Page 1080 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 60 Myelodysplastic Syndromes 963

ESAs are no longer routinely used for management of anemia in who show a predilection for bleeding. In general, patients should be
solid tumor patients, where studies have shown them to be associated transfused prophylactically rather than waiting for bleeding to occur.
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with an increased risk of poor outcomes. Similar findings have also Although there are few large studies comparing transfusion strategies
been noted in patients without cancer receiving ESAs for anemia specifically for MDS patients, a recent study of patients with other
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associated with renal failure. Such a risk has not consistently been hematologic malignancies showed that for most patients (including
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shown in MDS, although most studies published to date have not those with AML), a prophylactic strategy using a trigger of 10 × 10
had long follow-up periods. The risk of thromboembolism has largely cells/L led to fewer significant hemorrhages than a therapeutic strategy
been correlated with the degree of improvement in hemoglobin, with in which patients were transfused only when bleeding. 417
patients targeted to hemoglobins over 12 mg/dL at greatest risk. Thrombopoietin (TPO) analogs, which are standard therapeutic
Given this, the consensus recommendation in MDS is to initiate an options for refractory chronic idiopathic thrombocytopenia purpura
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ESA at hemoglobin <10 g/dL and target a level between 11–12 g/ (ITP), are not yet approved by any regulatory agencies for use in
dL. 404 MDS. The two major formulations approved in ITP are romiplostim,
a “peptibody” consisting of 14 amino acid peptides that bind the
extracytoplasmic domain of the TPO receptor fused to an IgG1 heavy
Management of Neutropenia and Infections chain, and eltrombopag, a small molecule without TPO homology
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that nevertheless binds and activates the TPO receptor. Romiplos-
As referenced previously, patients with MDS often become neutro- tim is administered as intermittent subcutaneous injections, whereas
penic but also appear to have other qualitative immune defects that eltrombopag is an oral formulation that is taken daily.
are not accurately represented by the ANC, 392,393 and infection is the Both agents have shown efficacy in terms of reducing platelet
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leading cause of death in MDS. Despite this, supplementation transfusions and clinically significant bleeding events and increasing
with either G-CSF (filgrastim, tbo-filgrastim and others) or GM-CSF platelet counts in early-phase trials in MDS. 420–424 In patients with
(sargramostim) has not consistently been shown to improve outcomes IPSS low or intermediate-1 risk MDS who had platelet counts less
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in MDS patients. 405–407 Nevertheless, it is reasonable to consider a than 50 × 10 /L, romiplostim consistently led to significant improve-
trial of growth factor (usually G-CSF, because of less frequent adverse ments in platelet count, which were durable in about half of
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effects) in lower-risk IPSS patients with significant neutropenia, typi- patients. A similarly designed phase I/II trial of eltrombopag is
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cally defined as an ANC <1000/mm . Supplementation in higher-risk ongoing.
patients, particularly those with any degree of excess blasts, is not However, concerns have been raised about the safety of TPO
usually recommended in the absence of chemotherapy, because of agonists in patients with MDS. First, a number of studies in ITP
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lingering concerns about promoting expansion of leukemic clones. have shown an increase in marrow reticulin fibrosis in subsets of
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Other therapeutic strategies for immune supplementation, including patients. While the absolute risk of fibrosis has not been deter-
granulocyte transfusion and cytokine administration, have not been mined, and fibrosis has been moderate in most patients, some have
shown to be helpful. 409 speculated that the process could be accelerated within the abnormal
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A thorough understanding of appropriate antibiotic use is an marrow microenvironment of MDS patients. Second, there is
important component in the care of MDS patients. Patients should concern about increased blast proliferation in the presence of TPO
be counseled to seek medical attention for any fever greater than agonists, since some blasts have functional TPO receptors. A random-
100.4°F/38.4°C, and those who are neutropenic should be hospital- ized controlled trial of romiplostim versus placebo (the only phase
ized and started on antibiotics while an appropriate search for infec- III study of either agent in MDS to date) was stopped early by the
tion is undertaken. A thorough discussion of treating febrile study’s safety monitoring committee because of interim analysis sug-
neutropenia can be found elsewhere in the text, but should begin gesting a higher rate of progression to AML in the romiplostim
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with an antibiotic that covers a broad spectrum of gram-negative arm. At the time the study was stopped, 10 of 167 patients in the
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organisms including Pseudomonas species. Although prophylactic romiplostim group had progressed to AML, compared to two of 83
antibiotics should not be started routinely, they may be appropriate in the placebo group. Since the study was far from completion of
for selected patients who demonstrate a pattern of recurrent infec- accrual at the time it was stopped, the risk of disease progression
tions. 411,412 There is less consensus about prophylactic antivirals or could not be definitively assessed and the AML progression rate
antifungal medications, and the efficacy of the latter depends on local eventually nearly equalized; nevertheless, the manufacturer has now
microbiologic isolates and epidemiologic patterns. added a warning of risk of MDS progression to romiplostim’s label.
Until there is more conclusive evidence evaluating the link between
TPO analogs and the risk of disease progression, neither romiplostim
Management of Thrombocytopenia and Bleeding or eltrombopag can be recommended for routine treatment of MDS-
associated thrombocytopenia outside a clinical trial, although patients
Modest thrombocytopenia is common across many subtypes of MDS, with refractory bleeding who fail to respond to platelet transfusions
while severe depression of platelet counts is more frequently seen in could consider trying one of these agents palliatively.
patients with higher-risk IPSS scores or those undergoing active
treatment with hypomethylating agents or chemotherapy. Overall,
bleeding is the second most common cause of nonleukemic death in Management of Iron Overload
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MDS patients. Conventional wisdom and observational studies (Transfusional Hemosiderosis)
indicate that the risk of bleeding with trauma begins to increase at a
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platelet count near 50 × 10 cells/L and that of spontaneous hemor- Although it is clear that MDS patients who undergo repeated blood
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rhage does not increase significantly until the count is below 10–20 transfusions carry an increased risk of developing iron overload,
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× 10 cells/L. However, these cutoffs may underestimate the bleeding the importance of this relative to other disease-related risks, and how
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risk in MDS patients, many of whom have qualitative defects in to assess and respond to it, remains a matter of some debate. MDS
platelet function that are not captured by the platelet count. A number is distinct from pediatric illnesses associated with iron overload,
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of retrospective studies have evaluated the significance of thrombo- in which the benefit of chelation has been well established, in
cytopenia in MDS, all of which have found that thrombocytopenia that many MDS patients will not live long enough for the clinical
confers a poor prognosis caused by both the risk of bleeding and, in impact of end-organ iron deposition to be realized. Registry data
some cases, an elevated risk of transformation to AML. 330,413–415 suggest that patients with higher transfusion requirements have a
As with red blood cells, management of thrombocytopenia can greater risk of complications, 429,430 but registry data cannot prove the
either involve transfusions or use of growth factors. Many institutions direction of the relationship—that is, whether the transfusions lead
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use a standard transfusion threshold of 10 × 10 cells/L, but as to complications or whether the need for transfusion is simply a
discussed earlier, a higher goal may be appropriate in selected patients marker of more severe disease or underlying comorbidities. Other