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Blood, Vol. 91 No. 5 (March 1), 1998:
pp. 1810-1819
Survival With Bone Marrow Transplantation Versus Hydroxyurea or
Interferon for Chronic Myelogenous Leukemia
By
Robert Peter Gale,
Rüdiger Hehlmann,
Mei-Jie Zhang,
Joerg Hasford,
John M. Goldman,
Hermann Heimpel,
Andreas Hochhaus,
John P. Klein,
Hans-Jochem Kolb,
Philip B. McGlave,
Jakob R. Passweg,
Philip A. Rowlings,
Kathleen A. Sobocinski,
Mary M. Horowitz, and
the German CML Study Group
From the International Bone Marrow Transplant Registry, Health
Policy Institute, Medical College of Wisconsin, Milwaukee, WI; the
Division of Bone Marrow and Stem Cell Transplantation, Salick Health
Care, Inc, Los Angeles, CA; III. Medizinische Klinik, Klinikum
Mannheim, Universität Heidelberg, Mannheim, Germany; Institut
für Medizinische Informationsverarbeitung, Biometrie u.
Epidemiologie, München, Germany; the Royal Postgraduate Medical
School, Hammersmith Hospital, London, UK; University of Ulm, Ulm,
Germany; Universität München, München, Germany; and
the University of Minnesota, Minneapolis.
 |
ABSTRACT |
Hydroxyurea, interferon, and HLA-identical sibling bone
marrow transplantation are common therapies for chronic myelogenous leukemia (CML) in chronic phase. Which is best is controversial. The
purpose of this study was to compare survival of patients with CML
receiving HLA-identical sibling transplants versus hydroxyurea or
interferon. The transplant cohort included 548 recipients of HLA-identical sibling transplants, reported to the International Bone
Marrow Transplant Registry. The nontransplant cohort included 196 patients receiving hydroxyurea (n = 121) or interferon (n = 75) on
a randomized trial of the German CML Study Group. Survivals were
compared using proportional hazards regression with fixed and
time-dependent variables to adjust for patient differences and changing
risks over time. For the first 18 months after diagnosis, mortality was
higher in the transplant than the nontransplant cohort (relative risk
[RR], 5.85; P < .0001). From 18 to 56 months, mortality was
similar (RR, 0.80; P = .38). After 56 months, mortality was
lower in the transplant cohort (RR, 0.16; P < .0001).
Seven-year survival probabilities (95% confidence interval) were 58%
(50% to 66%) with transplant and 32% (22% to 41%) with hydroxyurea or interferon. There was a significant survival advantage for hydroxyurea or interferon in the first 4 years after diagnosis and for
transplants starting 5.5 years after diagnosis. For transplants done
within 1 year of diagnosis, the survival advantage for transplantation began earlier. Survival advantage for transplants was greater and
occurred earlier in patients with intermediate- and high-risk prognostic features than in those with low-risk features. This study
confirms higher early mortality, but a long-term survival advantage for
HLA-identical sibling transplants over hydroxyurea or interferon in
CML.
| |
INTRODUCTION |
OPTIMAL THERAPY for chronic myelogenous
leukemia (CML) in chronic phase is controversial. Interferon
and/or hydroxyurea are common treatments. Although hydroxyurea
controls white blood cell and platelet levels, it rarely produces
cytogenetic remissions, prolongs survival only modestly, and does not
cure.1-3 Interferon also controls white blood cell and
platelet levels; however, in contrast to hydroxyurea, it produces
cytogenetic remissions in some patients. In some studies, persons
treated with interferon survive longer than those treated with
hydroxyurea or busulfan.4-10 It is too early to know if
there are cures with interferon, but the frequency will be low.
Treatment-related mortality with hydroxyurea and/or interferon
is negligible; median survival is 3 to 7 years. Features at
diagnosis associated with shorter survival include older age, male sex,
high levels of myeloblasts and platelets, and
splenomegaly.11-15
HLA-identical sibling bone marrow transplantation is also used to treat
CML in chronic phase, especially in younger patients. Five-year
leukemia-free survival is 50% to 60%.16-20 This contrasts with hydroxyurea therapy where there is no leukemia-free survival and
with interferon therapy where 5-year leukemia-free survival is rare.
However, transplants are associated with 20% to 30% treatment-related mortality. Factors associated with lower leukemia-free survival after
chronic phase transplants include older age, prior treatment with
busulfan, T-cell depletion of donor bone marrow, and intervals from
diagnosis to transplant greater than 1 year.16-23
Because most persons with CML can expect 4 or more years survival with
hydroxyurea or interferon, the decision to do a transplant early, with
its attendant risk of treatment-related mortality, is
difficult.24,25 However, delaying transplant increases
transplant-related mortality and decreases the likelihood of
cure.16,21 We compared survival of 548 people with CML
receiving HLA-identical sibling transplants in chronic phase and
reported to the International Bone Marrow Transplant Registry (IBMTR)
with survival of 196 treated with hydroxyurea or interferon on a
randomized trial of the German CML Study Group.
| |
MATERIALS AND METHODS |
Transplant cohort.
The study included 548 patients with CML in chronic phase,  15 and
 55 years of age, diagnosed between 1983 and 1991, treated with
interferon with or without hydroxyurea (n = 131) or hydroxyurea alone
(n = 417) followed by a non-T-cell depleted HLA-identical sibling bone
marrow transplant with posttransplant methotrexate and cyclosporine for
graft-versus-host disease prophylaxis. Patients were reported to the
IBMTR by 116 centers (Table 1). Median interval between diagnosis and
transplant was 10.1 (range, 2 to 84) months; 331 (60%) patients were
transplanted within 1 year of diagnosis. Median follow-up was 4.3 years.
The IBMTR is a voluntary working group of over 300 transplant centers
worldwide that contribute detailed data on their allogeneic and
identical twin bone marrow transplants to a Statistical Center at the
Medical College of Wisconsin.26,27 Participants are required to report all consecutive transplants. The IBMTR database includes 40% to 45% of allogeneic transplant recipients since 1970. Computerized error checks, physician review of submitted data, and
on-site audits of participating centers ensure data quality. Transplant
outcomes estimated using IBMTR data are similar to those reported by
large nonparticipating centers for comparable patients.
Nontransplant cohort.
The study included 196 patients with CML in chronic phase, 15 and
55 years of age, diagnosed between 1983 and 1990 and treated with
hydroxyurea (n = 121) or interferon (n = 75) on a randomized trial of
the German CML Study Group comparing busulfan, hydroxyurea, and
interferon for newly diagnosed CML in chronic phase.8,28 Details of this trial are published; it enrolled about 10% of the CML
cases in West Germany over a 7.5-year period. Patients were treated in
60 centers. In the trial, survival of patients treated with busulfan
was inferior to those treated with either hydroxyurea or interferon;
there was not a statistically significant difference in survivals of
patients receiving hydroxyurea or interferon. Patients receiving
busulfan were excluded from the current study. Ninety-five patients
receiving hydroxyurea or interferon, but older than 55 years at
diagnosis, and 14 with greater than 10% circulating blasts at
diagnosis were also excluded from analysis. Median follow-up was 6.5 years. Sixty-five patients in the German study received a transplant at
a median interval of 20.0 (range, 3.1 to 77.4) months after diagnosis;
they were censored at time of transplant.
Statistical methods.
Characteristics of the transplant and hydroxyurea/interferon groups
were compared using the  2 test for categorical variables
and the Wilcoxon two-sample test for continuous variables.
Comparing outcomes in the transplant and nontransplant groups required
adjustment for two sources of bias: differences in time to treatment
(time to transplant) and differences in baseline characteristics of
patients. To address the first source of bias, which results from the
fact that patients must survive in chronic phase a sufficient length of
time for a transplant to be done, a left-truncated Cox regression model
of time to death was used.29,30 At each time point in this
model, the risk set in the nontransplant cohort consists of all
patients still under study, while the risk set in the transplant cohort
includes only those with a waiting time to transplant less than the
current time point and who are still under study.
To adjust for differences in baseline characteristics, we used two
approaches. First associations between survival and potential prognostic variables were evaluated in each group separately using Cox
proportional hazards regression with a backwards stepwise approach.
Variables considered were: age (> v 35 years), sex, white
blood cell count (< 100, 100 to 199, and 200 × 109/L), platelets (<150, 150 to 699, and 700 × 109/L), blasts (0, 1 to 3, 4%), spleen size (0, 1 to 4, 5 to 9, and 10 cm below the costal margin), hemoglobin at diagnosis
(> v 12 g/dL) and year of diagnosis (< and 1988). All
of these have been reported to affect survival in conventionally
treated patients in prior studies. Variables significantly associated with survival in either the transplant or nontransplant cohorts were
included as covariates in subsequent survival comparisons. When tests
for interaction between significant covariates and type of treatment
(transplant v hydroxyurea or interferon) showed significance,
covariates were adjusted separately for each treatment. The
proportionality assumption of the Cox model was tested by adding a
time-dependent covariate for each covariate. The proportionality assumption did not hold for treatment effect, indicating that the
relationship between treatment and outcome differed over time. To
determine regions of the treatment period where the relative risk (RR)
of mortality between the two treatment groups was constant, a series of
Cox models with different cut-off points for time-dependent treatment
effects were fit.31 The final model chosen was the one
giving the largest partial likelihood. In this model, treatment was
considered as a time-dependent covariate with different coefficients for 0 to 18, >18 to 56, and >56 months after diagnosis. Adjusted probabilities of survival were then generated from the final Cox model
stratified on treatment and weighted averages of covariate values using
the sample proportion as the weight function.32 Adjusted
probabilities represent predicted outcomes for similar groups of
patients receiving each treatment. Estimates and 95% point-wise
confidence intervals for differences in survival were obtained by
computing estimates of survival for each treatment group separately
using the sample proportion as the weight function.
The second strategy to adjust for differences in baseline
characteristics was to analyze the impact of Sokal score on outcome in
the transplant and nontransplant cohorts and stratify comparisons of
treatment effects by Sokal risk group. Sokal score is a widely used
predictor of survival in conventionally treated CML.11-13 Comparisons in each stratum also used left-truncated Cox
regression with time-dependent treatment effects as described above.
Survival probabilities for each stratum were calculated using the
left-truncated Kaplan-Meier method.
| |
RESULTS |
Patient characteristics.
Table 1 compares characteristics of
patients receiving transplants with those of patients receiving
hydroxyurea or interferon. There were significant differences between
the cohorts in distributions of age, white blood cell counts, spleen
size, percent blasts in the blood, and year of diagnosis.
Table 2 shows results of analyses evaluating associations between patient characteristics and survival. Age, sex, spleen size, and year of diagnosis were significant predictors. Tests of interaction indicated a differential effect of
year of diagnosis in the transplant and nontransplant cohorts.
Transplant versus hydroxyurea or interferon.
The relative risk of death between the two groups changed with time
after diagnosis. Using Cox regression, we identified three discrete
time periods after diagnosis with relative risks of death for
transplant versus nontransplant treatment that differed: 18, >18 to
56, and >56 months. In the first 18 months after diagnosis, patients
in the transplant cohort had a higher risk of death than those
receiving hydroxyurea or interferon (RR, 5.85; P < .0001). Between 18 and 56 months, the risk of death was similar for patients in
the two cohorts (RR, 0.80; P = .38). After 56 months, patients still at risk in the transplant cohort had a lower subsequent risk of
death than those still at risk in the nontransplant cohort (RR, 0.16;
P < .0001). Figure 1 shows
adjusted probabilities of survival after diagnosis, calculated from the
Cox models and adjusting for time to transplant, age, sex, spleen size,
and year of diagnosis. The 7-year probability of survival (95%
confidence interval) was 58% (50% to 65%) with transplant and 32%
(22% to 41%) with hydroxyurea or interferon.
Figure 2 shows differences in survival
probabilities between the two cohorts (survival probability with
transplant minus survival probability with hydroxyurea or interferon)
over time with 95% point-wise confidence intervals for the
differences. Differences greater than zero indicate a survival
advantage for transplants at that point in the disease course; those
less than zero indicate a survival advantage for hydroxyurea or
interferon. The 95% confidence intervals that do not include zero
indicate significantly different outcomes. There was a statistically
significant survival advantage for hydroxyurea or interferon in the
first 2.5 years after diagnosis and a significant advantage for
transplants after 5.5 years; survivals were similar between 2.5 and 5.5 years.
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| Fig 1.
Adjusted probabilities (from Cox regression model) of
survival after diagnosis of CML in persons receiving HLA-identical
sibling bone marrow transplants or nontransplant therapy with
hydroxyurea or interferon.
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| Fig 2.
Differences (with 95% confidence interval) in adjusted
probabilities of survival after diagnosis of CML between patients
receiving HLA-identical sibling bone marrow transplants versus
hydroxyurea or interferon. Differences were calculated as probability
of survival with transplant minus probability of survival with
nontransplant treatment. A negative difference indicates a survival
disadvantage for transplant; a positive difference indicates an
advantage for transplants. A 95% confidence interval that does not
include zero indicates a statistically significant difference.
|
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Transplants within 1 year of diagnosis.
We repeated these analyses, restricting the transplant cohort to 331 patients transplanted 1 year after diagnosis. These patients have
earlier risks of transplant-related death, but better long-term
transplant outcomes.16,21 Again, the RR of death in the
transplant and nontransplant cohorts differed over time. In the first
18 months after diagnosis, the transplant cohort had a higher risk of
death than the nontransplant cohort (RR, 5.01; P < .0001).
Between 18 and 56 months after diagnosis, the RR was 0.42 (P = .008), and after 56 months, 0.08 (P = .0005). Figure 3 shows adjusted probabilities of
survival after diagnosis, calculated from the Cox models. The 7-year
probability of survival was 67% (56% to 75%) with a transplant
within 1 year of diagnosis and 30% (21% to 40%) with hydroxyurea or
interferon. Figure 4 shows differences in
survival probabilities between the two cohorts (transplant in the first
year - hydroxyurea or interferon) over time. There was a significant
survival advantage for chemotherapy in the first 1.8 years after
diagnosis and a significant advantage for transplant after 4.8 years.
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| Fig 3.
Adjusted probabilities (from Cox regression model) of
survival after diagnosis of CML in persons receiving HLA-identical
sibling bone marrow transplants within 1 year of diagnosis or
nontransplant therapy with hydroxyurea or interferon.
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| Fig 4.
Differences (with 95% confidence interval) in adjusted
probabilities of survival after diagnosis of CML between patients
receiving HLA-identical sibling bone marrow transplants within 1 year
of diagnosis versus hydroxyurea or interferon. Differences were
calculated as probability of survival with transplant in the first year
after diagnosis minus probability of survival with nontransplant
treatment. A negative difference indicates a survival disadvantage for
transplant; a positive difference indicates an advantage for
transplants. A 95% confidence interval that does not include zero
indicates a statistically significant difference.
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Association between Sokal score and outcome.
Sokal scores based on sex, spleen size, hematocrit level, platelet
count, and percent of blasts in the blood at diagnosis were assigned to
each patient in the two cohorts (Table 1). There were insufficient data
to assign a Sokal score in 211 transplant recipients; however, survival
of these patients was similar to the 337 transplant recipients assigned
a Sokal score (Fig 5A). Patients were
classified as low-, intermediate-, and high-risk as
published.11
Survival in the transplant cohort did not differ among the three risk
groups (Fig 5A). Transplant patients were not, therefore, stratified by
risk group in subsequent comparisons. In the nontransplant cohort,
low-risk patients had significantly longer survivals than intermediate-
and high-risk patients, who were similar to each other (Fig 5B).
Figure 6A shows probabilities of survival
after diagnosis for transplant recipients and low-risk patients
receiving hydroxyurea or interferon. The 7-year probability of survival
was 58% (52% to 64%) with transplant and 49% (34% to 63%) with
hydroxyurea or interferon. Although the curves cross at about 6 years,
there was not a statistically significant advantage for transplant
until 7.8 years after diagnosis. Figure 6B compares probabilities of survival for patients receiving transplant within 1 year of diagnosis with low-risk patients receiving hydroxyurea or interferon. The 7-year
probability of survival was 67% (60% to 73%) with transplant and
49% (34% to 63%) with hydroxyurea or interferon. The curves cross at
5 years, with a statistically significant advantage for transplants
after about 6.5 years from diagnosis.
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| Fig 6.
Adjusted probabilities of survival after diagnosis of CML
in low-risk persons receiving hydroxyurea or interferon versus persons receiving an HLA-identical sibling bone marrow transplant (A) at any
time after diagnosis or (B) within 1 year of diagnosis.
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Figure 7A shows probabilities of survival
after diagnosis for transplant recipients and intermediate- and
high-risk patients receiving hydroxyurea or interferon. The 7-year
probability of survival was 58% (52% to 64%) with transplant and
21% (12% to 31%) with hydroxyurea or interferon. The curves cross at
3.5 years, with a statistically significant advantage for transplant
after 4.7 years. Figure 7B compares probabilities of survival for
patients receiving transplant within 1 year of diagnosis with
intermediate- and high-risk patients receiving hydroxyurea or
interferon. The 7-year probability of survival was 67% (63% to 73%)
with transplant and 21% (12% to 31%) with hydroxyurea or interferon.
The curves cross at 2.2 years, with a statistically significant
advantage for transplants after about 4 years from diagnosis.
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| Fig 7.
Adjusted probabilities of survival after diagnosis of CML
in intermediate- and high-risk persons receiving hydroxyurea or interferon versus persons receiving an HLA-identical sibling bone marrow transplant (A) at any time after diagnosis or (B) within 1 year
of diagnosis.
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| |
DISCUSSION |
The best treatment for CML in chronic phase is controversial.
HLA-identical sibling bone marrow transplants can cure a substantial proportion of patients with CML, but have high treatment-related mortality. In contrast, hydroxyurea and interferon have little treatment-related mortality and prolong survival, but cure few, if any,
patients. This study confirms the initial survival disadvantage of
transplants, but also the later advantage; the latter becomes significant between 4 and 8 years after diagnosis, depending on when in
chronic phase transplants are performed and disease-related prognostic
factors. Importantly, the early survival disadvantage of transplants is
increased and the later survival advantage is decreased by delaying
transplants beyond the first year after diagnosis. This results from
increased treatment-related mortality and relapse with transplants done
later.16,21
The nontransplant cohort in this study included patients receiving
hydroxyurea or interferon, treatments with comparable survival in the
data set we used.8 This study set differs from other reports in which interferon treatment seemed to have better survival than hydroxyurea in nonrandomized and randomized settings. Differences between the German CML Study and these other studies were recently discussed in detail, including on-study criteria, risk profiles, drug
doses, and schedules and frequency of cytogenetic
testing.33-36 However, the 62-month median survival of the
hydroxyurea and interferon cohort in this study is similar to that
reported in other studies of interferon (55 to 72 months) so the
comparison between transplant and nontransplant therapy applies to most
patients with CML who are 55 years old. Additionally, the late
advantage of transplants is seen even when compared with nontransplant
therapy in low-risk patients in the German trial, who may be more
similar to those in other interferon trials. Whether a strategy of
early transplant for interferon nonresponders and delayed transplant
for interferon-responders would improve survival can only be determined
in a prospective trial.
The only type of transplant we studied were those from HLA-identical
siblings. Because treatment-related mortality after transplants from
other related and unrelated donors is substantially
higher,37-39 our conclusions may not apply to these
settings. It is likely that the time point after which alternative
donor transplants show better survival over hydroxyurea or interferon
is later.
This study confirms a long-term survival advantage for transplants and
further indicates that the survival advantage is greatest for persons
with intermediate- and high-risk prognostic features at diagnosis and
when transplants are performed early. It quantifies the trade-off
between early mortality and long-term leukemia-free survival with
transplants versus hydroxyurea or interferon for newly diagnosed CML
and provides data for counseling patients deciding between therapies.
| |
FOOTNOTES |
Submitted May 13, 1997;
accepted October 22, 1997.
Supported by Public Health Service Grant No. PO1-CA-40053 from the
National Cancer Institute, the National Institute of Allergy and
Infectious Diseases, and the National Heart, Lung and Blood Institute;
the German Bundesminister für Forschung und Technologie, Förderkennzeichen No. 01ZW044 and 01ZP9001;
grants from Alpha Therapeutic Corporation; Amgen, Inc; Anonymous; Astra
Pharmaceutical; Baxter Healthcare Corporation; Bayer Corporation;
Biogen; Blue Cross and Blue Shield Association; Lynde and Harry Bradley
Foundation; Bristol-Myers Squibb Company; Frank G. Brotz Family
Foundation; Cancer Center, Medical College of Wisconsin; CellPro, Inc;
Centeon; Center for Advanced Studies in Leukemia; Chimeric Therapies,
Inc; Charles E. Culpeper Foundation; Eleanor Naylor Dana Charitable Trust; Eppley Foundation for Research; Genentech, Inc; Glaxo
Wellcome Company; Hoechst Marion Roussel, Inc; Immunex Corporation;
Janssen Pharmaceutica; Kettering Family Foundation; Kirin Brewery
Company; Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation;
Herbert H. Kohl Charities, Inc; Eli Lilly Company Foundation; Nada and Herbert P. Mahler Charities; Milstein Family Foundation; Milwaukee Foundation/Elsa Schoeneich Research Fund; Samuel Roberts Noble Foundation; Ortho Biotech Corporation; John Oster Family Foundation; Elsa U. Pardee Foundation; Jane and Lloyd Pettit Foundation; Alirio Pfiffer Bone Marrow Transplant Support Association; Pfizer, Inc; Pharmacia and Upjohn; RGK Foundation; Sandoz Pharmaceuticals; Schering-Plough International; Walter Schroeder Foundation; Searle; Stackner Family Foundation; Starr Foundation; Joan and Jack Stein Charities; and Wyeth-Ayerst Laboratories.
Address reprint requests to Mary M. Horowitz, MD, MS, International
Bone Marrow Transplant Registry, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
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Abstract
Introduction
Abstract
