Long-term follow-up of allogeneic HSCT for CML reveals significant improvement in the outcome over the last decade
- First Online:
- Cite this article as:
- Weisser, M., Ledderose, G. & Jochem Kolb, H. Ann Hematol (2007) 86: 127. doi:10.1007/s00277-006-0196-z
- 68 Views
Allogeneic hematopoetic stem cell transplantation (HSCT) is still the only curative therapeutic option for chronic myelogenous leukemia (CML). To examine the development of allogeneic HSCT at our center over the past two decades (decade 1: 1984–1994; decade 2: 1995–2005), all CML patients transplanted in first chronic phase (n = 234) were analyzed with respect to patient characteristics, overall survival, transplant-related mortality (TRM), and relapse incidence. The median follow up time was 54 months (range 1–218). The incidence of acute graft vs host disease (GvHD) °II–IV and extensive chronic GvHD were not different between the two decades (p = 0.894 and p = 0.422, respectively). There was also no difference in the relapse incidence (23 vs 26%, p = 0.869). One-year TRM and overall survival were improved in the later decade (33 vs 18%, p = 0.011 and 62 vs 73% at 5 years, p = 0.063, respectively). The major reason for improved outcome in decade 2 was the improved management of acute GvHD and infections in the early phase after transplantation (p = 0.026). In conclusion, the past decade has seen significant improvement in the performance of allogeneic HSCT for CML.
KeywordsChronic myelogenous leukemiaAllogeneic transplantation
The therapeutic strategies for patients with chronic myelogenous leukemia (CML) have changed substantially over the past few years. In particular, the advent of the tyrosine kinase inhibitor imatinib mesylate has revolutionized the conventional treatment in CML. Imatinib has shown remarkable efficacy in association with a low toxicity profile. By targeting the BCR-ABL protein kinase, imatinib inhibits the molecular basis of CML. Imatinib has caused apoptosis in BCR-ABL-positive cell lines in vitro and, moreover, has demonstrated significant impact on the outcome of CML patients in vivo [2, 3, 10, 14, 16]. Despite high rates of cytogenetic remissions and molecular responses, it is doubtful whether patients can be definitely cured by imatinib alone. Thus, at present, allogeneic hematopoetic stem cell transplantation (HSCT) is still the only curative treatment option in CML.
Allogeneic HSCT has been used successfully for the treatment of CML for more than two decades. The classical conditioning regimen has been 12 Gy of total body irradiation (TBI) or busulfan (BU, 16 mg/kg) plus cyclophosphamide (CY) [13, 17]. Long-term survival has been achieved in up to 75% of the patients, depending on their individual pretransplant risk scores . It has been demonstrated that the curative potential of allogeneic HSCT not only relies on cytoreduction caused by the intensity of the conditioning regimen, but also the graft vs leukemia (GvL) effect provided by the transfer of donor immune cells. The existence of a GvL effect first became evident as CML patients who had relapsed after allogeneic HSCT were successfully transferred into molecular remission by donor lymphocyte infusion [7, 8].
Due to a considerable rate of transplant-related mortality (TRM)—approximately 25% [4, 5]—the procedure has been limited to young patients in good medical condition. The main reasons for this high TRM are therapy-related toxicity, infectious complications, and graft vs host disease (GvHD) [6, 12]. Due to the high rate of TRM, the survival benefit of allogeneic HSCT as compared to conventional therapy—e.g., interferon α—is observed 5 to 6 years post-HSCT . At present, imatinib is considered the treatment of choice for newly diagnosed CML patients. Comparative data on allogeneic HSCT are lacking and the optimal timing of allogeneic HSCT for CML patients under imatinib treatment is unknown. In current trials, allogeneic HSCT is often postponed to the time after failure or resistance to imatinib.
Considering the progress in conventional therapy, the aim of this study was to examine the possible progress in the outcome of allogeneic HSCT achieved over the last two decades. Therefore, the outcomes of all CML patients in the first chronic phase (CP) transplanted at our center were analyzed.
Patients and methods
n = 234
p = 0.046
52 males/35 females
87 males/60 females
p = 0.521
p < 0.001
p = 0.028
Time to Tx (months)
p < 0.001
Time to Tx < 2 years
p = 0.036
64 low risk
121 low risk
p = 0.135
23 high risk
26 high risk
Median risk score 
p = 0.220
Reduced intensity conditioning 
p < 0.001
ATG in conditioning
p < 0.001
The vast majority of patients received standard-intensity conditioning (n = 199) consisting of either BU 16 mg/kg plus CY 120 mg/kg or 12 Gy TBI plus CY 120 mg/kg. From 1990 onwards, antithymocyte globulin (ATG) 20–160 mg/kg was applied as described previously . From 1998 onwards, patients above the age of 45 years received a reduced-intensity conditioning consisting of 8 Gy TBI, fludarabine 120 mg/m2, CY and ATG as described previously . Of the patients in decade 2, 35/147 (24%) received this reduced-intensity conditioning, while 112/147 patients (76%) received standard-intensity conditioning. In decade 1, all patients received standard-intensity conditioning (p < 0.001, Table 1).
GvHD-prophylaxis and stem cell source
GvHD-prophylaxis consisted of cyclosporine A and a short course of methotrexate (15 mg/m2 on day 1, 10 mg/m2 on days 3 and 6). The initial cyclosporine dose was 5 mg/kg daily. Cyclosporine blood levels were aimed at 250–500 ng/ml.
The stem cell source was bone marrow in all cases transplanted in decade 1 and in 139/147 cases in decade 2. Eight patients received peripheral blood stem cells (p = 0.028).
Definition of relapse
A relapse was defined as reappearance of Ph+ metaphases in bone marrow by cytogenetic analysis or hematological signs of CML in peripheral blood or bone marrow, after engraftment and achievement of complete remission. Relapse was defined as cytogenetical if it occurred without hematological or clinical signs of disease. Relapse was defined as hematological if hematological or clinical signs of disease preceded or accompanied cytogenetic conformation.
Statistical analysis of the obtained data was performed using Fisher’s exact test, log-rank test, and Kaplan–Meier analysis where appropriate. Results were significant at a level of p < 0.05 at both sides. Data analysis was performed by using SPSS 11 for Windows software.
Acute and chronic GvHD
The incidence of acute GvHD °II–IV was 49/87 (56%) in decade 1 and 84/147 (57%) in decade 2 (p = 0.894). A °IV acute GvHD was observed in 7/87 (8%) and 6/147 (4%) cases (p = 0.242). The incidence of extensive chronic GvHD was 17/87 (20%) in decade 1 and 36/147 (24%) in decade 2 (p = 0.422).
TRM and acute complications
TRM +365 and acute toxicity
GvHD or infection as a cause of TRM
Other causes of TRMa
Extensive chronic GvHD
Relapse and overall survival
Another factor associated with improved OS was younger age (p = 0.017). The combination of female donor and male recipient and administration of ATG during conditioning did not reach statistical significance (p = 0.081 and p = 0.102, respectively). There was no evidence that the type of donor (sibling or unrelated) had an impact on OS (p = 0.540). A multivariate analysis of factors that influenced OS in univariate analysis revealed that age (p = 0.026) and the time from diagnosis (p = 0.018) were the only independent prognostic factors for OS. In addition, a subanalysis was performed excluding the patients that had received a reduced-intensity-conditioning regimen. This revealed that the improvement achieved in the second decade further increased (OS: p = 0.029 and TRM365: p = 0.004)
Imatinib mesylate has lead to a dramatic improvement in the treatment of CML patients. Despite missing comparative data, allogeneic HSCT is currently offered in the state of resistance to imatinib or high-risk CML patients. To examine possible improvement in the field of allogeneic HSCT, we analyzed the outcome of all CML patients transplanted in first CP at our center. The incidence of relapse was not different between the two decades and is comparable to the published relapse rates for CML after HSCT [1, 9].
It has been demonstrated previously that advanced age, advanced stage, an unrelated donor as compared to a sibling donor, the combination of male recipient and female donor, and a longer time from diagnosis to HSCT adversely influenced transplantation results . With respect to the EBMT risk score , the patient cohorts of both decades were comparable. In the second decade, a lower TRM and an improved OS were demonstrated, while the relapse rate remained in the same range. Thus, the reasons for the improvement were examined. GvHD °II–IV and relapse incidence were not different between the two decades. However, there was a trend towards less severe GvHD (°IV: 4 vs 8%). The administration of ATG may have influenced this development, confirming previous reports showing a dose-dependent benefit of ATG on the outcome of allogeneic HSCT in CML [15, 19]. In addition, we found that mortality from GvHD and infections was reduced in decade 2. GvHD and infections are closely linked to each other as the need of escalated immunosuppression increases the risk of opportunistic infections, while infections may also trigger GvHD. Possible reasons for the improved management of GvHD and infections are the advances in supportive care including modern antibiotics, antifungal, antiviral, and new immunosuppressive drugs, the introduction of noninvasive ventilation in the ward, and improved nursing. Another reason for improved outcome in the second decade may of course be the advances in HLA-matching, e.g., high-resolution HLA typing. Recently, the introduction of reduced-intensity conditioning regimens has enabled older and sicker patients to become eligible for allogeneic HSCT. In the present study, a reduced-intensity-conditioning regimen  was applied in 35 elderly CML patients in the second decade. A subanalysis excluding these patients revealed that the differences in outcome increased further. This observation is possibly caused by the decision to offer a reduced-intensity-conditioning regimen to patients who would not have been able to be successfully treated with a standard-intensity-conditioning regimen.
To examine the influence of time from diagnosis to HSCT of the last two decades, patients were divided into those transplanted within 2 years from primary diagnosis and those transplanted more than 2 years after diagnosis. Those patients transplanted in the later decade within 2 years from diagnosis showed superior OS and lower TRM. TRM at 1 year was reduced in these patients to 11%, which is in the range of a previous report using an nonmyeloablative conditioning regimen . Interestingly, the outcome of those patients transplanted in the early phase of the disease in decade 1 was in the range of patients transplanted more than 2 years after diagnosis in decade 2, underlining the impact of early transplantation on the outcome. Patients transplanted in decade 2 within 2 years from diagnosis had a 5-year OS of 80%. The median EBMT risk score in these patients was 2. Thus, in comparison to the EBMT data  and the German CML trial , we were able to document improved TRM, as well as improved OS. As the present report is a single-center analysis, a center effect may also have caused this observation. It possibly implicates that allogeneic HSCT should be performed at specialized centers. Other known risk factors were neglected. CMV statuses of the donor and the recipient were not sufficiently available in decade 1. Pretreatment with BU was not relevant in decade 2 but may have had an impact on outcome in decade 1.
In conclusion, this retrospective analysis of a large cohort of CML patients revealed a significant improvement in the outcome of allogeneic HSCT over the last decade. Yet, as demonstrated by multivariate analysis, pretransplant risk factors age and time from diagnosis remain the strongest predictors of outcome. Early transplantation provided remarkably low TRM, as well as high long-term OS. The advent of new-generation tyrosine kinase inhibitors may even lengthen the time from diagnosis to HSCT and thereby decrease the curative potential. This has to be taken into account in the therapeutic strategy of CML patients.