Page 1108 - Hematology_ Basic Principles and Practice ( PDFDrive )

978 Part VII Hematologic Malignancies

offered. Despite this, all patients who are potential candidates for determined, although this prognostic scoring system is used less
HSCT should be referred to a transplantation center early in their frequently.
disease course so that a discussion regarding the appropriateness of
transplantation can occur and a donor search can be initiated, where
appropriate. The correct timing of HSCT is therefore of paramount Molecular Prognostic Factors
importance, and decisions regarding the timing of HSCT should be
made on more than patient preference alone. Perhaps even more than in AML, mutation analysis undoubtedly led
The most widely used clinical prognostic system is the IPSS, to a shift from rudimentary clinical prognostic models to molecularly
which can predict both nontransplantation outcomes as well as MAC defined models for prognosis and to guide therapy in MDS. As many
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transplantation outcomes. 90,91 The IPSS-R will eventually supplant as 75% of patients can be found to have one or more mutations.
the IPSS as the dominant prognostic scoring system. Several groups Numerous individual genes and whole genome expression profiling
have attempted to validate this newer prognostic construct with have demonstrated significant associations with MDS outcome, and
transplant outcomes. A cohort of 519 MDS patients were reported now, some of these mutational profiles have been associated with
by the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) and transplantation outcome.
their outcomes were stratified by IPSS-R. In addition to the IPSS-R, Examining a cohort of 87 patients who underwent allogeneic
MK and the HCT comorbidity index independently predicted out- transplantation at Dana-Farber Cancer Institute, Bejar et al were able
comes. The 5-year survival outcomes were 71%, 58%, 39%, and to demonstrate the adverse prognostic impact of three specific muta-
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23% in the low, intermediate, high, and very high risk patients when tions on outcome after transplantation. In this cohort, although
classified by the IPSS-R. 92 92% of subjects had at least one identifiable mutation, those with
Several Markov decision models have suggested that the optimal TET2 and DNMT3A had worse prognoses that those without these
timing of transplantation is with the diagnosis of Intermediate-2 or mutations, whereas those with mutations in TP53 had the worst
higher disease, 90,93 although one more heterogeneous analyses sug- outcomes, with no subjects surviving beyond 2 years after transplan-
gested that even patients with Intermediate-1 risk disease should be tation. Mutations in TP53 were extremely powerful predictors of
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offered transplantation. Most recently, the first decision model relapse, and were better prognosticators than cytogenetic status;
utilizing the IPSS-R was presented. The results of this analysis sug- subjects with complex karyotypes in the absence of TP53 mutations
gested immediate transplantation for all patients with Intermediate had similar outcomes to subjects without complex karyotypes, pos-
risk disease by IPSS-R, and delayed transplantation for those with sibly heralding the decline of the cytogenetic signature as the most
low risk disease. 95 important prognostic marker in transplantation. In addition, this
A shortcoming of all of these analyses is the inability to provide finding calls into question the role of conventional HSCT off clinical
treatment decision guidance at clinically relevant times for patients trials for those with the poorest risk profiles, since in the absence of
not undergoing immediate HSCT, because other important clinical strategies to reduce relapse after transplantation, transplantation
events, such as a new transfusion requirement, recurrent infection, or appears to offer little benefit.
recurrent bleeding episodes certainly could be considered triggers to
move on to transplantation. Thus it is useful to subdivide patients
with lower-risk MDS into more-refined prognostic groups that may Incorporating Comorbidity for Patient and Conditioning
benefit from HSCT. Intensity Selection Before Transplantation
Transfusion frequency and resultant iron overload have both been
demonstrated to be important prognostic factors in HSCT outcomes. With increased comorbidity comes an increase in the rate of adverse
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Platzbecker et al compared the effects of transfusion dependency outcomes in hematologic malignancies, and, in particular, the treat-
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at the time of HSCT. Even though the transfusion-dependent ment of MDS. Previously, it was demonstrated that age alone
group had more low-risk features, OS was inferior, with a 3-year cannot be used as a surrogate for comorbidity, as demonstrated by
OS of 49% compared with 60% in the transfusion-independent an analysis of over 500 individuals with MDS who underwent a first
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group (p = 0.1). The Pavia group examined a cohort of patients RIC transplantation. Several comorbidity scores have been devel-
stratified by IPSS to determine the relevance of the newer World oped to help provide prognostic information in myeloid malignan-
Health Organization (WHO) histologic classification scheme and cies. In MDS, the Hematopoietic Cell Transplantation Comorbidity
to determine if transfusion requirement influenced outcomes among Index, developed by Sorror and colleagues, 102,103 has been shown to
different IPSS groups. For patients with low- and intermediate-1 carry prognostic value, even in patients with MDS not undergoing
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risk IPSS scores, the WHO histologic classification scheme signifi- transplantation. The consideration of comorbidity before HSCT
cantly differentiated survival among the different histologic subtypes is even more relevant now that RIC has been shown to be effective
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within each IPSS range. More importantly, the authors demon- in the treatment of MDS, and patients can elect to undergo RIC
strated a significant effect on survival based on the requirement for transplantation. Patients were divided into four separate groups, with
transfusion support. As would be expected, outcomes in patients each group being defined on the basis of comorbidity and malignant
with higher-grade myelodysplasia were affected less by transfusion disease risk. Within each of the four risk groups, patients who
requirement than were patients with less-advanced WHO histologic underwent MAC and RIC were compared with each other. As
classifications. As a result, the impact of transfusion requirement expected in each of the four groups, the RIC arm experienced higher
was then incorporated into the WHO Prognostic Scoring System relapse rates but lower treatment-related mortality rates when com-
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(WPSS). In this system, the effect of regular transfusion require- pared with the MAC arm. As a result, disease-free and overall survival
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ment (defined as requiring at least one transfusion every 8 weeks in was similar between conditioning arms in all four groups. More
a 4-month period) was given the same regression weight as progress- recently, an enhanced index that incorporates both age and clinical
ing between cytogenetic risk groups. In contrast to the initial IPSS comorbidity was developed and demonstrated even more prognostic
publication, which carries prognostic information only at the time power than either of the components alone. In this scoring system
of initial MDS diagnosis, this model was time dependent, such that those with the highest age-adjusted comorbidity scores have nonre-
patients could be continually reevaluated by the scoring model and lapse mortality that might exceed 50% at 5 years, with concomitant
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updated prognostic information could be generated at any time in survival that is less than 20%. Transplantation for this group of
the patient’s treatment course. As such, the development of new individuals should be seriously considered outside the spectrum of
cytogenetic changes or the development of a transfusion need adds routine practice.
useful information that helps guide treatment decisions, including The effects of elevated ferritin levels on HSCT until recently have
5
the decision to proceed to HSCT as well as estimating transplanta- been largely limited to patients undergoing MAC transplantation.
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tion outcomes. Determining at which WPSS stage transplantation We previously reported that an elevated pre-HSCT serum ferritin
outcomes are superior to nontransplantation therapy has yet to be level was strongly associated with lower overall and disease-free