Annals of Hematology

, Volume 86, Issue 2, pp 127–132

Long-term follow-up of allogeneic HSCT for CML reveals significant improvement in the outcome over the last decade

Authors

    • Clinical Cooperative Group for Haematopoetic Cell Transplantation, Department of Medicine IIIUniversity of Munich, Klinikum Grosshadern and GSF-National Research Center for Environment and Health
  • Georg Ledderose
    • Clinical Cooperative Group for Haematopoetic Cell Transplantation, Department of Medicine IIIUniversity of Munich, Klinikum Grosshadern and GSF-National Research Center for Environment and Health
  • Hans Jochem Kolb
    • Clinical Cooperative Group for Haematopoetic Cell Transplantation, Department of Medicine IIIUniversity of Munich, Klinikum Grosshadern and GSF-National Research Center for Environment and Health
Original Article

DOI: 10.1007/s00277-006-0196-z

Cite this article as:
Weisser, M., Ledderose, G. & Jochem Kolb, H. Ann Hematol (2007) 86: 127. doi:10.1007/s00277-006-0196-z

Abstract

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.

Keywords

Chronic myelogenous leukemiaAllogeneic transplantation

Introduction

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 [5]. 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 [4]. 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

Patients

From 1984–2005, 234 CML patients underwent allogeneic HSCT in first CP at our center from an HLA-identical sibling (n = 131) or an unrelated donor (n = 103). All patients had given their written consent for the procedure. The patient characteristics are shown in Table 1.
Table 1

Patient characteristics

n = 234

1984–1994

1995–2005

 

 

87

147

 

Age

36

39

p = 0.046

Range

16–58

17–62

 

Sex

52 males/35 females

87 males/60 females

p = 0.521

Donor

 Sib

69

62

p < 0.001

 URD

18

85

 

 HLA-id

87

147

 

SC source

  

p = 0.028

 BM

87

139

 

SC

0

8

 

Stage

 1 CP

87

147

 

Time to Tx (months)

23

16

p < 0.001

Time to Tx < 2 years

46/87

99/147

p = 0.036

Donor/recipient sex

64 low risk

121 low risk

p = 0.135

Combinationa

23 high risk

26 high risk

 

Median risk score [5]

2 (1–5)

2 (0–5)

p = 0.220

GvHD-prophylaxis

CsA/MTX

CsA/MTX

 

Reduced intensity conditioning [18]

0

35

p < 0.001

ATG in conditioning

19

147

p < 0.001

Sib sibling, URD unrelated donor, HLA-id HLA-identical, BM bone marrow, SC stem cell, Tx transplant

aHigh risk: female donor, male recipient; low risk: all other combinations

Conditioning regimen

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 [15]. 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 [18]. 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

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.

Results

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 at day +365 was 29/87 (33%) in decade 1 and 27/147 (18%) in decade 2 (p = 0.011; Fig. 1). To examine the effect of time from diagnosis to transplantation over the last two decades, patients were separated with respect to transplantation within and 2 years after diagnosis. The median European group for Blood and Marrow Transplantation (EBMT) risk score [5] for all four groups was 2. The lowest TRM was demonstrated in patients transplanted early in decade 2 with 11% (11/99, p = 0.002; Fig. 2). TRM of those patients transplanted in decade 2 after 2 years was 33% (16/48). In decade 1, early transplantation resulted in a TRM of 33% (15/46), as compared to 34% (14/41, Fig. 2). Causes of death in the early phase post-HSCT were analyzed for both decades. Mortality from GvHD and infectious complications was 20/87 (23%) in decade 1 and 17/147 (12%) in decade 2 (p = 0.026). Other lethal complications like veno-occlusive disease bleeding or cardiac and renal failure were not different between the two cohorts (p = 0.336, Table 2). Other factors associated with improved TRM were younger age (p = 0.015) and the administration of ATG during conditioning (p = 0.009). There was no evidence that the type of donor (sibling vs unrelated; p = 0.218) or the combination of female donor and male recipient (p = 0.120) had an impact on TRM. A multivariate analysis of factors that influenced TRM in univariate analysis revealed that age (p = 0.015) was the only independent prognostic factor for TRM, while time from diagnosis to HSCT revealed borderline significance (p = 0.073).
https://static-content.springer.com/image/art%3A10.1007%2Fs00277-006-0196-z/MediaObjects/277_2006_196_Fig1_HTML.gif
Fig. 1

Kaplan–Meier plot of TRM at day +365 in decade 1 (1984–1994) and decade 2 (1995–2005)

https://static-content.springer.com/image/art%3A10.1007%2Fs00277-006-0196-z/MediaObjects/277_2006_196_Fig2_HTML.gif
Fig. 2

Kaplan–Meier plot of TRM at day +365 in decade 1 (1984–1995) and decade 2 (1995–2005) with respect to early and late transplantation: DI < 2y decade 1 within 2 years from diagnosis. DI > 2y decade 1 more than 2 years after transplantation. DII > 2y decade 2 more than 2 years after diagnosis. DII < 2y decade 2 within 2 years from diagnosis

Table 2

TRM +365 and acute toxicity

 

1984–1994

1995–2005

p value

TRM365

29 (33%)

27 (18)

0.011

GvHD or infection as a cause of TRM

20 (23%)

17 (12%)

0.026

Other causes of TRMa

9 (10%)

10 (7%)

0.336

Acute GvHD

 II–IV

49 (56%)

84 (57%)

0.894

 IV

7 (8%)

6 (4%)

0.242

Extensive chronic GvHD

17 (20%)

36 (24%)

0.422

aVeno-occlusive disease, bleeding complications, heart and renal failure

Relapse and overall survival

The probability of relapse at 5 years was 23% in decade 1 and 26% in decade 2 (p = 0.869; Fig. 3). After a median follow up of 54 months (range 1–218), the overall survival (OS) at 5 years was 62% in decade 1, as compared to 73% in decade 2 (p = 0.063; Fig. 4). Again, patients were separated with respect to transplantation within and after 2 years from diagnosis. Highest OS at 5 years was demonstrated for patients transplanted in decade 2 within 2 years from diagnosis (80%, p = 0.007; Fig. 5). OS at 5 years of those patients transplanted in decade 2 longer than 2 years from diagnosis was 59%. In decade 1, early transplantation resulted in a 5-year OS of 65%, as compared to 56% for those patients transplanted longer than 2 years from diagnosis.
https://static-content.springer.com/image/art%3A10.1007%2Fs00277-006-0196-z/MediaObjects/277_2006_196_Fig3_HTML.gif
Fig. 3

Kaplan–Meier plot of relapse incidence in decade 1 (1984–1994) and decade 2 (1995–2005)

https://static-content.springer.com/image/art%3A10.1007%2Fs00277-006-0196-z/MediaObjects/277_2006_196_Fig4_HTML.gif
Fig. 4

Kaplan–Meier plot of OS in decade 1 (1984–1994) and decade 2 (1995–2005)

https://static-content.springer.com/image/art%3A10.1007%2Fs00277-006-0196-z/MediaObjects/277_2006_196_Fig5_HTML.gif
Fig. 5

Kaplan–Meier plot of OS in decade 1 (1984–1994) and decade 2 (1995–2005) with respect to early and late transplantation. DI < 2y decade 1 within 2 years from diagnosis. DI > 2y decade 1 longer than 2 years from transplantation. DII > 2y decade 2 more than 2 years after diagnosis. DII < 2y decade 2 within 2 years from diagnosis

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)

Discussion

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 [5]. With respect to the EBMT risk score [5], 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 [18] 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 [11]. 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 [5] and the German CML trial [4], 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.

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© Springer-Verlag 2006