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1358 Part X: Malignant Myeloid Diseases Chapter 87: Myelodysplastic Syndromes 1359

reported increased survival in ESA-treated patients compared to con- c-Mpl, a randomized study comparing romiplostim to placebo in low-
trols. 344,368 There is evidence that marrow erythroid cells of MDS patients er-risk patients showed no increase in AML progression in patients
who respond to erythropoietin have a different gene expression pattern receiving active treatment, although this study was stopped early by
than do those of nonresponders. 369 its Data Safety Monitoring Committee because of concern about such
Filgrastim (G-CSF) combined with erythropoietin may produce a progression. Another theoretical risk based on thrombopoietin-over-
401
response more frequently than with an ESA alone, perhaps as a result expressing murine models, marrow reticulin formation, appears to be
of lineage crosstalk of growth factors at the progenitor cell level. 360,370 uncommon in immune thrombocytopenia (ITP), but has not been sys-
This combination does not appear to affect the risk of leukemic trans- tematically investigated in romiplostim-treated patients with MDS. A
402
formation and may have a positive impact on survival in those with low model to predict response to romiplostim based on platelet transfusion
transfusion needs. 371 need and serum thrombopoietin (TPO) level that parallels the similar
model for ESAs based on RBC transfusion and serum erythropoietin
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Granulocyte-Stimulating Factors (EPO) level has recently been developed. The pathophysiology of ITP
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Infection is the major cause of mortality in MDS. Both neutropenia overlaps that of MDS, and other treatments for ITP such as rituximab or
and granulocyte dysfunction contribute to the risk of infection. 373,374 γ-globulin may be beneficial in cases of lower-risk MDS where the
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Granulocyte transfusions are of little utility, and, unfortunately, ran- degree of thrombocytopenia is disproportionate to other cytopenias.
domized, double-blind studies have not shown that any cytokine pro-
376
longs survival or reduces morbidity in MDS. Treatment with GM-CSF Iron-Chelation Therapy
(sargramostim) or G-CSF (filgrastim) increases neutrophil counts and The magnitude of risk from iron overload in patients with receiving
function in some patients, but this is inconsistent. 360,377,378 G-CSF recep- frequent RBC transfusions compared to the risk of death intrinsic to
tor expression on hematopoietic progenitor cells may be low in some the disease and the utility of chelation therapy is one of the most con-
patients with MDS and prevents response to endogenous or exoge- troversial areas in MDS clinical management. 403–406 Claims-based data
379
nously administered G-CSF. Rare remissions have been reported in suggest increased risk of complications in transfused patients with
hypoplastic AML/MDS with G-CSF alone. 380 MDS, but correlation does not prove causation and patients at higher
The most common adverse effects of G-CSF and GM-CSF include risk of complications may have been more likely to be transfused (e.g.,
bone pain, low-grade fevers, and soreness at the injection site. Rare diabetic patients might have had more renal insufficiency and insuffi-
serious complications such as splenic rupture, have been reported with cient EPO production, rather than repeated transfusion causing pancre-
use of G-CSF. Pegfilgrastim may allow less-frequent dosing than fil- atic islet injury via hemosiderosis and inducing diabetes mellitus). 407,408
381
grastim, but is poorly studied in MDS, in which leukemoid reactions Retrospective comparisons suggest superior outcomes in chelated
and splenic ruptures have been described. 376,382,383 G-CSF is not gen- patients compared to unchelated patients, but are subject to confound-
erally recommended for those with intermediate-2 risk or high-risk ing by patient selection bias. 409–412
384
IPSS scores because of the risk of leukemoid reactions. In one review, Despite the absence of high-quality evidence from prospective
22 of 83 reported cases of MDS treated with G-CSF or GM-CSF had trials, numerous consensus guidelines have been published regarding
an increase in marrow blast percentage, and AML evolved in 12 of the treatment of iron overload in MDS. These guidelines make gen-
413
69 patients. An increased percentage of abnormal macrophages has been eral recommendations about iron monitoring and chelation in RBC
reported during G-CSF therapy. Use of these agents without chemo- transfusion-requiring patients, but emphasize that there is no prospec-
385
therapy in oligoblastic leukemias carries a risk of promoting expansion tively validated threshold for either the number of units of transfused
of leukemic blast cells. Combinations of growth factors alone with blood or the level of serum ferritin that should trigger iron chelation,
386
maturing agents (so-called differentiating therapy) such as retinoic acid as patients accumulate iron at different rates and serum ferritin is sen-
have not significantly improved response or survival rates. 387,388 sitive to other influences such as inflammation. Most guidelines take
414
into account the patient’s candidacy for AHSCT, life expectancy, and
Platelet and Megakaryocyte Growth Factors evidence of iron-related organ damage. 415,416 Several guidelines use a
Low-dose IL-11 (oprelvekin), a megakaryocyte growth factor, was serum ferritin greater than 1000 mcg/L and a transfusion history of 20
studied in patients with symptomatic thrombocytopenia associated to 30 RBC units as a threshold for starting iron-chelation therapy, but
*
*
with marrow failure syndromes including MDS, but efficacy was low this strategy is not validated. The use of T2 /R2 magnetic resonance
and adverse effects such as fluid retention and atrial dysrhythmias were imaging techniques may allow noninvasive assessment of organ iron
common. 389,390 Although this drug is approved by the FDA, it is rarely deposition, 331,332,417 but it is not clear whether labile plasma iron levels or
used and uncommonly reimbursed by third-party payers. total-body iron burden poses a greater risk. 418,419
Initial development of thrombopoietin analogues was halted in Both deferoxamine given subcutaneously or intravenously and
the 1990s, but newer thrombopoietin-receptor agonists have shown deferasirox given orally are available for chelation therapy in MDS
391
efficacy in MDS. Romiplostim (formerly AMG-531), a peptibody that patients. Deferasirox rapidly reduces labile plasma iron and mobilizes
stimulates the thrombopoietin receptor (c-Mpl), can decrease thrombo- iron stores and is more convenient than deferoxamine, but in both U.S.
cytopenia and reduce platelet transfusion needs and clinically significant and European studies, one-half of patients discontinued deferasirox
bleeding events in patients with MDS and severe thrombocytopenia, therapy within a year of study enrollment because of disease progres-
including both those who are receiving no treatment and those who sion or adverse effects (renal insufficiency, rash, and gastroenterologic
are receiving therapy with azacitidine, lenalidomide or decitabine. 392–395 distress). 418,420 There are several reports of improved hematopoiesis in
The optimal MDS romiplostim dose determined by early clinical stud- chelated patients. 421,422
ies, 750 mcg subcutaneously once weekly, is higher than that required
for immune thrombocytopenia. Eltrombopag, an orally administered Low-Dose Cytarabine
small molecule c-Mpl agonist, has also shown efficacy in early phase Since the early 1980s, 423–425 low-dose cytarabine at doses of 5 to
MDS studies. 376,396–400 20 mg/m per day by subcutaneous injection every 12 hours for 8 to
2
Although there was initially concern about AML progression 16 weeks or by continuous intravenous infusion has been used in
with romiplostim therapy as some leukemic blasts express functional MDS in lieu of intensive chemotherapy. 426–429 Although this approach

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