Unrelated Transplants for High-risk Adult Acute Lymphoblastic Leukaemia

Christelle Ferrà, Josep-Maria Ribera
European Haematology, 2009;3(1):45-9
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Abstract

Standard chemotherapy has a poor outcome in adult patients with high-risk acute lymphoblastic leukaemia (ALL). Allogeneic haematopoietic stem cell transplant (alloSCT) is the treatment of choice, and SCT with alternative progenitors should be considered in the absence of a matched sibling donor. There is great heterogeneity in the data on unrelated SCT for adult patients with high-risk ALL. Many studies include both paediatric and adult patients, or provide combined data from ALL and acute myeloid leukaemia (AML) patients. Moreover, the follow-up of the reported series is highly variable, and the definition of high-risk criteria varies from one study to another. The reported disease-free survival (DFS) for adult ALL patients ranges from 30 to 70%, and leukaemia relapse (14–47%) is an important cause of treatment failure. Despite great improvements in recent years, transplant-related mortality (TRM) from unrelated SCT (USCT) remains unacceptably high (29–36%). The human leukocyte antigen (HLA) disparity in the unrelated donor setting with a high incidence of graft-versus-host disease (GvHD) and delayed immunological reconstitution with a high incidence of infectious events in the unrelated cord blood SCT are the most important causes of morbidity and mortality in unrelated transplants. Disease status at transplant and the presence of acute and/or chronic GvHD are the most important factors determining relapse in high-risk ALL adult patients undergoing USCT.
Keywords
Acute lymphoblastic leukaemia, allogeneic haematopoietic progenitor transplant, unrelated cord-blood transplant, adult, unrelated donor haematopoietic stem cell transplant
Disclosure The authors have no conflicts of interest to declare.
Received: May 22, 2009 Accepted June 26, 2009
Correspondence: Christelle Ferrà, Department of Clinical Haematology, Institut Català d’Oncologia, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, C/ Canyet s/n, 08916–Badalona, Spain. E: cferra@iconcologia.net

The outcome of adults with high-risk acute lymphoblastic leukaemia (ALL) features at diagnosis, slow responders or those with recurrent disease is poor with standard chemotherapy. Autologous stem cell transplantation (ASCT) has not demonstrated a clear advantage over chemotherapy for ALL patients in complete remission due to the high relapse rate,1–4 and allogeneic SCT (alloSCT) – even if associated with a higher transplant-related mortality (TRM) – remains the best therapeutic option for such high-risk ALL patients.5–9 In standard-risk ALL, the role of alloSCT remains uncertain in patients in first complete remission (CR). However, the UKALL/XII/Eastern Cooperative Oncology Group (ECOG) 2993 and the Dutch–Belgian Cooperative Trial Group for Hematology Oncology (HOVON)-18 ALL/HOVON-37 ALL studies have recently shown a survival advantage for those patients receiving a sibling-matched alloSCT.2,10 The expected disease-free survival (DFS) in high-risk adult patients is between 30 and 40%,11 and in most centres such patients are considered for an alternative donor SCT if a matched-sibling donor is not available, which reportedly occurs in about two-thirds of patients.12–14 Alternative haematopoietic sources can be partially human leukocyte antigen (HLA)-matched family donors, unrelated donors (UDs) or unrelated cord blood units, the latter having emerged as an option for unrelated SCT (USCT) even in adult patients.15–20 Despite some groups having reported a similar outcome for related and unrelated SCT in adult ALL patients,14,21–24 there seems to be a trend towards a poorer outcome in USCT due to a higher TRM.25 However, long-term results of adult patients receiving an alloSCT from an alternative source are scarce. The best choice of unrelated progenitor source and the best timing for the USCT remain matters of concern for many haematologists, especially in adult patients.

Indication for Unrelated Stem Cell Transplantation in Adult Acute Lymphoblastic Leukaemia

High-risk criteria in ALL patients include disease stage beyond the first CR and patients with first remission if they have poor-risk cytogenetics (t[9;22], t[4;11], t[1; 19], complex karyotype [more than four cytogenetic abnormalities] and low hypodiploidy/near triploidy), a slow response to induction chemotherapy (more than four weeks to achieve the first CR), failure to achieve complete CR after one induction course, leukocytosis at diagnosis (>30x109/l in B-precursor ALL or >100x109/l in T-cell ALL [T-ALL]) or age >35 years. Moreover, a significant level of minimal residual disease (MRD) has recently been associated with a poor outcome despite good prognostic features at diagnosis and the patients being in morphological remission.26–28

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