Which patients should I transplant with acute lymphoblastic leukemia?

Abstract

Allogeneic hematopoietic cell transplantation for acute lymphoblastic leukemia (ALL) offers curative therapy for patients who are in complete remission. Historically, there was great hesitation to offer this modality to patients with ALL due to the high attendant morbidity and mortality. Furthermore, the outstanding results in childhood ALL led many to believe that significant long-term survival could be achieved using chemotherapy-based regimens alone. The International ALL Study jointly conducted by ECOG and MRC completely changed perceptions indicating, surprisingly to many, that transplantation – particularly for patients at standard risk – offered a significant survival advantage. There followed trials of more intensive chemotherapy demonstrating improved results that may obviate the need for allogeneic transplantation. While a certain controversy reigns, there are unequivocal high-risk scenarios where allogeneic transplantation still forms the core of curative therapy. Such transplants should be performed as early as possible in the course of the disease once remission has been obtained.

Introduction

Acute lymphoblastic leukemia (ALL) is a heterogonous and aggressive disease. In children, due to aggressive chemotherapeutic regimens, the cure rate of ALL approaches 90%. In adult patients the 5-year overall survival (OS) rate is relatively low, estimated to be 40–45% [1]. Allogeneic stem cell transplantation (allo SCT) was demonstrated to be significantly better than conventional chemotherapy in the largest prospective study of transplantation in ALL, the International ALL Study, conducted jointly by the Eastern Cooperative Oncology Group in the United States and the Medical Research Council in the United Kingdom – ECOG E2993/MRC UKALLXIII trial [2]. In a donor versus no donor analysis, allo SCT in first complete remission (CR1) resulted in better OS and disease-free survival (DFS) in standard-risk ALL patients. Despite a lower relapse rate also in high-risk patients, a survival advantage could not be demonstrated in patients older than 40 years; the high non-relapse mortality abrogated the benefit due to the potent graft-versus-leukemia (GvL) effect.

In recent years, many studies reported that adolescents and young adults (AYA) with ALL may benefit from pediatric-like (i.e., more intensive) chemotherapy protocols, leading to improved survival, which may even be superior to what can be achieved with an allo SCT [3], [4], [5], [6], [7], [8]. Moreover, the development of new and sensitive techniques to monitor minimal residual disease (MRD) may serve as a very potent tool in assessing response to therapy at critical milestones, suggesting that allo SCT may be reserved for specific high-risk subgroups of patients with ALL. However, importantly, both of these premises have yet to be proven to benefit the overall outcome in adult ALL. Lastly, continued discoveries of new disease-related genetic aberrations enhances the process of redefining the risk of ALL subgroups and, in some categories, developing new targeted therapies that currently are being integrated into existing therapeutic strategies. Considering this, the roles of allo SCT over the treatment course of ALL patients need to be continuously evaluated, ideally in prospective randomized studies.

This review will critically assess the overall strategy of transplantation in ALL, particularly in light of new prognostic factors and advances in therapeutic strategies. Specific subgroups of patients may be identified in whom allo SCT remains the cornerstone of management, irrespective of improvement in the chemotherapeutic management of ALL [Table 1].