Advertisement
Journal of Clinical Oncology  
Search for:
Limit by:
  Browse by Subject or Issue
Home Search or Browse JCO My JCO Subscriptions Customer Service Site Map

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Save to my personal folders
Right arrow Download to citation manager
Right arrowRights & Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Journal of Clinical Oncology, Vol 17, Issue 6 (June), 1999: 1858
© 1999 American Society for Clinical Oncology

Monitoring Treatment and Survival in Chronic Myeloid Leukemia

Italian Cooperative Study Group on Chronic Myeloid Leukemia and Italian Group for Bone Marrow Transplantation

Address reprint requests to Michele Baccarani, MD, Division of Hematology, University Hospital, P. le S. Maria della Misericordia, 33100 Udine, Italy; email ematologia{at}drmm.uniud.it


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 
PURPOSE: To monitor treatment results and survival in chronic myeloid leukemia after allogeneic bone marrow transplantation (alloBMT) and the introduction of interferon alpha (IFN{alpha}).

PATIENTS AND METHODS: Disease course was monitored in 840 patients younger than 56 years who were registered onto prospective studies between 1984 and 1991 and were assigned to conventional chemotherapy (CHT) or IFN{alpha} therapy. One hundred twenty of these patients received allogeneic bone marrow in the chronic phase from an HLA-identical sibling without T-cell depletion (standard alloBMT).

RESULTS: Patient distribution by risk and by presenting features was the same in the transplantation and nontransplantation cohorts, but age was different (median, 32 v 42 years). Results were analyzed by age and by Sokal's relative risk. Among low-risk patients, 10-year survival rates with standard alloBMT versus IFN{alpha} therapy versus CHT were 57% v 49% (P = .76) v 25% (P = .001), respectively, and among patients at higher risk, rates were 54% v 17% (P = .01) v 12% (P = .001). Among patients <= 32 years old, the 10-year survival rates were 65% v 35% (P = .05) v 24% (P = .001), respectively, but for patients older than 32 years, 10-year survival rates were 46% for standard alloBMT versus 31% for IFN{alpha} therapy (P = .62) versus 16% for conventional CHT (P = .05). The data did not change when the calculations were based on the transplantations that were performed within 1 year of diagnosis.

CONCLUSION: Any policy of standard alloBMT was associated with significantly longer survival compared with conventional CHT, irrespective of age and risk. When the comparison was made with IFN{alpha} therapy, a policy of standard alloBMT, including early transplantation, was found to increase survival only in those patients who were younger or at intermediate or high risk.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 
FOR MANY YEARS, management of chronic myeloid leukemia (CML) was based on the use of cytotoxic drugs that were usually given conservatively, as much as was required to reduce and control leukemic-cell mass and to improve quality of life (so-called conventional chemotherapy [CHT]). With CHT, median survival time ranged between 3 and 4 years, and only occasionally were patients long-term survivors (>= 10 years).1-5 When allogeneic bone marrow transplantation (alloBMT) was shown to induce true remissions, long-term survival, and cures, it quickly became the treatment of choice,6-17 and there was pressure to increase the age limit to more than 50 years and to use alternative, unrelated marrow donors.17-25 At the same time, there were changes in other treatments as well, including substitution of hydroxyurea (HU) for busulfan26 and the introduction of interferon alfa (IFN{alpha}).27-38 To evaluate the role of alloBMT in CML, it is difficult to resort to classic, prospective randomized studies, as was done for chemotherapy and radiotherapy,39 splenectomy,40,41 IFN{alpha} therapy,31-37 and combination IFN{alpha} and low-dose cytarabine therapy38. No study of CML has been planned as yet with the aim of prospectively evaluating the outcome of alloBMT with respect to other treatments. Many reports are available on the results and the effects of alloBMT, but these reports emanate from BMT centers and registries and not from other sources. The Italian Cooperative Study Group on Chronic Myeloid Leukemia is a working group that was established in 1973 and is composed of more than 70 hospitals and research centers in Italy. Prospective studies of CML were being performed from 1984 to 1991 for different purposes.31,32,42-44 During that time, patients who were registered onto these studies were assigned either to conventional CHT or to IFN{alpha} therapy, but an option for alloBMT was always prospectively available, providing the opportunity to monitor the outcome of alloBMT and other treatment procedures in an unbiased, unselected, prospective series of patients.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 
Patient Recruitment
Between January 1984 and December 1991, 840 consecutive new cases of Philadelphia chromosome (Ph)–positive CML in chronic phase, in patients younger than 56 years old and previously untreated for the disease, were reported to the Group, representing approximately 42% of the total number of cases expected to occur in Italy during the same period. The first 331 patients were registered between January 1984 and June 1986 onto a prospective study of prognosis42,43 and were treated with conventional CHT. These cases were analyzed and reported elsewhere.45 The records are updated and the cases are included in this study. The second group of 211 patients was registered between July 1986 and June 1988 onto a prospective study of treatment, in which the patients were assigned at random at a ratio of 1 to 2 either to conventional CHT (67 patients) or to IFN{alpha} (Roferon-A; Hoffman-La Roche, Basel, Switzerland) therapy (144 patients).31,32 The third cohort, 298 patients, was registered between July 1988 and December 1991 onto a prospective trial of HU, IFN{alpha} (Roferon-A), and subsequent autologous BMT (ABMT).44

Treatment
Treatment is summarized in Table 1. The dosage of IFN{alpha} was 9 MIU/d until disease progression, with appropriate dose adaptation or discontinuation in case of toxicity, as described elsewhere.31,32 The doses of HU and busulfan were not predetermined. ABMT was performed during the first chronic phase in 47 cases (6%) and after progression to accelerated or blastic phase in 16 cases (2%). Twenty-five patients (3%) underwent allografting in the blastic phase. All patients who underwent autografting, as well as the patients who underwent allografting in the blastic phase, were included for any calculations in the CHT or IFN{alpha} therapy cohorts.


View this table:
[in this window]
[in a new window]
  		Table 1. Treatment
 

An option for alloBMT existed in all three studies at all times, irrespective of treatment allocation and treatment results. AlloBMT was performed in the chronic phase in 181 (21%) of 840 cases. Some patients received T-cell–depleted marrow, and some patients received transplants from alternative donors (Table 2). Because the practice of regular depletion of T cells from identical sibling marrows has largely been abandoned and because use of transplants from alternative donors was experimental during the study period, cases involving these approaches were excluded, and only the 120 cases of unmanipulated transplantation of marrow from HLA-identical siblings were considered for results and comparisons. The treatment administered to these 120 patients, who accounted for 14% of the original 840 patients, will be referred to henceforth as standard alloBMT. The age and risk distribution of these patients is shown in Table 3. Risk distribution was balanced, but age distribution was not, because only a small proportion of the patients who were more than 40 years old underwent alloBMT. Seventy-three patients underwent alloBMT within 12 months of study registration (median, 12 months; mean, 15.1 ± 10.4 months). The latest standard transplantation was performed 60 months after registration. The antileukemic treatment, conditioning regimen, and graft-versus-host disease prophylaxis are listed in Table 4.


View this table:
[in this window]
[in a new window]
  		Table 2. Marrow Donors
 

View this table:
[in this window]
[in a new window]
  		Table 3. Age and Risk Distribution
 

View this table:
[in this window]
[in a new window]
  		Table 4. Treatment Received Before Standard alloBMT, Conditioning Regime, and Graft-Versus-Host Disease (GVHD) Prophylaxis
 

Definitions and Response Assessment
Accelerated or blastic phase was identified as previously reported.31,32 The risk was calculated and defined according to Sokal's formula, which takes into account age, spleen size, platelet count, and percentage of myeloblasts in peripheral blood.46

The cytogenetic response was defined31,32 according to the percentage of Ph-negative metaphases, the response being defined as complete (Ph-negative 100%), major (Ph-negative 66% to 99%), minor (Ph-negative 33% to 65%), or minimal (Ph-negative 1% to 32%). In the patients who underwent allografting, as well as in the patients who achieved a complete cytogenetic response to IFN{alpha} therapy, response and relapse definition did not include molecular data, because these data were not available for all cases and laboratory techniques were not standardized.

Statistical Methods
For any calculation and comparison, patients were divided into three main groups. The first group included the 120 patients who underwent unmanipulated alloBMT in the chronic phase from HLA-identical siblings (standard alloBMT group). The second and third groups included all patients who did not undergo alloBMT in the chronic phase and who were assigned either to conventional CHT (CHT group, n = 337) or to IFN{alpha} therapy (IFN{alpha} therapy group, n = 322), including the patients who underwent autografting as well as the patients who were treated with alloBMT in the blastic phase. The remaining 61 patients, who underwent non-standard alloBMT in the chronic phase, were always excluded from analysis.

Clinical and hematologic features were compared using the {chi}2 test or the Student's t test. P values were always two-sided. Records of all cases were updated as of June 1997, at which time 586 patients (70%) were dead and follow-up for the 254 living patients ranged between 66 and 160 months (median, 102 months). The log-rank test for heterogeneity and trend and the Cox proportional hazards regression for covariate analysis of censored data on survival were used to identify and select prognostic variables within each group.47,48 Overall survival was calculated by the method of Kaplan and Meier49 from study registration to death or to June 1997. Survival and leukemia-free survival after alloBMT were calculated by the same method from transplantation to death or to hematologic relapse, whichever came first, or to June 1997. Survival calculations were truncated at 10 years, when 100 of the original 840 patients were still at risk.

Calculating survival from the same date for all study patients and using registration as that date result in clinically meaningful data. However, evaluation of outcome of alloBMT is distorted, because alloBMT itself is a time-dependent variable. Therefore, in this report, we present rates of survival after registration, but all comparisons were made using the method of Mantel and Byar.50 With this method, patients who underwent alloBMT entered the transplantation cohort only at the time of transplantation, so that at each time interval the respective death rate was calculated based on the number of patients who were actually at risk of dying during that interval. An alternative method was to calculate the survival of non-BMT patients based only on the patients who were alive and in the chronic phase at a time that was equal to the median time from registration to BMT. This calculation provided similar data, which are not presented in this report.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 APPENDIX
 REFERENCES
 
Non-AlloBMT Patients
A complete hematologic response was obtained in 62% of cases in the CHT group and in 60% of cases in the IFN{alpha} therapy group. The overall cytogenetic response rate, from minor to complete, was 4% for CHT and 35% for IFN{alpha} therapy. In both treatment groups, a number of pretreatment variables were significantly related to overall survival, but by multivariate Cox analysis, only Sokal's relative risk was found to be significant (P = .0001 in both cohorts). In the IFN{alpha} therapy cohort, overall survival was also influenced by response to treatment. Among the 201 patients who achieved a complete hematologic response, median survival time had not yet been reached and the 10-year survival rate was 57% (95% confidence interval [CI], 46% to 66%). The survival rates for the patients who achieved minor, major, or complete cytogenetic responses to IFN{alpha} therapy are shown in Fig 1. The 10-year survival rate was 68% (95% CI, 56% to 79%).



View larger version (7K):
[in this window]
[in a new window]
  		Fig 1. Survival of patients assigned to IFN{alpha} treatment who achieved a minor, major, or complete cytogenetic response and never underwent alloBMT (n = 109). Survival was calculated by the method of Kaplan-Meier from the 24th month of treatment.

 

AlloBMT Patients
In June 1997, 62 patients (52%) were alive and in continuous complete remission. Forty-three patients (36%) died from transplant-related complications. Fifteen patients (12%) relapsed, with the latest relapse occurring after 88 months. These patients were treated again either with a second transplantation (n = 6) or with donor lymphocyte infusion and IFN{alpha} (n = 8); seven of the 15 patients were alive and in remission in June 1997. The overall and relapse-free survival rates for these 120 standard alloBMT patients are shown in Fig 2. At 10 years after BMT, the overall survival rate was 55% (95% CI, 45% to 65%) and the leukemia-free survival rate was 50% (95% CI, 40% to 60%). Unlike in the IFN{alpha} therapy and CHT groups, in the standard alloBMT group survival was not significantly affected by Sokal's relative risk. Also, patient sex, registration period, time from registration to transplantation, and IFN{alpha} treatment before transplantation did not significantly affect BMT outcome. Survival after BMT was negatively correlated only with age (P = .03).



View larger version (9K):
[in this window]
[in a new window]
  		Fig 2. Overall survival (a) and leukemia-free survival (b) of 120 patients who underwent alloBMT in the chronic phase. The 10-year overall survival rate was 55% (95% CI, 45% to 65%) and the 10-year leukemia-free survival rate was 50% (95% CI, 40% to 60%). Survival is calculated from BMT.

 

Standard AlloBMT Compared With Conventional CHT and IFN{alpha} Therapy
The main presenting features of the patients who underwent standard alloBMT in the chronic phase and of the patients who did not undergo allografting in the chronic phase and who were treated with conventional CHT or IFN{alpha} are listed in Table 5. A borderline difference (P = .06) was noticed only for hemoglobin levels and WBC count, but neither hemoglobin levels nor WBC count was related to prognosis in any group. The main difference between groups was age. Median age at diagnosis was 42.0 and 41.5 years in the CHT and the IFN{alpha} therapy groups, respectively, whereas median age was 32 years in the standard alloBMT group.


View this table:
[in this window]
[in a new window]
  		Table 5. Comparison of Standard alloBMT Cohort, CHT Cohort, and IFN{alpha} Therapy Cohort
 

Figure 3 shows the overall survival from the time of registration of patients who underwent standard alloBMT in the chronic phase and of patients who did not undergo allografting in the chronic phase and who were assigned either to IFN{alpha} therapy or to conventional CHT. The median survival time had not yet been reached in the BMT cohort, was 72 months in the IFN{alpha} therapy cohort, and was 54 months in the CHT cohort. Ten-year survival rates were 55% (95% CI, 46% to 65%), 32% (95% CI, 26% to 39%), and 18% (95% CI, 14% to 22%), respectively. On the basis of these numbers and the patterns of the curves shown in Fig 3, overall survival seems to have been much better in the standard alloBMT group, but when the difference is calculated with the Mantel-Byar statistics that take into account that standard alloBMT is a time-dependent variable itself, the difference remains significant only in the CHT group (P < .0001) and not in the IFN{alpha} therapy group (P = .12).



View larger version (12K):
[in this window]
[in a new window]
  		Fig 3. Overall survival (from registration) of patients who underwent alloBMT in the chronic phase (n = 120) (a) and patients who did not undergo allografting in the chronic phase and were assigned to IFN{alpha} therapy (n = 322) (b) or CHT (n = 337) (c). Mantel-Byar, P = .12 (BMT v IFN{alpha} therapy) and < .0001 (BMT v CHT).

 

Because Sokal's relative risk influenced survival in the CHT and IFN{alpha} therapy cohorts but not in the standard alloBMT cohort, and because age influenced survival in the standard alloBMT cohort but not in the other groups, we calculated and compared again survival by risk and by age. Figures 4 and 5 show the survival from time of registration among low-risk patients and among intermediate- and high-risk patients (these last two groups were combined because the number of high-risk patients was small). Standard alloBMT was always associated with better survival than was conventional CHT, irrespective of risk (Mantel-Byar, P <= .001). Survival was better with standard alloBMT than with IFN{alpha} therapy only in the higher-risk group (Mantel-Byar, P = .01), whereas in the low-risk group the difference was not significant (Mantel-Byar, P = .76). Figures 6 and 7 show the survival from time of registration according to age. The cutoff value of 32 years was selected because it was the median age of standard alloBMT patients. Here again, survival with standard alloBMT was always better than with conventional CHT, irrespective of age (Mantel-Byar, P = .0001 and .05, respectively), but survival was better with standard alloBMT than with IFN{alpha} therapy only among patients 32 or younger (Mantel-Byar, P = .05); among patients who were more than 32 years old, the difference was not significant (Mantel-Byar, P = .62).



View larger version (11K):
[in this window]
[in a new window]
  		Fig 4. Overall survival (from registration) of low-risk patients (Sokal's relative risk < .8) who underwent alloBMT in the chronic phase (n = 59) (a) and low-risk patients who did not undergo allografting in the chronic phase and were assigned to IFN{alpha} therapy (n = 159) (b) or CHT (n = 153) (c). Mantel-Byar, P = .76 (BMT v IFN{alpha} therapy) and .001 (BMT v CHT).

 


View larger version (12K):
[in this window]
[in a new window]
  		Fig 5. Overall survival (from registration) of intermediate- and high-risk patients (Sokal's relative risk >= .8) who underwent alloBMT in the chronic phase (n = 61) (a) and those who did not undergo allografting in the chronic phase and were assigned to IFN{alpha} therapy (n = 163) (b) or CHT (n = 184) (c). Mantel-Byar, P = .01 (BMT v IFN{alpha} therapy) and .0001 (BMT v CHT).

 


View larger version (11K):
[in this window]
[in a new window]
  		Fig 6. Overall survival (from registration) of patients age 32 or younger who underwent alloBMT in the chronic phase (n = 66) (a) and patients age 32 or younger who did not undergo allografting in the chronic phase and were assigned to IFN{alpha} therapy (n = 89) (b) or CHT (n = 79) (c). Mantel-Byar, P = .05 (BMT v IFN{alpha} therapy) and .0001 (BMT v CHT).

 


View larger version (12K):
[in this window]
[in a new window]
  		Fig 7. Overall survival (from registration) of patients older than 32 years who underwent alloBMT in the chronic phase (n = 54) (a) and patients older than 32 years who did not undergo allografting in the chronic phase and were assigned to IFN{alpha} therapy (n = 233) (b) or CHT (n = 258) (c). Mantel-Byar, P = .62 (BMT v IFN{alpha} therapy) and .05 (BMT v CHT).

 

Because many previous studies involving large series of patients found that the earlier the transplantation was performed, the better were the results,8,12,14,51 we examined the effects of a policy of early BMT. Early BMT was defined a posteriori as transplantation performed within 1 year of diagnosis, taking into account that 1 year was the median time from registration to standard alloBMT. The effects of a policy of early transplantation were evaluated by comparing survival of patients who received such treatment with survival of all the other patients, including those who never underwent transplantation as well as those who received transplants later. It should not be overlooked that a policy of IFN{alpha} therapy first does not necessarily prevent patients from having to undergo later transplantation, whether it is good or bad. Seventy-three patients underwent early standard alloBMT, and their survival was calculated irrespective of risk, because risk had no effect on outcome. The survival of patients who received IFN{alpha} therapy and did not undergo early BMT was calculated separately for low-risk patients and higher-risk patients, because risk had a significant influence on outcome. The results are shown in Fig 8. Mantel-Byar P values were .95 for early-BMT patients versus low-risk patients who received IFN{alpha} and .0009 for early-BMT patients versus higher-risk patients who received IFN{alpha}, which shows that a substantial advantage of early BMT is detectable only in higher-risk patients. Compared with conventional CHT, early standard BMT was always better in terms of survival (data not shown).



View larger version (11K):
[in this window]
[in a new window]
  		Fig 8. Overall survival (from registration) of patients who underwent alloBMT in the chronic phase within 12 months of registration (early BMT, n = 73) (a) and all other patients assigned to IFN{alpha} therapy who were at low risk (n = 174) (b) or higher risk (n = 176) (c). Mantel-Byar, P = .95 (early BMT v IFN{alpha} therapy, low risk) and .0009 (early BMT v IFN{alpha} therapy, higher risk).

 


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
APPENDIX
 REFERENCES
 
This is a report of a prospective program of surveillance of treatment outcome and of survival based on data from a multicenter CML registry. We analyzed records of 840 consecutive patients, of whom 120 underwent standard alloBMT. These cases are a substantial sample of the total number of cases expected to occur in Italy in 8 years (approximately 2,000) and of the total number of cases of standard alloBMT reported to the Italian registry over the same period (320). The proportions are the same (840 of 2,000, or 42%; and 120 of 320, or 37.5%), and we are not aware of any possible bias concerning data collection or selection. The focus of this report is alloBMT, because alloBMT is the only treatment capable of achieving very long survival without maintenance, as well as cures,6-17 but prospective controlled studies of alloBMT in CML are not available and all data on alloBMT in CML originated from transplantation registries and centers. In a previous report,45 we described the effect of alloBMT in patients treated with conventional CHT. In the current report, we extend and update the outcome of alloBMT in the setting of conventional CHT, and we describe the effect of alloBMT in patients prospectively assigned to IFN{alpha} treatment.

Dividing the patients in the study into three treatment cohorts was necessary for simplification. However, the study period was long (1984 to 1997), and it would be naive to expect that all of the patients could receive the same treatment throughout the study. As a matter of fact, some patients underwent autografting, others were treated with alloBMT in the blastic phase, some patients received IFN{alpha} even though they were in the CHT group, and others never received IFN{alpha}, despite the fact that they had been assigned to IFN{alpha} therapy. All of these patients remained in their respective non-BMT cohorts, and we believe that there are no statistical procedures that can work out the complexity of the treatment of a chronic disease when the outcome is overall survival.

The major difference between the standard alloBMT cohort and the other two cohorts, patients receiving conventional CHT or IFN{alpha}, concerned age distribution. Among standard alloBMT patients, this distribution was shifted to the left. Although a uniform distribution of transplantation by age was not anticipated, this finding was somewhat of a surprise and showed that although the upper age limit for a standard alloBMT can be as high as 60 years, older patients underwent transplantation much less frequently than did younger patients. This is important because as many as 50% of all patients who are eligible for BMT are between 40 and 55 years of age (Table 3), and it could be unwise to estimate or predict survival in that age group on the basis of the small fraction of patients actually selected for alloBMT.

Ensuring that cases and controls were properly matched, verifying that treatment procedures and treatment results were representative, and evaluating outcome separately by age and by risk were all required to evaluate the effect of alloBMT in the absence of a prospective randomized study. However, we believe that the basic requirement is that all subjects—patients and controls—be drawn from the same cohort and be recruited and registered prospectively, over the same period, by the same institutions and using predefined treatment guidelines or protocols. When these requirements are fulfilled, interpretation remains difficult and involves the same problems as does interpretation of comparisons between patients who responded to a certain treatment and patients who did not.52 In this study, alloBMT was a time-dependent variable that could influence the survival of transplantation patients, because in a standard Kaplan-Meier's plot, all transplantation patients enter the calculation from registration but are not at any risk of death until the time of transplantation. To account for that bias, the differences between survival curves were calculated using the method devised by Mantel and Byar for heart transplantation.50 However, the comparison always remains biased, because although the Mantel-Byar method accounts for the time-dependency of alloBMT, it cannot account for other selection or candidacy bias (treatment of a patient whose disease progressed or who died before transplantation would always be considered a failure in the nontransplantation cohort and the patient would never enter the transplantation cohort).

An alternative method of evaluating the effect of alloBMT on survival was used in a joint study of the International Bone Marrow Transplant Registry and the German Chronic Myeloid Leukemia Study Group.53 In this study, the transplantation cohort (n = 548) and the nontransplantation cohort (n = 196) were not drawn from the same source, the nontransplantation cohort included both HU- and IFN{alpha}-treated patients, and the patients who were treated with IFN{alpha} were a minority (75 patients) and their treatment was limited by protocol rules.33,36 Therefore, in that study the survival advantage of alloBMT was more evident, but, as in our study, the advantage was greater among higher-risk patients than among low-risk patients.

In a disease like CML, in which several different treatments can be administered sequentially, evaluating the effect of a treatment on overall survival requires that two variables be taken into consideration: the timing of the treatment and the possibility of using a treatment as salvage treatment after a previous treatment failure. For that reason, and because many BMT reports have shown that the earlier the transplantation, the better the results,8,12,14,51 we made an attempt to compare the cases of patients who underwent early standard alloBMT with all of the other cases, including those of patients who underwent later transplantation, because a policy of transplantation not performed early does not necessarily prevent patients from having to undergo later transplantation. Results did not change, but the effect of pretreatment on the outcome of a subsequent transplantation is still a matter of debate. A possible adverse effect of prior IFN{alpha} therapy on transplant-related mortality was reported in some studies54,55 but not in others.56-60

During the last few years, all treatment policies regarding CML have evolved and improved, including policies of conventional CHT, IFN{alpha} therapy, and BMT.12,16,26,30,32,34,37,38 Several other still experimental procedures, such as ABMT,16,61 alloBMT from alternative donors,18-25 allogeneic lymphocyte infusion,62-64 and immunotherapy,65-67 are also in use and are likely to become more common. Continuous surveillance of treatment outcome is critical, as an adjunct to prospective randomized trials, whenever they can be done. Because of the prolongation of survival recently achieved with several treatment procedures, an increasing number of cases and a much longer period are required to test treatment effects. During the study period, standard alloBMT was clearly more convenient than conventional CHT, irrespective of age and risk. Comparison between effects of alloBMT and those of IFN{alpha} therapy is more complex, as shown in Table 6. Among the low-risk patients in our study, 10-year survival was not significantly different, irrespective of age, whereas in the case of higher-risk patients, the results of alloBMT were significantly better only for younger patients. This is not surprising, because younger patients are at a lower risk of dying from transplantation and low-risk patients are more likely to respond to IFN{alpha} therapy. Patients who achieve a cytogenetic response with IFN{alpha} therapy have the longest survival (Fig 1), a fact that highlights the importance of early treatment decisions for better selection.68 In our study, 32 years was chosen as the age cutoff value because that was the median age of the patients who underwent standard alloBMT. However, age is a continuous variable for survival after BMT, and using other age cutoff values would lead to the same conclusion. In larger studies of BMT8,12,14,51 BMT results were also significantly influenced by transplantation timing. This relationship was not significant in our study, but that should not imply that the transplantation date can be delayed, once the decision to perform transplantation has been made.


View this table:
[in this window]
[in a new window]
  		Table 6. Ten-year Survival of Standard alloBMT Patients and IFN{alpha} Therapy Patients
 

Three points should be emphasized. First, these conclusions apply to overall survival and not to leukemia-free survival, because without alloBMT a leukemia-free condition was only episodically detected, in this as well as in other series.16,69,70 Second, these conclusions concern standard alloBMT only and cannot be extended to alloBMT from mismatched or unrelated donors, although most recent reports claim that the outcome of unrelated-donor BMT is similar to that of standard alloBMT24,25 and that unrelated-donor BMT is the first-line treatment for CML.71 Finally, ours is not a report of a prospective comparison of three treatments. For comparison between conventional CHT and IFN{alpha} therapy, one can rely on randomized studies.31-37 But for alloBMT, only the data presented here were available. Patient recruitment and treatment policy were truly prospective, but an option for alloBMT existed at all times and it was not possible to determine how many patients could have received transplants and what the fates of the patients were who had matched family donors and did not undergo transplantation.


   APPENDIX
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX
REFERENCES
 
Members of the Italian Cooperative Study Group on Chronic Myeloid Leukemia and Italian Group for Bone Marrow Transplantation
Members who actively participated in the study: G. Martinelli, N. Testoni, G. Rosti, E. Zuffa, and G. Bandini, Bologna; G. Alimena, E. Montefusco, W. Arcese, G. Melloni, and F. Mandelli, Rome; S. Merante, M. Lazzarino, and E.P. Alessandrino, Pavia; G. Specchia and V. Liso, Bari; F. Gualandi and A. Bacigalupo, Genoa; L. Luciano and B. Rotoli, Naples; A. Nosari, L. Gargantini, and P. Marenco, Milan; S. Tringali and I. Majolino, Palermo; L. Ruberto, M. Lombardo, and P. di Bartolomeo, Pescara; G. Nicolini, C. Delfini, and M. Galimberti, Pesaro; A. Di Tucci and G. Broccia, Cagliari; M. Bertini and P. Pregno, Turin; A. Tabilio and F. Aversa, Perugia; S. Ciolli, F. Leoni, and A. Bosi, Firenze; S. Rupoli and P. Leoni, Ancona; A. Capucci and T. Izzi, Brescia; A. Montuoro and A. De Laurenzi, Rome; A. Rambaldi and P. Viero, Bergamo; C.A. Bodenizza, M. Carotenuto, and S. Giovanni, Rotondo; A. D'Emilio and E. Di Bona, Vicenza; S. Sica and G. Leone, Rome; F. Papineschi and M. Petrini, Pisa; D. Russo, R. Fanin, D. Damiani, and M. Michieli, Udine; A. Ambrosetti and G. Perona, Verona; P. Guglielmo and R. Giustolisi, Catania; A.M. Liberati and E. Donti, Perugia; M. Girino and E. Ascari, Pavia; A. Fasanaro and R. Cimino, Naples; D. Dini and S. Sacchi, Modena; F. Ronco and P. Iacopino, Reggio Calabria; D. Ferrero and A. Pileri, Turin; M. Mangoni and C. Carlo Stella, Parma; F. Palmieri and E. Volpe, Avellino; R. Quaini and P. Coser, Bolzano; M. Cantonetti and S. Amadori, Rome; G.L. Scapoli and G. Castoldi, Ferrara; F. Ciccone and S. Nardelli, Latina; R. Perricone and A. Cajozzo, Palermo; S. Pardini and M. Longinotti, Sassari; G. Pinotti and A. Venco, Varese; M. Pizzuti and F. Ricciuti, Potenza; C. Bergonzi, S. Morandi, and A. Porcellini, Cremona; M. Risso and E. Damasio, Genova; A. Di Francesco and D. Quaglino, L'Aquila; C. Musolino and G. Squadrito, Messina; S. Iaccarino and A. Abbadessa, Naples; E. Miraglia and R. De Biasi, Naples; P. Galieni and F. Lauria, Siena; G. Rege Cambrin and P. Sivera, Turin; A. Pinto and V. Zagonel, Aviano; M. Monaco, Foggia; P. Avanzini and L. Gugliotta, Reggio Emilia; A. Novarino, Turin; C. Uderzo, Milan; D. Caloro, Bari; A. Gallamini, Cuneo; M. Clavio, Genova; A. Gabbas, Nuoro; and A. Capaldi, Turin.

Members of the writing committee for the Italian Cooperative Study Group on Chronic Myeloid Leukemia: Sante Tura, Gianantonio Rosti, Mauro Fiacchini, Antonio de Vivo, and Francesca Bonifazi (Institute of Hematology and Clinical Oncology "L. and A. Seràgnoli," Bologna University, Bologna, Italy); Michele Baccarani, Domenico Russo, Renato Fanin, and Mario Tiribelli (Division of Hematology and Department of Bone Marrow Transplantation, Udine University, Udine, Italy); Eliana Zuffa (Division of Hematology, S. Maria delle Croci Hospital, Ravenna, Italy); and Enrico Montefusco (Institute of Hematology, La Sapienza University, Rome, Italy).

Members of the writing committee for the Italian Group for Bone Marrow Transplantation: William Arcese (Institute of Hematology, La Sapienza University, Rome, Italy), Andrea Bacigalupo (Division of Hematology and Bone Marrow Transplantation, S. Martino Hospital, Genoa, Italy), and Giuseppe Bandini (Institute of Hematology and Clinical Oncology "L. and A. Seràgnoli," Bologna University, Bologna, Italy).


   ACKNOWLEDGMENTS
 
Supported by the National Research Council of Italy and Associazione Italiana per la Ricerca sul Cancro, Milan.

We thank J.L. Pico, Institut Gustave Roussy, Villejuif, France; A. Mellon, Fred Hutchinson Cancer Research Center, Seattle, WA; T. Hayward, Royal Marsden Hospital, Surrey, United Kingdom; A. Devergie, Hôpital St. Louis, Paris, France; and D. Niederwieser, Innsbruck, Austria.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 
1. Galton DAG: Chemotherapy of chronic myelocytic leukemia. Semin Hematol 6:323-343, 1969[Medline]

2. Tura S, Baccarani M, Zaccaria A: Chronic myeloid leukemia. Haematologica 71:169-176, 1986[Medline]

3. Sokal JE, Baccarani M, Russo D, et al: Staging and prognosis in chronic myeloid leukemia. Semin Hematol 25:49-61, 1988[Medline]

4. Talpaz M, Kantarjian HM, Kurzrock R, et al: Therapy of chronic myelogenous leukemia: Chemotherapy and interferons. Semin Hematol 25:62-73, 1988[Medline]

5. Cervantes F, Robertson JE, Rozman C, et al: Long-term survivors in chronic granulocytic leukaemia: A study by the International CGL Prognosis Study Group. Br J Haematol 87:293-300, 1994[Medline]

6. Doney K, Buckner D, Sale GE, et al: Treatment of chronic granulocytic leukemia by chemotherapy, total body irradiation and allogeneic bone marrow transplantation. Exp Hematol 6:738-747, 1978[Medline]

7. Goldman JM, McCarthy DM, Hows JM, et al: Marrow transplantation for patients in the chronic phase of chronic granulocytic leukaemia. Lancet 2:623-625, 1982[Medline]

8. Thomas ED, Clift RA, Fefer A, et al: Marrow transplantation for the treatment of chronic myelogenous leukemia. Ann Intern Med 104:155-163, 1986

9. Goldman JM, Gale RP, Horowitz MM, et al: Bone marrow transplantation for chronic myelogenous leukemia in chronic phase. Ann Intern Med 108:806-814, 1988

10. Champlin RE, Goldman JM, Gale RP: Bone marrow transplantation in chronic myelogenous leukemia. Semin Hematol 25:74-80, 1988[Medline]

11. Sullivan KM, Weiden PL, Storb R, et al: Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia. Blood 73:1720-1728, 1989[Abstract/Free Full Text]

12. Clift RA, Appelbaum FR, Thomas ED: Treatment of chronic myeloid leukemia by marrow transplantation. Blood 82:1954-1956, 1993[Free Full Text]

13. Gratwohl A, Hermans J, Niederwieser D, et al: Bone marrow transplantation for chronic myeloid leukemia: Long-term results. Bone Marrow Transplant 12:509-516, 1993[Medline]

14. 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 84:2036-2043, 1994[Abstract/Free Full Text]

15. Silberman G, Crosse MG, Peterson EA, et al: Availability and appropriateness of allogeneic bone marrow transplantation for chronic myeloid leukemia in 10 countries. N Engl J Med 331:1063-1067, 1994[Abstract/Free Full Text]

16. Kantarjian HM, O'Brien S Anderlini P, et al: Treatment of chronic myelogenous leukemia: Current status and investigational options. Blood 87:3069-3081, 1996[Free Full Text]

17. McGlave P: Chronic leukemias, in Beatty PG (ed): Clinical and managed care issues in blood and marrow transplantation for hematologic diseases: Report of a symposium, 14 March 1996, Washington, DC. Exp Hematol 25:1195-1208, 1997[Medline]

18. McGlave PB, Beatty P, Ash R, et al: Therapy for chronic myelogenous leukemia with unrelated donor bone marrow transplantation: Results in 102 cases. Blood 75:1728-1732, 1990[Abstract/Free Full Text]

19. Marks DI, Cullis JO, Ward KN, et al: Allogeneic bone marrow transplantation for chronic myeloid leukemia using sibling and volunteer unrelated donors: A comparison of complications in the first 2 years. Ann Intern Med 119:207-214, 1993[Abstract/Free Full Text]

20. McGlave P, Bartsch G, Anasetti C, et al: Unrelated donor marrow transplantation therapy for chronic myelogenous leukemia: Initial experience of the National Marrow Donor Program. Blood 81:543-550, 1993[Abstract/Free Full Text]

21. Aversa F, Tabilio A, Terenzi A, et al: Successful engraftment of T-cell-depleted haploidentical "three-loci" incompatible transplants in leukemia patients by addition of recombinant human granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells to bone marrow inoculum. Blood 84:3948-3955, 1994[Abstract/Free Full Text]

22. Speiser DE, Hermans J, van Biezen A, et al: Haploidentical family member transplants for patients with chronic myeloid leukaemia: A report of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant 19:1197-1203, 1997[Medline]

23. Devergie A, Apperley JF, Labopin M, et al: European results of matched unrelated donor bone marrow transplantation for chronic myeloid leukemia: Impact of HLA class II matching. Bone Marrow Transplant 20:11-13, 1997[Medline]

24. Dini G, Lamparelli T, Rondelli R, et al: Unrelated donor marrow transplantation for chronic myelogenous leukaemia. Br J Haematol 102:544-552, 1998[Medline]

25. Hansen JA, Gooley TA, Martin PJ, et al: Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med 338:962-968, 1998[Abstract/Free Full Text]

26. Hehlmann R, Heimpel H, Hasford J, et al: Randomized comparison of busulfan and hydroxyurea in chronic myelogenous leukemia: Prolongation of survival by hydroxyurea. Blood 82:398-407, 1993[Abstract/Free Full Text]

27. Talpaz M, Kantarjian HM, McCredie K, et al: Hematologic remission and cytogenetic improvement induced by recombinant human interferon alpha in chronic myelogenous leukemia. N Engl J Med 314:1065-1068, 1986[Abstract]

28. Talpaz M, Kantarjian H, Kurzrock R, et al: Interferon-alpha produces sustained cytogenetic responses in chronic myelogenous leukemia. Ann Intern Med 114:532-538, 1991

29. Ozer H, George SL, Schiffer CA, et al: Prolonged subcutaneous administration of recombinant alfa2b 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 82:2975-2984, 1993[Abstract/Free Full Text]

30. Kantarjian HM, Smith TL, O'Brien S et al: Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-alpha therapy: The Leukemia Service. Ann Intern Med 122:254-261, 1995[Abstract/Free Full Text]

31. Italian Cooperative Study Group on Chronic Myeloid Leukemia: A prospective comparison of alpha-IFN and conventional chemotherapy in Ph+ chronic myeloid leukemia: Clinical and cytogenetic results at 2 years in 322 patients. Haematologica 77:204-214, 1992[Medline]

32. Italian Cooperative Study Group on Chronic Myeloid Leukemia: Interferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. N Engl J Med 330:820-825, 1994[Abstract/Free Full Text]

33. Hehlmann R, Heimpel H, Hasford J, et al: Randomized comparison of interferon-alfa, busulfan and hydroxyurea in chronic myelogenous leukemia. Blood 84:4064-4077, 1984[Abstract/Free Full Text]

34. Allan NC, Richards SM, Shepherd PCA UK Medical Research Council's Working Parties for Therapeutic Trials in Adult Leukaemia: UK Medical Research Council randomised, multicentre trial of interferon-alfa n1 for chronic myeloid leukaemia: Improved survival irrespective of cytogenetic response. Lancet 345:1392-1397, 1995[Medline]

35. Ohnishi K, Ohno R, Tomonaga M, et al: A randomized trial comparing interferon-alfa with busulfan for newly diagnosed chronic myelogenous leukemia in chronic phase. Blood 86:906-916, 1995[Abstract/Free Full Text]

36. The German and Italian Chronic Myeloid Leukemia Study Groups Writing Committee (Hasford J Baccarani M, Hehlmann R, et al): Interferon-alpha and hydroxyurea in early chronic myeloid leukemia: A comparative analysis of the Italian and German chronic myeloid leukemia trials with interferon-alpha. Blood 87:5384-5391, 1996[Abstract/Free Full Text]

37. Chronic Myeloid Leukemia Trialists' Collaborative Group: Interferon alfa versus chemotherapy for chronic myeloid leukemia: A meta-analysis of seven randomized trials. J Natl Cancer Inst 89:1616-1620, 1997[Abstract/Free Full Text]

38. Guilhot F, Chastang C, Michallet M, et al: Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. N Engl J Med 337:223-229, 1997[Abstract/Free Full Text]

39. Medical Research Council's Working Party for Therapeutic Trials in Leukaemia: Chronic granulocytic leukaemia: Comparison of radiotherapy and busulphan therapy. BMJ 1:201-208, 1968

40. Medical Research Council's Working Party for Therapeutic Trials in Leukaemia: Randomized trial of splenectomy in Ph1-positive chronic granulocytic leukaemia, including an analysis of prognostic features. Br J Haematol 54:415-430, 1983[Medline]

41. Italian Cooperative Study Group on Chronic Myeloid Leukemia: Results of a prospective randomized trial of early splenectomy in chronic myeloid leukemia. Cancer 54:333-338, 1984[Medline]

42. Italian Cooperative Study Group on Chronic Myeloid Leukemia: Prospective confirmation of a prognostic classification for Ph+ chronic myeloid leukemia. Br J Haematol 69:463-466, 1988[Medline]

43. Italian Cooperative Study Group on Chronic Myeloid Leukemia: Confirmation and improvement of Sokal's prognostic classification of Ph+ chronic myeloid leukemia: The value of early evaluation of the course of the disease. Ann Hematol 63:307-314, 1991[Medline]

44. Italian Cooperative Study Group (ICSG) on Chronic Myeloid Leukemia: Karyotypic conversion by interferon as preparative treatment for autologous BMT in Ph positive CML. Leuk Lymphoma 11:277-280, 1993 (suppl 1)

45. Italian Cooperative Study Group on Chronic Myeloid Leukaemia: Evaluating survival after allogeneic bone marrow transplant for chronic myeloid leukaemia in chronic phase: A comparison of transplant versus no-transplant in a cohort of 258 patients first seen in Italy between 1984 and 1986. Br J Haematol 85:292-299, 1993[Medline]

46. Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in "Good-risk" chronic granulocytic leukemia. Blood 63:789-799, 1984

47. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized trials requiring prolonged observations in each patient: II. Analysis and examples. Br J Cancer 35:1-39, 1977[Medline]

48. Cox DR: Regression models and life tables. J R Stat Soc 34:187-200, 1972

49. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958

50. Mantel N, Byar DP: Evaluation of response-time data involving transient states: An illustration using heart-transplant data. J Am Stat Assoc 69:81-86, 1974

51. Goldman JM, Szydlo R, Horowitz MM, et al: Choice of pretransplant treatment and timing of transplant for chronic myelogenous leukemia in chronic phase. Blood 82:2235-2238, 1993[Abstract/Free Full Text]

52. Anderson JR, Cain KC, Gelber RD: Analysis of survival by tumor response. J Clin Oncol 1:710-719, 1983[Abstract]

53. Gale RP, Hehlmann R, Zhang MJ, et al: Survival with bone marrow transplantation versus hydroxyurea or interferon for chronic myelogenous leukemia. Blood 91:1810-1819, 1998[Abstract/Free Full Text]

54. Beelen DW, Graeven U, Elmaagacli AH, et al: Prolonged administration of interferon-alpha in patients with chronic-phase Philadelphia chromosome-positive chronic myelogenous leukemia before allogeneic bone marrow transplantation may adversely affect transplant outcome. Blood 85:2981-2990, 1995[Abstract/Free Full Text]

55. Morton AJ, Gooley T, Hansen JA, et al: Impact of pre-transplant interferon-alpha on outcome of unrelated donor marrow transplants for chronic myeloid leukemia in first chronic phase. Proceedings of the 39th annual meeting of the American Society of Hematology. Blood 90:123a, 1997 (suppl 1, abstr 536)

56. Giralt SA, Kantarjian HM, Talpaz M, et al: Effect of prior interferon alfa therapy on the outcome of allogeneic bone marrow transplantation for chronic myelogenous leukemia. J Clin Oncol 11:1055-1061, 1993[Abstract/Free Full Text]

57. Shepherd P, Richards S, Allan N: Survival after allogeneic bone marrow transplantation (BMT) in patients randomized into a trial of IFN alpha versus chemotherapy: No significant adverse effect of prolonged IFN alpha administration. Proceedings of the 37th annual meeting of the American Society of Hematology. Blood 86:94a, 1995 (suppl 1, abstr 363)

58. Horowitz MM, Giralt S, Szydlo R, et al: Effect of prior interferon therapy on outcome of HLA-identical sibling bone marrow transplants for chronic myelogenous leukemia (CML) in first chronic phase. Proceedings of the 38th annual meeting of the American Society of Hematology. Blood 88:682a, 1996 (suppl 1, abstr 2716)

59. Tomas JF, Lopez-Lorenzo JL, Requena MJ, et al: Absence of influence of prior treatment with interferon on the outcome of allogeneic bone marrow transplantation for chronic myeloid leukemia. Bone Marrow Transplant 22:47-51, 1998[Medline]

60. Zuffa E, Bandini G, Bonini A, et al: Prior treatment with alpha-interferon does not adversely affect the outcome of allogeneic BMT in chronic phase chronic myeloid leukemia. Haematologica 83:231-236, 1998[Abstract/Free Full Text]

61. McGlave PB, De Fabritiis P, Deisseroth A, et al: Autologous transplants for chronic myelogenous leukaemia: Results from eight transplant groups. Lancet 343:1486-1488, 1994[Medline]

62. Kolb HJ, Mittermüller J, Clemm CH, et al: Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 76:2462-2465, 1990[Abstract/Free Full Text]

63. Kolb HJ, Schattenberg A, Goldman JM, et al: Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 86:2041-2050, 1995[Abstract/Free Full Text]

64. Bacigalupo A, Soracco M, Vassallo F, et al: Donor lymphocyte infusion (DLI) in patients with chronic myeloid leukemia following allogeneic bone marrow transplantation. Bone Marrow Transplant 19:927-932, 1997[Medline]

65. Bocchia M, Korontsvit T, Xu Q et al: Specific human cellular immunity to bcr-abl oncogene-derived peptides. Blood 87:3587-3592, 1996[Abstract/Free Full Text]

66. ten Bosch GJA Joosten AM, Kessler JH, et al: Recognition of bcr-abl positive leukemic blasts by human CD4+ T cells elicited by primary in vitro immunization with a bcr-abl breakpoint peptide. Blood 88:3522-3527, 1996[Abstract/Free Full Text]

67. Choudhyry A, Gajewski JL, Liang JC, et al: Use of leukemic dendritic cells for the generation of antileukemic cellular cytotoxicity against Philadelphia chromosome-positive chronic myelogenous leukemia. Blood 89:1133-1142, 1997[Abstract/Free Full Text]

68. Sacchi S, Kantarjian HM, Smith TL, et al: Early treatment decisions with interferon-alfa therapy in early chronic-phase chronic myelogenous leukemia. J Clin Oncol 16:882-889, 1998[Abstract]

69. Lee MS, Kantarjian H, Talpaz M, et al: Detection of minimal residual disease by polymerase chain reaction in Philadelphia chromosome-positive chronic myelogenous leukemia following interferon therapy. Blood 79:1920-1923, 1992[Abstract/Free Full Text]

70. Hochhaus A, Lin F, Reiter A, et al: Variable numbers of bcr-abl transcripts persist in CML patients who achieve complete cytogenetic remission with interferon-alfa. Br J Haematol 91:126-131, 1995[Medline]

71. Lee SJ, Kuntz KM, Horowitz MM, et al: Unrelated donor bone marrow transplantation for chronic myelogenous leukemia: A decision analysis. Ann Intern Med 127:1080-1088, 1997[Abstract/Free Full Text]

Submitted August 10, 1998; accepted February 16, 1999.




This article has been cited by other articles:


Home page
 BloodHome page
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]

Home page
 BloodHome page
H. M. Kantarjian, J. E. Cortes, S. O'Brien, R. Luthra, F. Giles, S. Verstovsek, S. Faderl, D. Thomas, G. Garcia-Manero, M. B. Rios, et al.
Long-term survival benefit and improved complete cytogenetic and molecular response rates with imatinib mesylate in Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia after failure of interferon-{alpha}
Blood, October 1, 2004; 104(7): 1979 - 1988.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
H. M. Kantarjian, J. E. Cortes, S. O'Brien, F. Giles, G. Garcia-Manero, S. Faderl, D. Thomas, S. Jeha, M. B. Rios, L. Letvak, et al.
Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome-positive chronic myelogenous leukemia: high incidence of early complete and major cytogenetic responses
Blood, January 1, 2003; 101(1): 97 - 100.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
H. M. Kantarjian, S. O'Brien, J. E. Cortes, S. A. Giralt, M. B. Rios, J. Shan, F. J. Giles, D. A. Thomas, S. Faderl, M. De Lima, et al.
Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia
Blood, August 13, 2002; 100(5): 1590 - 1595.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
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]