregulation of
its downstream targets are of clinical importance. Indeed, the remarkable
synergy between MLL gene amplification and loss of 5q in MDS and AML are
reported to result in an extremely poor overall survival rate of 30 daysref.
Moreover, these data provide an important clue regarding the mechanism
of disease evolution. It should be stressed that the impact of dysregulated
MLL and HOX gene activation is likely to extend beyond the subgroup of
patients with CCAs, as MLL and HOXA9 were also significantly upregulated
in unselected MDS patient samples, including those with normal karyotypesref
abnormality :
family expression :
often involves monosomy 7, together with mutations of the NF1 generef.
In a study of 1663 cases of MDS, 1098 (66%) had a single chromosomal abnormality,
237 (22%) were monosomic for chromosome 7, and 431 (39%) had a partial
deletion of chromosome 5. Other abnormalities included chromosomes 6, 9,
11, 12, 13, and 17. Importantly, most of these genetic abnormalities correlate
with prognosis. After intensive chemotherapy, 60% of patients with an apparently
normal karyotype entered complete remission (average duration, 16 months),
while patients with chromosome 5 or 7 deletions or complex chromosomal
abnormalities had a 20% remission rate (average duration, 4 to 5 months).
Similarly, secondary MDS usually displays mono-somies of chromosome 5 or
7 or partial deletions involving 5q or 7q, with chromosome 7 defects associated
with decreased survival timeref.
Although the majority of putative tumor suppressors in MDS have not been
cloned, many chromosomal translocation-mediated oncogenesref
and a few of the tumor suppressors have been identified. For example, genes
inactivated in MDS comprise a relatively small number of cases and include
P53, RB, WT-1, NF1, AML1, C/EBP, b-catenin (CTNNA1)
and nucleophosmin (NPM)ref1,
ref2.
However, only 2 of these genes (P53 and CTNNA1) lie within the clinically
prominent chromosomal deletions in MDS or MPD, suggesting that many of
the principal tumor suppressors responsible for these myeloid diseases
have yet to be identified
or May-Grunwald-Giemsa
because Wright's stain alone may not adequately demonstrate cytoplasmic
granules (Brunning RD, Matutes E, Harris NL, et al. Acute myeloid leukemia:
introduction. In: Jaffe ES, Harris NL, Stein H, Vardiman JW (Eds). World
Health Organization Classification of Tumours. Pathology and Genetics of
Tumours of the Haematopoietic and Lymphoid Tissues. IARC Press: Lyon; 2001:77-105).
Iron
stains
of the marrow aspirate are essential to detect ringed sideroblasts. Blood
and marrow smears should be examined for dyplasia, the percentage of blasts
and monocytes (nonspecific esterase stains may be helpful to detect monocytes
in the marrow), and ringed sideroblasts. The enumeration of blasts is important
for diagnosis, classification and prediction of prognosisref1,
ref2.
In myeloid neoplasms, myeloblasts, monoblasts, and megakaryoblasts are
included in the blast calculation. Small, dysplastic megakaryocytes are
not blasts and should not be counted as such. Erythroid precursors are
also not counted as blasts, except in rare cases of "pure" erythroleukemia
in which primitive erythroblasts account for the majority of cells. In
myelomonocytic proliferations, promonocytes are included as "blast equivalents"
(Brunning RD, Matutes E, Harris NL, et al. Acute myeloid leukemia: introduction.
In: Jaffe ES, Harris NL, Stein H, Vardiman JW (Eds). World Health Organization
Classification of Tumours. Pathology and Genetics of Tumours of the Haematopoietic
and Lymphoid Tissues. IARC Press: Lyon; 2001:77-105)"ref.
Substitution of the percent of CD34+ cells determined by flow
cytometry for a visual blast count is discouraged. Although hematopoietic
cells that express CD34 are blasts, not all blasts express CD34. In addition,
dilution of the marrow sample by peripheral blood during aspiration and
processing of the sample for flow cytometry analysis complicates comparison
between the visual count and the CD34 value. Although a bone marrow biopsy
specimen is not always necessary to establish a diagnosis of MDS, it offers
valuable diagnostic and prognostic informationref1,
ref2.
Dysplasia, particularly of megakaryocytes, can be appreciated in well-prepared
biopsies, and evidence of disruption of the normal marrow architecture,
such as abnormal localization of immature precursors (ALIP), lends further
support for the diagnosis of MDS. Moreover, the biopsy provides confirmation
of the blast percentage and distribution, and serves as a source for immunohistochemical
studies that may have diagnostic and prognostic value. An underappreciated
role of the biopsy is that it may provide evidence for another disease
that can mimic MDS clinically, such as lymphoma
or metastatic tumor.
In cases of MDS that are hypocellular or associated with fibrosis, the
biopsy is essential for diagnosis.
and alcohol
and growth-factor
therapy
or parvovirus B19
infections),
but multilineage dysplasia can also be a transient, reactive change.
Causes of secondary dysplasia must be considered and excluded by appropriate
clinical and laboratory studies prior to rendering a diagnosis of MDS.
Furthermore, a small number of dysplastic erythroid, granulocytic or
megakaryocytic cells can be seen in marrow specimens from normal individualsref.
Hence, the guideline that 10% of the cells in a lineage should be dysplastic
to consider the lineage as dysplastic and as evidence for MDS is a reasonable
rule of thumbref.
The quality of the specimen is a common obstacle in the accurate diagnosis
of MDS. For example, hypogranularity of the cytoplasm of neutrophils is
a well-accepted feature of dysplasia, but visualization of neutrophil granules
is critically dependent on an optimal stain. The diagnosis of MDS should
never be based on "pale granulocytes" without other features to substantiate
the diagnosis.6 Biopsies should be of adequate size for evaluation (at
least 1-2 cm) and should extend into the marrow well past the cortical
bone. The marrow immediately under the cortical bone is normally less cellular
than deeper marrow. In a case of MDS, the combination of cytopenias in
the blood and a superficial, apparently hypocellular biopsy specimen might
result in an erroneous diagnosis of aplastic anemia. Even when these guidelines
are carefully followed, the diagnosis of MDS may remain problematic because
of morphologic features that are not clear-cut
is well known, and cytogenetic studies have been included in most of the
predictive scoring systems developed for MDSref
(Olney HJ, Le Beau MM. The cytogenetics and molecular biology of the myelodysplastic
syndromes. In: Bennett JM (ed). The Myelodysplastic Syndromes, Pathobiology
and Clinical Management. Marcel Dekker, Inc: New York; 2002). No cytogenetic
abnormality is specific for MDS or for a specific morphologic subgroup
of MDS. However, some unique cytogenetic/morphologic correlations exist,
the most common of which is the "5q-
syndrome". Although it might be expected that chromosomal abnormalities
would ultimately lead to the discovery of the genetic lesions important
in the pathogenesis of MDS, progress in this area has been slow. The pathogenesis
of MDS is likely a multi-step process that involves a number of insults
to the genome of a marrow stem cell, many of which are cytogenetically
silent. The search for genes critical to disease pathogenesis is further
complicated because the characteristic chromosomal abnormalities in
MDS involve loss of genetic material. Currently it is not clear whether
the loss of genetic material involves the total loss of function of a tumor
suppressor gene, a tumor suppressor gene that acts by haploinsufficiency,
or through some other associated defect that has not yet been discovered.
Gene expression profiling of cDNA from patients with MDS has recently been
reported. Genes reportedly upregulated include those involved in cell proliferation,
including members of the Ras gene family, and some that are downregulated,
reportedly including genes encoding anti-apoptotic proteinsref.
Cytogenetic subgroups:
,
and no monocytosis, the diagnosis is RCMD. In cases of RCMD with at least
15% ringed sideroblasts, the diagnosis is RCMD with ringed sideroblasts
(RCMD-RS). Whether there are major clinical or biologic differences between
RCMD and RCMD-RS is not yet clear. Data recently published by Germing and
associates in a study that included 284 patients with RCMD showed no significant
difference in survival or progression to AML between RCMD and RCMD-RSref.
A study by Nosslinger et al has taken exception to the WHO proposal in
regard to the benefit of further subtyping RA and RARS patients according
to the finding of multilineage dysplasia. In their study, patients with
RCMD had a better survival than did those with RA or RARSref.
However, in that study, not only were the WHO criteria for RCMD not used
but a number of patients classified as having RA and RARS had neutropenia
and/or thrombocytopenia, which would not be expected if these diseases
were also defined by the WHO criteria. An important problem in this group
of diseases is the possibility of misdiagnosis of MDS due to overinterpretation
of dyspoiesis that is secondary to a nonclonal disorder. This is particularly
problematic in the diagnosis of RA. Erythroid dysplasia is difficult to
define precisely, and the threshold for its recognition is variable from
one observer to another. The WHO classification does not entirely eliminate
this problem, but the establishment of minimal quantitative thresholds
of dysplasia for RA, RARS, RCMD, and RCMD-RS should result in more consistency
and accuracy in diagnosis. Whether RARS with unilineage erythroid dysplasia,
as defined in the WHO classification, is a myelodysplastic disorder remains
to be determined. However, until more reliable markers of erythroid dysplasia
are widely available, the category of RA will likely continue to include
some cases that are nonclonal erythroid disorders. In addition, occasional
patients may present with cytopenias affecting more than one cell lineage
and have multilineage dysplasia but not at the 10% level required for a
diagnosis of RCMD. If blasts are fewer than 5% in the bone marrow, such
cases are difficult to classify or even to recognize as MDS with confidence.
In cases like these a presumptive diagnosis of RCMD might be appropriate.
However, in such cases as well as for cases suspected to be RA, if there
is no evidence of clonality by genetic studies, the WHO recommends observation
for 6 months prior to making a diagnosis of MDS. RAEB is divided into 2
subgroups, RAEB-1 and RAEB-2, depending on the number of blasts in the
blood and bone marrow. Data from the International Workshop on Prognostic
Factors in MDS indicated that patients with > 10% blasts in the bone marrow
have a shorter median survival and a higher rate of transformation to acute
leukemia than do those with fewer than 10% blastsref.
In view of these data, the WHO classification recognizes 2 groups of patients
with RAEB, RAEB-1 and RAEB-2, depending on the % of blasts in the blood
and marrow and the presence or absence of Auer
rods.
Similar to AML, it is anticipated that additional myelodysplastic syndromes
with a characteristic constellation of clinical, genetic, and pathologic
findings will be identified.:
from 30% to 20% blasts in the bone marrow or peripheral blood with elimination
of the FAB category of
morphology (sometimes with the favorable translocation t(8;21)) can have
< 20% morphologic "blasts" and merit prompt treatmentref.
The assessment of hypocellular MDS is complicated by the dearth of cells
for qualitative microscopic analysis, although cytogenetic studies can
be helpful, particularly in patients with secondary MDS, a condition in
which hypocellularity is often present. Notwithstanding these difficulties,
the identification of hypoplastic MDS depends upon the application of current
standards by which the diagnosis of MDS is made.
from the MDS category into a new group of diseases, the myelodysplastic/myeloproliferative
diseases|
|
|
|
|
| refractory anemia (RA) | anemia
no or rare blasts < 1 x 109/L monocytes |
erythroid dysplasia only
< 10% grans or megas dysplastic < 5% blasts < 15% ringed sideroblasts [ (5q31-). Average survival : 7 years (not evolving to acute leukemia)] |
|
| refractory anemia with
ringed sideroblasts (RARS) / acquired idiopathic sideroblastic anemia |
anemia
no blasts |
erythroid dysplasia only
< 10% grans or megas dysplastic > 15% ringed sideroblasts < 5% blasts [5q31-, 5% evolve to AML ] |
|
| refractory cytopenia with
multilineage dysplasia (RCMD) |
cytopenias (bicytopenia or pancytopenia)
no or rare blasts no Auer rods
< 1 x 109/L monocytes |
dysplasia in > 10% of cells in 2 or more
myeloid cell lines < 5% blasts in marrow no Auer rods
< 15% ringed sideroblasts |
|
| refractory cytopenia with multilineage
dysplasia and ringed sideroblasts (RCMD-RS) |
cytopenias (bicytopenia or pancytopenia)
no or rare blasts no Auer rods
< 1 x 109/L monocytes |
dysplasia in > 10% of cells in two or more
myeloid cell lines > 15% ringed sideroblasts < 5% blasts no Auer rods |
|
| refractory anemia with excess blasts (RAEB) (5 < blasts in bone marrow < 20%) | refractory anemia with excess blasts - 1 (RAEB-1) | cytopenias
< 5% blasts no Auer rods
< 1 x 109/L monocytes |
unilineage or multilineage dysplasia
5-9% blasts no Auer rods |
| refractory anemia with excess blasts - 2 (RAEB-2) | cytopenias
5-19% blasts Auer rods
+/-
< 1 x 109/L monocytes |
unilineage or multilineage dysplasia
10-19% blasts Auer rods
+/- |
|
| myelodysplastic syndrome, unclassified (MDS-U) | cytopenias
no or rare blasts no Auer rods |
unilineage gran or mega dysplasia
< 5% blasts no Auer rods |
|
| MDS
associated with isolated del (5q) / 5q syndrome : although deletions
of 5q may be observed in a wide spectrum of de novo and therapy-related
acute myeloid leukemias and myelodysplastic processes, the 5q syndrome
is narrowly defined as de novo MDS with an isolated cytogenetic
abnormality involving deletions between bands q21 and q32 of chromosome
5. Detailed mapping experiments of this region of chromosome 5 have provided
evidence that the gene(s) involved in this syndrome is different than that
affected in other subgroups of MDS and AML associated with del(5q)ref1,
ref2.
In the 5q
syndrome there is usually a refractory macrocytic
anemia,
normal to increased platelet count, and increased numbers of megakaryocytes,
many of which have hypolobated nuclei. The number of blasts in the bone
marrow and blood is < 5%ref1,
ref2.
There is usually long survival. Additional cytogenetic abnormalities or
> 5% blasts in the blood or marrow is exclusionary for the diagnosis. |
refractory macrocytic anemia
< 5% blasts platelets normal or increased |
normal to increased megakaryocytes
with hypolobulated nuclei < 5% blasts no Auer rods
isolated del (5q) |
|
.
The patient remained in remission for nearly 1 year despite the discontinuation
of GM-CSF treatment. Several lines of evidence suggest that normal hematopoiesis
was restored after GM-CSF treatment. First, the cytogenetic anomaly, which
was present before GM-CSF, completely disappeared after three cycles of
treatment. Cytogenetic conversion was documented by conventional karyotypic
evaluation of mitotic bone marrow cell preparations as well as by premature
chromosome condensation analysis of the nonmitotic cells of bone marrow
and peripheral blood. Second, the growth pattern and cycle status of bone
marrow granulocyte-macrophage (CFU-GM) and erythroid (BFU-E) progenitor
cells were found to be normal during remission. Third, X chromosome-linked
RFLP-methylation analysis of DNA from mononuclear cells (> 80% lymphocytes)
and mature myeloid elements showed a polyclonal pattern. These findings
suggest that restoration of hematopoiesis in this patient after GM-CSF
treatment may have resulted from suppression of the abnormal clone and
a selective growth advantage of normal elementsref.
The 76-year-old patient was admitted to our hospital with a fever and a
productive cough; a diagnosis of pneumonia was thus made. Following treatment
with antibiotics, the patient's condition improved, and MDS was diagnosed
from peripheral blood and bone marrow examinations after the patient recovered
from the infection. The patient achieved a sustained haematological CR
that was confirmed by morphological and flow cytometric examination after
treatment with G-CSF alone, although chromosomal abnormalities persisted.
According to the literature, in almost all patients with acute myeloid
leukaemia or MDS who were reported to achieve CR by G-CSF, the course was
associated with infection, although our case did not have this complication
during the course of G-CSF therapy. Patients with G-CSF alone without infection
can achieve CR and that this may be related to a differentiation effect
of G-CSF based on persistent chromosomal abnormality in this caseref,
which has both anti-angiogenic and TNF inhibitory properties, represents
the first agent in this class to be investigated in MDS. In a Phase II
trial of thalidomide performed at the Rush Presbyterian Cancer Instituteref,
15 of 83 (18%) evaluable patients experienced either red blood cell transfusion
independence or a > 50% decrease in transfusion burden, whereas improvement
in non-erythroid lineages was uncommon. Dose escalation beyond 200 mg daily
was limited by cumulative neurological toxicity and is likely unnecessary.
An aggressive dose-escalation schema of 200 mg to 1000 mg daily evaluated
by the North Central Cancer Treatment Group study was compromised by excessive
early attrition due to toxicity at a median interval of 2.5 monthsref.
Prolonged drug treatment, when tolerated, appears necessary to maximize
hematological benefit. Median interval to erythroid response was 16 weeks
in the Rush trial (range, 12-20 weeks), with an erythropoietic response
rate of 29% among the 51 patients completing a minimum of 12 weeks of study
treatment. The overall clinical benefit of low-dose thalidomide in MDS
was evaluated in a national randomized, placebo-controlled Phase III trial
completed in the fall of 2003, the results of which should soon be available.ref
is a 4-amino glutarimide derivative of thalidomide that lacks the neurological
toxicities of the parent compound. It is a potent modulator of ligand-induced
cellular response with biological effects that range from potentiation
of antigen-initiated immune response, to modulation of integrin affinity,
suppression of trophic response to angiogenic molecules, and promoting
progenitor responsiveness to erythropoietin (List AF, Tate W, Glinsmann-Gibson
B, Baker A. The immunomodulatory thalidomide analog CC5013 inhibits trophic
response to VEGF in AML cells by abolishing cytokine-induced PI3-Akt activation
(abstract). Blood. 2002;100(11):139). Among 36 evaluable patients with
MDS either with symptomatic or transfusion-dependent anemia treated with
lenalidomide in a safety and efficacy trial, 24 (67%) experienced an erythroid
response according to IWG criteria, with 21 patients experiencing sustained
transfusion independence (List AF, Kurtin SE, Glinsmann-Gibson BJ, et al.
Efficacy of CC5013 in myelodysplastic syndromes (MDS). N Engl J Med. 2004).
Response
rate varied by cytogenetic pattern and was highest among patients with
a chromosome 5q31.1 deletion (91%) compared to a normal karyotype (68%)
or other chromosome abnormality (17%) [P = 0.009]. Similarly, patients
with lower risk IPSS categories experienced a higher frequency of erythroid
response compared to patients with higher risk disease (72% vs 25%);
however, few patients had Intermediate-2 or High-risk disease (n = 4).
Unlike cytokine therapy, cytogenetic remissions were common, with 65%
of informative patients experiencing > 50% reduction in abnormal metaphases,
including 10 (57%) complete cytogenetic remissions. Major cytogenetic response
occurred most commonly in patients with a chromosome 5q31.1 interstitial
deletion (9 of 11 patients). Perhaps of greater importance, responses appear
durable. After a median follow-up of 81 weeks, median duration of transfusion-independence
had not been reached (48+; range, 13+ to > 101 weeks) with median sustained
hemoglobin of 13.2 g/dL (range, 11.5-15.8 g/dL). Neutropenia (67%) or thrombocytopenia
(57%) > grade 3 NCI-CTC was the most common adverse event and was dose
dependent, necessitating treatment interruption or dose-reduction in 61%
of patients. Lenalidomide has completed multicenter Phase II trials in
transfusion-dependent patients with Low- or Intermediate-1 risk MDS and
either chromosome 5q31.1 deletion (n = 148) or other karyotypic abnormalities
(n = 215). The results of the trial, if sufficiently encouraging, are expected
to undergo accelerated review by the US Food and Drug Administration (FDA)
and may secure a new position in the management of ineffective erythropoiesis
for patients with MDS. Among 148 patients with MDS associated with chromosome
5q31 deletion (only 27% with 5q-
syndrome) who received 10 mg of lenalidomide for 21 days every
4 weeks or daily, 112 had a reduced need for transfusions (76%; 95% confidence
interval [CI], 68 to 82) and 99 patients (67%; 95% CI, 59 to 74) no longer
required transfusions, regardless of the karyotype complexity. The response
to lenalidomide was rapid (median time to response, 4.6 weeks; range, 1
to 49) and sustained; the median duration of transfusion independence had
not been reached after a median of 104 weeks of follow-up. The maximum
hemoglobin concentration reached a median of 13.4 g per deciliter (range,
9.2 to 18.6), with a corresponding median rise of 5.4 g per deciliter (range,
1.1 to 11.4), as compared with the baseline nadir value before transfusion.
Among 85 patients who could be evaluated, 62 had cytogenetic improvement,
and 38 of the 62 had a complete cytogenetic remission. There was complete
resolution of cytologic abnormalities in 38 of 106 patients whose serial
bone marrow samples could be evaluated. Moderate-to-severe neutropenia
(in 55% of patients) and thrombocytopenia (in 44%) were the most common
reasons for interrupting treatment or adjusting the dose of lenalidomideref.
has broad biological properties that derive from its ability to bind covalently
and deplete cellular sulfhydryl-rich proteins such as glutathione, as well
as anti-angiogenic properties. Arsenic in its trivalent form inhibits glutathione
peroxidase to potentiate peroxide generation, disrupt mitochondrial respiration
and mitochondrial membrane integrity, repress anti-apoptotic proteins and
initiate caspase-mediated apoptotic responseref.
In MDS and AML, the antiproliferative effects of ATO relate in part to
its ability to suppress myeloblast elaboration of VEGF-A and its direct
cytotoxicity to neovascular endotheliumref.
Not surprisingly, bone marrow specimens from patients with MDS, which natively
harbor lower glutathione reserves compared to normal hematopoietic progenitorsref,
also demonstrate increased apoptotic susceptibility to ATO that is enhanced
by GM-CSF stimulationref.
Preliminary results of 3 clinical trials indicate that ATO has modest activity
in both lower- and higher-risk MDS (List AF, Schiller GJ, Mason J, et al.
Trisenox® (arsenic trioxide) in patients with myelodysplastic syndromes
(MDS): preliminary findings in a phase II clinical study [abstract]. Blood.
2003;102:423; Raza A, Lisak LA, Tahir S, et al. Trilineage responses to
arsenic trioxide (Trisenox®) and thalidomide in patients with myelodysplastic
syndromes (MDS), particularly those with inv(3)(q21q26.2) [abstract]. Blood.
2002;100:795; Vey N, Dreyfus F, Guerci A, et al. Trisenox® (arsenic
trioxide) in patients (pts) with myelodysplastic syndromes (MDS): Preliminary
results of a phase 1/2 study [abstract]. Presented at the 8th Congress
of the European Hematology Association, Lyon, France, 12-15 June 2003).
The doses and schedules applied in these studies vary, ranging from monthly
cycles of two sequential weekly treatments of 0.25 mg/kg/day for 5 days
followed by a 2-week treatment hiatus to a dose-intense induction with
0.30 mg/kg/day for 5 days followed by 0.25 mg/kg/day twice weekly maintenance
for 15 weeks. Overall, approximately 20-25% of patients have experienced
hematological
improvement, with few complete or partial remissions. Although erythroid
responses predominate, hematologic benefit is not limited to the erythroid
lineage and responses may be sustained for prolonged periods after treatment
cessation. Given the manageable toxicity of ATO, combination trials are
in progress, which may build upon the results obtained with monotherapy.
is currently completing Phase II investigation in MDSref
inhibitors : SU5416, SU11248, PTK787, AG13736,
: constitutive Ras/MAPK activation is demonstrable in 40-60% of CMML cases,
resulting either from mutations within RAS alleles or from reciprocal translocations
deregulating RTKsref.22,29
In the absence of mutations, sustained activation of the Ras/MAPK cascade
may occur through a constitutive upstream signal. Perhaps the most important
therapeutic discovery in the management of CMML in recent years is the
activity of imatinib in patients harboring a reciprocal chromosome translocation
involving chromosome 5q33. Although a number of chromosomes and genes may
partner in the gene rearrangements, the clinical phenotype is distinct,
recognized by the WHO classification as CMML with eosinophilia (CMML-Eos),
but arising from the generation of novel fusion genes involving the PDGFß
receptor with constitutive RTK signalingref1,
ref2
(List AF, Sandberg AA, Doll DC. Myelodysplastic syndromes. In: Lee RG,
Bithell TC, Foerster J, Athens JW, Lukens JN, eds. Wintrobe’s
Clinical Hematology (11th Ed). Lippincott Williams & Wilkins; 2004:2207-2234).1,30,31
Transgenic mouse models have shown that these novel RTK fusion genes are
singularly responsible for the generation of these myeloproliferative disorders
and are selectively responsive to PDGFß kinase inhibitorsref.
Imatinib binds to the ATP-binding pocket of the PDGFß receptor analogous
to its interaction with BCR/ABL to act as a potent inhibitor of receptor
kinase activity. Among 5 patients reported to date, each achieved rapid
hematological control and sustained complete cytogenetic remission with
imatinib monotherapyref
have had limited investigation in MDS. SU5416 (Sugen Inc, S. San Francisco,
CA), represents the only agent of its class to complete Phase II investigation.
Like most RTK antagonists, specificity is relative, with activity extending
to other type III receptors such as those for the PDGFß, FLT3, and
c-kit ligands. A multicenter trial involving patients with higher-risk
MDS or AML yielded minimal reduction in leukemia burden and a corresponding
degree of hematological benefit despite increased apoptotic index in the
myeloblast populationref
(Albitar M, Smolich BD, Cherrington JM, et al. F. Effects of SU5416 on
angiogenic factors, proliferation and apoptosis in patients with hematological
malignancies [abstract]. Blood. 2001;98(11):110). Clinical development
of this agent was limited by its insolubility and requirement for twice
weekly intravenous administration. Investigation of the orally bioavailable
analogue SU11248 in patients with AML ended prematurely owing to limiting
nonhematological organ toxicities (Foran J, Paquette R, Copper M, et al.
A phase I study of repeated oral dosing with SU11248 for the treatment
of patients with acute myeloid leukemia who have failed or are not eligible
for conventional chemotherapy [abstract]. Blood. 2002;100:558). Despite
the disappointing early results of this class of agents in myeloid malignancies,
clinical investigation of potent and orally active receptor antagonists
continues. The Cancer and Leukemia Group B (CALGB) is investigating PTK787
(Novartis, East Hanover, NJ) in patients with low- and higher-risk MDS
using a once daily administration schedule
inhibitor : PKC412
inhibitor : SC10469
inhibitor : AG3340 (PrinomastatTM)ref
: R115777 (ZarnestraTM), SCH66336 (lonafarnib; SarasarTM)
: activating point mutations of the RAS proto-oncogene are detected in
fewer than 20% of unselected patients with MDS but are common in CMML.1
The RAS gene superfamily encodes guanosine triphosphate hydrolases (GTPase)
that serve as critical regulatory elements in signal transduction, cellular
proliferation and maintenance of the malignant phenotype. Farnesylation
of carboxy-terminal consensus sequences by farnesyl protein transferase
(FPT) represents the first and rate limiting post-translational modification
of Ras-GTPases that is requisite for membrane association and transforming
activityref.
The farnesyl transferase inhibitors (FTI) represent a novel class of potent,
oral inhibitors of Ras and other prenylation-dependent proteins. These
agents are able to modulate multiple signaling pathways that have been
implicated in the pathobiology or progression of CMML and MDS in the absence
of salvage isoprenylation pathways. Preliminary results of Phase I/II studies
in MDS and CMML indicate promising hematopoietic promoting activity that
extends to non-erythroid lineagesref1,
ref2,
ref3.
Tipifarnib (R115777, ZarnestraTM; Janssen Pharmaceuticals, Beerse, Belgium,
and Spring House, PA) and lonafarnib (SCH66336 or SarasarTM; Schering-Plough
Research Institute, Kenilworth, NJ) are the leading non-peptide, heterocyclic
oral FTIs that have completed Phase I and II clinical studies in hematological
malignanciesref1,
ref2,
ref3.
In Phase I and II trials of tipifarnib performed in patients with MDS or
AML, treatment with 300-600 mg bid for 21 days every 4-6 weeks, yielded
partial or complete responses in 20-30% of patients, without relation to
RAS mutation statusref1,
ref2
(Lancet JE, Gojo I, Gotlib J, et al. Tipifarnib (ZarnestraTM) in previously
untreated poor-risk AML and MDS: Interim results of a phase 2 trial (abstract).
Blood. 2003;102(Suppl 1):176). Interim results of a multicenter Phase II
trial involving patients with either advanced MDS or elderly patients with
AML who were not candidates for conventional chemotherapy induction showed
promising clinical benefit. Among 98 evaluable patients treated with 600
mg bid for 21 days every 4-6 weeks, 21% achieved a complete remission (CR),
whereas 44% experienced either a CR, partial remission or hematologic improvement
with a median duration or remission approaching 5.5 months (Lancet JE,
Gojo I, Gotlib J, et al. Tipifarnib (ZarnestraTM) in previously untreated
poor-risk AML and MDS: Interim results of a phase 2 trial (abstract). Blood.
2003;102(Suppl 1):176). Given the favorable treatment-related mortality
(7%) compared to induction chemotherapy, this novel class of agents may
create a new paradigm for the treatment of advanced MDS and AML in the
elderly. Importantly, the activity of this class of agents cannot be ascribed
solely to the inhibition of constitutively active RAS proteins. Efficacy
and safety studies of lonafarnib administered in a continuous schedule
have shown a comparable frequency of hematologic improvement but a somewhat
lower apparent frequency of CRref.
Toxicity profiles also differ with diarrhea and hypokalemia limiting at
300 mg twice daily. In an expanded Phase II trial in 67 patients with MDS
or CMML, erythroid responses were reported in 35%, platelet responses in
22% of thrombocytopenic patients, and a 50% or greater reduction in blast
percentage was observed in 43% of patients with excess blasts. A Phase
III randomized trial is planned to investigate the clinical benefit and
frequency of platelet response to lonafarnib in patients with CMML or advanced
MDS with severe thrombocytopenia. Interestingly, 3 patients with proliferative
CMML (WBC > 12,000/µL) experienced rapid and sustained leukocytosis,
which in 2 cases was complicated by pulmonary infiltrates that resolved
either after study drug withdrawal or treatment with dexamethasone (Buresh
A, Perentesis J, Rimsza L, et al. Hyperleukocytosis complicating lonafarnib
treatment in patients with chronic myelomonocytic leukemia. Leukemia. 2004)
The latter findings closely resemble the leukemia differentiation syndrome
reported with retinoid therapy for APL and may be linked to the unique
ability of lonafarnib and perhaps other FPT inhibitors to activate ß-1
and ß-2 integrins and promote both heterotypic and homotypic adhesion
of CMML cells.28 Overall, the frequency of leukemoid response to lonafarnib
treatment was higher in patients with proliferative (> 12,000/µL)
compared to nonproliferative CMML (54% versus 11%; P = 0.025). Close clinical
monitoring of patients with proliferative variants receiving FTI treatment
may be warranted, with consideration for early introduction of cytoreductive
therapy.
(75 mg/m2/day SC daily for 7 days. Repeat cycle every 28 days; Grade 3-4
leukopenia (59%), neutropenia (81%), infection (20%), thrombocytopenia
(70%), nausea/vomiting (2%), myelosuppression graded using CALBG criteria
1 treatment-related death, 69% of patients RBC transfusion-dependent at
baseline. Emetogenic potential level 1ref)
and decitabine
: there are very few randomized treatment studies, with the exception of
a trial comparing 5-azacytidine administered subcutaneously with "best
supportive care."ref
The 5-azacytidine group had a reduction in transfusion requirement in approximately
one-third of patients as well as a delayed time to leukemic transformation
and an improved "quality of life."ref
There was no survival benefit, however, perhaps reflecting the cross-over
to 5-azacytidine in nonresponders, and an inexorable rapid falloff in overall
survival in both groups. On the basis of these data, 5-azacytidine was
recently approved by the US Food and Drug Administration (FDA) for the
treatment of all FAB types of MDS. While the long-term results are disappointing
(median survival ~19 months in the 99 patients initially randomized to
5-azacytidine), some patients do enjoy substantial clinical benefit. The
study also demonstrates the feasibility of conducting randomized trials
in MDS, although these studies can be complex and require a minimum of
175-200 patients. Phase I and II trials have also been published evaluating
decitabineref1,ref2,
which is similar in structure and function to 5-azacytidine, but which
currently has to be administered intravenously. A randomized Phase III
trial, similar in design to the 5-azacytidine study but without a provision
for cross-over, has recently been completed. Very preliminary results are
available on the company websiteref,
describing a 10% rate of CR and with a crude survival curve at best reminiscent
of the 5-azacytidine results. Both 5-azacytidine and decitabine are cytotoxic
when given in higher doses but have other mechanisms of action, including
DNA demethylation. This is particularly true of decitabine when it is administered
in lower dosesref.
Demethylation potentially reactivates genes that are transcriptionally
silenced by DNA methylation of their promoters. The silenced genes are
postulated to be critical in terms of providing a proliferation and survival
advantage to the malignant cells in some cancers, and restoring their expression
can lead to cell death. A great deal remains to be learned about the effect
of reactivating specific genes with the additional task of proving whether
the induction of previously suppressed gene expression is in fact responsible
for any clinical responses observedref.
and CC5013
: since the original description by Raza and colleaguesref,
thalidomide has been widely used by many clinicians on an ad hoc basis,
although there are few additional series with significant numbers of patients.
A report from the North Central Cancer Treatment Group (Moreno-Aspitia
A, Geyer S, Chin-Yang L, et al. N998B: multicenter phase II trial of thalidomide
in adult patients with myelodysplastic syndromes [abstract]. Blood. 2003;102)
described the outcome in 73 patients (43 with lower IPSS scores and 30
with less favorable [1.5-3.5] scores). The starting dose of thalidomide
was 200 mg/day with an attempt to increase the dose by 50 mg/week. Only
1 patient achieved a partial response and only 7 had hematologic improvement
that was sustained for at least 2 months. Most patients stopped therapy
because of side effects or disease progression, and only 44% of patients
completed 3 months of treatment. This study can be faulted because of the
rapid dose escalation schedule, which may have contributed to the relatively
short time on treatment. It is possible that lower doses administered for
longer periods of time may have been more effective. Nonetheless, this
multicenter study failed to confirm preliminary single institution data
and may be representative of the response rates to be expected. CC5013
(Revlimid, Celgene Corp.) is an orally administered immunomodulatory analog
of thalidomide that is appreciably more active than thalidomide in a variety
of in vitro systems and that does not have the problems with sedation,
constipation and neuropathy that have limited the chronic and higher dose
use of thalidomide. List et alref
have reported on a cohort of 45 patients, largely with low IPSS stage disease.
24 of 36 "evaluable" patients enjoyed an erythroid response, including
20 major responses defined as a substantial improvement in hemoglobin or
a reduction/elimination of transfusion requirements. The maximum improvement
was to a hemoglobin of 12.9 g/dL with a mean increase of 5.1 g/dL in
responders. Relapses have occurred in 3 of these responders to date.
There was striking benefit in the group of patients with the 5q- cytogenetic
abnormality, with complete cytogenetic response in 10/11 such patients,
only 1 of whom has relapsed thus far. In contrast, 1/7 patients with other
cytogenetic abnormalities had a cytogenetic response. The apparent specificity
of these cytogenetic responses is different from trials with other agents
and is most striking. The mechanism for the apparent disproportionately
good effect in the 5q- patients is not known. The major toxicity was myelosuppression,
necessitating weekly monitoring of blood counts. Count falls were noted
in the 5q- responders, sometimes with slow recovery, perhaps reflecting
the impaired residual normal hematopoiesis characteristic of patients with
MDS. Two large multi-institutional Phase II trials focusing on patients
with lower risk MDS or the 5q- syndrome have recently been completed.
has been evaluated in small Phase II trials using doses of .25 mg/kg intravenously
days 1-5 and 8-12 every 28 days (Vey N, Dreyfus F, Guerci A, et al. Trisenox
(arsenic trioxide) in patients with myelodysplastic syndrome (MDS): preliminary
results of a phase 1/2 study [abstract]. Blood. 2003;102:422a) or .30 mg/kg
daily for 5 days followed by .25 mg/kg twice a week for up to 15 weeks
(List A, Schiller GH, Mason J, et al. Trisenox (arsenic trioxide) in patients
with myelodysplastic syndromes (MDS): preliminary findings in a phase II
clinical study [abstract]. Blood. 2003;102:423a). Hematologic responses
were noted in 7/28 and 13/50 "evaluable" patients, and were largely erythroid
in nature, with only 5 of the 12 "major" responders achieving RBC transfusion
independence. Responses were often delayed, occurring after 1.5-5.8 months
of therapy, and the treatment was cumbersome because of the need for frequent
electrolyte monitoring and electrocardiograms. Grade 3 and 4 myelosuppression,
as well as a variety of other side effects, were noted. Further details
from full publications are needed to better interpret these data, including
information on other patients who were treated but not yet evaluated. It
was not obvious whether specific subgroups of patients tended to benefit
from treatment and it is presently unclear how or when to utilize arsenic
trioxide in patients with MDS or whether these results are superior to
what has been noted with other agents, or indeed to supportive care alone,
particularly in terms of quality of liferef.
: since the original, perhaps surprising publication from the NIH describing
both hematologic improvement and some sustained CRs in a group of MDS patients
treated with ATGref,17
others have confirmed these findings, although with somewhat lower response
rates and concerns about the side effects of this treatment in older patientsref1,
ref2.
Yazji and colleagues from the MD Anderson Cancer Center reported that 5/31
MDS patients (16%) had varying degrees of hematologic improvement including
1 CR after treatment with ATG and a planned 6 months of cyclosporineref.
The cyclosporine was poorly tolerated in this older patient population
and was given for only a median of 1 month. It is unclear whether cyclosporine
adds to the results achieved with ATG alone. Responses are seen most frequently,
but not exclusively, in patients with refractory anemia. Elimination of
clonal lymphoid populations, which may possibly suppress normal hematopoiesis,
has been noted after treatment of MDS with ATGref.
In this regard, both CC5013 and thalidomide are immunomodulatory. Retrospective
analyses suggest that responses may be highest in individuals with HLA-DR15ref
and further studies to help predict the likelihood of benefit in individual
patients are needed. In addition, many patients treated on the original
NIH trial had what was felt to be "hypocellular" MDS. It can be quite difficult
to distinguish between aplastic anemia and MDS in such circumstances, although
the presence of cytogenetic abnormalities, which can develop progressively
over time, is more indicative of MDS. It remains unclear whether patients
with very hypocellular marrows may benefit preferentially from immunosuppressive
approaches. Similarly, there are no data about the response rate following
other types of therapy in patients with hypocellular MDS.
: currently, allogeneic stem cell transplantation (SCT) represents the
only curative therapy for patients with MDS. Transplantation is usually
reserved for younger patients with more advanced disease and is often felt
to be precluded in older patients, even in those without other medical
problemsref.
The use of reduced-intensity conditioning regimens permits transplants
in selected older individuals. Ho et al performed reduced-intensity allogeneic
transplants in 75 patients with different IPSS prognostic groups of MDS,
using largely HLA-identical siblings or unrelated donors (MUD)ref.
The median age was 54 years (up to age 70) for the sibling transplants
and 51 years (up to 65 years) for the MUD recipients. Nontransplant-related
mortality was low in both groups (8%) at 200 days. With relatively short
follow-up, disease-free survival was 83% in the low-risk INT-1 group patients,
67% in the Int-2 but only 31% in the IPSS high-risk patients. Whether these
results are an improvement over what might be seen with supportive care
in INT-1 patients requires much longer follow-up and eventually consideration
of a comparative trial. Certainly, given the risks of SCT, patients with
low-risk disease must be selected very carefully and have some evidence
of progressive disease. Higher relapse rates in patients with more advanced
leukemias and MDS are an issue following conventional SCT, and it is unknown
whether "full" conditioning regimens could have produced better antileukemic
effects and fewer relapses. This is an important issue for younger patients
with MDS and leukemia to whom either type of transplant could be offered,
although at this time it appears to be the informal consensus among transplant
physicians to utilize myeloablative conditioning regimens in younger patients
for whom this is considered to be an option.
antagonist : cyclosporine-A, quinine sulfate, LY335979 (zosuquidar trihydrochloride)