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Potentially Curative, but Procedure-Related Mortality and Morbidity Can Be High

Allogeneic stem-cell transplantation (SCT) involving human leukocyte antigen (HLA)-matched siblings or matched unrelated donors (MUDs) is currently the only known possibility for cure of chronic myeloid leukaemia (CML). Access to transplantation is limited by availability of suitable donors and patient age. Patients older than 50-55 years of age generally are not candidates for the procedure because of its associated morbidity and mortality^{17, 18}. Overall, only 15%-20% of patients will be candidates for HLA-matched sibling SCT³, which may be increased by 5%-10% through the use of MUDs^{3, 51}. Standard allogeneic SCT can result in lasting molecular remissions or cures in about 50% of patients eligible for the procedure; however, substantial differences among risk groups exist^{8, 52, 53}.

Baseline Prognostic Factors for Transplantation

The European Group for Blood and Marrow Transplantation identified a set of prognostic variables associated with worse prognosis for patients with CML who underwent allogeneic SCT (Table 1), including⁸:

• Older age
• Interval of more than 1 year from diagnosis to SCT
• Advanced CML disease phase
• Donor recipient sex match (female donor and male recipient), and
• Degree of donor-host matching type (non-HLA matched identical sibling)

Table 1. EMBT Transplantation Risk Score.The table lists the prognostic factors and the corresponding risk score, and reports 5-year overall survival rates, as they were calculated in the original European Group for Blood and Marrow Transplantation (EMBT) report⁵² and in the subsequent Center for International Blood and Marrow Transplant Research (CIEBMTR) study⁵³ All EMBT and CIEBMTR patients were treated by conventional allogeneic SCT procedures between 1989 and 1997. Leukaemia-free survival (calculated in the EBMT study only) at 5 years was 61% for risk score 0-1, 47% for risk score 2, 37% for risk score 3, 35% for risk score 4, and 19% for risk score 5-7.

Depending on risk score and phase of CML disease, 5-year overall survival ranged from 11% to 72%⁸. Five-year survival rates of 40%-70% have been reported for patients who received transplants during early chronic-phase CML^3,51,54,55. Transplantation within 1 year of diagnosis and in the chronic phase of disease is preferred^51,56,57. The use of pretreatment hydroxyurea seems to improve outcome as compared with pretreatment with busulfan^{17, 48, 51}, whereas prolonged administration of IFN-α in chronic-phase CML before SCT may adversely affect outcome^{48, 58}. Delay in transplantation and advanced-phase disease seems to have a negative impact on outcome. In accelerated disease, 22%-43% of patients achieve disease-free survival for 4-5 years^{51, 52, 59}, whereas only 15%-20% of patients in blast crisis are alive 2-3 years after SCT^{17, 51, 60}.

The rate of relapse after allogeneic SCT can range from approximately 10%-20% in patients who are good candidates, to 70%-80% in patients who receive transplants in the accelerated phase of the disease^{3, 17, 39, 61}. In addition, SCT is associated with significant morbidity, including severe graft-versus-host disease (GVHD), immunosuppression, and organ toxicities. The rate of morbidity varies greatly. For example, studies report an 8%-63% rate of grades 2-4 acute GVHD^{48, 60}. For patients who do not have HLA-matched siblings, the use of MUDs is another SCT option; however, the success rates with MUDs generally have been lower, with more significant morbidity and mortality⁶². Overall, the mortality rate associated with allogeneic SCT in chronic-phase CML is approximately 10% for patients <50 years of age in early chronic phase treated with HLA-matched sibling marrow¹⁷, but it has been reported to be as high as 41% for poorer candidates⁴⁸. The risk of mortality associated with SCT increases in advanced-phase disease. Mortality rates of approximately 50% in accelerated-phase CML^{51, 59, 60} and greater than 60% in blast crisis have been reported ⁶⁰.

Current Treatment Options

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