A 32-year-old Polish plumber with a young family is receiving treatment for Philadelphia-positive acute lymphoblastic leukaemia (Ph+ ALL) and has achieved complete remission (CR) with induction therapy. He has no siblings but has been offered a stem cell transplantation (SCT) if a suitable unrelated donor can be identified. He is concerned about the risk of transplant and the long-term side effects.
What are the chances of finding a suitable donor?
Is he likely to benefit from a transplant?
What are the likely long-term complications of transplantation?
Acute lymphoblastic leukaemia (ALL) is rare, with 730 new cases diagnosed annually in the UK. Peaks of incidence occur under the age of 5 years, during the middle thirties and at over 60 years. The appearance of an aberrant chromosome 22, the Philadelphia chromosome, resulting from a reciprocal translocation t(9;22), is the classic founding event of chronic myeloid leukaemia (CML). However, the Philadelphia chromosome is frequently found in ALL lymphoblasts, accounting for 14% of patients presenting between the ages of 25 and 35 years.1 The translocation produces the BCR-ABL fusion gene that encodes a constitutively active tyrosine kinase contributing to malignant transformation in Ph+ ALL.
Due to high relapse rates, patients with Ph+ ALL fare worse than their Ph– counterparts and 5-year disease-free survival (DFS) following standard chemotherapy is less than 10% compared to 30%–65% in Ph– ALL.
Haemopoietic SCT permits high doses of cytotoxic therapy to be given, since the principle toxicity of such therapy – bone marrow failure – is ameliorated by infusion of stem cells shortly after high-dose therapy is completed. Autologous stem cells may be obtained from the patient prior to high-dose therapy but may be contaminated by tumour cells. Allogeneic stem cells, derived from a donor, are tumour free and may mediate a ‘graft-versus-leukaemia’ (GvL) effect. Genetic disparity between patient and donor influences the incidence of graft rejection, GvL and graft-versus-host disease (GvHD) that may complicate allogeneic SCT. Donor suitability is primarily dictated by the genetic constraints of the human leukocyte antigen (HLA) system. Three loci are key to selection and donors should ideally be identical to the patient at each HLA-A, HLA-B and HLA-DR pair. Siblings inherit one haplotype from each parent and have a theoretical chance of 1/4 of being a ‘6/6’ match with one another. It is customary to type volunteer unrelated donors at several additional loci since many other alleles, likely to be mismatched in an unrelated donor, exert an influence on the potential outcomes of SCT. The chances of finding a suitable unrelated donor within the international donor registries are frequently better than 80% but are influenced by the ethnicity of the patient, as most registered donors are of Northern European origin.
Myeloablative therapy, combining total body irradiation (TBI) and chemotherapy, followed by donor SCT has been successful in eradicating Ph+...