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1360 Part X: Malignant Myeloid Diseases Chapter 87: Myelodysplastic Syndromes 1361

demethylation is associated with clinical responses, although it is Patients who are younger than age 60 years have higher remission
unclear whether the same cells are being compared pre- and posttreat- rates with AML-like regimens—rates up to 50 percent —and can be
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ment, and clonal shift could account for these results. Adverse events considered for intensive therapy, but this is usually only done as a bridge
associated with decitabine are similar to those observed with azaciti- to AHSCT. Patients older than age 60 years have a median survival
dine. Oligodeoxynucleotide antisense approaches to DNA methyltrans- of only 9.5 months with this approach and the survival is reduced to
ferase-1 inhibition are also being explored in MDS. 521 4 months in those with unfavorable karyotypes, indicating a lack of
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Therapy with demethylating agents in patients who are not suit- benefit in this group. In addition to the standard combination of
able candidates for AHSCT usually continues for as long as it seems like anthracycline and cytarabine, other regimens, such as liposomal dauno-
the patient is deriving benefit and as long as the drug is well tolerated. rubicin and topotecan with or without thalidomide, did not result in
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For patients who are going to AHSCT, these agents may be helpful as clinical benefit in patients with AML or high-risk MDS. The so-called
a bridge to transplant, and retrospective studies show that pretrans- FLAG-Ida regimen (fludarabine, cytarabine, idarubicin, and G-CSF)
plant treatment with azacitidine is at least as effective as treatment with resulted in 53 percent complete remissions and 11 percent improve-
induction chemotherapy. 522 ment in 45 patients with high-risk myeloid malignancies, 13 of whom
had MDS. CPX-351, a liposomal nanoparticle with cytarabine and
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Histone Deacetylase Inhibitors daunorubicin in a fixed 5:1 ratio is currently being studied in patients
Inhibitors of histone deacetylation exhibit in vitro synergy with with AML arising from MDS and may be more effective than standard
hypomethylating agents and have clinical activity in MDS, albeit lim- anthracycline-based regimens.
ited, when they are used as single agents. This class of drugs is under
active investigation at many centers. 523,524 Numerous agents are being Allogeneic Hematopoietic Stem Cell Transplantation
studied and include valproic acid, 525,526 vorinostat (SAHA), mocetin- AHSCT has been used to treat various types of MDS in patients rang-
ostat (MGCD0103), panobinostat (LBH589), pracinostat and oth- ing in age from 1 month to older than 70 years. 545,546 AHSCT remains
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ers. Belinostat had no activity. Randomized trials combining histone the only treatment that can cure patients with the disease. Condition-
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deacetylation inhibitors with DNA methyltransferase inhibitors are ing regimens have consisted of cyclophosphamide plus irradiation,
ongoing, such as the U.S.–Canadian Intergroup study S1117, which fludarabine and busulfan, fludarabine and melphalan, or busulfan
530
compares azacitidine monotherapy to azacitidine plus lenalidomide plus cyclophosphamide. Most patients have received transplants from
and azacitidine plus vorinostat. 531,532 In a randomized cooperative histocompatible sibling donors, but the use of unrelated donors and
group trial of azacitidine with or without entinostat (MS-275), the of cord blood and haploidentical donors has increased. Patients with
combination arm was not associated with an increase in response rate higher-risk karyotypes and more advanced disease do more poorly with
but was associated with more adverse events, including fatigue and transplantation, as do those with certain higher-risk genotypes such as
thrombocytopenia. 533 a TP53 mutation. Despite the increased age of donors and recipients and
increased use of unrelated donors, transplantation outcomes in MDS
Failure of Hypomethylating Agents are improving, in part as a result of molecular tissue typing and better
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In higher-risk patients whom azacitidine or decitabine has failed, overall supportive care. Numerous factors such as disease stage, patient age,
life expectancy is less than 6 months and patients who receive only sup- comorbidities, prior therapies, type of donor, and source of stem cells
portive/palliative care have a life expectancy of only 3 to 4 months. 534,535 need to be considered when recommending AHSCT to MDS patients.
Novel approaches are needed for this group of patients. A randomized AHSCT for MDS should be performed before the disease pro-
trial of rigosertib, an injectable phosphatidylinositol-4,5-bisphosphate gresses to AML, but modeling of data from the International Bone Mar-
3-kinase (PI3K) kinase/polo-like kinase 1 (PLK-1) inhibitor, in high- row Transplant Registry suggests that patients (age 60 to 70 years) with
er-risk patients for whom azacitidine or decitabine had failed showed lower-risk disease have net loss of life whether fully myeloablative con-
no survival benefit of the active agent compared with low-dose cytara- ditioning or reduced-intensity conditioning is used. 548,549 When T-cell
536
bine or supportive care controls. An oral formulation of rigosertib is depletion is used to prevent graft-versus-host disease, the best outcomes
being studied in lower-risk patients. 537 occur in those who are transplanted while in remission, because T-cell
A new dinucleotide decitabine-guanosine hypomethylating agent depletion diminishes the graft-versus-leukemia effect. 550
with increased resistance to cytidine deaminase degradation, SGI-110, Poor-risk cytogenetic patterns may increase risk of relapse but
has activity in relapsed/refractory patients. 538,539 The quinolone deriv- not of nonrelapse mortality, but elevated pretransplant serum ferritin
ative vosaroxin, the nucleoside analogue sapacitabine, and inhibitors is correlated with less-favorable outcomes. 414,551 In one retrospective
of PLK-1, such as volasertib, are also undergoing clinical trials in this series, blast percentage less than 5 percent at time of transplantation was
setting. the best predictor of improved disease-free survival, and myeloablative
conditioning was associated with lower relapse risk but could not over-
Intensive Chemotherapy Similar to That Used for Acute come the unfavorable effect of increased disease burden. Patients with
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Myelogenous Leukemia secondary MDS have comparable outcomes after AHSCT as those with
Intensive chemotherapeutic regimens containing standard doses of de novo MDS when high-risk cytogenetics are considered. 553,554
cytarabine, an anthracycline, with or without etoposide (Chap. 88) Pretransplantation neutropenia is also associated with inferior out-
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result in remission in fewer than 20 percent of patients with high-risk comes as a result of infection-related mortality. Prior therapy with
MDS, primarily because of incomplete hematopoietic recovery or recov- demethylating agents does not appear to increase the toxicity of trans-
ery with dysplastic/leukemia cells, and are no longer commonly used. plantation and whether it will improve outcomes by decreasing disease
The advanced age of many patients with MDS and the high frequency burden has yet to be studied systematically. 556,557 Posttransplantation
of cardiac, renal, immunologic, and other organ system impairment in therapy with azacitidine and decitabine is also being explored, either as
most patients are thought to be largely responsible for the poor out- maintenance therapy, in an attempt to augment graft-versus-leukemia
come. In a randomized trial of patients with WHO-defined AML and effect, or in an attempt to stave off imminent relapse. 496,558
up to 30 percent blasts (oligoblastic leukemia), azacitidine was superior The morbidity and mortality of various transplantation approaches
to a daunorubicin and cytarabine induction regimen. 540 for MDS remain high—at least 20 percent of patients—and currently

Kaushansky_chapter 87_p1341-1372.indd 1361 9/21/15 11:06 AM