Acute Lymphoblastic Leukaemia in Adults: Findings and Implications of the Recent International ALL Trial
Acute lymphoblastic leukaemia (ALL) is the most common malignant disease of childhood, but can also occur in adults. Whilst long-term survival rates in childhood ALL have steadily improved over the past 50 years, adults with ALL fare much more poorly, a problem due in part to the lack of large-scale randomised trials in treating adult ALL. The largest ever study to look specifically at adult ALL is the International ALL trial, initiated in 1993, and its results have recently been published, addressing in particular the role of stem cell transplantation in ALL treatment. The trial (known as UKALL XII in the UK) confirms the efficacy of current chemotherapy in inducing disease remission. It addresses the issue of whether patients with the Philadelphia chromosome should receive allogeneic stem cell transplants, reporting that this gives a small but significant improvement in outcome, and challenges the current view that in Philadelphia-negative ALL, patients deemed to be ‘higher-risk’ benefit more from transplantation. Autologous stem cell transplantation, previously thought to prolong survival in adult ALL, is shown to be worse than conventional chemotherapy. The UKALL XII data have not yet been published for imatinib, a BCR-ABL fusion protein inhibitor useful in Philadelphia-positive disease, but will undoubtedly add to a growing body of knowledge with the potential to improve outcomes in this often overlooked form of cancer.
Acute lymphoblastic leukaemia (ALL) is a malignant disease characterised by the uncontrolled proliferation of immature white blood cells, lymphoblasts, which infiltrate the bone marrow and other organs . It is well-known as the most common malignancy of childhood, with a peak age incidence of 3-7 years, but also as one of the most treatable cancers: over the past 50 years, ALL survival in children has steadily improved [1, 2], such that cure rates for the best risk groups are now >90% [2, 3]. Whilst this has made childhood ALL treatment one of the great success stories of modern oncology, the survival statistics for adult patients present a stark contrast, with long term survival rates almost invariably below 40% . This discrepancy has been attributed to various factors, including different lymphoblast differentiation blocks, an abundance of less favourable cytogenetic abnormalities in adult disease, and poorer drug tolerance and compliance in adults [2, 4]. Aside from less favourable disease characteristics, progress in treating adult ALL has been impeded by its rarity: less than 1 case per 100 000 person-years . This has made difficult the construction of large-scale randomised trials, which are essential tools in evaluating the complex chemotherapy regimes used to treat leukaemias. However, this is currently set to change: the UK Medical Research Council (MRC) has long been a pioneer in the study of adult ALL, and has recently published the results of the largest ever trial in this field, the International ALL Trial (otherwise known as the UKALL XII study) [3, 6, 7]. After discussing the background to ALL and the history of the MRC’s adult ALL trials, this review will consider the results that UKALL XII has yielded, and their implications for the future of this difficult disease.
Clinical features and cytogenetics of ALL
The presenting features of ALL are similar in both children and adults. Infiltration of the bone marrow by rapidly-dividing lymphoblasts causes marrow failure, with consequent anaemia, thrombocytopenia and neutropenia. These may manifest in many ways; lethargy, recurrent infections and easy bruising are frequently seen. Examination may reveal hepatosplenomegaly, lymphadenopathy, and rarely testicular swelling from malignant infiltration. Essential investigations include a full blood count, and a bone marrow aspirate and/or trephine. A hypercellular marrow with >20% leukaemic blast cells (Figure 1) will confirm the diagnosis of acute leukaemia, but cell surface markers on the blast cells may need to examined by flow cytometry to determine their exact lineage as lymphoid or myeloid .
Figure 1: Bone marrow appearance of ALL. Note the numerous lymphoblasts with high nuclear:cytoplasmic ratio.
Once ALL has been diagnosed, analysis of the cells’ chromosomes is carried out to look for significant abnormalities. This information is important in determining the prognosis and treatment of the leukaemia, as well as in monitoring the response to therapy [2, 5]. One key abnormality with prognostic significance is the Philadelphia chromosome. This is a translocation of chromosomes 9 and 22, fusing the genes BCR and ABL to create a constitutively active protein kinase which deregulates cellular proliferation (Figure 2) . It is the most common cytogenetic abnormality in ALL, and is associated with a poor prognosis ; crucially, its incidence increases with age: around 3% of children are Philadelphia-positive (Ph+), compared with 25% of adults overall and >50% of adults aged over 50 [5, 9, 10].
Figure 2: The Philadelphia Chromosome. Translocation of chromosomes 9 and 22 creates the constitutively active BCR-ABL tyrosine kinase, inhibited by imatinib.
Clinical trials in adult ALL
Prior to the 1980s, children and adults with ALL were entered into the same clinical trials, on the assumption that age would not be a factor influencing the response to treatment to any significant degree. However, it eventually became clear that long-term survival for adults was not improving at the same rate that it was for children: while the 8-year event-free survival for children with ALL increased from around 10% to over 30% between 1962 and 1979 [1, 2], it languished at around 25% for adults . In 1980, the situation began to be addressed, with the initiation of the MRC’s first adult-only trial, UKALL IX. However, this randomised just 266 patients overall, and its successor UKALL XA only 450. These are small numbers when compared to the 1171 patients recruited into the equivalent paediatric trial, UKALL X [11, 12], and the fact that neither of these studies managed to draw conclusions about the efficacy of one treatment over another may in part be due to the low statistical power conferred by their small scale.
Given this history, one of the more exciting events in our understanding of adult ALL has been the implementation of UKALL XII, the largest ever randomised trial looking at treatment and prognosis of ALL in adults. A collaboration between the UK’s MRC and the United States Eastern Co-operative Oncology Group (ECOG), it was initiated in 1993, for all newly diagnosed untreated ALL patients aged 15-59. . 1929 patients were eventually recruited. The aim was to answer two fundamental questions about adult ALL :
1. Can allogeneic stem cell transplantation improve outcomes for all adult patients with ALL?
2. Which of the following is better for maintaining disease-free survival?
a. Autologous stem cell transplantation
The treatment protocol that was used is broadly outlined in Figure 3.
Figure 3: Summary of the UKALL XII treatment protocol. Patients were randomised to one of three treatment subgroups (shown in red, blue and green). *If a suitable sibling donor could not be found for Ph+ patients, searching for a matched unrelated donor was also tried.
Current Principles of Treatment
The initial goal in treating newly diagnosed ALL is to induce remission, using a combination of chemotherapeutic agents to eliminate >99% of the leukaemic blasts : the ‘induction’ phase in Figure 3. One of the earliest published conclusions of UKALL XII has been to vindicate the efficacy of the current induction regime, showing that 91% of patients achieve complete remission from disease after their induction chemotherapy: this represents a higher proportion than in previous, smaller studies . After remission has been achieved, it must be maintained, essentially in one of two ways: chemotherapeutic drugs, or stem cell transplantation (SCT).
The principle of SCT is to destroy the patient’s own bone marrow by a combination of total body irradiation and chemotherapy, and then replace it either with cells from a suitable tissue-typed donor (allogeneic transplant), or with the patient’s own cells, these having been previously stored (autologous transplant). Whilst allogeneic SCT offers the possibility of a cure for ALL patients deemed to have high-risk disease, transplants are limited in scope by their extremely high mortality rate, which has been around 30-53% during the last 10 years . Additionally, complications such as graft-versus-host disease are common, and can be debilitating for sufferers .
Since adults with ALL are much less likely than children to achieve a cure with chemotherapy alone, it is very important to determine which adults will benefit most from transplantation, and for whom the risk of complications is too great to justify a transplant. Previously, the consensus has been that all adults deemed to have ‘high-risk’ disease – older age, higher white blood cell count at diagnosis and poor cytogenetics all contribute to risk – should have a transplant when they achieve their first complete remission, as should adults who relapse, once their ALL has been brought into remission again . Ph+ adult ALL has traditionally been assumed to benefit from transplantation, due to its short remission time and poor response to chemotherapy. However, UKALL XII has now provided good evidence that allogeneic transplantation does indeed confer a “modest” improvement in overall survival in this type of disease: an intention-to-treat analysis showed that 5-year survival was 34% for patients with a donor, versus 25% for those without [7, 10].
Ph- disease carries an inherently better prognosis, so the risk-benefit balance for transplantation is harder to determine, and again, the value of having a large study is the power to discern more accurately those groups who will benefit from different treatments. Whilst previous studies have concluded that Ph- patients with higher risk disease should be transplanted, the conclusion in UKALL XII was actually that ‘standard risk’ patients benefit more from allogeneic transplants than higher risk patients . Standard-risk disease was defined as age 35 or under and WBC <100 (B-lineage ALL) or <30 (T-lineage ALL) at diagnosis, and these patients (n = 239) were found to have significantly better long-term survival and relapse rates than equivalent patients receiving chemotherapy or autologous transplants (n = 323); overall survival was 62% versus 52% at 5 years. High-risk patients also had a decreased relapse rate, but had higher non-relapse mortality; this high transplant-related mortality was attributed by the authors to older patients having more co-morbidities . This finding gives a new criterion on which haematologists can base the decision to transplant, although further work would be useful to elucidate more factors underlying successful transplantation.
Another conclusion with implications for clinical practice is the failure of UKALL XII to demonstrate an advantage of autologous SCT over conventional chemotherapy for consolidation and maintenance of remission. Whilst previous studies have indicated that autografts may confer a long-term survival advantage , a large sample from UKALL XII has indicated that this is not the case in Ph- disease: 5-year overall survival was worse in those patients randomised to autografts (n = 229) versus chemotherapy (n = 227), at 37% vs 46% . As graft-related mortality and morbidity are not insignificant, the decision to perform autologous transplantation  should not be undertaken lightly, and this finding provides good quality evidence that may help to curb unnecessary transplantation practices.
Futures: imatinib in Ph+ ALL?
One further issue that UKALL XII has the potential to shed light on is the value of imatinib in the treatment of adult ALL. Imatinib (trade name Glivec®) is a small-molecule inhibitor of the BCR-ABL fusion protein produced as a result of the Philadelphia chromosome . It has been successfully used to induce remission in chronic myeloid leukaemia and Ph+ ALL , having significant activity against relapsed or refractory disease in the latter case, and fewer side-effects than the conventional salvage chemotherapy given in relapsed ALL . Imatinib was introduced into the UKALL XII protocol for Ph+ patients in 2004 , but only the results from before this change have been published so far.
The question as to how imatinib may best be used in adult ALL has naturally arisen previously, and some studies have attempted to address it. One group looked at newly diagnosed ALL in elderly patients (aged >55 years), on the basis that its lower toxicity than conventional chemotherapy or transplantation might make it particularly beneficial in this group. Whilst imatinib sent 96% of patients into remission, as compared to 50% by chemotherapy, there was no significant difference in 2-year survival between the two groups, this being 42% overall . These results are likely to reflect rapid development of drug resistance , a problem which may be addressed in future by the licensing of new imatinib analogues, some of which are currently in trials . When the UKALL XII results from patients receiving imatinib are published, it will be interesting to see whether this drug does have the potential to increase long-term survival in a large cohort, and whether it will affect the risk-benefit ratio for allogeneic transplantation in Ph+ disease.
Many findings have been discussed in this article, but the most important question must always be, ‘what are their implications for clinical practice?’. It is safe to say that UKALL XII has provided a large-scale study with the power to conclusively evaluate the value of different treatments. Whilst it has validated current chemotherapeutic intervention in adult ALL to a certain extent, it has shown that autologous SCT has no place in its treatment. Allogeneic transplantation may have some value in Ph- disease, although it can no longer be recommended in older, higher-risk patients in its current form. In Ph+ disease, it still remains the treatment of choice, but this may well change with the advent of further data on BCR-ABL fusion protein inhibitors. Overall, this is an era of fast-moving research in adult ALL, and there is realistic hope that survival rates may soon begin to improve.
1. Pui CH., et al. Acute lymphoblastic leukaemia. N Engl J Med. 1998;339:605-615.
2. Pui CH., et al. Treatment of acute lymphoblastic leukaemia. N Engl J Med. 2006;354:166-178. doi: 10.1056/NEJMra052603
3. Goldstone AH., et al. In adults with standard-risk acute lymphoblastic leukaemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintentance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008;111:1827-1833. doi: 10.1182/blood-2007-10-116582
4. Plasschaert SLA., et al. Prognosis in childhood and adult acute lymphoblastic leukaemia: a question of maturation? Cancer Treat Rev. 2004;30:37–51. doi: 10.1056/NEJM199808273390907
5. Moorman AV., et al. Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood. 2007;109:3189-3197. doi: 10.1182/blood-2006-10-051912
6. Rowe JM. Optimal management of adults with ALL. Br J Haematol. 2009;144:468-483. doi: 10.1111/j.1365-2141.2008.07513.x
7. Fielding AK., et al. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome–positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALLTrial MRC UKALLXII/ECOG2993. Blood. 2009;113:4489-4496. doi: 10.1182/blood-2009-01-199380
8. Schouten HC. Diagnosis, staging and prognostic factors. Ann Oncol. 2007;18(Suppl 1):i22-i28. doi: 10.1093/annonc/mdl446
9. Pui CH., et al. Acute lymphoblastic leukaemia. N Engl J Med. 2004;350:1535-1548. doi: 10.1056/NEJMra023001
10. Fielding AK., et al. Allogeneic haematopoietic stem cell transplant in Philadelphia-positive acute lymphoblastic leukaemia. Bone Marrow Transplant. 2008;41:447-453. doi:10.1038/sj.bmt.1705904
11. Durrant IJ., et al. Results of Medical Research Council trial UKALL IX in acute lymphoblastic leukaemia in adults: report from the Medical Research Council Working Party on Adult Leukaemia. Br J Haematol. 1993;85:84-92. doi:10.1111/j.1365-2141.1993.tb08649.x
12. Durrant IJ., et al. Intensification of treatment for adults with acute lymphoblastic leukaemia: results of U.K. Medical Research Council randomized trial UKALL XA. Br J Haematol. 1997;99:84-92. doi:10.1046/j.1365-2141.1997.3613175.x
13. Rowe JM., et al. Induction therapy for adults with acute lymphoblastic leukaemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005;106:3760-3767. doi: 10.1182/blood-2005-04-1623
14. Avivi I., et al. Bone marrow transplant in Ph+ ALL patients. Bone Marrow Transplant. 2003;31:623-632. doi:10.1038/sj.bmt.1703899
15. Larson RA. Allogeneic hematopoietic cell transplantation for adults with ALL. Bone Marrow Transplant. 2008;42:S18-S24. doi: 10.1016/j.hoc.2009.07.006
16. Savage DG., et al. Imatinib mesylate – a new oral targeted therapy. N Engl J Med. 2002;346:683-693. doi: 10.1056/NEJMra013339
17. Druker BJ, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukaemia and acute lymphoblastic leukaemia with the Philadelphia chromosome. N Engl J Med. 2001;344:1038-1042. doi: 10.1056/NEJM200104053441402
18. Wassmann B., et al. A randomized multicenter open label phase II study to determine the safety and efficacy of induction therapy with imatinib (Glivec, formerly STI571) in comparison with standard induction chemotherapy in elderly (>55 years) patients with Philadelphia chromosome-positive (Ph+/BCR-ABL+) acute lymphoblastic leukaemia (ALL) (CSTI571ADE 10). Ann Hematol. 2003;82:716-720. doi: 10.1056/NEJM200104053441402
19. Ottmann OG., et al. Imatinib Compared with Chemotherapy as Front-Line Treatment of Elderly Patients With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukaemia (Ph+ALL). Cancer. 2007;109:2068-2076. doi: 10.1002/cncr.22631
20. Gruber F., et al. Impact of tyrosine kinase inhibitors on patient outcomes in Philadelphia chromosome-positive acute lymphoblastic leukaemia. Br J Haematol. 2009;145:581-597. doi: 10.1111/j.1365-2141.2009.07666.x