|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 2 (July 15), 1998:
pp. 394-401
Association Between Pretransplant Interferon- and Outcome After
Unrelated Donor Marrow Transplantation for Chronic Myelogenous
Leukemia in Chronic Phase
By
A. James Morton,
Ted Gooley,
John A. Hansen,
Frederick R. Appelbaum,
Barbara Bruemmer,
Jean W. Bjerke,
Reg Clift,
Paul J. Martin,
Effie W. Petersdorf,
Jean E. Sanders,
Rainer Storb,
Keith M. Sullivan,
Ann Woolfrey, and
Claudio Anasetti
From the Fred Hutchinson Cancer Research Center and the University of
Washington, Seattle, WA.
 |
ABSTRACT |
Treatment options for patients diagnosed with chronic myelogenous
leukemia (CML) in chronic phase (CP) who lack a suitable related donor
for marrow transplantation include hydroxyurea, interferon-
(IFN-), or transplantation from an unrelated donor (URD). Most
studies support the view that treatment with IFN- results in
prolonged survival compared with hydroxyurea therapy. Some patients are
offered URD transplantation as a second-line treatment; however, the
impact of pretransplant IFN- on the outcome of URD transplantation
is uncertain. To address this question, we evaluated the effect of
pretransplant IFN- therapy in 184 patients undergoing URD
transplantation for CML in CP at a single center. Of the 184 patients,
114 did not receive IFN-, whereas 22, 23, and 25 patients received
IFN- for, respectively, 1 to 5, 6 to 12, and more than 12 months
before transplant. Pretransplant IFN- therapy administered for  6
months was associated with an increased risk of severe (grades III-IV)
acute graft-versus-host disease (GVHD; relative risk [RR], 3.0; 95%
confidence interval [CI], 1.4 to 6.2; P = .004) and
mortality (RR, 2.1; 95% CI, 1.3 to 3.5; P = .003) relative
to less than 6 months or no IFN- therapy. Increased mortality
occurred between 100 and 365 days after transplant (P = .005), was limited to patients with severe acute GVHD, and was due to
chronic GVHD refractory to immunosuppressive therapy. Other variables
associated with mortality included HLA-DRB1 or DQB1 (but not HLA-A or
B) mismatched donors, age greater than 50 years, weight 110% of
ideal body weight, and the absence of cytomegalovirus (CMV) or fungal
prophylaxis. For patients treated with IFN- for less than 6 months
before transplant, who were  50 years of age, received a HLA-A, B,
DRB1, and DQB1 matched URD transplant, and received CMV and fungal
prophylaxis after transplant (n = 48), survival was 87% ± 5% at 5 years. These data provide a rationale for immediate transplantation in
preference to extended treatment with IFN- when the patient is 50
years of age and has an HLA-compatible unrelated volunteer donor.
| |
INTRODUCTION |
INTERFERON- (IFN-) has demonstrated
activity against chronic myelogenous leukemia (CML) and in most
randomized studies has offered benefit when instituted in early chronic
phase (CP).1-3 Cytogenetic responses (90% Philadelphia
chromosome-positive metaphases) occurred in 20% to 60% of patients,
becoming apparent after a median of 12 months of
treatment.4 Major cytogenetic responses (<35%
Philadelphia chromosome-positive metaphases) were achieved in 10% to
40% of patients,5-8 but molecular remissions, defined by
the absence of bcr-abl mRNA determined by polymerase chain reaction,
have rarely been described.9 Survival at 4 years was 90%
for patients achieving a major cytogenetic response after 12 months of
therapy with IFN-, 75% for patients achieving a partial cytogenetic
response (35% to 90% Philadelphia chromosome-positive metaphases),4 and 10% to 50% for those failing to achieve
a cytogenetic response.4,7 Median overall survival for
patients treated with IFN- alone varies from 5 to 6 years,1-3,6-8 compared with 3 to 4.5 years for hydroxyurea
or busulfan therapy.1-3,10,11 IFN- combined with
cytarabine has significantly improved cytogenetic response and survival
compared with IFN- alone.12
Allogeneic transplantation from an HLA-identical sibling donor offers
curative treatment for the majority of patients with CML in CP and a
5-year survival of 65% to 90%, depending on the interval from
diagnosis to transplant.13 Survival is similar after
transplantation in CP from a single locus HLA-A or B mismatched family
donor,14,15 whereas survival after transplantation from a
family member mismatched for a single HLA-DR antigen is worse (~50%
at 5 years).16 Only 35% of patients have an HLA-identical sibling donor, whereas a further 5% benefit from an extended family search.14 The recruitment of a large number of volunteer
donors has resulted in the availability of HLA-A, B, DR serologically matched unrelated donors (URD) for up to 75% of Caucasian patients in
the US National Marrow Donor Program and other registries worldwide. Recent studies have demonstrated the importance of donor matching for
DRB117 and DQB118 to reduce the risk of severe
acute graft-versus-host disease (GVHD) and donor matching for HLA-A, B
and C19 alleles to decrease the risk of graft failure.
Although early studies suggested inferior survival after URD compared
with sibling donor transplantation,20-24 better prevention
of cytomegalovirus (CMV) and fungal disease has substantially improved
outcome after URD transplantation.25
In the absence of an available sibling donor, physicians are often
faced with the choice of either treating patients in early CP with
IFN- or an URD transplant. Some investigators recommend an initial
12-month trial of IFN-, followed by an URD transplant if there is no
cytogenetic response to IFN- therapy.4 Previous reports
have evaluated the impact of IFN- on outcome of related donor
transplants26,27 with contradictory conclusions, reflecting differences in sample size and duration of IFN- therapy considered. Others point out the many unanswered questions in this
choice.28 The aim of this study was to assess the impact of
pretransplant therapy with IFN- on patient outcome after URD
transplantation.
| |
PATIENTS AND METHODS |
Study patients.
Between January 1988 and December 1994, 184 consecutive patients with
Philadelphia chromosome-positive CML in CP underwent URD
transplantation at the Fred Hutchinson Cancer Research Center. Treatment protocols were approved by the Institutional Review Board,
and written informed consent was obtained from all patients or their
legal guardians. The diagnosis and disease stage were confirmed
by hematological and cytogenetic evaluations performed within 14 days before admission for transplantation.29 The protocol exclusion criteria were age greater than 55 years; availability of a
HLA identical sibling or a one HLA-A, B or DR antigen incompatible family member; life expectancy severely limited by a disease other than
malignancy; cardiac disease requiring therapy; severe hepatic disease
including acute hepatitis; severe pulmonary disease including fibrosis;
creatinine greater than 2 times normal; leukoencephalopathy; brain irradiation with greater than 3,000 cGy; chest irradiation with
greater than 1,500 cGy; and positive human immunodeficiency virus (HIV)
serology.
Pretransplant treatment of CML.
Details of pretransplant treatment were obtained from patient history
and referring physician notes and flow sheets. Patients were classified
as IFN- recipients if they received therapy at doses of 9 × 106 U/m2/wk for at least 4 weeks. Treatment
intervals in which the patient received 9 × 106
U/m2/wk of IFN- were added, with the total duration of
pretransplant IFN- calculated to the nearest month. The time period
between the last dose of IFN- and the day of transplant was
calculated to the nearest month. Evaluation was made by chart review,
with the observer (A.J.M.) blinded to patient transplantation outcomes.
HLA typing and donor matching.
The analysis of HLA matching was based on typing for HLA-A and B
antigens by serological methods and typing of HLA-DRB1 and HLA-DQB1
alleles by DNA hybridization with sequence-specific oligonucleotide probes (SSOP). The population of 184 URD transplants included 129 HLA
matched pairs, 15 pairs mismatched for HLA-A (n = 7) or HLA-B (n = 8),
28 pairs mismatched for HLA-DRB1 (n = 12) or HLA-DQB1 (n = 16), and 12 pairs multiply mismatched, including 7 pairs mismatched for HLA-A or B
and HLA-DRB1 or DQB1 and 5 pairs mismatched for HLA-DRB1 and HLA-DQB1.
Transplant procedure and supportive care.
Conditioning for the 184 patients included cyclophosphamide (60 mg/kg
on each of 2 consecutive days) and fractionated total body irradiation
(TBI), with 80% of patients receiving 12 Gy and the others receiving
exposures varying from 13.2 to 15.75 Gy. All patients received
unmodified bone marrow and short course methotrexate in conjunction
with cyclosporine for GVHD prophylaxis, as previously
published.30 CMV-seronegative patients received blood
products from CMV-seronegative donors or leukocyte-depleted blood
products from CMV-seropositive donors. From November 16, 1990 until
August 5, 1991, CMV-seropositive patients were randomized to receive
ganciclovir or placebo at the time of engraftment to prevent CMV
disease.31,32 Subsequently, CMV-seropositive patients received ganciclovir at the time of engraftment. Since December 17, 1993, CMV-seronegative recipients have been treated with ganciclovir at
the first sign of CMV antigenemia as detected by fluorescence assay.
Patients receiving ganciclovir prophylaxis at engraftment or at the
first signs of CMV antigenemia and donor/recipient pairs in which both
were CMV seronegative were coded as receiving CMV prophylaxis. From
July 1990 to March 1992, patients were randomized to receive
fluconazole or placebo from the pretransplant period until day +75
posttransplant for fungal prophylaxis.33 After March 1992, all patients received fluconazole prophylaxis. Acyclovir was
administered to herpes simplex virus (HSV)-seropositive patients from
the pretransplant period until day +30 or discharge from the in-patient
unit. Fifty-nine patients received granulocyte-macrophage colony-stimulating factor (GM-CSF; 250 µg/m2/d)34,35 starting on day 0 as part of a
phase II or phase III trial, whereas 32 patients received granulocyte
colony-stimulating factor (G-CSF; 5 µg/kg/d) due to the absence of
neutrophil recovery at day +21.
Engraftment.
Patients were evaluable for graft failure when survival exceeded 28 days. Graft failure was defined by the following: (1) the absolute
neutrophil count did not surpass 500/µL at any time before second
transplant, relapse or death; (2) the absolute neutrophil count
decreased to less than 100/µL for at least three consecutive determinations at least 1 day apart after initial engraftment and did
not recover before relapse, second transplant, or death; or (3) absence
of donor T cells as documented by informative variable number tandem
repeat polymorphisms or by fluorescent in situ hybridization with a
Y-chromosome-specific probe in gender mismatched transplants. Platelet
independence was defined as the maintenance of an unsupported platelet
count exceeding 20,000/µL for 7 consecutive days.
GVHD.
Acute GVHD was assessed in patients surviving at least 14 days,
excluding patients with primary graft failure. Severity of acute GVHD
was graded by the Glucksberg criteria.36,37 Acute GVHD
grades II-IV was treated with prednisone 2 mg/kg for 14 days and then
tapered at 0.2 mg/kg every 5 days based on response.38 GVHD
response to prednisone therapy over the first 80 days posttransplant was graded as follows: sensitive, indicating GVHD improvement in one or
more organs without recurrence on the standard prednisone taper;
dependent, indicating GVHD recurring on prednisone taper before day 80;
and refractory, indicating GVHD progression after 7 days of prednisone
therapy or failure to improve in one or more organs after 14 days of
prednisone therapy. Patients were assessed for chronic GVHD between day
+80 and day +100 and graded by standard criteria.39
Relapse.
Relapse was defined by the persistence of any Philadelphia chromosomes
in metaphases after day +50 on two occasions at least 1 month apart and
after an attempt had been made to withdraw any immunosuppressive
therapy, or by the presence of frank hematological relapse. Censors
were defined as the day of last contact.
Statistical analysis.
Clinical endpoints included times to reach an absolute neutrophil count
greater than 500/µL and a self sustaining platelet count greater than
20,000/µL, graft failure, cumulative incidence of severe acute and
clinical extensive chronic GVHD, time to relapse, and survival.
Continuous covariates were compared by two-sided Wilcoxon rank-sum
tests, whereas differences between categorical variables were compared
by two-tailed Fisher's exact tests. Cumulative incidence40
estimates were used to measure the incidence of acute GVHD, clinical
extensive chronic GVHD, relapse, and transplant-related mortality.
Survival estimates were obtained by the method of Kaplan and Meier. The
 2 test was used to test for homogeneity of event
distribution across strata for events in which the duration of
follow-up exceeded the time to the last occurrence of complications
such as acute GVHD and clinical extensive chronic GVHD. The log-rank
test was used to test homogeneity of time to event distributions across strata in which follow-up of all subjects failed to exceed the last
time point that an event occurred in the study population, such as
relapse, nonrelapse mortality, and survival. The independence of
covariates with significance levels less than 10% in the univariable analyses was tested by logistic regression or by Cox regression. Covariates were added to the models in a stepwise fashion based on
their significance in univariable analyses. All covariates that added
information to the model at the .05 significance level as measured by
the likelihood ratio test were included in the final model.
Variables examined in all analyses included patient and donor age,
donor/patient gender match, donor parity, parous female donor/male recipient pairing, donor/patient CMV match, CMV and fungal prophylaxis, disease duration, pretransplant weight 110% of
ideal body weight, HLA match, pretransplant busulfan, pretransplant IFN-, time off IFN- pretransplant, uncorrected marrow cell dose, and TBI dose. Duration of therapy with IFN- before transplant was
initially categorized as none, 1 to 5 months, 6 to 12 months, and
greater than 12 months. After examination of the data, the duration of
therapy with IFN- before transplant was subsequently categorized as
0 to 5 and 6 months based on the similarity of outcome for 0 and 1 to
5 months of pretransplant IFN-, and the similarity of outcome for 6 to 12 and greater than 12 months of pretransplant IFN-. All
evaluations were based on data available as of December 31, 1996. Statistical analyses were performed using STATA statistical software
5.0 (Stata Corp, College Station, TX).
| |
RESULTS |
Patient characteristics.
Demographic and treatment characteristics are shown in
Table 1. One hundred fourteen patients
(62%) did not receive IFN-, whereas 70 (38%) were treated with
IFN- before transplantation for a median of 10 months (range, 1 to
64 months): 22 for 1 to 5 months, 23 for 6 to 12 months, and 25 for
greater than 12 months. IFN- was discontinued a median of 2 months
(range, 0 to 47 months) before URD transplantation for the following
reasons: lack of compliance with IFN (n = 21), patient or physician
preference for transplantation (n = 19), lack of cytogenetic remission
by 1 year of treatment (n = 16), or uncontrolled blood cell counts (n = 14). Five of 70 (7%) patients had developed chronic
toxicity attributed to IFN: psoriasis (n = 2), hypothyroidism (n = 2), or immune hemolytic anemia (n = 1). Based on the analysis of
the association between posttransplant survival and duration of
treatment with IFN- in 4 patient groups, classified as no IFN-
and IFN- for 1 to 5, 6 to 12, or greater than 12 months, subsequent
analyses of GVHD, relapse, and mortality considered the two categories of pretransplant therapy with IFN- for 0 to 5 months or 6 months. Patients receiving IFN- for 6 months were less likely to weigh 110% of their ideal body weight, had lower serum albumin, had lower
performance status score, had longer disease duration at the time of
transplant, and were transplanted in the later years of the study
period.
Engraftment.
Twelve patients (6.7%) failed to engraft or developed late graft
failure. There was no detectable association between pretransplant therapy with IFN- and graft failure (P = .8).
Median time to achieve an absolute neutrophil count greater than
500/µL was 22 days (range, 14 to 38 days) and platelet transfusion
independence was 22 days (range, 5 to 167 days). Neutrophil and
platelet recovery were not affected by pretransplant IFN-. Platelet
recovery was delayed by the presence of any HLA disparity between
patient and donor (P = .04) and was accelerated for patients
less than 20 years old (P = .02).
GVHD.
One hundred thirty-eight of 175 evaluable patients (79%) developed
grades II-IV acute GVHD and 69 of 175 evaluable patients (39%)
developed grades III-IV acute GVHD. Pretransplant treatment with
IFN- for 6 months was not associated with the development of
grades II-IV acute GVHD (79% v 79%, P = 1).
Conversely, the incidence of grades III-IV acute GVHD was 55% in
patients treated with IFN- for 6 months pretransplant, compared
with 34% for those treated for less than 6 months (P = .009;
Fig 1). Pretransplant patient performance
status score and serum albumin levels were not associated with
increased GVHD. By multivariate analysis, pretreatment with IFN- for
6 months (relative risk [RR], 3.0; 95% confidence interval [CI],
1.4 to 6.2; P = .004) and multiple HLA mismatches (RR, 6.1;
95% CI, 1.5 to 25; P = .01) were associated with an increased
risk of grades III-IV acute GVHD, whereas CMV prophylaxis was
protective (RR, 0.3; 95% CI, 0.2 to 0.7; P = .002). Restricting the multivariate analysis to HLA matched URD transplants, 6 months of IFN- remained predictive for the development of grades
III-IV acute GVHD (55% v 28%; RR, 3.4; 95% CI, 1.5 to 8.1; P = .005).
View larger version (11K):
[in this window]
[in a new window]
| Fig 1.
Cumulative incidence of grades III-IV acute GVHD after
unrelated donor transplant. (A) 0 to 5 months of IFN- pretransplant (cumulative incidence, 0.34; n = 128), (B) 6 months of IFN- pretransplant (cumulative incidence, 0.55; n = 47) (P = .01, by the 2 test).
|
|
Acute GVHD was prednisone-dependent or refractory in 50 of 175 (29%)
evaluable patients. Patients who had received pretransplant treatment
with IFN- for 6 months were at increased risk of
prednisone-dependent or refractory acute GVHD (43% v 23%,
P = .01). Multivariate analysis identified three factors
predictive for the development of prednisone-dependent or refractory
acute GVHD: multiple HLA mismatches (RR, 12; 95% CI, 2.9 to 52;
P = .001), CMV prophylaxis (RR, 0.3; 95% CI, 0.1 to 0.6;
P = .001), and 6 months of IFN- (RR, 2.9; 95% CI, 1.3 to
6.5; P = .008). When the analysis was restricted to HLA-matched URD transplants, 6 months of pretransplant IFN- remained
predictive for the development of prednisone-dependent or refractory
acute GVHD (37% v 18%; RR, 3.1; 95% CI, 1.2 to 8.1;
P = .02).
One hundred two of 142 (72%) patients who were engrafted and in
cytogenetic remission at day +100 developed clinical extensive chronic
GVHD. The incidence of clinical extensive chronic GVHD was similar for
patients treated pretransplant with IFN- for 0 to 5 months (76/104
[73%]) or 6 months (26/38 [68%]).
Relapse.
Eight of 172 (5%) durably engrafted patients developed cytogenetic
relapse of CML at a median of 311 days posttransplant (range, 56 to
1,090 days). Pretransplant therapy with IFN- was not associated with
the development of relapse posttransplant.
Survival.
One hundred six patients remain alive with an actuarial 5-year survival
of 55% ± 4% and a median follow-up of 1,474 days (range, 609 to
3,028 days). Survival was significantly worse for those patients who
had received pretransplant IFN- for 6 months (43% ± 8%) than
for those treated with IFN- for 0 to 5 months (60% ± 5%;
Fig 2; P = .05). There was no
difference in survival for patients treated with IFN- for 1 to 5 months pretransplant (67% ± 10%) and those not treated with
IFN- (59% ± 5%; P = .7). By multivariate analysis,
IFN- therapy for 6 months pretransplant was independently
associated with an increased risk of posttransplant death (RR, 2.1;
95% CI, 1.3 to 3.5; P = .003). Pretransplant patient performance status score and serum albumin levels were not associated with decreased survival. In the multivariable model, time from diagnosis to transplantation did not achieve significance, did not
significantly alter the log likelihood ratio
(Table 2), and did not change the
regression coefficient or confidence interval associated with therapy
with IFN- for 6 months (not shown). There was no apparent effect
of time from diagnosis to transplant for the 114 patients who had not
received treatment with IFN- pretransplant. In relation to time
interval from diagnosis to transplant 1 year, the relative risk was
0.9 for the interval greater than 1 to 3 years (P = .9), and
the relative risk was 1.0 (P = .9) for the interval greater
than 3 years. Treatment with IFN- for 6 months before transplant
remained associated with increased mortality (RR, 2.0; 95% CI, 1.1 to
3.7; P = .03) when the analysis was restricted to HLA-matched
URD transplants. The association between pretransplant IFN- for 6
months and survival was independent of the time interval between the
last treatment with IFN- and transplantation (P = .4).
View larger version (11K):
[in this window]
[in a new window]
| Fig 2.
Product-limit estimate of survival categorized by
duration of pretransplant IFN-. (A) 0 to 5 months of IFN-
pretransplant, 5-year survival 60% ± 5%, (n = 136). (B) 6
months of IFN- pretransplant, 5-year survival 43% ± 8% (n = 48) (P = .05, by the log-rank test).
|
|
The cumulative incidence of transplant-related mortality was
significantly higher for those patients receiving IFN- for 6 months than those receiving IFN- for 0 to 5 months before transplant (56% v 38% at 5 years; P = .05). Mortality from
causes other than relapse during the first 100 days was 15% in
patients who had received IFN- for 6 months before transplant and
13% in patients who had received IFN- for 0 to 5 months (P = .7). Increased nonrelapse mortality occurred between day 100 and day
365 posttransplant in patients who had received IFN- 6 months
before transplant (37% v 15%, P = .003;
Fig 3) and was limited to those patients who developed prednisone-dependent or refractory acute GVHD
(Table 3). The difference between the two
patient groups was due to deaths from refractory clinical extensive
chronic GVHD with or without infection. There was no difference in the
rates of subsequent nonrelapse mortality for patients alive at 1 year
posttransplant. Nonrelapse mortality between 1 and 5 years was 16% in
patients who had received pretransplant IFN- for 0 to 5 months and
18% in patients who had received IFN- for 6 months (P = .8).
View larger version (11K):
[in this window]
[in a new window]
| Fig 3.
Cumulative incidence of nonrelapse mortality
categorized by duration of therapy with IFN- pretransplant. (A) 0 to
5 months of IFN- pretransplant, 0.38 (n = 136). (B) 6 months of
IFN- pretransplant, 0.56 (n = 48) (P = .05, by the
log-rank test).
|
|
View this table:
[in this window]
[in a new window]
|
Table 3.
Association Between Pretransplant IFN- for 6
Months and Mortality From Day 100 to Day 365 Posttransplant, Stratified According to Severity of Acute GVHD
|
|
For those patients treated with IFN- for 0 to 5 months
pretransplant, who were 50 years of age, received a HLA-A, B, DRB1, DQB1 matched URD transplant for CML in CP, and received CMV and fungal
prophylaxis after transplantation (n = 48), the cumulative incidence of grades III-IV acute GVHD was 21%, the estimated 5-year survival was 87% ± 5%, and the 5-year survival free of
cytogenetic relapse was 74% ± 6% (Fig
4).
View larger version (15K):
[in this window]
[in a new window]
| Fig 4.
Five-year survival, survival free from cytogenetic
relapse, and cytogenetic relapse after HLA-A, B, DRB1 and DQB1-matched unrelated donor transplantation for patients 50 years old, who received IFN- for 0 to 5 months before transplant, and received CMV
and fungal prophylaxis after transplant (n = 48). (A) 5-year survival
87% ± 5%. (B) 5-year survival free from cytogenetic relapse 74% ± 6%. (C) 5-year cumulative incidence of relapse 13%. Four of 6 relapses followed graft failure and autologous reconstitution. The
median follow-up of surviving patients is 1,128 days.
|
|
| |
DISCUSSION |
The aim of this study was to evaluate the impact of pretransplant
therapy with IFN- on the outcome of marrow transplantation from URDs
for CML in CP. After adjusting for other pretransplant risk factors
previously shown to be associated with survival,25 we found
that IFN- administered for 6 months was associated with lower
survival. This was due to an increase in the incidence of severe acute
GVHD that was difficult to control with prednisone therapy. Increased
mortality occurred between day 100 and day 365 and was due to
complications of chronic GVHD that was refractory to treatment.
The effect of treatment with IFN- for 6 months on the development
of severe acute GVHD and survival was independent of the time interval
from the last treatment with IFN- to the transplant. Thus,
pretransplant IFN- therapy has a long-lasting effect that predisposes to the development of severe acute GVHD after
transplantation. Interferons are known to enhance HLA class I gene
expression and therefore the presentation of major and minor
histocompatibility antigens,41,42 which in turn could lead
to more severe GVHD reactions. However, the effect of IFN- on HLA
gene expression is expected to be transient and is unlikely to explain
the long-lasting effect of IFN after its discontinuation. Reasons for
the long-lasting effect of IFN- after its discontinuation are not
clear. Prolonged treatment with IFN- results in chronic toxicity,
including depression, fatigue, anorexia, and weight loss.43
We found that patients treated with IFN- for 6 or more months had
lower body weight, lower serum albumin levels, and lower performance
status scores than patients treated with IFN- for less than 6 months. It is conceivable that the weakened physical condition from
chronic IFN- toxicity contributed an increased risk of
transplant-related complications, including death.
In a previous analysis of URD transplantation for CML at our
institution, we found that prolonged time from diagnosis to
transplantation was an adverse prognostic factor for
survival.25 The current study has also considered the
impact of pretransplant treatment with IFN-. Because time from
diagnosis and length of treatment with IFN- are correlated, it can
be difficult to determine whether these variables act independently on
survival or interact in some way. When time from diagnosis was added to
the multivariable model already considering the variable IFN- for
6 months, the likelihood ratio test indicated that the model was only
marginally improved (P = .06). On the other hand, the addition
of the variable IFN- for 6 months significantly improved the model
that was already considering the effect of time from diagnosis
(P = .007). Furthermore, there was no association between time
from diagnosis and survival for the 114 patients who were not treated
with IFN- pretransplant. Therefore, the association between
pretransplant administration of IFN- and posttransplant outcome is
independent of the effect of time from diagnosis to transplant. In
addition, our study suggests that the association between prolonged
interval from diagnosis to transplant and poor survival may be due to
pretransplant therapy with IFN-.
Two previous reports have evaluated the impact of pretransplant IFN-
on the posttransplant course. A study from the M.D.Anderson Cancer
Center26 reviewed 77 patients undergoing HLA-identical sibling transplantation, including 41 patients in CP, 23 who were treated with IFN- for 9 to 343 weeks before transplant. The study found no statistically detectable differences in the rate of grades II-IV acute GVHD or 3-year survival. The investigators noted a suggestion towards improved survival for patients who had not been
treated with IFN- before transplant (66% ± 13% v 56% ± 10%), with an initial separation of the survival curves during
the first 12 months after transplant. Beelen et al27
included 133 patients with CML in CP who received transplants from
HLA-identical siblings (n = 103) or alternative donors (n = 30).
Pretransplant IFN- was categorized as 12 months or greater than 12 months based on the median time to observe a cytogenetic response. No
difference was seen in the incidence of grades II-IV acute GVHD, but
survival was reduced in patients treated with IFN- for greater than
12 months. The investigators noted an increased risk of death from infectious causes after day 120 for patients treated with IFN- for
greater than 12 months, similar to our results. They also noted a high
rate of graft failure after alternate donor transplantation if the
recipients were treated with IFN- before
transplantation.27 We were unable to confirm an association
between patient treatment with IFN- before transplant and marrow
graft dysfunction.
In keeping with previous reports, we found that a single mismatch for
HLA-A or B did not increase the risk of grades III-IV acute GVHD or
decrease survival as compared with fully HLA-matched URD
transplants.44 These patients were all less than 36 years of age and 14 of 15 were mismatched within cross-reactive antigen groups. In contrast, a single HLA-DRB1 or HLA-DQB1 mismatch was associated with worse outcome. Poorest survival followed multiple mismatched transplants. These results confirm previous observations regarding the importance of allele matching for HLA-DRB1 and DQB1 in
URD transplantation.17,18
The survival of patients treated with IFN- for 0 to 5 months before
transplant, who were 50 years of age or less, received a HLA-matched
URD transplant, and received CMV and fungal prophylaxis was 87% ± 5% at 5 years, similar to survival after HLA-identical sibling
transplantation and comparable to the survival described for patients
achieving a major cytogenetic response to treatment with IFN-. With
no relapses observed after 3 years, it is likely that most of the
patients alive 5 years after an URD transplant are cured of CML. The
data presented here provide a rationale for immediate transplantation
in preference to prolonged treatment with IFN- when the patient is
50 years of age or less and has available a HLA-matched or HLA-A or B
mismatched URD.
| |
FOOTNOTES |
Submitted December 29, 1997;
accepted April 29, 1998.
Supported in part by National Institutes of Health Grants No. CA 15704, CA 18029, CA 18221, and A1 33484. A.J.M. is the recipient of a grant
from the Leukemia Foundation of Queensland, Australia.
Address correspondence to Claudio Anasetti, MD, Clinical Research
Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N,
Seattle, WA 98109.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
REFERENCES |
1.
Italian Cooperative Group on Chronic Myeloid Leukemia:
Interferon -2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia.
N Engl J Med
330:820,
1994[Abstract/Free Full Text]
2.
German CML Study Group:
Randomized comparison of interferon- with busulfan and hydroxyurea in chronic myelogenous leukemia.
Blood
84:4064,
1994[Abstract/Free Full Text]
3.
Allan NC Richards SM,
Shepherd PC:
UK Medical Research Council randomized, multicenter trial of interferon- for chronic myeloid leukemia: Improved survival irrespective of cytogenetic response.
Lancet
345:1392,
1995[Medline]
[Order article via Infotrieve]
4.
Kantarjian HM,
Smith TL,
O'Brien S,
Beran M,
Pierce S,
Talpaz M:
Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon- therapy.
Ann Intern Med
122:254,
1995[Abstract/Free Full Text]
5.
Talpaz M,
Kantarjian HM,
McCredie K,
Trujillo JM,
Keating MJ,
Gutterman JU:
Hematologic remission and cytogenetic improvement induced by recombinant human interferonA in chronic myelogenous leukemia.
N Engl J Med
314:1065,
1986[Abstract]
6.
Talpaz M,
Kantarjian H,
Kurzrock R,
Trujillo JM,
Gutterman JU:
Interferon-alpha produces sustained cytogenetic responses in chronic myelogenous leukemia.
Ann Intern Med
114:532,
1991
7.
Kloke O,
Niederle N,
Qiu JY,
Wandl U,
Moritz T,
Nagel-Hiemke M,
Hawig I,
Opalka B,
Seeber S,
Becher R:
Impact of interferon alpha-induced cytogenetic improvement on survival in chronic myelogenous leukemia.
Br J Haematol
83:399,
1993[Medline]
[Order article via Infotrieve]
8.
Ozer H,
George SL,
Schiffer CA,
Rao K,
Rao PN,
Wurster-Hill DH,
Arthur DD,
Powell B,
Gottlieb A,
Peterson BA,
Rai K,
Testa JR,
LeBeau M,
Tantravachi R,
Bloomfield C:
Prolonged subcutaneous administration of recombinant 2b interferon in patients with previously untreated Philadelphia chromosome-positive chronic-phase chronic myelogenous leukemia: Effect on remission duration and survival: Cancer and Leukemia Group B Study 8583.
Blood
82:2975,
1993[Abstract/Free Full Text]
9.
Opalka B,
Wandl UB,
Becher R,
Kloke O,
Nagel-Hiemke M,
Moritz T,
Beer U,
Seeber S,
Niederle N:
Minimal residual disease in patients with chronic myelogenous leukemia undergoing long-term treatment with recombinant interferon -2b alone or in combination with interferon  .
Blood
78:2188,
1991[Abstract/Free Full Text]
10.
Sokal JE,
Cox EB,
Baccarani M,
Tura S,
Gomez G,
Robertson J,
Tso CY,
Braun TJ,
Clarkson BD,
Cervantes F,
Rozman C,
the Italian Cooperative CML Study Group:
Prognostic discrimination in good risk chronic granulocytic leukemia.
Blood
63:789,
1984[Abstract/Free Full Text]
11.
Kantarjian HM,
Keating MJ,
Smith TL,
Talpaz M,
McCredie KB:
Proposal for a simple synthesis prognostic staging system in chronic myelogenous leukemia.
Am J Med
68:1,
1990
12.
Guilhot F,
Chastang C,
Michallet M,
Guerci A,
Harousseau J,
Maloisel F,
Bouabdallah R,
Guyotat D,
Cheron N,
Nicolini F,
Abgrall J,
Tanzer J:
Interferon alpha-2B combined with cytarabine versus interferon alone in chronic myelogenous leukemia.
N Engl J Med
337:223,
1997[Abstract/Free Full Text]
13.
Appelbaum FR,
Clift RG,
Radich J,
Anasetti C,
Buckner CD:
Bone marrow transplantation for chronic myelogenous leukemia.
Semin Oncol
22:405,
1995[Medline]
[Order article via Infotrieve]
14.
Beatty PG,
Clift RA,
Mickelson EM,
Nisperos BB,
Flournoy N,
Martin PJ,
Sanders JE,
Stewart P,
Buckner CD,
Storb R,
Thomas ED,
Henson JA:
Marrow transplantation from related donors other than HLA-identical donors.
N Engl J Med
313:765,
1985[Abstract]
15.
Anasetti C,
Beatty PG,
Storb R,
Martin PJ,
Mori M,
Sanders JE,
Thomas ED,
Hansen JA:
Effect of HLA incompatibility on graft-versus-host disease, relapse, and survival after bone marrow transplantation for patients with leukemia or lymphoma.
Human Immunol
29:79,
1990[Medline]
[Order article via Infotrieve]
16.
Anasetti C,
Etzioni R,
Petersdorf EW,
Martin PJ,
Hansen JA:
Marrow transplantation from unrelated volunteer donors.
Annu Rev Med
46:169,
1995[Medline]
[Order article via Infotrieve]
17.
Petersdorf EW,
Longton GM,
Anasetti C,
Martin PJ,
Mickelson EM,
Smith AG,
Hansen J:
The significance of HLA-DRB1 matching on clinical outcome after HLA-A, B, DR identical unrelated donor marrow transplantation.
Blood
86:1606,
1995[Abstract/Free Full Text]
18.
Petersdorf EW,
Longton GM,
Anasetti C,
Mickelson EM,
Smith A,
Martin PJ,
Hansen JA:
Definition of HLA-DQ as a transplantation antigen.
Proc Natl Acad Sci USA
93:15358,
1996[Abstract/Free Full Text]
19.
Petersdorf EW,
Longton GM,
Anasetti C,
Mickelson EM,
McKinney SK,
Smith A,
Martin PJ,
Hansen JA:
Association of HLA-C disparity with graft failure after marrow transplantation from unrelated donors.
Blood
89:1818,
1997[Abstract/Free Full Text]
20.
Beatty PG,
Ash R,
Hows JM,
McGlave PB:
The use of unrelated bone marrow donors in the treatment of patients with chronic myelogenous leukemia: Experience of four marrow transplant centers.
Bone Marrow Transplant
4:287,
1989[Medline]
[Order article via Infotrieve]
21.
McGlave PB,
Beatty PG,
Ash R,
Hows JM:
Therapy for chronic myelogenous leukemia with unrelated donor bone marrow transplantation: Results in 102 cases.
Blood
75:1728,
1990[Abstract/Free Full Text]
22.
McGlave P,
Bartsch G,
Anasetti C,
Ash R,
Beatty P,
Gajewski J,
Kernan N:
Unrelated donor marrow transplantation for chronic myelogenous leukemia: Initial experience of the National Marrow Donor Program.
Blood
81:543,
1993[Abstract/Free Full Text]
23.
Marks DI,
Cullis J,
Ward KN,
Lacey S,
Szydlo R,
Hughes T,
Schwarer AP,
Lutz E,
Barrett AJ,
Hows JM,
Batchelor JR,
Goldman JM:
Allogeneic bone marrow transplantation for chronic myeloid leukemia using sibling and volunteer unrelated donors.
Ann Intern Med
119:207,
1993[Abstract/Free Full Text]
24.
Drobyski WR,
Ash RC,
Casper JT,
McAuliffe T,
Horowitz M,
Lawton C,
Keever C,
Baxter-Lowe LA,
Camitta B,
Garbrecht F,
Pietryga D,
Hansen R,
Chitambar CR,
Anderson T,
Flomenberg N:
Effect of T-cell depletion as graft-versus-host disease prophylaxis on engraftment, relapse, and disease free survival in unrelated marrow transplantation for chronic myelogenous leukemia.
Blood
83:1980,
1994[Abstract/Free Full Text]
25.
Hansen J,
Gooley T,
Martin PJ,
Appelbaum F,
Chauncey TR,
Clift RA,
Petersdorf EW,
Radich J,
Sanders JE,
Storb R,
Sullivan KM,
Anasetti C:
Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia.
N Engl J Med
338:962,
1998[Abstract/Free Full Text]
26.
Giralt SA,
Kantarjian HM,
Talpaz M,
Rios MB,
Giglio AD,
Andersson BS,
Przepiorka D,
Diesseroth AB,
Champlin RE:
Effect of prior interferon alfa therapy on the outcome of allogeneic bone marrow transplantation for chronic myelogenous leukemia.
J Clin Oncol
11:1055,
1993[Abstract/Free Full Text]
27.
Beelen DW,
Graeven U,
Elmaagacli AH,
Niederle N,
Kloke O,
Opalka B,
Schaefer UW:
Prolonged administration of interferon- in patients with chronic phase chronic myelogenous leukemia before allogeneic bone marrow transplantation may adversely affect transplant outcome.
Blood
85:2981,
1995[Abstract/Free Full Text]
28.
Goldman J:
Optimizing therapy for chronic myeloid leukemia.
N Engl J Med
337:270,
1997[Free Full Text]
29.
Thomas ED,
Clift RA,
Fefer A,
Appelbaum FR,
Beatty P,
Bensinger WI,
Buckner CD,
Cheever MA,
Deeg HJ,
Doney K,
Flournoy N,
Greenberg P,
Hansen JA,
Martin P,
McGuffin R,
Ramberg R,
Sanders JE,
Singer J,
Stewart P,
Storb R,
Sullivan K,
Weiden PL,
Witherspoon R:
Marrow transplantation for the treatment of chronic myelogenous leukemia.
Ann Intern Med
104:155,
1986
30.
Storb R,
Deeg HL,
Whitehead J,
Appelbaum FR,
Beatty P,
Bensinger W,
Buckner CD,
Clift RA,
Doney KC,
Farewell V,
Hansen JA,
Hill R,
Strout P,
Sullivan KW,
Witherspoon RP,
Yee G,
Thomas ED:
Methotrexate and cyclosporinee compared with cyclosporinee alone for prophylaxis of acute graft-versus-host disease after bone marrow transplantation for leukemia.
N Engl J Med
314:729,
1986[Abstract]
31.
Goodrich JM,
Bowden RA,
Fisher L,
Keller C,
Schoch G,
Meyers JD:
Ganciclovir prophylaxis to prevent cytomegalovirus disease after allogeneic marrow transplant.
Ann Intern Med
118:173,
1993[Abstract/Free Full Text]
32.
Goodrich JM,
Boeckh M,
Bowden R:
Strategies for the prevention of cytomegalovirus disease after marrow transplantation.
Clin Infect Dis
19:287,
1994[Medline]
[Order article via Infotrieve]
33.
Slavin MA,
Osborne B,
Adams R,
Levenstein MJ,
Schoch G,
Feldman AR,
Meyers JD,
Bowden RA:
Efficacy and safety of fluconazole for fungal infections after marrow transplant A prospective, randomized, double-blind study.
J Infect Dis
171:1545,
1995[Medline]
[Order article via Infotrieve]
34. (abstr, suppl 1)
Anasetti C,
Anderson G,
Appelbaum F,
Buckner D,
Martin P,
Nemunaitis J,
Singer J,
Storb R,
Sullivan K,
Thomas ED,
Hansen J:
Phase III study of rh GM-CSF in allogeneic marrow transplantation from unrelated donors.
Blood
82:1799a,
1993
35.
Nemunaitis J,
Anasetti C,
Buckner CD,
Appelbaum FR,
Shannon-Daucy K,
Hansen J,
Dinger JW:
Long-term follow-up of 103 patients who received recombinant human granulocyte-macrophage colony stimulating factor after unrelated donor bone marrow transplantation.
Blood
84:865,
1994
36.
Glucksberg H,
Storb R,
Fefer A,
Buckner CD,
Neiman PE,
Clift RA,
Lerner KG,
Thomas ED:
Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors.
Transplantation
18:295,
1974[Medline]
[Order article via Infotrieve]
37.
Thomas ED,
Storb R,
Clift RA,
Fefer A,
Johnson JL,
Neiman PE,
Lerner KG,
Glucksberg H,
Buckner CD:
Bone-marrow transplantation (second of two parts).
N Engl J Med
292:895,
1975[Medline]
[Order article via Infotrieve]
38.
Doney KC,
Weiden PL,
Storb R,
Thomas ED:
Treatment of graft-versus-host disease in human allogeneic marrow graft recipients: A randomized trial comparing antithymocyte globulin and corticosteroids.
Am J Hematol
11:1,
1981[Medline]
[Order article via Infotrieve]
39.
Sullivan KM,
Shulman HM,
Storb R,
Weiden PL,
Witherspoon RP,
McDonald GB,
Schubert MM,
Atkinson K,
Thomas ED:
Chronic graft versus host disease in 52 patients. Adverse natural course and successful treatment with combination immunosuppression.
Blood
57:267,
1981[Abstract/Free Full Text]
40.
Pepe M,
Longton G,
Pettinger M,
Moro M,
Fisher L,
Storb R:
Summarizing data on survival, relapse and chronic graft-versus-host disease after bone marrow transplantation: motivation for and description of new methods.
Br J Haematol
83:602,
1993[Medline]
[Order article via Infotrieve]
41.
Baron S,
Tyring S,
Fleischmann W,
Coppenhaver DH,
Niesel DW,
Klimpel GR,
Stanton GJ,
Hughes TK:
The interferons. Mechanism of action and clinical applications.
JAMA
266:1375,
1991[Abstract/Free Full Text]
42.
Schmidt H,
Kellermann-Kegreiss E,
Steiert I,
Walz J,
Zinser R,
Muller CA:
Differential regulation of human leukocyte antigen class I genes by interferon in vivo and in vitro.
J Immunother
14:169,
1993
43.
Quesada JR,
Talpaz M,
Rios A,
Kurzrock R,
Gutterman JU:
Clinical toxicity of interferons in cancer patients: a review.
J Clin Oncol
4:234,
1986[Abstract]
44. (suppl 1)
Hansen J,
Petersdorf E,
Yoon Choo S,
Martin PJ,
Anasetti C:
Marrow transplantation from HLA partially matched relatives and unrelated donors.
Bone Marrow Transplant
15:128,
1995
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
A. Quintas-Cardama and J. E. Cortes
Chronic Myeloid Leukemia: Diagnosis and Treatment
Mayo Clin. Proc.,
July 1, 2006;
81(7):
973 - 988.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Cwynarski, I. A. G. Roberts, S. Iacobelli, A. van Biezen, R. Brand, A. Devergie, J. M. Vossen, M. Aljurf, W. Arcese, F. Locatelli, et al.
Stem cell transplantation for chronic myeloid leukemia in children
Blood,
August 15, 2003;
102(4):
1224 - 1231.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. V. Melo, T. P. Hughes, and J. F. Apperley
Chronic Myeloid Leukemia
Hematology,
January 1, 2003;
2003(1):
132 - 152.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. M. Kantarjian, M. Talpaz, S. O'Brien, T. L. Smith, F. J. Giles, S. Faderl, D. A. Thomas, G. Garcia-Manero, J.-P. J. Issa, M. Andreeff, et al.
Imatinib Mesylate for Philadelphia Chromosome-positive, Chronic-Phase Myeloid Leukemia after Failure of Interferon-{alpha}: Follow-Up Results
Clin. Cancer Res.,
July 1, 2002;
8(7):
2177 - 2187.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. G. Savage and K. H. Antman
Imatinib Mesylate -- A New Oral Targeted Therapy
N. Engl. J. Med.,
February 28, 2002;
346(9):
683 - 693.
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. J. Druker, S. G. O'Brien, J. Cortes, and J. Radich
Chronic Myelogenous Leukemia
Hematology,
January 1, 2002;
2002(1):
111 - 135.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
S. J. Lee, J. P. Klein, C. Anasetti, J. H. Antin, F. R. Loberiza, B. J. Bolwell, C. F. LeMaistre, M. R. Litzow, D. Marks, E. K. Waller, et al.
The effect of pretransplant interferon therapy on the outcome of unrelated donor hematopoietic stem cell transplantation for patients with chronic myelogenous leukemia in first chronic phase
Blood,
December 1, 2001;
98(12):
3205 - 3211.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Lenssen, B. Bruemmer, S. N. Aker, and G. B. McDonald
Nutrient Support in Hematopoietic Cell Transplantation
JPEN J Parenter Enteral Nutr,
July 1, 2001;
25(4):
219 - 228.
[Abstract]
[PDF]
|
|
|
|
|
|
|
E. Jonasch and F. G. Haluska
Interferon in Oncological Practice: Review of Interferon Biology, Clinical Applications, and Toxicities
Oncologist,
February 1, 2001;
6(1):
34 - 55.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
P. B. McGlave, X. O. Shu, W. Wen, C. Anasetti, A. Nademanee, R. Champlin, J. H. Antin, N. A. Kernan, R. King, and D. J. Weisdorf
Unrelated donor marrow transplantation for chronic myelogenous leukemia: 9 years' experience of the National Marrow Donor Program
Blood,
April 1, 2000;
95(7):
2219 - 2225.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Giralt, R. Szydlo, J. M. Goldman, J. Veum-Stone, J. C. Biggs, R. H. Herzig, J. P. Klein, P. B. McGlave, G. Schiller, R. P. Gale, et al.
Effect of short-term interferon therapy on the outcome of subsequent HLA-identical sibling bone marrow transplantation for chronic myelogenous leukemia: an analysis from the International Bone Marrow Transplant Registry
Blood,
January 15, 2000;
95(2):
410 - 415.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Hehlmann, A. Hochhaus, H.-J. Kolb, J. Hasford, A. Gratwohl, H. Heimpel, W. Siegert, J. Finke, G. Ehninger, E. Holler, et al.
Interferon-alpha Before Allogeneic Bone Marrow Transplantation in Chronic Myelogenous Leukemia Does Not Affect Outcome Adversely, Provided It Is Discontinued at Least 90 Days Before the Procedure
Blood,
December 1, 1999;
94(11):
3668 - 3677.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. T. Silver, S. H. Woolf, R. Hehlmann, F. R. Appelbaum, J. Anderson, C. Bennett, J. M. Goldman, F. Guilhot, H. M. Kantarjian, A. E. Lichtin, et al.
An Evidence-Based Analysis of the Effect of Busulfan, Hydroxyurea, Interferon, and Allogeneic Bone Marrow Transplantation in Treating the Chronic Phase of Chronic Myeloid Leukemia: Developed for the American Society of Hematology
Blood,
September 1, 1999;
94(5):
1517 - 1536.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Faderl, M. Talpaz, Z. Estrov, and H. M. Kantarjian
Chronic Myelogenous Leukemia: Biology and Therapy
Ann Intern Med,
August 3, 1999;
131(3):
207 - 219.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. W. Beelen, A. H. Elmaagacli, and Prof. U. W. Schaefer
The Adverse Influence of Pretransplant Interferon-alpha (IFN-alpha ) on Transplant Outcome After Marrow Transplantation for Chronic Phase Chronic Myelogenous Leukemia Increases With the Duration of IFN-alpha Exposure
Blood,
March 1, 1999;
93(5):
1779 - 1781.
[Full Text]
[PDF]
|
|
|
|
|
|
|
F.X. Mahon, C. Faberes, S. Pueyo, P. Cony-Makhoul, R. Salmi, J.M. Boiron, G. Marit, C. Bilhou-Nabera, A. Carrere, M. Montastruc, et al.
Response at Three Months Is a Good Predictive Factor for Newly Diagnosed Chronic Myeloid Leukemia Patients Treated by Recombinant Interferon-alpha
Blood,
December 1, 1998;
92(11):
4059 - 4065.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. W. Petersdorf, T. A. Gooley, C. Anasetti, P. J. Martin, A. G. Smith, E. M. Mickelson, A. E. Woolfrey, and J. A. Hansen
Optimizing Outcome After Unrelated Marrow Transplantation by Comprehensive Matching of HLA Class I and II Alleles in the Donor and Recipient
Blood,
November 15, 1998;
92(10):
3515 - 3520.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Abstract
Introduction
Abstract