Treatment
Historical Perspective
Stem-Cell Transplantation
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.1,2 Overall, only 15%-20% of patients will be candidates for HLA-matched sibling SCT,3 which may be increased by 5%-10% through the use of MUDs.3,4 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.5-7
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), including:5
- 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) report6 and in the subsequent Center for International Blood and Marrow Transplant Research (CIEBMTR) study7 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.
Click on the image to enlarge
Depending on risk score and phase of CML disease, 5-year overall survival ranged from 11% to 72%.5 Five-year survival rates of 40%-70% have been reported for patients who received transplants during early chronic-phase CML. Transplantation within 1 year of diagnosis and in the chronic phase of disease is preferred.4,10,11 The use of pretreatment hydroxyurea seems to improve outcome as compared with pretreatment with busulfan,1,4,12 whereas prolonged administration of IFN-α in chronic-phase CML before SCT may adversely affect outcome12, 13. 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,4,6,14 whereas only 15%-20% of patients in blast crisis are alive 2-3 years after SCT.1,4,15
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.1,3,16,17 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.12,15 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 mortality.18 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 marrow,1 but it has been reported to be as high as 41% for poorer candidates12. The risk of mortality associated with SCT increases in advanced-phase disease. Mortality rates of approximately 50% in accelerated-phase CML4, 14, 15 and greater than 60% in blast crisis have been reported .15
>>1 2 3 4 References:
1. Faderl S, Kantarjian HM, Talpaz M. Chronic myelogenous leukemia: update on biology and treatment. Oncology (Williston Park).1999;13:169-180; discussion 181, 184.
2. Kantarjian HM, Giles FJ, O'Brien SM, Talpaz M. Clinical course and therapy of chronic myelogenous leukemia with interferon-alpha and chemotherapy. Hematol Oncol Clin North Am. 1998;12:31-80.
3. Sawyers CL. Chronic myeloid leukemia. N Engl J Med. 1999;340:1330-1340.
4. Passweg JR, Rowlings PA, Horowitz MM. Related donor bone marrow transplantation for chronic myelogenous leukemia. Hematol Oncol Clin North Am. 1998;12:81-92.
5. Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia. Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108:1809-1820.
6. Gratwohl A, Hermans J, Goldman JM, et al. Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Lancet. 1998;352:1087-1092.
7. Passweg JR, Walker I, Sobocinski KA, Klein JP, Horowitz MM, Giralt SA. Validation and extension of the EBMT Risk Score for patients with chronic myeloid leukaemia (CML) receiving allogeneic haematopoietic stem cell transplants. Br J Haematol. 2004;125:613-620.
8. Galton DA. Myleran in chronic myeloid leukaemia; results of treatment. Lancet. 1953;264:208-213.
9. Goldman JM. Chronic myeloid leukemia. Curr Opin Hematol. 1997;4:277-285.
10. Hehlmann R, Hochhaus A, Berger U, Reiter A. Current trends in the management of chronic myelogenous leukemia. Ann Hematol. 2000;79:345-354.
11. Petersdorf E, Anasetti C, Servida P, Martin P, Hansen J. Effect of HLA matching on outcome of related and unrelated donor transplantation therapy for chronic myelogenous leukemia. Hematol Oncol Clin North Am. 1998;12:107-121.
12. Silver RT, Woolf SH, Hehlmann R, et al. An evidence-based analysis of the effect of busulfan, hydroxyurea, interferon, and allogeneic bone marrow transplantation in treating the chronic phase of chronic myeloid leukemia: developed for the American Society of Hematology. Blood. 1999;94:1517-1536.
13. 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. 1995;85:2981-2990
14. 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 allogenic marrow transplants during chronic phase of chronic myeloid leukemia. Blood. 1999;94:3960-3962.
15. Gratwohl A, Hermans J, Niederwieser D, et al. Bone marrow transplantation for chronic myeloid leukemia: long-term results. Chronic Leukemia Working Party of the European Group for Bone Marrow Transplantation. Bone Marrow Transplant. 1993;12:509-516.
16. Faderl S, Talpaz M, Estrov Z, Kantarjian HM. Chronic myelogenous leukemia: biology and therapy. Ann Intern Med. 1999;131:207-219.
17. Horowitz MM, Rowlings PA, Passweg JR. Allogeneic bone marrow transplantation for CML: a report from the International Bone Marrow Transplant Registry. Bone Marrow Transplant. 1996;17(Suppl 3):S5-S6.
18. McGlave PB, Shu XO, Wen W, et al. Unrelated donor marrow transplantation for chronic myelogenous leukemia: 9 years' experience of the national marrow donor program. Blood. 2000;95:2219-2225.