HOW TO MANAGE... How to manage lower-risk myelodysplastic syndromes

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HOW TO MANAGE... How to manage lower-risk myelodysplastic syndromes
Leukemia (2012) 26, 390–394
& 2012 Macmillan Publishers Limited All rights reserved 0887-6924/12
www.nature.com/leu
HOW TO MANAGE...
How to manage lower-risk myelodysplastic syndromes
MA Sekeres
Leukemia Program, Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute,
Cleveland, OH, USA
Patients with lower-risk myelodysplastic syndromes (MDSs),
usually defined as having an International Prognostic Scoring
System score of 1.0 or less, and/or o5% myeloblasts, comprise
the majority of newly diagnosed and established MDS patients
and have a survival measured in years. Most will eventually
require therapy for their disease, usually when MDS-related
symptoms or transfusion requirements accelerate and outweigh potential drug-related toxicities. The decision of when to
initiate therapy is far from straightforward. Erythropoiesis
stimulating agents yield responses in up to 40% of appropriately selected patients, while disease-modifying drugs,
including lenalidomide, azacitidine, decitabine and anti-thymocyte globulin, can evoke responses as high as 67% in patient
subgroups. Newer therapies hold the promise of activity in
patients who have failed standard regimens.
Leukemia (2012) 26, 390–394; doi:10.1038/leu.2011.223;
published online 9 September 2011
Keywords: MDS; therapy; outcomes
Setting the stage for thinking about treating lower-risk MDS
The myelodysplastic syndromes (MDSs) are a heterogeneous
collection of clonal hematopoietic disorders defined by dysplasia of hematopoietic precursors and commonly associated with
bone marrow hypercellularity, with resulting compromised
hematopoiesis and peripheral blood cytopenias.1,2 As such,
MDS really represents a collection of cancers, with the
pathobiology of lower-risk subtypes characterized by a predominance of pro-apoptotic, pro-inflammatory cytokines and
abnormalities in the bone marrow microenvironment, and
higher-risk MDS typified by hypermethylation of tumor suppressor genes, activation of proliferative signals and a karyotypic
profile similar to that seen in older patients with acute myeloid
leukemia (AML).3–6 Clonal abnormalities have now been
identified in 80% of MDS patients using complementary
metaphase karyotyping and single-nucleotide polymorphism
array technology.7
The age-adjusted incidence rate of MDS in the United States
(US) is estimated to be 3.4 per 100 000 people.8 These data
come from the Surveillance, Epidemiology and End Results
program of the National Cancer Institute and the CDC (Centers
for Disease Control and Prevention) and were collected from
2001 to 2003. While this would translate to B10 000 new cases
per year, it is considered likely to be an underestimate, as the
rate has increased over time, from 3.3 per 100 000 people in
2001 to 3.8 in 2004, in large part due to improved reporting
practices within cancer registries.9 The US incidence rate is
Correspondence: Dr MA Sekeres, Leukemia Program, Department of
Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig
Cancer Institute, Desk R35, 9500 Euclid Avenue, Cleveland,
OH 44195, USA.
E-mail: sekerem@ccf.org
Received 1 July 2011; accepted 6 July 2011; published online 9
September 2011
similar to that reported in western European countries such as
England/Wales and Sweden (3.6 per 100 000), Germany (4.1 per
100 000) and France (3.2 per 100 000), but higher than is seen in
Japan (1.0 per 100 000), where patients are diagnosed a median
of 10–12 years younger than in western countries.10–13
Approximately 75% of newly diagnosed patients have lowerrisk disease (French-American-British categories of refractory
anemia and refractory anemia with ring sideroblasts; World
Health Organization categories of refractory anemia, refractory
anemia with ring sideroblasts, refractory cytopenia with
unilineage or multilineage dysplasia, MDS with deletion of
chromosome 5q (del (5q)), and MDS unclassified; and IPSS
(International Prognostic Scoring System) scores of low and
intermediate-1), and patients in these subgroups have a
predicted survival measured in years; the remaining 25% have
higher-risk MDS (French-American-British categories of refractory anemia with excess blasts; World Health Organization
categories of refractory anemia with excess blasts 1 and 2; and
IPSS categories of intermediate-2 and high risk).14 With a
median survival of o1.5 years, higher-risk MDS patients require
immediate initiation of disease-modifying therapy, regardless of
peripheral blood values. Patients with lower-risk disease often
have the luxury of delaying treatment. Whether or not a heavily
transfusion-dependent patient with IPSS lower-risk disease
should truly be considered ‘lower-risk’ is a subject of debate,
and would elevate a patient’s risk score in other prognostic
classification schemes.15,16
How I decide when to start treating lower-risk MDS
The first step in making this decision is to determine what the
patient sitting in front of you knows about his or her diagnosis.
Most initially have their MDS described to them as benignsounding conditions, such as a ‘bone marrow disorder’ (80%) or
‘anemia’ (56%). Only 6–7% have even been told they have a
‘cancer’ or ‘leukemia’.17 It is a challenge, then, to discuss
therapies with substantial side effect profiles (when compared
with the more common medications these septuagenarians and
octogenarians are prescribed to control cholesterol and blood
pressure) without first educating patients about the severity of their
diagnosis. Most patients (55%) have no knowledge of their IPSS
risk, and 42% do not know their bone marrow blast percentage.
The next step is to determine the degree to which a patient’s
symptoms are compromising his or her health-related quality of
life. Lower-risk MDS patients report that, on average, their
physical health is ‘not good’ almost 6 days out of every month,
and that their disease limits their usual activities 4 days per
month.17 No study has demonstrated an outcome benefit in
early initiation of erythropoiesis stimulating agents (ESAs) or
disease-modifying therapies. While hematopoietic stem cell
transplantation is recognized as the only curative therapy for
MDS, the survival advantage of this approach when compared
Managing lower-risk MDS
MA Sekeres
391
with other MDS therapies has been shown only in the context of
a Markov decision analysis with narrow inclusion criteria, and
even then specifically in higher-risk patients when offered as
initial therapy.18 As patient reticence, comorbidities, lack of
available donors and lack of insurance coverage will make this a
viable option in o5% of patients,14 other treatments will be
used the majority of the time, and can be considered essentially
palliative.
It stands to reason, then, that intervention is required only
when a patient’s disease-related symptoms, or need for frequent
transfusions, outweigh the anticipated side effects of a drug.
Therapies I carry in my bag of tricks for treating lower-risk
MDS
ESAs are a good first step. A number of trials have been
published using ESAs alone, at varying schedules and doses, or
in combination with granulocyte colony stimulating factor or
granulocyte macrophage colony stimulating factor, in MDS
patients, with responses of B40% in lower-risk patients using
IWG (International Working Group) criteria for response.19–29
Given the deleterious effect of ESAs on progression-free and
overall survival in solid tumors (in at least eight studies), should
they be avoided in MDS patients? No MDS patients were
included in these worrisome trials, and three retrospective
studies actually suggest a survival advantage for ESAs when
compared with groups receiving best supportive care or diseasemodifying therapies, possibly through their effect on minimizing
transfusion needs in patients (and thus significant volume shifts
and the theoretical potential for iron overload), from Nordic,
French and US analyses.30–32 All three studies attempted to
control for selection biases by using inclusion criteria or
multivariate analyses that adjusted for differences between
patient groups in baseline characteristics.
How do you determine which patients are most likely to
benefit from ESAs? Two decision tools may be helpful. The
first33,34 identified predictors of response to a combination of
ESAs and granulocyte colony stimulating factor. It found that
patients with low transfusion needs (o2 units packed red blood
cell (pRBC) transfusions every 4 weeks) and a low baseline
serum erythropoietin level (o500 IUFthe ‘good’ ESA predictive group) had a 74% chance of responding to ESAs, while
those with high transfusion needs (X2 units pRBC every 4
weeks) and a high serum erythropoietin level (4500 IUFthe
‘poor’ ESA predictive group) had only a 7% chance of
responding. Patients who had a mixed picture fell into an
‘intermediate’ ESA predictive group and had a 23% chance of
responding to ESAs.
A second decision tool incorporated individual patient data,
including response rates, survival and quality of life, on 799
patients treated with either ESAs (394 patients) or diseasemodifying agents (405 patients) and applied these data to the
Hellstrom-Lindberg model to determine the most appropriate
up-front therapy for lower-risk patients.35 This treatment
algorithm suggested that lower-risk MDS patients falling into a
‘good’ ESA predictive group should initially be treated with
ESAs, while others (those falling into ‘intermediate’ or ‘poor’ ESA
predictive groups) should probably be treated with diseasemodifying therapies initially.
Recall that the response rate to ESAs in appropriately selected
patients is 40%, and the median response duration is B2
yearsFmeaning that most patients will not respond to these
growth factors, and those that do will lose their response
eventually.30,36 For these patients, FDA (Food and Drug
Administration)-approved options are limited. Probably, the
best approach is lenalidomide, particularly in lower-risk patients
with the del (5q) cytogenetic abnormality.
Lenalidomide appears to function by selectively suppressing
the del (5q) clone through inhibition of haplodeficient cell-cycle
regulatory targets coded within the 5q31 commonly deleted
region37,38 complemented by effects on the bone marrow
microenvironment.
The phase II registration study focused on patients with lowerrisk, transfusion-dependent MDS with the del(5q) abnormality
(MDS-003).39 Lenalidomide was administered at a dose of 10 or
10 mg/day for 21 or 28 days of a 28-day cycle. Among 148
patients enrolled, 99 (67%) achieved transfusion independence,
including every patient who experienced a cytogenetic
response. The median duration of RBC transfusion independence was 2.2 years (range, 0.1–4.4 years). Subsequently, a
phase III, double-blind trial of lenalidomide at two different
doses vs supportive care in lower-risk, transfusion-dependent
del(5q) MDS patients (MDS-004) demonstrated transfusion
independence responses lasting 46 months in 43–52% of
subjects, compared with 6% of controls. The cytogenetic
response rate was 25–50% and the 3-year AML risk was 25%.
Features predictive for transfusion independence response to
lenalidomide include younger age, shorter duration of MDS,
lower transfusion needs and treatment-related thrombocytopenia. Patients whose platelets declined by 50% or more within
the initial 8 weeks of treatment were significantly more likely to
achieve pRBC transfusion independence, compared with
patients experiencing less severe myelosuppression.40 Treatment-related thrombocytopenia also correlated with cytogenetic
responses, emphasizing the importance of successful suppression of the del (5q) clone with lenalidomide to achieve
meaningful responses.
Lenalidomide often is used off-label for the treatment of
lower-risk, transfusion-dependent MDS patients who do not
harbor the del (5q) lesion, based on a phase II study similar in
design to the registration study.41 Of 215 patients enrolled, 56
(26%) achieved transfusion independence. Duration of response
was less than for del (5q) patients, at a median of 41 weeks
(range, 8–136 weeks). Grade 3 or 4 myelosuppression occurred
in only 20–25% of patients, and unlike for del(5q) patients, was
not associated with subsequent attainment of a transfusion
independence response to therapy.
Concern has been raised recently regarding the risk of
secondary malignancies following lenalidomide exposure,
particularly in populations of patients with multiple myeloma
who have been treated with doses of lenalidomide that are higher
than those used in MDS patients. On 8 April 2011, the US FDA
announced its intention to review multiple myeloma clinical trial
data to formally assess whether or not the risk of developing new
types of cancers was higher in lenalidomide-treated patients,
compared with those who did not take the drug. Whether these
increased risks translate to MDS patients is unknown. A recent
analysis of combined data from MDS-003 and MDS-004 of 286
del(5q) MDS patients treated with lenalidomide, with a median
follow-up of B3 years, showed a rate of AML evolution of 17% at
2 years, while another analysis of 381 untreated del(5q) MDS
patients, with a median follow-up of B4 years, showed a rate of
AML evolution of 17% at 5 years.42,43
Okay, but what if my unfortunate patient does not have an
isolated anemia?
The therapies discussed so far target RBC deficiencies.
If a lower-risk MDS patient presents with thrombocytopenia
Leukemia
Managing lower-risk MDS
MA Sekeres
392
necessitating platelet transfusions, or resulting in bleeding
episodes, options are even more limited.
A phase I/II study in lower-risk MDS patients of romiplostim, a
peptibody that increases platelet production through the thrombopoietin receptor (c-Mpl) and has been approved for use in
patients with idiopathic thrombocytopenic purpura, has been
completed.44 Of 44 patients enrolled into 1 of 4 dose cohorts to
receive weekly injections of 300, 700, 1000 or 1500 mg
romiplostim, 41 continued into the extension phase of the study
with continued weekly injections, and 19 (46%) achieved durable
platelet responses.45 Caution must be used in treating MDS
patients with romiplostim, however, as two subjects progressed to
AML during the study, and four others had transient increases in
blast percentage. A randomized phase II study has just completed
enrollment. Eltrombopag, another thrombopoietic growth factor,
is being studied in higher-risk MDS patients.
Particularly in lower-risk MDS patients with pancytopenia,
two other approaches may be worthwhile. The first is antithymocyte globulin-based regimens, which capitalize on the
theory that some lower-risk MDS subtypes may arise through
T-cell mediated bone marrow destruction, similar to what
occurs in aplastic anemia. These require an inpatient admission
for monitoring of infusion-related adverse events; a steroid taper
to ward off serum sickness; and are often coupled with other
immunosuppressive agents, such as cyclosporine. Responses
approach 30%, are higher in patients who are HLA DRB15 þ ,
younger, and have a shorter duration of transfusion dependence,
and may be durable.46,47
Hypomethylating agents, such as azacitidine and decitabine,
also can be used in lower-risk patients who fail other
approaches or in whom ESAs would not be effective. Response
rates are similar to off-label lenalidomide use, typical of historic
responses to other disease-modifying drugs used in clinical trials
in the lower-risk population.48 A patient’s cytopenias or quality
of life must be severe enough, though, to warrant the adverse
events associated with these drugs, which may be more severe
to other lower-risk, disease-modifying approaches.
On the topic of iron chelation
To chelate or not to chelateythat is the question. A number of
outstanding reviews on this topic have been written, and could
easily consume the space of this entire review article.49–52
While consensus guidelines support chelation therapy for MDS
patients with increased transfusion requirements (420–50
lifetime RBC transfusions) or with serum ferritin levels
42000 ng/ml, chelation therapy should be initiated with
extreme caution, as it has never been shown prospectively to
have an impact on end-organ function or on survival in MDS
patients, and was approved by the US FDA based on limited
data in MDS patients. Moreover, its use should be further limited
to patients with lower-risk disease with a predicted prolonged
survival, as higher-risk disease MDS patients are unlikely to live
long enough to appreciate any benefits from chelation. Oral
deferasirox and parenteral deferoxamine are the two ironchelating agents currently available in the US. Both medications
appear have similar efficacy in depleting iron stores in patients
with MDS.53
What I wish I had in my bag of tricks to treat lower-risk MDS
The good news is help is on the way. The development plan for
newer agents has incorporated the fact that most lower-risk
Leukemia
patients will have been treated for their disease with existing
drugs, and thus are enrolling treated patients onto advanced
stage clinical trials. Some of these drugs include ezatiostat, a
glutathione analog prodrug GSTP-1 inhibitor that has yielded
response rates (some bi- and tri-lineage) in up to 35% of lowerrisk patients in phase I and II studies;54 oral azacitidine, with a
response rate of 53% among 15 MDS patients in a phase I
trial;55 alemtuzumab, an anti-CD52 monoclonal antibody with
a response rate of almost 80% in a study from the National
Institutes of Health, albeit in a group of patients highly selected
for factors such as HLA-DR15 status, age and months of
transfusion dependency;56 and siltuximab, an anti-IL-6 monoclonal antibody.57
Conflict of interest
The author declares no conflict of interest.
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