Page 1079 - Hematology_ Basic Principles and Practice ( PDFDrive )

962 Part VII Hematologic Malignancies

Despite these challenges, all patients with MDS should be offered 8–9 mg/dL or the patient has symptoms referable to anemia. More
some form of therapy. For elderly patients or those with serious restrictive transfusion strategies, such as those suggested by studies in
comorbid conditions who are too unwell to undergo active treatment, inpatient or critical care settings, 374,375 may be appropriate in younger,
this may consist primarily of supportive care and possibly hospice or healthy patients, while some older patients, particularly those with
palliative care service referral. Other patients with lower-risk disease significant comorbid cardiac disease, may benefit from more liberal
may benefit from a period of observation, or judicious use of transfu- strategies targeting a hemoglobin of 9–10 mg/dL. 376,377 Unless the
sion and growth factor support, balanced in carefully selected cases patient is an HSCT candidate (in which case irradiated blood is
with chelation therapy to prevent or relieve iron overload. Patients essential), there is no consensus about leukocyte depletion or irradia-
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with higher-risk disease may derive benefit from treatment with tion of the product. Since many patients with MDS will receive
hypomethylating agents or other conventional therapies, and those hundreds of units of PRBCs over the course of their disease, preven-
patients with high-risk disease who meet other selection criteria tion and appropriate management of iron overload is also of substan-
should be referred for consideration of hematopoietic stem cell tial importance. 379,380
transplantation (HSCT). Finally, patients should whenever possible
be encouraged to participate in clinical trials to the extent that this
remains consistent with their personal goals of care. Erythropoiesis-Stimulating Agents
Once the decision to pursue active treatment has been made, there
are at least three major points to consider. One is the choice of initial Transfusion dependency is a negative predictor of outcome in
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treatment modality, which is guided in large part by risk stratification. MDS. While transfusion requirement may to some extent may be
This should typically start by computation of the IPSS-R, but IPSS-R a marker of more severe hematopoietic insufficiency and worse
score should not be the sole consideration in choosing therapy; for disease not captured by other prognostic markers, the poor outcomes
instance, a very young patient with otherwise lower-risk MDS that may also be a reflection of the adverse effects of repetitive transfusion,
has evolved quickly may still warrant consideration of a stem cell including accumulation of toxic iron species, immune modulation,
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transplant, and an elderly patient with very high risk disease may and a risk of infection. Given these facts, the administration of
nevertheless opt not to pursue treatment with a hypomethylating ESAs has been heavily investigated in MDS in an attempt to spare
agent after a thorough discussion of the risks and potential benefits. patients from unnecessary transfusions.
Second, there are a number of special cases for which there is no clear More than 20 studies of ESAs have been conducted in MDS,
consensus about the single best treatment strategy; these include and 20% to 50% of patients experience meaningful, sustained
patients with lower-risk disease who have a dominant cytopenia other improvements in their hemoglobin level in response to ESA
than anemia, anemic patients with lower-risk disease who lack del(5q) supplementation. 383–388 Predictors of response include lower pretreat-
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but also have an elevated serum EPO, and patients with high-risk ment serum EPO levels (<500 U/L, but especially <100 U/L),
390
disease who have progressed on a hypomethylating agent but are not lower IPSS scores, normal blast counts, normal or low-risk cytoge-
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candidates for transplant. netics, and lower serum and marrow levels of inflammatory cyto-
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Finally, since therapies other than allogeneic HSCT are rarely if kines. The serum EPO level should be evaluated in the context of
ever curative, defining what constitutes a meaningful response can be the degree of anemia; a trial of an ESA is usually reasonable in patients
a nontrivial endeavor. Objective criteria for response were proposed with EPO levels up to 200–300 U/L, which, while technically elevated
by an International Working Group (IWG) in 2000 and revised in on most laboratory reference scales, is still lower than would be
2006, and include hemoglobin, number of metaphases with abnormal predicted for most MDS patients’ degree of anemia. Patients with
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karyotypes, and percentage of the marrow involved by blasts. EPO levels over 500 U/L, on the other hand, are unlikely to respond
However, improvements in these objective variables may not always to any dose or duration of ESA.
coincide with the ways patients perceive changes in their quality of There are two major formulations of ESA available in the United
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life 370,371 or MDS-related symptoms, and these perceptions may be States. Epoetin alfa, the shorter-acting of the two, can either be given
more likely to impact patients’ decisions to continue or discontinue at a dose of 150–300 U/kg three times weekly, or in a fixed dose of
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active therapy for their disease. 40,000 to 60,000 units once weekly. Higher doses above 60,000 U/
393
weekly have not proven to be more effective. Darbepoetin alfa is
longer acting and is typically given in doses of 500 µg once every
Lower-Risk Disease 3 weeks. Retrospective comparisons of the two agents have not
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shown a significant difference in efficacy. Other ESA formulations
Many patients with lower-risk MDS do not require active treatment are available outside the Unites States, such as epoetin zeta and bio-
directed at the underlying disease process, but this does not mean equivalent ESAs. Although there is some increase in response with
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they require no treatment at all. In fact, providing appropriate sup- longer duration of therapy, in practical terms, a trial of 12 weeks
portive care is an important undertaking that can at times be complex is reasonable. Before starting therapy, other causes of anemia should
and time-consuming, and requires a detailed understanding of the be ruled out. In particular, response can be suboptimal if patients are
evidence behind the available supportive measures. 372 absolutely or even relatively iron deficient, and oral or parenteral iron
supplementation may be reasonable in patients with ferritin levels at
the lower end of the normal range.
Management of Anemia One limitation of the numerous studies of ESAs in MDS patients
is the lack of a consistent definition of response, since most studies
Because most MDS patients become anemic at some point during predated uniform IWG criteria. Some studies define this based on a
their disease, appropriate management of their anemia is of critical hemoglobin increase (usually improvement by 1–2 g/dL), 397,398 while
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importance. Management can be broken down into two main others have defined response by transfusion reduction or quality of
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components: transfusion support and use of erythropoiesis-stimulating life metrics. In practice, any of these improvements could be a
agents (ESAs). reasonable criterion for continuation of therapy. Of particular inter-
est, supplementation with ESA has not been shown to increase the
rate of progression to acute leukemia, and one comparative trial
Transfusion Support showed a nonsignificant trend toward a decreased risk of leukemia,
400
although the biologic basis for this is not clear. In addition, several
Many, if not most, patients with MDS will require packed red blood studies have shown an improvement in response in patients supple-
cell (PRBC) transfusion during the course of their disease. To mini- mented with a combination of ESA and G-CSF, especially in RARS,
mize the risks associated with repetitive transfusion, it is usually likely caused by pleiotropic effects of both growth factors on hema-
appropriate to reserve transfusion until the hemoglobin is below topoietic progenitors. 399,401