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© 2003 American Society for Clinical Oncology
Differences in Outcome in Adolescents With Acute Lymphoblastic Leukemia: A Consequence of Better Regimens? Better Doctors? Both?Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI A SERIES of systematic clinical trials in children with acute lymphoblastic leukemia (ALL) has resulted in such high cure rates that many of the current trials are designed to evaluate less intensive therapy to achieve similar results with fewer long-term side effects. Of note is that most of these advances resulted from empirically derived chemotherapeutic approaches, which antedated both our current understanding of the marked biologic heterogeneity of this disease and the coining of the word "translational." The application of immunophenotyping, cytogenetic, molecular genetic, and most recently, gene array analyses,1 has parsed ALL into many groupings with different biologic features, with the latest astounding observation that many, if not most, cases of pediatric ALL derive from mutations acquired in utero.2,3 Interestingly, although these more sophisticated immunophenotypic, cytogenetic, and molecular genetic classifications have marked prognostic implications, particularly in children, they generally do not provide insight into mechanisms of drug resistance and treatment failure. It is hoped that new generations of pharmacokinetic, pharmacogenomic, and cellular pharmacology studies will permit more directed and less empiric usage of chemotherapy regimens in the future4,5 The outcome for ALL in adults is considerably less favorable, with overall cure rates of < 30%. Factors contributing to this marked difference include a much higher incidence of the Philadelphia chromosome in adults; a much lower incidence of favorable findings such as hyperdiploidy and the molecularly detected Tel/AML1 mutation; poorer tolerance of intensive chemotherapy and, in particular, L-asparaginase and high-dose methotrexate. For example, prolonged treatment with L-asparaginase was an important feature of one of the more successful programs in higher-risk childhood ALL,6 but it has been difficult to deliver similar doses to older patients. An article in this issue of the journal by Boissel et al indicates that another factor might be the application of different treatment regimens, and the authors hint that "disparities in treating attitudes between pediatric and adult departments" might be contributory as well.7 These authors compared the outcome of 15- to 20-year-old adolescents with ALL treated in France on either the pediatric FRALLE-93 or adult LALA-948 clinical trials. Except for a 2-year difference in median age, the 77 patients in the pediatric trials and the 100 patients in the adult trials had a similar incidence of known unfavorable prognostic factors with actually a slightly higher frequency of hyperdiploid karyotypes in the LALA-94 group. With a median follow-up of about 3.5 years, the complete response (CR) rate (94% v 83%), event-free survival (EFS) at 5 years (67% v 41%), and disease-free survival (DFS) in complete responders (72% v 49%) were superior in the pediatric group, and multivariable analysis confirmed the independent influence of treatment trial on outcome. This was a retrospective analysis and not a randomized trial, and some relatively minor methodologic quibbles can be raised, including somewhat different criteria for referral for transplantation, discrepancies in the evaluation for Tel/AML1, and unknown biases for referral to pediatric or adult treatment centers. Are these provocative results a Gallic anomaly? Probably not. The Children’s Cancer Group (CCG) and the Cancer and Leukemia Group B (CALGB) have reported a similar analysis comparing outcome in ALL patients aged 16 to 21 years who were treated from 1988 to 1998.9 One hundred three patients were treated on sequential CALGB studies that employed a common treatment regimen,10 and 196 patients were treated by CCG institutions.11 Again, there was little apparent difference between the two groups in prognostic factors. Although the CR rates were similar (96%, CCG; 93%, CALGB), there was a huge difference in 6-year EFS (64%, CCG; 38%, CALGB). The US studies were presented in a pediatric session at the American Society of Hematology and engendered vigorous discussion about the differences in the regimens and the absence of data on the actual drug dosage delivered in the two cohorts. Most uncomfortable for us outnumbered adult hematologists in attendance were the cries about "better doctors" from some of our usually collegial pediatric oncology colleagues. "Better" perhaps (but I think less likely); "different," most certainly. ALL is the most common leukemia found in children and perhaps the most common cancer treated by pediatric oncologists. In contrast, ALL in adults is much less common than acute myeloid leukemias, myeloproliferative disorders, or chronic leukemias. Virtually all children with ALL are referred to pediatric centers and treated on clinical trials by physicians who focus primarily on this disease with experienced support teams. In contrast, as with most adult tumors, most patients with ALL seen by adult oncologists in the United States are probably not treated on clinical trials. More critical, however, is that they are generally treated by physicians and support teams who see many fewer patients with this disorder. Approximately 25% of patients treated on CALGB ALL studies were seen at nonuniversity settings (Larson R, personal communication, November 2002), whereas 40% of the patients entered on the last two Southwest Oncology Group (SWOG) frontline ALL studies were accrued from Community Clinical Oncology Programs (CCOP) or affiliate centers (Kopecky K, personal communication, November 2002). Most oncologists who treat adults concentrate on the treatment of solid tumors and infrequently encounter patients with acute leukemia, and they encounter patients with ALL even less often. In addition, even most adult university centers do not have well-defined leukemia programs with leukemia-focused staff. Of note is that the outcome in the SWOG studies did not differ significantly according to the type of institution in which the patients were treated, although a large number of centers entered only a few patients over the many years these studies were open. ALL regimens are remarkably complex and prolonged, using multiple drugs (many of which are given orally, with the potential for variable patient compliance), frequent intrathecal therapies, and cranial irradiation. A quick glance at Table 1 from the paper by Boissel et al is a reminder of the convoluted nature of these ALL treatment regimens. Pediatricians administer these treatments with a military precision on the basis of a near-religious conviction about the necessity of maintaining prescribed dose and schedule come hell, high water, birthdays, Bastille Day, or Christmas. There are, however, remarkably few data documenting the necessity of this rigor or the degree to which it can actually be achieved, particularly with increasing patient age. Nor is there information as to whether university-based or community oncologists who treat adults are "better" at protocol adherence, although it is likely that neither are up to pediatric standards (mea culpa, as well). Boissel et al suggest that there was excellent protocol adherence in both the FRALLE and LALA groups during induction, albeit with a 5-day-longer interval in starting the second course of treatment in the adult study. There is less information available from the CALGB/CCG abstract, but the CR rates were identical, which indicates good dose administration during induction. This is not particularly surprising, because induction is usually administered in the hospital and is generally more straightforward than the outpatient postremission courses, where deviations are much more common. Indeed, the lower DFS in the French comparison and the lower EFS despite similar CR rates in the US studies emphasize the importance of the components of the postremission induction therapies. Differences between the regimens are the other obvious consideration. The complexities of the regimens make exact comparisons difficult. In general, the pediatric trials administer more corticosteroids, sometimes on a fractionated schedule, and considerably more L-asparaginase, although the CALGB regimen gave 14 doses of L-asparaginase during 7 weeks of the first 3 months of treatment and was actually patterned after "high-risk" pediatric protocols. Adult programs also usually cap the dose of vincristine at 2 mg, which may or may not be an important issue. The CALGB and LALA protocols called for the use of cyclophosphamide/ifosphamide, which was omitted in the FRALLE protocol. However, one of the few randomized trials in adults that attempted to dissect the importance of different components of the treatment programs failed to show a benefit from the addition of cyclophosphamide.12 How can some of these uncertainties be addressed in the future? It is hoped that when the CALGB/CCG studies are reported in full, there will be an analysis of the doses actually delivered (and by which doctors) and that this information will be captured more fully in future studies. It is desirable that planned studies in this age group should include both adult and pediatric cooperative groups and initially build on the template of the pediatric regimens. More young adults should be referred to research treatment centers with experience in the management of ALL and captured for clinical trials (only about 10 such patients per year were seen by the CALGB). Because the CALGB had similar results in patients aged 21 to 29 years, eligibility for these more intensive studies should be extended to older patients as well, with careful assessment of tolerability. The practice of using the same chemotherapy protocols to treat an adult population that spans 5 to 6 decades in age should be re-examined; it is possible that adolescents and younger adults (< 30 years old) may be relatively underdosed. Last, it is hoped that molecular genetic and proteomic evaluations will cast further light on the causes of the rather striking decreases in survival seen as patients age from childhood to adolescence. REFERENCES 1. Yeoh EJ, Ross ME, Shurtleff SA, et al: Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell 1:133–143, 2002[CrossRef][Medline]
2. Taub JW, Konrad MA, Ge Y, et al: High frequency of leukemic clones in newborn screening blood samples of children with B-precursor acute lymphoblastic leukemia. Blood 99:2992–2996, 2002
3. Maia AT, Ford AM, Jalali GR, et al: Molecular tracking of leukemogenesis in a triplet pregnancy. Blood 98:478–482, 2001 4. McLeod HL, Coulthard S, Thomas AE, et al: Analysis of thiopurine methyltransferase variant alleles in childhood acute lymphoblastic leukaemia. Br J Haematol 105:696–700, 1999[CrossRef][Medline] 5. Dervieux T, Hancock M, Evans W, et al: Effect of methotrexate polyglutamates on thioguanine nucleotide concentrations during continuation therapy of acute lymphoblastic leukemia with mercaptopurine. Leukemia 16:209–212, 2002[CrossRef][Medline] 6. Clavell LA, Gelber RD, Cohen HJ, et al: Four-agent induction and intensive asparaginase therapy for treatment of childhood acute lymphoblastic leukemia. N Engl J Med 315:657–663, 1986[Abstract]
7. Boissel N, Auclerc M-F, Lheritier V, et al: Should adolescents with acute lymphoblastic leukemia be treated as old children or young adults? Comparison of the French FRALLE-93 and LALA-94 trials. J Clin Oncol 21:774–780, 2003
8. Fiere D, Lepage E, Sebban C, et al: Adult acute lymphoblastic leukemia: A multicentric randomized trial testing bone marrow transplantation as postremission therapy. The French Group on Therapy for Adult Acute Lymphoblastic Leukemia. J Clin Oncol 11:1990–2001, 1993 9. Stock W, Satjer H, Dodge RK, et al: Outcome of adolescents and young adults with ALL: A comparison of Children’s Cancer Group (CCG) and Cancer and Leukemia Group B (CALGB) regimens. Blood 96:476a, 2000 (suppl)
10. Larson RA, Dodge RK, Linker CA, et al: A randomized controlled trial of filgrastim during remission induction and consolidation chemotherapy for adults with acute lymphoblastic leukemia: CALGB study 9111. Blood 92:1556–1564, 1998
11. Nachman JB, Sather HN, Sensel MG, et al. Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. N Engl J Med 338:1663–1671, 1998
12. Annino L, Vegna ML, Camera A, et al: Treatment of adult acute lymphoblastic leukemia (ALL): Long-term follow-up of the GIMEMA ALL 0288 randomized study. Blood 99:863–871, 2002
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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