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TRANSPLANTATION
A decision analysis of allogeneic bone marrow transplantation for the
myelodysplastic syndromes: delayed transplantation for low-risk
myelodysplasia is associated with improved outcome
Corey S. Cutler, Stephanie J. Lee, Peter Greenberg, H. Joachim Deeg, Waleska S. Pérez, Claudio Anasetti, Brian J. Bolwell,
Mitchell S. Cairo, Robert Peter Gale, John P. Klein, Hillard M. Lazarus, Jane L. Liesveld, Philip L. McCarthy, Gustavo A. Milone,
J. Douglas Rizzo, Kirk R. Schultz, Michael E. Trigg, Armand Keating, Daniel J. Weisdorf, Joseph H. Antin, and Mary M. Horowitz
Bone marrow transplantation (BMT) can
cure myelodysplastic syndrome (MDS),
although transplantation carries significant risks of morbidity and mortality. Because the optimal timing of HLA-matched
BMT for MDS is unknown, we constructed
a Markov model to examine 3 transplantation strategies for newly diagnosed MDS:
transplantation at diagnosis, transplantation at leukemic progression, and transplantation at an interval from diagnosis
but prior to leukemic progression. Analyses using individual patient risk-assessment data from transplantation and non-
transplantation registries were performed
for all 4 International Prognostic Scoring
System (IPSS) risk groups with adjustments for quality of life (QoL). For low and
intermediate-1 IPSS groups, delayed
transplantation maximized overall survival. Transplantation prior to leukemic
transformation was associated with a
greater number of life years than transplantation at the time of leukemic progression. In a cohort of patients under the age
of 40 years, an even more marked survival advantage for delayed transplantation was noted. For intermediate-2 and
high IPSS groups, transplantation at diagnosis maximized overall survival. No
changes in the optimal transplantation
strategies were noted when QoL adjustments were incorporated. For low- and
intermediate-1–risk MDS, delayed BMT is
associated with maximal life expectancy,
whereas immediate transplantation for intermediate-2– and high-risk disease is
associated with maximal life expectancy.
(Blood. 2004;104:579-585)
© 2004 by The American Society of Hematology
Introduction
Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders
characterized by ineffective hematopoiesis, marrow dysplasia, and
variable rates of transformation to acute myelogenous leukemia (AML).
The annual incidence in the United States is estimated to be between 3.5
and 12.6 in 100 000.1 Incidence rises with increasing age, with the
median age at diagnosis in the seventh decade.1
Survival after diagnosis of MDS varies from a few months to
several years. Among patients under the age of 60 years, median
survival is 4.6 years; it is significantly lower for those diagnosed
after the age of 60 years.2 There are numerous prognostic systems
developed to try to predict outcomes for patients with MDS.3-9 The
most widely used system, developed by the International MDS
Risk Analysis Workshop (IMRAW), is the International Prognostic
Scoring System (IPSS).2 The IPSS incorporates cytogenetics, bone
marrow myeloblast percentage, and peripheral blood counts to
predict survival.
From the International Bone Marrow Transplant Registry (IBMTR), Health
Policy Institute, Medical College of Wisconsin, Milwaukee; Dana-Farber
Cancer Institute, Boston, MA; Stanford University Medical Center, Stanford,
CA; VA Palo Alto Health Care System, Palo Alto, CA; Fred Hutchinson Cancer
Research Center, Seattle, WA; Cleveland Clinic Foundation, Cleveland, OH;
Case Western Reserve University, Cleveland, OH; Columbia University, New
York, NY; Center for Advanced Studies in Leukemia, Los Angeles, CA;
University of Rochester Medical Center, NY; Roswell Park Cancer Institute,
Buffalo, NY; Fundaleu, Buenos Aires, Argentina; British Columbia’s Children’s
Hospital, Vancouver, BC, Canada; Alfred I. duPont Hospital for Children,
Wilmington, DE; Princess Margaret Hospital, Toronto, ON, Canada; and
University of Minnesota, Minneapolis.
GlaxoSmithKline Inc; Human Genome Sciences; ICN Pharmaceuticals Inc;
ILEX Oncology; The Kettering Family Foundation; Kirin Brewery Company;
Ligand Pharmaceuticals Inc; Eli Lilly and Company; Nada and Herbert P.
Mahler Charities; Merck & Company; Millennium Pharmaceuticals; Miller
Pharmacal Group; Milliman USA Inc; Miltenyi Biotec; Irving I. Moskowitz
Foundation; National Marrow Donor Program; NeoRx; Novartis
Pharmaceuticals Inc; Novo Nordisk Pharmaceuticals; Orphan Medical Inc;
Ortho Biotech Inc; Osiris Therapeutics Inc; PacifiCare Health Systems; Pall
Medical; Pfizer US Pharmaceuticals; Pharmacia Corp; Pharmametrics;
Pharmion Corp; Protein Design Labs; Roche Laboratories; SangStat Medical;
Schering AG; StemCyte Inc; StemCell Technologies Inc; Stemco Biomedical;
StemSoft Software Inc; SuperGen Inc; Sysmex; THERAKOS, a Johnson &
Johnson Co; Unicare Life & Health Insurance; University of Colorado Cord
Blood Bank; ViaCell Inc; ViaCor Biotechnologies; WB Saunders Mosby
Churchill; and Zymogenetics Inc. C.S.C. is a Physician-Scientist of the
Leukemia Research Foundation of America and was supported by a fellowship
award from the Cancer and Leukemia Group B (CALGB).
Submitted January 28, 2004; accepted March 5, 2004. Prepublished online as
Blood First Edition Paper, March 23, 2004; DOI 10.1182/blood-2004-01-0338.
Supported by Public Health Service grant U24-CA76518 from the National
Cancer Institute, the National Institute of Allergy and Infectious Diseases, and
the National Heart, Lung and Blood Institute; and grants from Allianz Life/Life
Trac; American Cancer Society; American Red Cross; American Society of
Clinical Oncology; Amgen Inc; Anonymous donation to the Medical College of
Wisconsin; Aventis Pharmaceuticals; Baxter Healthcare Corp; Baxter
Oncology; Berlex Oncology; Blue Cross and Blue Shield Association; The
Lynde and Harry Bradley Foundation; Bristol Myers Squibb Oncology;
Cedarlane Laboratories Ltd; Cell Pathways; CelMed Biosciences; Centocor
Inc; Cubist Pharmaceuticals; Darwin Medical Communications Ltd; Dynal
Biotech ASA; Edwards Lifesciences RMI; Endo Pharmaceuticals Inc; Enzon
Pharmaceuticals Inc; Excess Inc; Fujisawa Healthcare Inc; Gambro BCT Inc;
BLOOD, 15 JULY 2004 䡠 VOLUME 104, NUMBER 2
An Inside Blood analysis of this article appears in the front of this issue.
Reprints: Mary M. Horowitz, International Bone Marrow Transplant Registry,
Medical College of Wisconsin, 8701 Watertown Plank Rd, PO Box 26509,
Milwaukee, WI 53226; e-mail: [email protected].
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734.
© 2004 by The American Society of Hematology
579
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580
BLOOD, 15 JULY 2004 䡠 VOLUME 104, NUMBER 2
CUTLER et al
Allogeneic stem cell transplantation currently is the only
potentially curative therapy for MDS. However, since most patients
with MDS are older than 60 years, few are candidates for
myeloablative transplantation. Approximately 25% of patients with
MDS are younger than 60 and may be considered for transplantation.2 Trials of stem cell transplantation demonstrate long-term
survival rates between 25% and 70%.10-14 Despite advances in
transplantation technology, there is still considerable morbidity and
mortality associated with this approach. Treatment-related mortality and overall survival are influenced by age, French-AmericanBritish (FAB) classification subtype, cytogenetic abnormalities, the
conditioning regimen used, and the duration of disease prior to
transplantation.10-12,14-17 The IPSS is reported to be a useful
predictor of transplantation outcome.18,19
The optimal timing of bone marrow transplantation from
HLA-identical siblings for MDS is unknown. Many patients enjoy
a long period after diagnosis without obvious disease progression.
For these patients, the risks of immediate morbidity and mortality
associated with transplantation are unacceptably high. Eventually,
however, most patients with MDS develop symptomatic cytopenias, or their disease evolves to a more aggressive phenotype or
transforms into AML, at which time stem cell transplantation is less
likely to be successful. Prospective comparisons of different
transplantation timing strategies are not available and are unlikely
to be performed because of the relatively small numbers of patients
affected and patient and physician treatment preferences. Consequently, physicians cannot reliably offer evidence-based recommendations to their patients regarding transplantation timing. To
address this problem, we performed a decision analysis examining
the optimal timing of bone marrow transplantation for MDS
patients with HLA-identical sibling donors.
Decision analysis is a statistical technique used to aid medical
decision making under conditions of uncertainty.20 The technique is
flexible and allows estimation of outcome given multiple variations
of initial testing conditions and assumptions. Treatment decisions
are suggested based on the area under the survival curves, thus
incorporating effects on both early and late mortality into the
treatment decision. The technique has been applied widely to
decision making in hematologic diseases.21-26
Patients and methods
Decision strategy
The primary decision examined in this study was the timing of myeloablative allogeneic stem cell transplantation from HLA-identical sibling donors
in patients with MDS. Three possible transplantation strategies were tested:
(1) transplantation at the time of diagnosis of MDS; (2) transplantation at
the time of progression to AML; (3) transplantation at a fixed time interval
after diagnosis. Analyses were performed for all 4 IPSS risk groups. Using
the decision software package DATA v3.5 (TreeAge Software, Williamstown, MA), a Markov decision model comparing the 3 strategies was
constructed (Figure 1).
A Markov decision model tracks survival outcomes as hypothetical
subjects transition between clinically relevant health states within the
model. Possible health states considered in this model included alive with
MDS, alive after undergoing transplantation for MDS, alive after transplantation with relapsed MDS, alive with AML, alive after undergoing
transplantation for AML, alive after transplantation with relapsed AML,
and dead (due to MDS, AML, transplant-related complications including
graft-versus-host disease (GVHD), disease relapse, or causes unrelated to
MDS, AML, or transplantation). As Figure 1 demonstrates, the “dead” state
is absorbing (there is no transition out of this state). The cycle length
Figure 1. Markov decision model. All patients began alive in the Alive-MDS state
and were able to transition after each 6-month cycle to other health states. Patients
could have remained in an alive state for any number of cycles without transitioning to
another health state. The BMT state was transitory and all subjects entering the BMT
state transitioned to another health state by the end of the cycle. MDS indicates
myelodysplastic syndrome; AML, acute myelogenous leukemia; BMT, bone marrow
transplantation.
between state transitions was 6 months, which was felt to best represent the
available data and clinical decision-making process. Transition rates
between the permissible states were calculated using database information
as described in “Data sources” and were allowed to vary based on primary
data for each of the IPSS risk levels.
Quality-of-life adjustments were made by incorporating utilities into the
decision model. Utilities are numerical representations of the perceived
value of a given health state and are expressed as values between 0 (a health
state equivalent to being dead) and 1 (perfect health). Analyses with and
without adjustments for quality of life were performed independently.
Data sources
All outcome data were derived from prospectively collected databases. All
statistical analyses were performed with the SAS v.8 software package
(SAS, Cary, NC).
Nontransplantation MDS cohort. Data on the outcome of patients not
undergoing transplantation were derived from the IMRAW database.2 The
IMRAW group has been following a cohort of primary MDS patients for
many years and represents the largest database of prospectively followed
and reported MDS patients in the medical literature. Both published data2
and unpublished extended follow-up data were provided by the IMRAW
group. Only individuals 60 years or younger at the time of entry to the
IMRAW cohort were included in this analysis. Since proliferative chronic
myelomonocytic leukemia was excluded by the IMRAW investigators,
these cases were also excluded from this analysis. Of the initial 816
individuals in the inception cohort, 184 patients were eligible for analysis
based on age and FAB subtype. Kaplan-Meier outcome curves of leukemiafree and overall survival were constructed for these 184 patients and were
stratified by IPSS risk group at the time of diagnosis. From the life tables,
6-month leukemic transformation and MDS-related mortality rates were
calculated and were transformed to transition probabilities for use in the
Markov model.
MDS transplantation cohort. Two groups of patients were combined
to construct the MDS transplantation cohort. The first group was composed
of patients who received allogeneic bone marrow transplants from HLAidentical siblings between January 1, 1990, and December 31, 1999, and
were registered with the International Bone Marrow Transplant Registry
(IBMTR). The IBMTR is a voluntary research organization that prospectively collects patient data on approximately 40% to 50% of all transplantation procedures performed in the United States. The second group of
patients included individuals who received allogeneic bone marrow transplants from HLA-identical siblings at the Fred Hutchinson Cancer Research
Center (FHCRC) between January 1, 1990, and December 31, 1999. There
was no overlap between these patient populations.
A total of 868 transplant recipients were considered for analysis. Of
these, 127 subjects were younger than 18 years old, 107 received peripheral
blood stem cell transplants, 142 had nonsibling, unrelated, or unknown
donors, and 56 used T-cell depletion as GVHD prophylaxis. These 432
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BLOOD, 15 JULY 2004 䡠 VOLUME 104, NUMBER 2
DECISION ANALYSIS FOR MDS
Table 1. Quality-of-life utilities
Range
Utility
Low
Alive with MDS
0.95
0.85
High
0.99
Alive after transplantation
0.92
0.80
0.95
Alive with AML
0.85
0.70
0.90
Alive with relapsed MDS/AML
0.57
0.50
0.70
Utilities are numerical representations of the perceived value of a given health
state and are expressed as values between 0 and 1. Utilities were incorporated into
quality-adjusted calculations and were tested across the ranges shown in sensitivity
analyses. MDS indicates myelodysplastic syndrome; AML, acute myelogenous
leukemia.
patients were therefore excluded from the analysis. Of the remaining 436
subjects, 260 individuals had sufficient data to calculate IPSS scores at the
time of transplantation. All patients received ablative conditioning regimens and received cyclosporine or tacrolimus with methotrexate prophylaxis for GVHD. A total of 81.2% of the cases were from the IBMTR and
the remaining cases from the FHCRC. In comparison with patients who
were not included in the analysis due to insufficient data to calculate an
IPSS score, patients included in the analysis were of similar ages (40.4
years vs 38.8 years, P ⫽ .12), had a similar sex distribution (55% male vs
56% male, P ⫽ .80), and had similar [pretransplantation hemoglobin levels
(94 g/L vs 93 g/L; P ⫽ .76), white blood cell counts (4.7 ⫻ 109/L vs
4.3 ⫻ 109/L; P ⫽ .51), and platelet counts (91.3 ⫻ 109/L vs 94.5 ⫻ 109/L;
P ⫽ .80). Patients included in the analysis had higher cytogenetic risk
scores (Mantel-Haenszel P ⫽ .02), but had a lower proportion of marrow
blasts prior to transplantation (8.2% vs 12.4%; P ⫽ .02) and a higher
proportion of unknown MDS subtypes (10.2% vs. 3.5%; P ⫽ .03). KaplanMeier probabilities of relapse-free survival, overall survival, and survival
following relapse were constructed. Relapse and transplant-related mortality rates were stratified by IPSS risk group at the time of transplantation, but
mortality after relapse was not. From the life tables, 6-month relapse,
relapse-free survival, and survival after relapse rates were generated and
were transformed to transition probabilities for use in the Markov model.
AML transplantation cohort. A cohort of patients who underwent
bone marrow transplantation from an HLA-identical sibling for AML
developing from primary MDS was obtained from the IBMTR. A total of
1155 patients was reported to the IBMTR between January 1, 1990, and
December 31, 1999, of whom 445 had underlying MDS. Of these 445
581
subjects, 53 were younger than 18 years old, 80 received peripheral blood
stem cells, and 82 received allografts from nonsibling related donors or
unrelated donors, leaving a total of 230 patients who were included this
analysis. Patients who had received induction chemotherapy for AML were
included in the analysis, regardless of remission status. Treatment-related or
secondary MDS were excluded. Kaplan-Meier outcome curves measuring
relapse-free survival, overall survival, and survival following relapse were
constructed. No stratification by original IPSS group was done. From the
life tables, 6-month relapse, relapse-free survival, and survival after relapse
rates were generated and were transformed to transition probabilities for use
in the Markov model.
Age- and sex-matched controls. Mortality rates for age- and sexmatched controls were obtained from US Census Bureau Information
(1998) and included in the model.
Baseline testing conditions, assumptions, and sensitivity analyses.
For the purposes of this analysis, a base case of a 35-year-old man with
newly diagnosed MDS and an available HLA-matched sibling donor was
used. Analyses for all 4 IPSS risk groups were performed independently. An
annual discount rate of 3% was used for all survival outcomes. Quality-oflife (QoL) data for patients with MDS are lacking in the literature.
Estimates from a similar decision analysis study of patients with AML were
used to attempt to adjust for QoL in this study.27 Those that were not
available from the literature were estimated using the available values as
benchmarks. Quality-of-life values can be found in Table 1, along with the
range of plausible values that were tested in sensitivity analyses. Other
assumptions refer to the rate of transplantation for patients with leukemic
transformation from MDS. It was assumed that up to 50% of individuals
with leukemic transformation of MDS would not undergo transplantation
due to death during induction chemotherapy, severe illness making ablative
transplantation infeasible, or refusal of the procedure. This assumption was
tested in sensitivity analyses. Other sensitivity analyses evaluated the
influence of QoL estimates and recipient age on transplant-related outcomes.
Results
Patients
Baseline characteristics for subjects included in this analysis are
found in Table 2. There were 184 individuals under the age of 60
years available for analysis from the IMRAW. Median follow-up
Table 2. Baseline characteristics of the registry data groups
Nontransplantation
Characteristic
No. of patients
MDS
IMRAW
184
Transplantation
MDS
IBMTR
193
MDS
FHCRC
67
Statistical differences
AML
IBMTR
P*
P†
P‡
230
49.8 (18-60)
39.4 (18-59)
45.6 (20-60)
41.7 (18-60)
⬍.0001
⬍.0001
NS
58.2
53.4
59.7
53.5
NS
NS
NS
⬍.0001
NS
NA
RA
51.6
30.57
38.81
NA
RARS
16.9
4.48
NA
RAEB
25.0
28.5
37.31
NA
RAEB-t
6.5
34.72
17.91
NA
Unknown
0
4.15
1.49
NA
⬍.0001
⬍.001
NA
31.0
9.84
2.99
NA
Age, y, median (range)
Male sex, %
FAB subtype, %
2.07
IPSS risk group, %
Low
Int-1
42.9
53.37
32.84
NA
Int-2
20.1
17.62
46.27
NA
High
6.0
19.17
17.91
NA
MDS indicates myelodysplastic syndrome; AML, acute myelogenous leukemia; Tx, transplant; FAB, French-American-British Classification of Myelodysplastic Syndrome;
RA, refractory anemia; RARS, refractory anemia with ringed sideroblasts; RAEB, refractory anemia with excess blasts; RAEB-t, refractory anemia with excess blasts in
transformation; IMRAW, Iinternational MDS Risk Assessment Workshop; IBMTR, International Bone Marrow Transplant Registry; FHCRC, Fred Hutchison Cancer Research
Center; NS, not significant; and NA, not applicable.
*Probability of testing MDS IMRAW versus all transplantations.
†Probability of testing MDS IBMTR versus MDS FHCRC.
‡Probability of testing MDS versus AML transplantation.
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582
BLOOD, 15 JULY 2004 䡠 VOLUME 104, NUMBER 2
CUTLER et al
Median survival for the AML transplantation cohort was 9.9
months. Relapse was noted in 9.5%, 13.5%, 21.9%, and 44.4% of
patients undergoing transplantation for low-, int-1–, int-2–, and
high-risk MDS groups, respectively (overall 21%). Among
patients undergoing transplantation for AML, 38.4% relapsed
after transplantation.
Decision model
Figure 2. Overall survival of patients included in the analysis. (A) Overall survival
of the International MDS Risk Assessment Workshop patients who did not undergo
stem cell transplantation, stratified by IPSS score at the time of diagnosis (P ⬍ .001
for differences in risk groups). (B) Overall survival of the IBMTR/FHCRC bone
marrow transplantation cohort of patients, stratified by IPSS risk score at the time of
transplantation (P ⬍ .001 for differences in risk groups).
for the entire cohort was 35.4 months (range, 1.4-206.7 months).
There were 260 individuals included in the MDS transplantation
cohort. Median follow-up of this cohort was 11.4 months (range,
0.1-131.6 months). In comparison to the nontransplantation cohort,
the transplantation cohort was younger, and had a higher proportion
of cases with more advanced MDS by FAB and IPSS criteria. The
IBMTR MDS transplantation cohort was younger and had lessadvanced IPSS scores than the FHCRC cohort.
The AML cohort was composed of 230 patients whose median
follow-up was 7.9 months (range, 0-115.2 months). There were no
significant differences in age or sex distribution between the MDS
and the AML transplantation cohorts.
Median survival of the nontransplantation cohort was 62.9
months. When stratified by IPSS score, median survivals were
141.1, 62.9, 22.5, and 4.9 months for the low-, intermediate-1
(int-1)–, intermediate-2 (int-2)–, and high-risk groups, respectively
(Figure 2A, P ⬍ .0001 for differences by log rank test). The 25%
leukemic transformation time was 31.2 months for the entire cohort
and 84.6, 19.2, and 2.7 months for the int-1–, int-2–, and high-risk
groups, respectively. The 25% transformation rate was not reached
in the low-risk group (P ⬍ .0001 for differences by log rank test).
Median survival for the MDS transplantation cohort was 14.0
months. When stratified by IPSS score, median survivals were
40.2, 20.5, 14.8, and 6.1 months for the 4 IPSS groups (Figure 2B;
P ⫽ .04 by log rank test). There were no differences in survival
outcomes between the IBMTR and FHCRC subgroups (P ⫽ .09).
The discounted life expectancies for the strategies of immediate
transplantation, transplantation at the time of AML progression,
and transplantation at a fixed interval after diagnosis for each of the
4 IPSS risk groups are shown in Table 3. Fixed time intervals of 2,
4, 6, and 8 years after diagnosis were chosen for analysis.
For low-risk and int-1–risk IPSS groups, transplantation at the
time of leukemic progression was associated with a higher life
expectancy than was the strategy of transplantation at the time of
diagnosis. For both of these risk groups, however, transplantation at
a fixed interval after diagnosis (but prior to the development of
AML) was the strategy that maximized overall discounted life
years. The gains in discounted life expectancy for delayed transplantation compared with transplantation at the time of diagnosis are
seen in Figure 3. For the more-advanced IPSS risk groups (int-2
and high), the strategy that maximized discounted life expectancy
was transplantation at the time of diagnosis. The decrement in life
expectancy associated with delayed transplantation in these groups
is shown in Figure 3.
Quality-adjusted discounted life expectancy was approximated
using the utility values shown in Table 1; results are shown in Table
4. Adjustment for QoL did not change the preferred treatment
strategy for any of the 4 IPSS risk groups; however, some strategies
were influenced by the estimated QoL parameters (such as the
strategy for low-risk disease). No decisions were sensitive to
varying (between 25% and 75%) the estimate of the proportion of
patients who would not undergo transplantation once MDS had
progressed to AML.
When all above analyses were limited to patients younger
than 40 years, the preferred treatment strategy for the low-risk
and int-1risk IPSS groups was transplantation at progression to
AML. All discounted life expectancy values were improved
when compared with the data analyzed in its entirety. These
analyses were insensitive to QoL parameters. For the int-2–risk
group, transplantation at the time of diagnosis remained the
preferred strategy. Analyses of the younger age cohort were
limited by the small numbers of patients and clinical events in
the nontransplantation group. There were too few high-risk
Table 3. Discounted life expectancy, in years, for alternative transplantation strategies
Transplantation at a fixed time point
Transplantation
at diagnosis
2y
4y
6y
8y
Transplantation at
AML progression
Low
6.51
6.86
7.47
7.46
7.49*
7.21
Int-1
4.61
4.74
4.72
5.02
5.20*
5.16
Int-2
4.93*
3.21
2.94
2.85
2.84
2.84
High
3.20*
2.75
2.75
2.75
2.75
2.75
Low
5.62
6.63
7.53
8.32
9.00
10.21*
Int-1
2.48
4.04
5.37
6.53
7.49
10.21*
Int-2
1.65*
1.48
1.51
1.52
1.53
1.53
High
—
—
—
—
—
—
Patients, by IPSS risk group
All patients
Patients younger than 40 y
— indicates insufficient data to perform analysis.
*Dominant strategies.
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BLOOD, 15 JULY 2004 䡠 VOLUME 104, NUMBER 2
DECISION ANALYSIS FOR MDS
Figure 3. Net benefit or loss of overall discounted life expectancy for the 4 IPSS
risk groups are shown above and below the x-axis. A net benefit for delaying
transplantation is noted for low and int-1 risk groups, whereas any delay in the time to
transplantation is associated with a loss in survivorship in the higher risk groups.
patients under the age of 40 years who did not undergo
transplantation to perform these analyses.
Discussion
Allogeneic hematopoietic stem cell transplantation is the only
curative treatment available for patients with MDS. However, stem
cell transplantation is associated with a significant risk of early
morbidity and mortality, causing reluctance to use this strategy for
first-line treatment of a disease with a variable natural history. The
International MDS Risk Assessment Workshop developed a prognostic system to predict overall survival and transformation to
acute leukemia in patients with newly diagnosed MDS treated with
conventional supportive therapy. However, the scoring system did
not address the difficult treatment decisions that patients with MDS
face if they have HLA-matched siblings and could tolerate a
myeloablative transplantation procedure.
Unfavorable prognostic variables that influence outcome after
transplantation for MDS include older age, high marrow blast
counts, marrow cytogenetics, and the use of induction chemotherapy prior to transplantation.13,15,17,28 All of these factors argue
in favor of transplantation early after the diagnosis of MDS,
regardless of IPSS risk group. In fact, one study demonstrated that
transplantation early after the diagnosis of MDS was associated
with the most favorable outcome.16 Despite these results, it remains
unclear whether early transplantation for all patients with MDS
leads to maximization of survival for the group as a whole. To
address this question, we performed a decision analysis using
clinical data from IMRAW, IBMTR and FHCRC.
583
This analysis demonstrated that life expectancy of patients with
low-risk IPSS scores (low- and int-1–risk groups) who have
HLA-identical siblings was higher when transplantation is delayed
by some period but performed prior to the development of AML.
This was particularly true for patients under the age of 40 years.
Since the prognosis of low- and int-1–risk patients with supportive
measures alone is excellent, with a median survival that exceeds a
decade in the low-risk IPSS group, it seems reasonable to avoid the
immediate risks of transplantation.2 The caveat, of course, is that it
is not possible to perfectly predict the time of transformation to
AML. For high-risk MDS (IPSS int-2 and high), transplantation
soon after the diagnosis confers the best prognosis, since the rate of
transformation to acute leukemia is high, with most patients
progressing within the first year.
The treatment algorithms suggested here apply to large groups
of patients; use in an individual patient must take into account
many patient-specific factors. For example, individual patient
risk-taking or risk-averting behaviors must be considered when
suggesting a potentially life-threatening procedure such as bone
marrow transplantation. Nonetheless, the suggested delay in transplantation for early-stage MDS seems to be contrary to popular
clinical practice, as the IPSS int-1–risk group represented the
largest subgroup of patients (46%) undergoing transplantation
reported to the IBMTR between 1989 and 1997.28 In this analysis,
these patients underwent transplantation a median of 6.2 months
from the time of diagnosis.
Quality-of-life considerations are also important. Quality of life
among patients with MDS may be influenced by factors such as
recurrent infection and transfusion dependence although there are
few data on this subject. Quality of life among transplant recipients
has been assessed in several studies.29-32 In a prior decision analysis
using physician surveys to estimate QoL, the utility of being alive
after stem cell transplantation was estimated to be between 0.9
and 0.98 for patients with and without chronic GVHD.23 In our
model, a utility of 0.92 was used based on the recent assumptions of Sung et al,27 but was tested over a broad range in
sensitivity analyses.
In contrast, very few assessments of QoL among patients with
MDS exist. A recent evaluation of transfusion-dependent patients
with MDS demonstrated a significant correlation between serum
hemoglobin and QoL measured via 3 independent validated tools.33
A trial of the DNA hypomethylating agent, azacytidine, demonstrated significant positive effects on QoL in patients with MDS.34-35
A direct integration of the QoL measures from these studies into the
utilities used in our analysis was not performed for a variety of
reasons, including the lack of a validated transformation algorithm
for the QoL tools used and the distinct differences in the population
Table 4. Quality-adjusted discounted life expectancy, in years, for alternative transplantation strategies
Transplantation at a fixed time point
Transplantation
at diagnosis
2 years
4 years
6 years
8 years
Transplantation at
AML progression
Low
5.99
6.37
6.98
7.00
7.05*
6.83
Int-1
4.23
4.41
4.42
4.72
4.89*
4.87
Int-2
4.53*
2.99
2.75
2.65
2.65
2.65
High
2.94*
2.53
2.53
2.53
2.53
2.53
Low
5.17
6.16
7.04
7.81
8.47
9.70*
Int-1
2.29
3.78
5.06
6.16
7.08
9.68*
Int-2
1.52*
1.39
1.43
1.44
1.45
1.45
High
—
—
—
—
—
—
Patients, by IPSS risk group
All patients
Patients younger than 40 y
— indicates insufficient data to perform analysis.
*Dominant strategies.
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584
BLOOD, 15 JULY 2004 䡠 VOLUME 104, NUMBER 2
CUTLER et al
surveyed (median ages 73 and 67 years vs 50 years).33-35 For the
purposes of this analysis, it was assumed that the QoL of patients
with MDS was at least equivalent to the posttransplantation state.
The utility of 0.95 was used and was tested broadly in sensitivity
analyses. When the QoL utilities were incorporated into the
decision model, a delayed approach to transplantation remained the
dominant strategy, however, some estimates were sensitive to the
QoL estimates at the extremes of the ranges tested.
There are several potential sources of bias in this analysis. One
factor to consider is selection bias in the time to transplantation in
the IBMTR/FHCRC group. In this cohort, the median time to
transplantation from diagnosis was 5.4 months. Regardless of
the timing of transplantation in the model, the IBMTR/FHCRC
cohorts were treated as a whole. This was felt to be acceptable,
since within IPSS subgroups, no differences in outcome were
noted when survival curves were stratified by time from
diagnosis to transplantation.
Another potential source of bias is the good outcome of the
IBMTR AML transplantation cohort. This group had a 5-year
overall survival of 36.5%, which compares favorably with other
reported series, but is consistent with other recent reports.13 Since
the IBMTR does not record data on patients for whom stem cell
transplantation was planned but could not be performed, we
assumed that up to 50% of patients with AML that had developed
from primary MDS would not proceed to transplantation for a
variety of reasons. Patients could become ineligible for transplantation due to severe illness or death during AML induction chemotherapy or the unavailability of their stem cell donor. When the
proportion of patients not proceeding to transplantation was varied
widely, the results noted in Table 3 were not significantly different.
A third considerable source of bias is the modeling of transplantation outcome based on IPSS score at the time of transplantation,
rather than at the time of diagnosis. The IPSS score was not
designed to provide prognostic information at the time of transplantation nor at any time after diagnosis. However, studies suggest that
this scoring system can provide useful prognostic information,
when scores at diagnosis and at the time of transplantation are
evaluated.18,28 If the data were analyzed using the IPSS score at
diagnosis, the higher-risk transplantation subgroups would be
comprised of heterogeneous mixtures of patients whose early MDS
was progressing and those in whom advanced MDS was recently
diagnosed. A final criticism of the design of this analysis is the
inclusion of patients with refractory anemia with excess of blasts
transformed (RAEB-t) according to the FAB classification of
myeloid malignancies. The current World Health Organization
(WHO) classification of myeloid diseases classifies patients with
more than 20% marrow blasts as having AML.36 Despite this, the
FAB classification and the IPSS remain broadly used clinical tools,
whereas the newer WHO classification of MDS is not yet widely
accepted.37,38 Transplantation outcomes for patients with RAEB
and RAEB-t were not statistically different in this analysis (data not
shown). Therefore, even using the newer diagnostic criteria of the
WHO and excluding patients who would be classified as AML by
the WHO, the results presented here remain valid.
The strategy that maximized survival for low-risk IPSS groups
(low and int-1) in this study was transplantation at a fixed interval
but prior to the development of AML for the entire cohort of
patients tested. It is likely that the best individual estimate for this
interval of time corresponds to important clinical events for the
patient with MDS, such as the development of a new cytogenetic
abnormality or the development of transfusion dependence. This
likely corresponds to the migration from a lower to a higher IPSS
risk category. The strategy of transplantation at the time of
progression from one IPSS risk group to another is an attractive one
for patients presenting with low-risk disease, however, we were
unable to test this strategy with the available data. Since transplantation outcomes for early-stage disease may be superior to those for
later-stage disease, this strategy makes sense if monitoring for
progression is employed.13
Nontransplantation therapy for MDS is changing, with novel
agents in development, the use of which may lead to transfusion
independence and improved quality of life in patients with MDS.
Similarly, novel transplantation technology may substantially reduce treatment-related morbidity and mortality and may reduce
relapse rates after transplantation. Examples of transplantation
innovations include the use of peripheral blood stem cells, which
have been associated with reduced transplant-related mortality and
increased survival in MDS, and nonmyeloablative conditioning
regimens, which have been associated with reduced peritransplantation morbidity and mortality.39,40 The impact of these novel
therapies and transplantation technologies on the decision to
undergo early or delayed stem cell transplantation is unknown and
were not evaluated in the present study. Also, although not
evaluated in this study, suggestions regarding the timing of
transplantation using unrelated histocompatible donors are likely to
be similar to those in this study. Since outcomes with unrelated
donors are generally not as favorable as with related donors,28,41 it
is likely that delayed transplantation for patients with low-risk
disease and unrelated donors is likely to provide the longest life
expectancy. Last, since the MDS classification for adults does not
adequately describe all the clinical syndromes that occur in
children, this analysis should not be used in decision making for
patients under the age of 18 years.
In summary, using decision analysis and prospectively collected
registry data, we have shown that delayed transplantation for IPSS
low and int-1 risk groups is associated with maximum discounted
and quality-adjusted discounted life years. We hypothesize that the
optimal timing of transplantation for this cohort is at the time of the
development of a new cytogenetic abnormality, the appearance of a
clinically important cytopenia, or the progression from one IPSS
group to a higher risk group. For patients with int-2 and high IPSS
risk scores, transplantation at the time of diagnosis is associated
with maximization of discounted life years for the entire cohort of
patients. These results should serve as a guide for treatment in the
absence of randomized data, and may be useful as a starting point
to begin discussion of treatment options with patients with MDS.
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2004 104: 579-585
doi:10.1182/blood-2004-01-0338 originally published online
March 23, 2004
A decision analysis of allogeneic bone marrow transplantation for the
myelodysplastic syndromes: delayed transplantation for low-risk
myelodysplasia is associated with improved outcome
Corey S. Cutler, Stephanie J. Lee, Peter Greenberg, H. Joachim Deeg, Waleska S. Pérez, Claudio
Anasetti, Brian J. Bolwell, Mitchell S. Cairo, Robert Peter Gale, John P. Klein, Hillard M. Lazarus,
Jane L. Liesveld, Philip L. McCarthy, Gustavo A. Milone, J. Douglas Rizzo, Kirk R. Schultz, Michael
E. Trigg, Armand Keating, Daniel J. Weisdorf, Joseph H. Antin and Mary M. Horowitz
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