ALL in Adults: How Can We Do Better?
ALL in Adults: How Can We Do Better?
The treatment of acute lymphoblastic leukemia (ALL) is one of the true success stories in hemato-oncology. Starting with the first pioneering trials with folic acid antagonists, conducted by Sidney Farber in 1948, every decade since has brought promising new treatment options and improvements in outcomes. With the rapid growth of modern molecular biology and immunology, beginning in the 1970s and 1980s, hematologists have acquired a deeper understanding of the molecular and immunological features of this rare, albeit molecularly extraordinarily complex, disease. Cure rates in pediatric ALL are now around 80% to 90%. However, there is still room for improvement, especially in adult ALL, where overall long-term cure rates usually do not exceed 50%. New treatment options are needed.
In their concise and up-to-date review, Drs. Mathisen, Jabbour, and Kantarjian review the current treatment principles of ALL in adults with a specific focus on novel or emerging therapeutic options. First—and importantly—they point out that the distinction between “childhood ALL” and “adult ALL” is not clear-cut. When does childhood end and adulthood begin? Many therapy studies have set a minimum age of 15 or 16 years as an inclusion criterion for treatment within adult studies. It has been argued that adolescent patients, ie, those in the transitional years between childhood and adulthood (age 15 to 20 years), do better with pediatric treatment regimens than with regimens designed for adults (see the recent review of this topic by Ram et al). However, as Mathisen et al rightly point out, this question is far from being unambiguously settled. A closer look at the treatment results in children clearly shows that outcomes in childhood ALL are age-dependent. Young children around 4 years old do best, and treatment results get worse with every additional year of age and approximate those of young adults receiving “adult regimens.” A better question might be: which elements of treatments used in childhood ALL could be beneficial in adult ALL? One especially intriguing candidate is L-asparaginase, which was traditionally used at significantly higher doses in children than in adults. The first studies in adults of an increased dose of pegylated L-asparaginase have shown promising results, albeit with an increased toxicity rate that must be closely monitored in the future.
A few promising classical cytostatic drugs have been incorporated into the armamentarium of effective drugs for ALL in the last several years. One such agent is nelarabine (Arranon), a novel purine analog that has shown a marked T-cell–cytotoxic potency and that currently is being evaluated as a first-line agent in T-lineage ALL.
Allogeneic stem-cell transplantation has yielded significant improvements in several ALL patient subgoups regarded as “high-risk.” These results have led some therapy study groups to recommend an allogeneic transplant for every adult ALL patient with an available donor. However, this treatment modality has severe adverse effects, and a significant percentage of patients die from complications induced by transplantation (severe infections resulting from long-term immunosuppression, acute or chronic graft-versus-host disease). Quality of life is often severely compromised in transplanted patients. As long as the potential complications cannot be better controlled, transplantation should not be generally recommended for every ALL patient, but rather for only those subgroups of patients for whom no better options exist.
The most interesting developments in drug therapy for adult ALL are occurring in two fields: (1) molecularly targeted therapies and (2) the use of antibodies, conjugated antibodies, or antibody constructs.
Twenty-five percent of adult ALL patients are BCR-ABL–positive. The prevalence of the BCR-ABL fusion gene is age-dependent and continuously increases from young ages to the age of 30 to 35 years, after which it remains constant without further increase. Around 45% of B-lineage ALL patients over the age of 35 years are BCR-ABL–positive. The long-term survival of these patients is poor with conventional chemotherapy but has significantly improved with the increased use of allogeneic stem-cell transplantation. The impressive success of imatinib (Gleevec) and second-line tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML) has led to the inclusion of these TKIs in treatment regimens for ALL. Several studies have shown good tolerability and an increased rate or better quality of molecular remission. However, ALL is not CML, and TKI monotherapy rapidly leads to the growth of resistant BCR-ABL–positive subclones. Most patients who receive a combination of a TKI plus chemotherapy eventually relapse; thus, an allogeneic transplant is currently recommended for all eligible BCR-ABL–positive patients. Some questions regarding the treatment of BCR-ABL–positive ALL still remain to be answered, including the optimal combination of a TKI plus chemotherapy and, importantly, the questions of whether and how TKI therapy should be continued after transplantation.
The addition of rituximab (Rituxan) to chemotherapy in adult patients with CD20-positive ALL has led to improvements in outcomes; thus, other antibodies, such as ofatumumab (Arzerra; an anti-CD20 antibody), or antibody-drug conjugates, such as inotuzumab ozogamicin (an anti-CD22 antibody linked to the cytotoxin calicheamicin), are currently being evaluated in clinical trials in adult ALL. Perhaps the most promising immunotherapeutic agent is blinatumomab. Blinatumomab is not an antibody but rather a BiTE (Bi-specific T-cell engager). It consists of two different covalently linked Fab antibody fragments and lacks an Fc fragment. It is therefore not capable of complement activation. One Fab fragment targets the CD3 antigen, expressed by T cells, while the other Fab fragment targets the CD19 antigen, expressed by B cells. Blinatumomab thus effectively leads to the juxtaposition of cytotoxic T cells and B lymphoblasts—and subsequently to the elimination of the blasts by the T cells. In the first phase II clinical study, which involved 21 patients with very unfavorable disease characteristics (ie, molecular relapse or persistence), 16 patients became minimal residual disease–negative. Blinatumomab was mostly well tolerated. An update on the clinical course of the trial participants will be published soon in Blood.
In summary, there are still several significant problems to be solved and questions to be answered regarding therapy for adult ALL. The extraordinarily high level of research interest in the field and the large number of high-quality clinical studies conducted offers good reason for optimism that these efforts will translate to further increases in life expectancy and quality of life for affected patients in the near future.
Financial Disclosure: The author has no financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
Acknowledgements: The author gratefully acknowledges research funding from the Jos Carreras Leukemia Foundation (Germany).
1. Farber S, Diamond LK. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N Engl J Med. 1948;238:787-93.
2. Ram R, Wolach O, Vidal L, et al. Adolescents and young adults with acute lymphoblastic leukemia have a better outcome when treated with pediatric-inspired regimens: systematic review and meta-analysis. Am J Hematol. 2012;87:472-8.
3. Möricke A, Zimmermann M, Reiter A, et al. Prognostic impact of age in children and adolescents with acute lymphoblastic leukemia: data from the trials ALL-BFM 86, 90, and 95. Klin Padiatr. 2005;217:310-20.
4. Gökbuget N, Baumann A, Beck J, et al. Peg-asparaginase intensification in adult acute lymphoblastic leukemia (ALL): significant improvement of outcome with moderate increase of liver toxicity in the German Multicenter Study Group for Adult ALL (GMALL) study 07/2003. Blood (AHS Annual Meeting Abstracts). 2010;116:494.
5. Burmeister T, Schwartz S, Bartram CR, et al. Patients’ age and BCR-ABL frequency in adult B-precursor ALL: a retrospective analysis from the GMALL study group. Blood. 2008;112:918-9.
6. Ottmann OG, Wassmann B, Pfeifer H, et al. Imatinib compared with chemotherapy as front-line treatment of elderly patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Cancer. 2007;109:2068-76.
7. Pfeifer H, Lange T, Wystub S, et al. Prevalence and dynamics of BCR-ABL kinase domain mutations during imatinib treatment differ in patients with newly diagnosed and recurrent BCR-ABL positive acute lymphoblastic leukemia. Leukemia. 2012;26:1475-81.
8. Topp MS, Kufer P, Gökbuget N, et al. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol. 2011;29:2493-8.