NcXHF

RECENT UPDATES IN MDS AND MDS/MPNS INCLUDING HEMATOPOIETIC CELL TRANSPLANTATION
MDS. Not included in any of the previously described scoring
systems is the presence of a monosomal karyotype (MK)
(i.e., the presence of two or more distinct autosomal monosomies
or a single monosomy associated with a structural
abnormality). 71-74 However, an association of MK with lower
survival, higher relapse incidence, and overall mortality after
alloSCT—even among patients with a complex karyotype—
has been reported consistently. 70,75-77
The effect of the IPSS-R on alloSCT outcomes recently was
demonstrated in an analysis from the Italian GITMO cooperative
group that included 374 patients with primary MDS.
Both IPSS-R and monosomal karyotypes were independently
associated to a lower overall survival and a higher relapse
probability by multivariate analysis. 78 In this study, a predictive
model of post-transplant outcome in patients with MDS
(Transplantation Risk Index) was originated based on the age
of the patient, IPSS-R category, monosomal karyotype, hematopoietic
cell transplantation (HCT)-specifıc comorbidity
index, and refractoriness to induction chemotherapy.
In addition to cytogenetics, other disease characteristics have
been associated with a poor prognosis in patients with MDS.
These include severe bone marrow fıbrosis, 79,80 refractory lifethreatening
cytopenias, 81-83 and gene mutations. 2,18,24,25,28,29,84-89
As to the effect on alloSCT outcome, bone marrow fıbrosis,
a recent EBMT retrospective analysis of 721 patients with
MDS demonstrated that only severe fıbrosis was shown to
affect survival, whereas patients with mild or moderate fıbrosis
had an alloSCT outcome comparable to patients without
bone marrow fıbrosis. 79 For gene mutations, an independent
association with a shorter post-transplant overall survival,
after adjusting for clinical variables and complex karyotype
status, recently has been reported for mutations in
TP53 and TET2. 90
Patient Characteristics
Apart from disease characteristics, host-specifıc risk assessment
in determining indications for alloSCT always should
be grounded on essential patient-related factors, including
age, comorbidities, and donor availability.
Although usually considered as a treatment option for patients
younger than age 60, over the last 2 decades the development
of reduced-intensity conditioning (RIC) regimens,
together with substantial progress in supportive care measures,
have resulted in an increase in the upper age limit to
age 70 (occasionally even older) in carefully selected very-fıt
patients. Because MDS are much more common in older
people (median age at diagnosis, over age 70), with only 10%
of patients younger than age 50, this age-limit extension
translates to a considerable expansion in the proportion of
patients for whom an alloSCT treatment strategy might be
presently contemplated. 91,92 Indeed, an international collaborative
retrospective comparison of two well-balanced cohorts
of medically fıt patients with high-risk MDS defıned by
age 60 to 70 and ECOG PS of 2 or less, treated with alloSCT
(103 patients) in case of donor availability, or 5-azacytidine
(75 patients) in case of no donor availability, suggested a survival
advantage in favor of allogeneic transplantation. 93 Additionally,
recently reported results of an international
collaborative decision analysis (evaluating both life expectancy
and quality-adjusted life expectancy) indicated a signifıcant
benefıt (p 0.001) of RIC alloSCT versus
nontransplantation therapies in patients’ age 60 to 70 with
intermediate-2/high-risk IPSS de novo MDS. 94
However, a sophisticated statistical analysis of a large
population of older patients with advanced MDS compared
alloSCT (247 patients, reported to the EBMT) with nontransplant
approaches (137 patients, reported to the Düsseldorf
registry). The analysis indicated a possible nonsignifıcant
survival disadvantage for the transplant cohort because of
the higher nonrelapse mortality. 95 These results suggest
that a prospective controlled randomized study that addresses
the “intention to go for transplant” question is absolutely
necessary. 95
Comorbidities have been shown to crucially affect alloSCT
clinical outcomes in several hematological malignancies.
These data led to the development of a hematopoietic cell
transplantation-specifıc comorbidity index (HCT-CI) as a
useful tool for risk assessment before transplantation. 96 The
risk-stratifıcation ability of the HCT-CI in patients transplanted
for AML and MDS subsequently was confırmed both
in the reduced-intensity and myeloablative conditioning
strategies. 97-100 The HCT-CI also was prospectively validated
by the GITMO group in a consecutive cohort of 1,937 patients
receiving alloSCT in Italy over 2 years, including 199
patients with MDS. In 2011, a time-dependent MDS-specifıc
Comorbidity Index (MDS-CI) was developed on a learning
cohort that included 840 patients diagnosed in Pavia, Italy. It
was subsequently validated in an independent cohort of 504
patients diagnosed in Düsseldorf, Germany. 101 Since it has
been shown to provide additional prognostic information on
patients stratifıed according to the IPSS-R, the MDS-CI may
represent a valuable tool in support of the HCT-CI when
evaluating patients for possible transplant indication.
High-serum ferritin and iron overload secondary to pretransplantation
transfusion also is associated with a substantial negative
effect on nonrelapse mortality after alloSCT. 102-110 Thus,
transfusion history in patients with MDS should be considered
for transplantation decision-making as well as for initiation
of a timely iron chelation therapy to prevent iron
accumulation before transplant.
When to Transplant
Although very heterogeneous, the natural course of MDS
typically is characterized by a disease progression with patients
exhibiting gradual worsening of peripheral blood cytopenias,
which eventually lead to transfusion dependency.
Sequential marrow examination, especially in the presence of
myeloblast excess (i.e., 5%), often can demonstrate an increase
in marrow blast–count culminating in AML evolution.
Cytogenetics tend to remain stable, even though the
occurrence of chromosome aberrancies (or additional ones,
when already present at diagnosis) occasionally may be observed.
Time-dependent disease modifıcations are outlined
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