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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Service d'Hématologie Greffe de Moelle
and Département de Bio-Informatique, Hôpital Saint Louis,
Paris, France; Fred Hutchinson Cancer Research Center, Seattle, WA;
Service de Greffe de Moelle, Institut Paoli Calmette, Marseille,
France; Center for Allogeneic Stem Cell Transplantation, Huddinge
University Hospital, Stockholm, Sweden; Service d'hematologie,
Hôpital Edouard Heriot, Lyon, France; and Department of Medicine,
Helsinki University Central Hospital, Finland.
In the early 1990s, 4 randomized studies compared conditioning
regimens before transplantation for leukemia with either
cyclophosphamide (CY) and total-body irradiation (TBI), or busulfan
(Bu) and CY. This study analyzed the long-term outcomes for 316 patients with chronic myeloid leukemia (CML) and 172 patients with
acute myeloid leukemia (AML) who participated in these 4 trials, now
with a mean follow-up of more than 7 years. Among patients with CML, no
statistically significant difference in survival or disease-free survival emerged from testing the 2 regimens. The projected 10-year survival estimates were 65% and 63% with Bu-CY versus CY-TBI, respectively. Among patients with AML, the projected 10-year survival estimates were 51% and 63% (95% CI, 52%-74%) with Bu-CY versus CY-TBI, respectively. At last follow-up, most surviving patients had
unimpaired health and had returned to work, regardless of the
conditioning regimen. Late complications were analyzed after adjustment
for patient age and for acute and chronic graft-versus-host disease
(GVHD). CML patients who received CY-TBI had an increased risk of
cataract formation, and patients treated with Bu-CY had an increased
risk of irreversible alopecia. Chronic GVHD was the primary risk factor
for late pulmonary disease and avascular osteonecrosis. Thus, Bu-CY and
CY-TBI provided similar probabilities of cure for patients with CML. In
patients with AML, a nonsignificant 10% lower survival rate was
observed after Bu-CY. Late complications occurred equally after both
conditioning regimens (except for increased risk of cataract after
CY-TBI and of alopecia with Bu-CY).
(Blood. 2001;98:3569-3574) Since the 1970s, allogeneic stem cell
transplantation after high-dose cyclophosphamide (CY) and total-body
irradiation (TBI) has been used successfully to treat myeloid
leukemia.1 Bone marrow transplantation (BMT) may fail
because of relapse, graft failure, or transplantation-related
complications. Studies of a busulfan (Bu) and CY regimen in the early
1980s2 were motivated by a desire to reduce toxicity and
improve the probability of long-term remission.3-6
Controversy concerning the optimal pretransplantation regimen for
patients with myeloid malignancies still persists.
During the early 1990s, 4 randomized studies were carried out to
address this controversy. For patients with acute myeloid leukemia
(AML) in first remission, a French study compared these 2 regimens and
found increased disease-free survival (DFS) and overall survival, and
decreased relapse and transplantation-related mortality with
CY-TBI.7 A second study from the Nordic group in patients
with AML, chronic myelogenous leukemia (CML), or lymphoid malignancies,
at different stages of the disease, also found better DFS and less
toxicity with CY-TBI compared to Bu-CY,8 in patients with
advanced diseases. In contrast, the Seattle group9 and a
French multicenter trial10 found that outcome with the
Bu-CY regimen was equivalent to CY-TBI with seemingly less early
toxicity with Bu-CY for patients with CML. A meta-analysis of these 4 trials (and one other trial comparing Bu-CY with TBI-etoposide),
examined 6 end points: survival, DFS, veno-occlusive disease, acute and chronic graft-versus-host disease (GVHD), and interstitial
pneumonitis.11 Trends suggested that survival and DFS were
better with TBI-based regimens than with Bu-CY, but the differences
were not statistically significant. In that study, a power analysis
suggested that Bu-CY was not likely to have a clinically relevant
survival advantage, but the analysis could not exclude the possibility
that such an advantage might exist for the TBI-based regimen.
The 4 studies comparing CT-TBI with Bu-CY were reported with follow-up
ranging from 24 to 42 months.7-10 In light of the
above-mentioned uncertainties, we decided to examine and update the
long-term follow-up of these randomized trials. Patients with acute
lymphoblastic leukemia or lymphoma (n = 42) included in the Nordic
trial were excluded and only patients with AML and CML were studied.
Our aims were to: (1) compare long-term survival, relapse, return to
work/school, and general health status according to the conditioning regimens; and (2) estimate incidence rates and risk factors of late complications. This study included 316 patients with CML and
172 patients with AML. The mean follow-up for surviving patients is now
more than 7 years after BMT.
Patients
In the original trials 494 patients with myeloid malignancies were
enrolled, and we were able to analyze the data for 488 patients (97.8%
of the patients). The remaining 6 (2.2%) patients were enrolled in
centers that declined to participate in this study. All patients
received 120 mg/kg CY (60 mg/kg, on each of 2 consecutive days). For
patients randomized in the Bu-CY regimen, 16 mg/kg Bu (1 mg/kg per dose
orally every 6 hours over 4 consecutive days) was administered. TBI
regimens varied in the different trials. In the Seattle study, all
patients received 12 Gy TBI in a fractionated regimen. In the 2 French
trials, most individuals (42 of 55 and 43 of 50 patients with CML and
AML, respectively) were given TBI in a fractionated regimen for a mean
total dose of 12 Gy. In the Nordic study, approximately two thirds of
the TBI patients received fractionated irradiation.
The combination of cyclosporine and short-course methotrexate was used
for prevention of GVHD disease in all 4 trials.14 In
addition, 17 patients with CML and 16 patients with AML received an
anti-interleukin-2 receptor (p55) antibody.15
Details of the original trials have been previously published: 2 trials
enrolled patients with CML only, one with AML only, and one with both
diseases (Table 1). Three of the 4 trials
enrolled only patients with early-stage diseases (ie, AML in first
complete remission or CML in first chronic phase).
Sex distribution was almost identical in the 4 trials (ratio of men to
women close to 60%). The cohort showed no difference in patient
selection or interval from diagnosis to transplantation in CML
patients, or time from first complete remission to transplantation in
patients with AML. In these early AML trials, no cytogenetic data were
available, but the distribution of AML subtypes according to the
French-American-British (FAB) classification did not differ according
to the conditioning regimens. Details concerning patients enrolled in
this study are summarized in Table 2.
Methods Updated survival and DFS as well as occurrence of late complications were obtained through a questionnaire sent to each French and Nordic center. Updates from the Fred Hutchinson Cancer Research Center (FHCRC) were obtained through the database of the long-term follow-up program, as previously reported.16 Specific requests included the occurrence, and date if any, of cataract, thyroid abnormalities, persistent alopecia (either partial or total), avascular osteonecrosis, pulmonary diseases (including obstructive bronchiolitis), secondary malignancies, return to work or school, and functional status at last follow-up (as assessed by the World Health Organization [WHO] score). Additional data included demographic and posttransplantation information (including data on acute and chronic GVHD).We encountered no difficulty in the definition of relapse for patients with AML. On the other hand, we found considerable difficulty in defining relapse for patients with CML, where hematologic, cytogenetic, or molecular criteria could be used.17,18 Furthermore, transient cytogenetic relapse has also been described after transplantation for CML. Differences in the definition of CML relapse could not be reconciled in this multi-institutional retrospective study. We therefore decided to take into account hematologic or cytogenetic relapses in CML as a binary variable (yes/no) according to referring center reports. Because the development of any late complication clearly depends on the frequency and methods used in searching such late complications, adjustments were made by stratifying by trial in the final models. Statistical analysis was performed separately in each diagnosis group (AML, CML). Times to occurrence of relapse, death, cataract, hypothyroidism or hyperthyroidism, persistent alopecia, avascular osteonecrosis, or late pulmonary diseases were estimated using the Kaplan-Meier method.19 Multivariable Cox models, stratified on the original trial, were fit to evaluate the influence of conditioning regimen, adjusted for patient-, disease-, and transplantation-related variables.20 For categorical variables, a dummy variable for each but one category was created, taking on the value of 1 for patients in that category and 0 otherwise. The proportionality of hazards was tested by using time-varying coefficients. Estimated hazard ratios (HRs) with a 95% confidence interval (95% CI) were computed. Finally, we evaluated the influence of conditioning regimen, adjusted for patient-, disease-, and transplantation-related variables (including chronic GVHD), with hair loss using multivariable (logistic) regression models. Estimated odds ratios (ORs) with 95% CI were given. All P values were 2-sided, with values of .05 or less indicating statistical significance. No correction was made for multiple comparisons. Statistical analysis used the SAS (SAS, Cary, NC) and S-Plus Software.
In patients with CML, no statistically significant differences in
survival or DFS were detected between the use of Bu-CY versus CY-TBI
before transplantation (Figure 1). The
projected 10-year survival estimates were 65% (95% CI, 57%-74%) and
63% (95% CI, 54%-73%) with Bu-CY and CY-TBI, respectively. The
corresponding estimates of DFS were 52% (95% CI, 43%-61%) and 46%
(95% CI, 36%-56%) with Bu-CY and CY-TBI, respectively.
In patients with AML, no statistically significant differences in
survival or DFS were detected between the use of Bu-CY versus CY-TBI
before transplantation (Figure 2). The
projected 10-year survival estimates were 51% (95% CI, 41%-62%) and
63% (95% CI, 52%-74%) with Bu-CY and CY-TBI, respectively. The
corresponding DFS estimates were 47% (95% CI, 36%-58%) and 57%
(95% CI, 44%-70%) with Bu-CY versus CY-TBI, respectively. DFS rates
were similar when the analysis was limited to patients with AML in
first complete remission or CML patients in first chronic phase
who did not receive the 33B3-1 antibody (data not shown).
The 5-year cumulative incidence of clinical extensive chronic GVHD reached 20% and 19% among patients with AML, and in 37% and 39% among patients with CML, with Bu-CY versus CY-TBI, respectively. The general health status was estimated through the WHO scale. Data
concerning AML patients were available for only half the patients and
were therefore not analyzed. In patients with CML, data on health
status at last follow-up were available for more than 75% of the
patients. More than 90% of these patients had normal health status or
minimal impairment (WHO score 0 and 1), as assessed by their referring
physician, without significant differences according to the
conditioning regimen (P = .32; Table 3).
Data concerning return to work were not recorded in the FHCRC data set. In the European studies, between 72% and 88% of the patients returned to school or work at date of last contact, without significant differences according to the conditioning regimen or according to the initial diagnosis (Table 3). We analyzed the incidence of late complications in AML and CML patients
with and without adjustment for age, acute GVHD, and chronic GVHD
(Table 4). The 7-year cumulative
incidence of cataracts reached 12.3% and 12.4% among patients with
AML (P = .82), and 16% and 47% (P = .0003)
among CML patients who received Bu-CY versus CY-TBI, respectively.
After adjustment for patient age and for acute and chronic GVHD, the
association between CY-TBI and cataracts among patients with CML
remained statistically significant (HR = 2.3; 95% CI, 1.3-4.0;
P = .004). The risk of cataracts was also associated with
chronic GVHD (HR = 3.0; 95% CI, 1.6-5.4; P = .0003).
The 7-year cumulative incidence of late pulmonary disease was 6% among patients with AML and 15% among patients with CML, with no differences according to the conditioning regimen. Chronic GVHD was associated with pulmonary complications among patients with CML (HR = 2.6; 95% CI, 1.3-5.2; P = .007). The 7-year cumulative incidence of avascular osteonecrosis was 6% and 7% among patients with AML (P = .95), and 3% and 10% among patients with CML (P = .03) who received Bu-CY versus CY-TBI, respectively. In multivariable analysis, the association between CY-TBI and osteonecrosis among patients with CML was not statistically significant (HR = 2.5; 95% CI, 0.8-7.4; P = .09). The risk of osteonecrosis was increased among patients with chronic GVHD (HR = 7.0; 95% CI, 1.8-26.5; P = .004) and decreased among older patients (HR = 0.93; 95% CI, 0.8-0.9; P = .002). Hypothyroidism was reported in only 6 patients, and hyperthyroidism was reported in only 1 patient. No further analysis was done because the number of patients was too small. Persistent impairment with hair regrowth was assessed in 194 patients (data not available from the FHCRC), representing 72% and 55% of the patients receiving Bu-CY and CY-TBI, respectively. The risk of alopecia was decreased in the CY-TBI group among patients with AML (OR = 0.3; 95% CI, 0.1-0.8; P = .02), but differences were not statistically significant among patients with CML (P = .25). The protective effect of CY-TBI remained statistically significant in the AML group after adjustment for age and for acute and chronic GVHD (HR = 0.19; 95% CI, 0.06-0.6; P = .004). The risk of persistent alopecia was increased among older patients with AML (OR = 1.04; 95% CI, 1.001-1.01; P = .05). In CML patients, chronic GVHD was associated with persistent alopecia (OR = 3.3; 95% CI, 1.1-9.6; P = .03). Secondary solid malignancies were reported in 5 patients (epidermoid carcinoma, n = 2; gastric carcinoma, n = 1; malignant melanoma, n = 1; and adenocarcinoma of unknown primary site, n = 1). Three cases occurred among patients who received CY-TBI, and 2 occurred among patients who received Bu-CY. No statistically significant differences were detected in the causes of death among patients who survived more than 2 years without relapse (data not shown).
Although the CY-TBI and Bu-CY regimens were introduced in the early 1980s as conditioning regimens before transplantation, it was only 10 years later that results of 4 randomized studies comparing both regimens were published.7-10 When reported, these studies had relatively short follow-up and even today, 20 years later, it was not clear if these 2 regimens could be used with similar efficacy in controlling leukemia and what was the spectrum of late complications that could be attributed to any of these regimens. This long-term follow-up examination of the 4 randomized studies provides more definitive answers in patients with CML but still cannot be definitive for patients with AML. Our current results thus clearly confirm previous results published by Clift and coworkers9 and Devergie and colleagues10 and extends, in a larger group of patients, the updated Seattle results showing similar long-term survival and DFS rates with the use of Bu-CY compared to CY-TBI as the preparative regimen for patients with CML.21 In patients with AML, prior results have been less clear. In the French study, Blaise and associates7 previously reported a statistically significant disadvantage in both the DFS and survival rates in the Bu-CY arm (a finding recently confirmed in an update of this French study22). A similar difference in the DFS rates among patients with AML has been found in a recent retrospective analysis of the IBMTR.23 In the Nordic study, the initial reports did not provide a separate analysis for patients with AML.8 In the updated results of this later study, Ringden and coworkers did not find a statistically significant difference in DFS between Bu-CY and CY-TBI regimens among patients with AML.13 In the current study, the advantage of the CY-TBI over Bu-CY was not statistically significant. In these early trials, no cytogenetic analysis was performed as a risk factor affecting the outcome of patients with AML.24,25 Furthermore, Bu plasma levels were not measured as a risk factor that strongly influences the risk of relapse after transplantation.26 These factors limit the interpretation of our results. The answer to this question could come from another trial with stratification on cytogenetic risk groups and with individually adjusted Bu levels, but it is very unlikely that such a trial will be done. In the European studies, 72% to 88% of the patients went back to school or work without significant differences according to the conditioning regimen or the initial diagnosis. Only the Nordic study has previously evaluated the incidence of late complications among patients who received Bu-CY as compared to those who received CY-TBI.13 These authors found that Bu-CY was associated with an increased risk of chronic GVHD, obstructive lung disease, and alopecia. In our analysis, the pretransplantation conditioning regimen did not influence the incidence of chronic GVHD. We found that late obstructive lung disease was associated with chronic GVHD27-30 but not with the use of Bu-CY as described in the Nordic study.13 The reason for the association between chronic GVHD and obstructive lung disease among patients with CML but not among patients with AML remains unclear. Only 9 patients with AML developed late pulmonary diseases, thus preventing any meaningful statistical analysis. Some patients with CML may have received Bu, an agent known to induce pulmonary fibrosis, before the transplantation, but data concerning the type and duration of pretransplantation treatment were not available for our study. We found an increased risk of alopecia in AML patients who received Bu-CY, similar to results of the Nordic study.13 Chronic GVHD was associated with alopecia in CML patients. Hair follicles are targets of GVHD, and alopecia has been associated with the sclerodermatous form of chronic GVHD.31 Although alopecia is not life-threatening, this complication does affect quality of life. In 7 patients who all received Bu-CY, alopecia was total and permanent. Cataract formation has long been described as a late complication of TBI.32 The 47% incidence rate of cataract after the use of TBI in our study fits with the incidence rate reported by Tichelli et al and that published by the FHCRC group.33,34 Cataract formation was also associated with chronic GVHD as described previously.33 This association most likely occurs through the effects of corticosteroids used to treat chronic GVHD.34 Associations between avascular osteonecrosis and younger age, prolonged steroid therapy, and TBI have also been described previously both in French and FHCRC retrospective studies.35,36 Hypothyroidism has been associated with the use of TBI32 and Bu-CY,37 but the number of cases was too small for meaningful analysis in our study. We found very few cases of late cancers, but the median follow-up was only 7 years. Because cancer incidence rates do not begin to increase until more than 6 years BMT,38,39 it is probably too soon to draw any conclusions about the risk of cancer after Bu-CY as compared with CY-TBI. It is already clear, however, that late cancers can occur after Bu-CY conditioning. For this reason, these patients should have close monitoring for second cancers after the transplantation. How can these findings be relevant to new paradigms for allogeneic transplantation conditioning regimens (nonmyeloablative conditioning),40-42 and in the era of STI571 (the bcr-abl inhibitor)43,44? Both use of nonmyeloablative conditioning regimen and of STI571 have led to highly encouraging results in phase I and II trials. This would probably lead to an extended role of allogeneic transplantation for older patients after nonmyeloablative conditioning regimen, and to reduced (or delayed) indication of transplantation in patients with CML. However, both of these new treatment modalities have only been recently introduced and follow-up is clearly lacking, as yet. Long-term results, such as those presented in this study, are therefore important as a referent treatment modality before results of phase III trials (comparing nonmyeloablative conditioning regimen versus standard Bu-CY or CY-TBI, or STI571 versus transplantation) will become available. On the other hand, these new therapeutic modalities may prove to be useful for the treatment of leukemia relapse. STI571 may be used as an alternative to donor lymphocyte infusion in patients with CML who relapse after transplantation. Nonmyeloablative conditioning followed by peripheral blood stem cell transplantation would probably reduced transplantation-related mortality in patients with AML who relapse after a first transplantation in which a conventional therapy has been used. In conclusion, Bu-CY and CY-TBI lead to similar long-term outcomes in patients with myeloid malignancies (although TBI provides slightly better long-term survival in patients with AML). Long-term complications, general health status, and return to work were mostly influenced by chronic GVHD and rarely by the conditioning regimens.
The authors thank Gary Schoch for providing the computerized data from the FHCRC, and all French physicians who sent updated information on patients included in the 2 randomized studies of the SFGM-TC: Dominique Maraninchi, Josy Reiffers, Jean Pierre Jouet, Noël Milpied, Michel Attal, Jean Jacques Sotto, Mathieu Kuentz, Norbert Ifrah, Pierre Bordigoni, Nicole Gratecos, François Guilhot, Denis Guyotat, Eliane Gluckman, and Jean Paul Vernant.
Submitted March 15, 2001; accepted July 30, 2001.
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.
Reprints: Gérard Socié, Service d'Hématologie, Greffe de Moelle, Hôpital Saint Louis, 1 Ave Claude Vellefaux, 75475, Paris Cedex 10, France; e-mail: gsocie{at}chu-stlouis.fr.
1. Thomas ED. Stem cell transplantation: past, present and future. Stem Cells. 1994;12:539-544[Medline] [Order article via Infotrieve]. 2. Santos GW, Tutschka PJ, Brookmeyer R, et al. Marrow transplantation for acute non-lymphocytic leukemia after treatment with busulfan and cyclophosphamide. N Engl J Med. 1983;309:1347-1353[Abstract].
3.
Geller RB, Saral R, Piantadosi S, et al.
Allogeneic bone marrow transplantation after high dose busulfan and cyclophosphamide in patients with acute nonlymphocytic leukemia.
Blood.
1989;73:2209-2218
4.
Biggs JC, Szer J, Crilley P, et al.
Treatment of chronic myeloid leukemia with allogeneic bone marrow transplantation after preparation with BuCy2.
Blood.
1992;80:1352-1357 5. Copelan EA, Biggs JC, Szer J, et al. Allogeneic bone marrow transplantation for acute myelogenous leukemia, acute lymphocytic leukemia, and multiple myeloma following preparation with busulfan and cyclophosphamide (Bucy2). Semin Oncol. 1993;20:33-38[Medline] [Order article via Infotrieve].
6.
Copelan EA, Biggs JC, Thompson JM, et al.
Treatment for acute myelocytic leukemia with allogeneic bone marrow transplantation following preparation with BuCy2.
Blood.
1991;78:838-843
7.
Blaise D, Maraninchi D, Archimbaud E, et al.
Allogeneic bone marrow transplantation for acute myeloid leukemia in first remission: a randomized trial of a busulfan-cytoxan versus cytoxan-total body irradiation as preparative regimen: a report from the Groupe d' Etudes de la Greffe de Moelle Osseuse.
Blood.
1992;79:2578-2582
8.
Ringden O, Ruutu T, Remberger M, et al.
A randomized trial comparing busulfan with total body irradiation as conditioning in allogeneic marrow transplant recipients with leukemia
9.
Clift RA, Buckner CD, Thomas ED, et al.
Marrow transplantation for chronic myeloid leukemia: a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide.
Blood.
1994;84:2036-2043
10.
Devergie A, Blaise D, Attal M, et al.
Allogeneic bone marrow transplantation for chronic myeloid leukemia in first chronic phase: a randomized trial of busulfan-cytoxan versus cytoxan-total body irradiation as preparative regimen: a report from the French Society of Bone Marrow Graft (SFGM).
Blood.
1995;85:2263-2268 11. Hartman AR, Williams S, Dillon JJ. Survival, disease-free survival and adverse effects of conditioning for allogeneic bone marrow transplantation with busulfan/cyclophosphamide vs total body irradiation: a meta-analysis. Bone Marrow Transplant. 1998;22:439-443[CrossRef][Medline] [Order article via Infotrieve].
12.
Davies SM, Ramsay NKC, Klein JP, et al.
Comparison of preparative regimens in transplants for children with acute lymphoblastic leukemia.
J Clin Oncol.
2000;18:340-347
13.
Ringden O, Remberger M, Ruutu T, et al.
Increased risk of chronic graft-versus-host disease, obstructive bronchiolitis, and alopecia with busulfan versus total body irradiation: long-term results of a randomized trial in allogeneic marrow recipients with leukemia.
Blood.
1999;93:2196-2201
14.
Storb R, Deeg HJ, Pepe M, et al.
Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: long-term follow-up of a controlled trial.
Blood.
1989;73:1729-1734 15. Blaise D, Olive D, Michallet M, Marit G, Leblond V, Maraninchi D. Impairment of leukaemia-free survival by addition of interleukin-2-receptor antibody to standard graft-versus-host prophylaxis. Lancet. 1995;345:1144-1146[CrossRef][Medline] [Order article via Infotrieve]. 16. Sullivan KM, Siadak M. Stem cell transplantation. In: Johnson FE,Virgo KS, eds. Cancer Patients Follow-up. St Louis, MO: Mosby; 1997:490-518.
17.
Guglielmi C, Arcese W, Hermans J, et al.
Risk assessment in patients with Ph+ chronic myelogenous leukemia at first relapse after allogeneic stem cell transplant: an EBMT retrospective analysis.
Blood.
2000;95:3328-3334
18.
Craddock C, Szydio RM, Klein JP, et al.
Estimating leukemia-free survival after allografting for chronic myeloid leukemia: a new method that takes into account patients who relapse and are restored to complete remission.
Blood.
2000;96:86-90 19. Kaplan EL, Meier P. Non parametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457-481[CrossRef]. 20. Cox DR. Regression models and life-tables (with discussions), series B. J R Stat Soc. 1972;34:184-192.
21.
Clift RA, Radich J, Appelbaum FR, et al.
Long-term follow-up of a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide for patients receiving allogeneic marrow transplants during chronic phase of chronic myeloid leukemia.
Blood.
1999;94:3960-3962
22.
Blaise D, Maraninchi D, Michallet M, et al.
Long-term follow-up of a randomized trial comparing the combination of cyclophosphamide with total body irradiation or busulfan as conditioning regimen for patients receiving HLA-identical marrow grafts for acute myeloblastic leukemia in first complete remission.
Blood.
2001;97:3669-3671 23. Litzow MR, Bolwell BJ, Camitta BM, et al. Comparison of allogeneic bone marrow transplantation with cyclophosphamide-total body irradiation versus busulfan-cyclophosphamide conditioning regimens for acute myelogenous leukemia in first remission [abstract]. Blood. 2000;96:480a.
24.
Slovak ML, Kopecky KJ, Cassileth PA, et al.
Karyotypic analysis predicts outcome of pre-remission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group study.
Blood.
2000;96:4075-4083
25.
Grimwade D, Walker H, Oliver F, et al.
The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial.
Blood.
1998;92:2322-2333
26.
Slattery JT, Clift RA, Buckner CD, et al.
Marrow transplantation for chronic myeloid leukemia: the influence of plasma busulfan levels on the outcome of transplantation.
Blood.
1997;89:3055-3060
27.
Folz RJ.
Mechanisms of lung injury after bone marrow transplantation.
Am J Respir Cell Mol Biol.
1999;20:1097-1099 28. Crawford SW. Noninfectious lung disease in the immunocompromised host. Respiration. 1999;66:385-395[CrossRef][Medline] [Order article via Infotrieve].
29.
Kantrow SP, Hackman RC, Boeckh M, Myerson D, Crawford SW.
Idiopathic pneumonia syndrome 30. Quabeck K. The lung as a critical organ in marrow transplantation. Bone Marrow Transplant. 1994;14:S19-S28. 31. Socie G, Cahn JY. Acute graft-versus-host disease. In: Barrett AJ,Treleaven J, eds. The Clinical Practice of Stem-Cell Transplantation. Vol 2. Oxford, United Kingdom: Isis Medical Media; 1998:595-618. 32. Sullivan KM, Agura E, Anasetti C, et al. Chronic graft-versus-host disease and other late complications of bone marrow transplantation. Semin Hematol. 1991;28:250-259[Medline] [Order article via Infotrieve]. 33. Benyunes MC, Sullivan KM, Deeg HJ, et al. Cataracts after bone marrow transplantation: long-term follow-up of adults treated with fractionated total body irradiation. Int J Radiat Oncol Biol Phys. 1995;32:661-670[CrossRef][Medline] [Order article via Infotrieve].
34.
Tichelli A, Gratwohl A, Egger T, et al.
Cataract formation after bone marrow transplantation.
Ann Intern Med.
1993;119:1175-1180 35. Fink JC, Leisenring WM, Sullivan KM, Sherrard DJ, Weiss NS. Avascular necrosis following bone marrow transplantation: a case-control study. Bone. 1998;22:67-71[Medline] [Order article via Infotrieve]. 36. Socie G, Cahn JY, Carmelo J, et al. Avascular necrosis of bone after allogeneic bone marrow transplantation: analysis of risk factors for 4388 patients by the Societe Francaise de Greffe de Moelle (SFGM). Br J Haematol. 1997;97:865-870[CrossRef][Medline] [Order article via Infotrieve]. 37. Toubert ME, Socie G, Gluckman E, et al. Short- and long-term follow-up of thyroid dysfunction after allogeneic bone marrow transplantation without the use of preparative total body irradiation. Br J Haematol. 1997;98:453-457[CrossRef][Medline] [Order article via Infotrieve].
38.
Curtis RE, Rowlings PA, Deeg HJ, et al.
Solid cancers after bone marrow transplantation.
N Engl J Med.
1997;336:897-904
39.
Deeg HJ, Socie G.
Malignancies after hematopoietic stem cell transplantation: many questions, some answers.
Blood.
1998;91:1833-1844
40.
McSweeney PA, Niederwieser D, Shizuru JA, et al.
Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus- tumor effects.
Blood.
2001;97:3390-3400 41. Barrett J, Childs R. Non-myeloablative stem cell transplants. Br J Haematol. 2000;111:6-17[CrossRef][Medline] [Order article via Infotrieve].
42.
Giralt S, Thall PF, Khouri I, et al.
Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation.
Blood.
2001;97:631-637
43.
Druker BJ, Sawyers CL, Kantarjian H, et al.
Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome.
N Engl J Med.
2001;344:1038-1042
44.
Druker BJ, Talpaz M, Resta DJ, et al.
Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia.
N Engl J Med.
2001;344:1031-1037
© 2001 by The American Society of Hematology.
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 |
|
 |
|
  G. Socie and B. R. Blazar Acute graft-versus-host disease: from the bench to the bedside Blood, November 12, 2009; 114(20): 4327 - 4336. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Diller, E. J. Chow, J. G. Gurney, M. M. Hudson, N. S. Kadin-Lottick, T. I. Kawashima, W. M. Leisenring, L. R. Meacham, A. C. Mertens, D. A. Mulrooney, et al. Chronic Disease in the Childhood Cancer Survivor Study Cohort: A Review of Published Findings J. Clin. Oncol., May 10, 2009; 27(14): 2339 - 2355. [Full Text] [PDF]
|
|
|
|
|
|
N. S. Kadan-Lottick, I. Dinu, K. Wasilewski-Masker, S. Kaste, L. R. Meacham, A. Mahajan, M. Stovall, Y. Yasui, L. L. Robison, and C. A. Sklar Osteonecrosis in Adult Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study J. Clin. Oncol., June 20, 2008; 26(18): 3038 - 3045. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. E.C. Broers, M. Bruinsma, S. J. Posthumus-van Sluijs, E.-J. Wils, H. Spits, B. Lowenberg, E. Braakman, and J. J. Cornelissen IL-7 mediated protection against minor antigen-mismatched allograft rejection is associated with enhanced recovery of regulatory T cells Haematologica, August 1, 2007; 92(8): 1099 - 1106. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Aschan Allogeneic haematopoietic stem cell transplantation: current status and future outlook Br. Med. Bull., October 5, 2006; (2006) ldl005v2. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Baccarani, G. Saglio, J. Goldman, A. Hochhaus, B. Simonsson, F. Appelbaum, J. Apperley, F. Cervantes, J. Cortes, M. Deininger, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet Blood, September 15, 2006; 108(6): 1809 - 1820. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Stelljes, M. Bornhauser, M. Kroger, J. Beyer, M. C. Sauerland, A. Heinecke, B. Berning, C. Scheffold, G. Silling, T. Buchner, et al. Conditioning with 8-Gy total body irradiation and fludarabine for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia Blood, November 1, 2005; 106(9): 3314 - 3321. [Abstract] [Full Text] [PDF]
|
|
|
|
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|
K. L. Syrjala, S. L. Langer, J. R. Abrams, B. E. Storer, and P. J. Martin Late Effects of Hematopoietic Cell Transplantation Among 10-Year Adult Survivors Compared With Case-Matched Controls J. Clin. Oncol., September 20, 2005; 23(27): 6596 - 6606. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. S. Baker, J. G. Gurney, K. K. Ness, R. Bhatia, S. J. Forman, L. Francisco, P. B. McGlave, L. L. Robison, D. S. Snyder, D. J. Weisdorf, et al. Late effects in survivors of chronic myeloid leukemia treated with hematopoietic cell transplantation: results from the Bone Marrow Transplant Survivor Study Blood, September 15, 2004; 104(6): 1898 - 1906. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. G. Kiehl, L. Kraut, R. Schwerdtfeger, B. Hertenstein, M. Remberger, N. Kroeger, M. Stelljes, M. Bornhaeuser, H. Martin, C. Scheid, et al. Outcome of Allogeneic Hematopoietic Stem-Cell Transplantation in Adult Patients With Acute Lymphoblastic Leukemia: No Difference in Related Compared With Unrelated Transplant in First Complete Remission J. Clin. Oncol., July 15, 2004; 22(14): 2816 - 2825. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.B. Lund, L. Brinch, J. Kongerud, and J. Boe Lung function 5 yrs after allogeneic bone marrow transplantation conditioned with busulphan and cyclophosphamide Eur. Respir. J., June 1, 2004; 23(6): 901 - 905. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. L. Syrjala, S. L. Langer, J. R. Abrams, B. Storer, J. E. Sanders, M. E. D. Flowers, and P. J. Martin Recovery and Long-term Function After Hematopoietic Cell Transplantation for Leukemia or Lymphoma JAMA, May 19, 2004; 291(19): 2335 - 2343. [Abstract] [Full Text] [PDF]
|
|
|
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M. Bornhauser, B. Storer, J. T. Slattery, F. R. Appelbaum, H. J. Deeg, J. Hansen, P. J. Martin, G. B. McDonald, W. G. Nichols, J. Radich, et al. Conditioning with fludarabine and targeted busulfan for transplantation of allogeneic hematopoietic stem cells Blood, August 1, 2003; 102(3): 820 - 826. [Abstract] [Full Text] [PDF]
|
|
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|
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G. Socie, N. Salooja, A. Cohen, A. Rovelli, E. Carreras, A. Locasciulli, E. Korthof, J. Weis, V. Levy, and A. Tichelli Nonmalignant late effects after allogeneic stem cell transplantation Blood, May 1, 2003; 101(9): 3373 - 3385. [Full Text] [PDF]
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S. M. Devine, B. Jahagirdar, K. van Besien, P. Moreau, and J.-L. Harousseau Reduced duration of cytopenias following melphalan conditioning and autografting for multiple myeloma Blood, May 13, 2002; 99(11): 4251 - 4252. [Full Text] [PDF]
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Top
Abstract
Introduction
a report from the Nordic Bone Marrow Transplantation Group.
Blood.
1994;83:2723-2730