Page 1084 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 60 Myelodysplastic Syndromes 967

studies showed better hypomethylation and an improved overall remission. Conventional chemotherapy alone is rarely curative in
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response rate when it was given at a dose of 20 mg/m once daily for MDS, and even those younger patients who achieve a complete
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5 consecutive days, the dosing strategy used in ADOPT. Some remission will need further consolidation, usually with an allogeneic
recent small studies have suggested an even different dosing strategy, stem cell transplant.
using frequent administration of low doses of decitabine (0.1–0.2 mg/
kg/day) in an attempt to minimize the cytotoxic effects of the drug
while catching more cells in S phase, when the demethylating activity Allogeneic Stem Cell Transplantation
of the drug would be most effective. 499
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Despite the widespread use of hypomethylating agents in MDS, Allogeneic HSCT is the only known curative therapy for MDS.
a number of key questions persist. Although studies have shown that This is thought to arise from the fact that MDS progenitor cells,
each can demethylate the promoters of specific tumor suppressors being transformed stem cells, are mostly quiescent and are thus rela-
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(e.g., P15INK4B for decitabine and PLCB1 for azacitidine), it is tively resistant to most chemotherapy. Allogeneic HSCT, on the other
not clear that this is the dominant in vivo mechanism. Some studies hand, leverages both the chemotherapy of the conditioning regimen
have shown increased demethylation in patients who respond to and the antitumor effect of the newly transplanted stem cells to
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hypomethylating agents, but this has not been a universal observa- eliminate all vestiges of the prior hematopoietic system. This is, of
tion, and neither pretreatment methylation levels (either global or at course, a simplified description of the best-case outcome for HSCT.
specific promoters) nor the net change in methylation with treatment The reality for most MDS patients is significantly more complicated,
have been consistently predictive of treatment responsiveness. 488,503 although outcomes have steadily improved in recent years as centers
Recent studies have also interrogated the impact of somatic mutations have gained more experience in transplanting older patients using
on hypomethylating agent sensitivity, and TET2 mutations in unrelated and even unmatched donors. 514
particular have been shown to increase the likelihood of HMA An exhaustive review of stem cell transplantation is beyond the
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response, but the overall impact of these findings in the long term scope of this chapter, but a few points specific to MDS bear mention.
remains unclear. Identification of patients for whom transplant might be a reasonable
option is an important first step. This group typically includes
patients younger than 60 years, who are often in otherwise good
“Histone” Deacetylase Inhibitors health and would otherwise be predicted to have a long life expec-
tancy. Older patients who are in otherwise excellent health may be
The observation that MDS frequently involves epigenomic abnor- considered for transplantation as well, usually with a reduced-intensity
malities has provoked interest in other modalities beyond the hypo- conditioning regimen. Although there is no official upper age limit
methylating agents. To date, the next most-studied class of agent is to eligibility, most centers are hesitant to transplant patients older
the histone deacetylase inhibitors, which as their name implies block than 75. 515
the deacetylation of histone residues as well as deacetylation of other The stage of disease is also important: in older patients, transplant
cellular protein. In vitro, application of these drugs leads to large-scale is usually reserved for those with excess blasts or other forms of
epigenetic modifications, but in vivo, the drugs have so far not proven higher-risk disease, but it is important to proceed to transplant before
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as effective as hypomethylating agents, at least when used alone. the disease has evolved into acute leukemia. On the other hand, some
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Several agents, however, remain in trials, including valproic acid, centers occasionally offer transplantation to younger patients with
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vorinostat, panobinostat, and belinostat. Many of these trials lower-risk categories of disease given that they have a longer latency
combine the HDAC inhibitor with some other therapy. One coop- period in which their disease could progress or evolve into leukemia.
erative trial of azacitidine with or without entinostat, E1905, showed This decision, however, is not completely uniform, and some data
no improvement in hematologic response in the entinostat arm, suggest that delayed stem cell transplantation is associated with better
which in fact displayed less demethylation than azacitidine alone, overall survival in patients with low and intermediate-1 IPSS scores
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perhaps suggesting some degree of pharmacologic antagonism. regardless of age. 516
However, in vitro data have also shown significant pharmacologic Once a decision has been made to proceed to transplant, other
differences between the different HDAC inhibitors, suggesting that decisions must follow. The first involves the source of the stem cells.
results for one drug may not be generalizable to the class as a whole. If a healthy, HLA-matched sibling is available, this is often prefera-
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Similar negative results were recently reported in the U.S./Canadian ble; however, reflective of the average age of MDS patients, most
Intergroup S1117, a large three-arm trial comparing azacitidine alone siblings are older and often have comorbidities, such as cancer or
to azacitidine plus vorinostat to azacitidine plus lenalidomide, as well other illnesses, that preclude them from consideration as donors. If
as a study of azacitidine with or without pracinostat. 509 a related donor is unavailable, the next best option is a search of the
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national donor registry for an HLA-matched unrelated donor.
Compared to related donors, transplant from unrelated donors carries
Induction Chemotherapy a higher rate of graft-versus-host disease as a consequence of minor
antigen mismatch. If a matched unrelated donor cannot be found,
AML-like induction regimens (e.g., cytarabine plus an anthracycline) options then include an unrelated donor transplant mismatched at
are not effective for most patients with MDS, with available studies one (or occasionally more) HLA loci, or an “alternative donor source,”
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suggesting a remission rate of less than 20%. Hematologic recovery which includes umbilical cord blood and haploidentical donors.
is often incomplete, and in many cases the chemotherapy mainly In the case of MDS patients, this latter type of transplant is often
serves to select for the malignant clone. In fact, a randomized trial obtained from one of the patient’s children.
comparing azacitidine to daunorubicin plus cytarabine in elderly The specific choice of conditioning regimen is likely less important
patients with higher-risk MDS showed that the patients treated with in MDS than in other hematologic diseases given the disease’s intrin-
azacitidine had better outcomes, although only small numbers of sic chemoresistance, as described earlier. Options include fludarabine
patients were treated with induction. 493 plus busulfan, fludarabine plus melphalan, busulfan plus cyclophos-
Induction chemotherapy, however, may be reasonable in selected phamide, or cyclophosphamide plus irradiation. Many older patients
younger patients; some studies have suggested remission rates of up with MDS are unlikely to tolerate myeloablative doses of condition-
to 50% in patients younger than 60, though these may have contained ing agents and are instead given reduced doses of conditioning agents.
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some patients with de novo AML, and the studies were performed These “reduced intensity conditioning” transplants rely more heavily
before the widespread availability of deep sequencing techniques that on the graft-versus-tumor effect of the transplant to eliminate the
might have shown persistence of clonal mutations even in the ablated malignant clone. 521,522 Given the intrinsic chemoresistance of MDS
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marrows. Adding other agents, such as liposomal doxorubicin, stem cells, however, this is usually a reasonable tradeoff. Following
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topotecan, and thalidomide, do not seem to improve the rates of transplant, patients must remain on immunosuppressive medications