|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2009.24.8518 on October 5 2009 © 2009 American Society of Clinical Oncology.
Toward a Total Cure for Acute Lymphoblastic LeukemiaSt Jude Children's Research Hospital and the University of Tennessee Health Science Center, Memphis, TN Steady progress in clinical trials for children and adolescents with acute lymphoblastic leukemia (ALL) has led to 5-year event-free survival rates as high as 79% to 86%.1–3 Thus, the focus of risk-directed treatment programs has narrowed to ALL subtypes that continue to resist conventional forms of intensive chemotherapy, and to strategies that could be used to spare certain subsets of patients from the morbidity or mortality associated with intensive treatment regimens. In this issue of Journal of Clinical Oncology, two impressive studies from the Children's Oncology Group4,5 and one from the Associazione Italiana di Ematologia ed Oncologia Pediatrica6 indicate substantial progress toward a total cure for ALL. Philadelphia chromosome–positive ALL accounts for 2% to 3% of childhood and approximately 25% of adult ALL cases and generally carries a dismal prognosis. Historically, fewer than one third of children with this leukemia could be cured with chemotherapy alone, while matched-related hematopoietic stem-cell transplantation was successful in up to two thirds of cases.7 Even with transplantation, the cure rates in adults seldom exceeded 20%.8 The introduction of tyrosine kinase inhibitors into intensive chemotherapy regimens has significantly improved the remission induction rate and the duration of complete remission in adults, leading to an increased proportion of patients eligible for allogeneic transplantation, which remains the treatment of choice in this patient population.9
Encouraged by the results of a phase I trial within the Children's Oncology Group, Schultz et al4 treated 92 children with newly diagnosed Philadelphia chromosome–positive ALL with an intensive chemotherapy regimen plus imatinib (340 mg/m2 per day) after remission induction. The duration of exposure was increased in a stepwise fashion, from 42 days in the first cohort of patients to 280 days in the fifth cohort. There were no excessive toxicities, and the early treatment result for the 44 patients in the fifth cohort was quite spectacular—the 3-year event-free survival rate was 80.5% (SE, 11.2%) compared with only 35.0% (SE, 4.4%) for the 120 patients in the historical control group. Importantly, the 25 patients in the fifth cohort who received chemotherapy plus imatinib fared at least as well as the 21 patients (from several cohorts) who underwent matched-related transplantation, or the 11 patients who underwent matched-unrelated transplantation (3-year event-free survival: 87.7% [SE, 10.9%] v 56.6% [SE, 21.5%] v 71.6% [SE, 19.0%]). The 3-year event-free survival rate (50.0% [SE, 35.4%]) for the nine patients with induction failure was also impressive. Minimal residual disease (MRD) levels at the end of remission induction failed to predict treatment outcome in the fifth cohort (3-year event-free survival, 88.2% [SE, 17.5%] for the 18 patients with MRD Even though more than 80% of the patients had completed treatment at the time of reporting the study, longer follow-up is needed to determine if imatinib indeed improves cure rates or merely prolongs the duration of disease-free survival, a caveat that was stressed by Schultz et al.4 The conclusion that 6 months of imatinib treatment after transplantation offered no advantage over transplantation alone is not well supported by the data, as the comparison was based on a transplantation group of 21 patients treated in the present study and nine historical controls. Newer and more potent tyrosine kinase inhibitors (dasatinib and nilotinib, for example) will obviously need to be tested in future clinical trials. It will also be important to ask if epipodophyllotoxins, anthracyclines, alkylating agents, or cranial irradiation (all of which were employed in this study) can be omitted or reduced without compromising treatment outcome. Given the relatively small number of patients with Philadelphia chromosome–positive ALL, international collaborative studies will be needed to address these issues in a statistically meaningful way and in a timely fashion. Many adolescents and young adults with ALL show resistance to standard intensive chemotherapy, posing difficult challenges to pediatric and adult oncologists alike. Nachman et al10 of the Children's Oncology Group were the first to demonstrate the benefit of postremission intensification therapy with additional doses of asparaginase, vincristine, and methotrexate for patients with high-risk ALL and slow early response to treatment. To take advantage of this advance, they devised another clinical trial for patients with high-risk ALL, including those age 10 years and older, which Nachman et al5 now report. The study yielded an excellent 5-year event-free survival rate of 71.5% (SE, 3.6%) and overall survival rate of 77.5% (SE, 3.4%) for the 262 patients who were age 16 to 21 years. The rates were even better (81.8% [SE, 5.5%] and 83.2% [SE, 6.8%], respectively) for the 88 patients with rapid early responses (defined by 25% or fewer bone marrow blasts on day 7 of remission induction), who were randomized to receive augmented (rather than standard) postinduction intensification therapy with additional doses of vincristine and pegylated asparaginase (in lieu of mercaptopurine during interim maintenance therapy), and increased doses of intravenous methotrexate without leucovorin rescue. Two other clinical trials yielding excellent outcomes for adolescents also featured early intensification therapy with vincristine and asparaginase,3,11 suggesting that this treatment component might have contributed to the improved outcome in adolescents and young adults. Indeed, one recent study for adults with Philadelphia chromosome–negative ALL featuring intensive asparaginase and vincristine also yielded an excellent 3-year survival rate, 83% (95% CI, 72% to 95%), in 41 young adults age 18 to 35 years; patients who tolerated 80% or more scheduled doses of asparaginase had a significantly better survival probability than the remaining patients.12 Neither Storring et al12 nor Nachman et al5 favor the use of allogeneic transplantation for young adults with standard-risk ALL. In the study by Nachman et al,5 there was no statistical difference in treatment outcome between patients with a rapid early response who were randomized to receive either one or two courses of postinduction intensification therapy, a result also reported for younger patients enrolled in the same study.13 Given the excellent treatment outcome, the lack of benefit from an additional course of delayed intensification including high-doses of dexamethasone, and the high rate of osteonecrosis in this study, it may be of interest to test if prednisone pulses, which were given every 4 weeks during maintenance therapy, can be omitted in adolescents and young adults with ALL and rapid early responses. Five cases of second malignancy (four myeloid malignancies and one large-cell lymphoma) were observed in this Children's Oncology Group trial.5 This outcome might be related to the use of a relatively high-dose of mercaptopurine (75 mg/m2 per day) in remission maintenance therapy. A prolonged duration and high-dose intensity of mercaptopurine treatment and low activity of thiopurine-S-methyltransferase have been associated with an increased risk of a secondary myeloid malignancy in one recent ALL study reported by the Nordic group.14 At St Jude Children's Research Hospital, we have prospectively studied the genetic polymorphism and activity of this enzyme, decreasing the starting dose of mercaptopurine to 60 mg/m2 in patients with a heterozygous deficiency. In our most recently completed study, only one of 498 patients developed a secondary myelodysplastic syndrome.3 MRD levels after remission induction afford a highly sensitive and specific marker of treatment response in ALL patients, accounting for leukemic-cell biologic features (intrinsic drug sensitivity), host pharmacokinetics and pharmacogenomics, treatment efficacy, and treatment protocol adherence.15,16 Even so, the optimal timing and method of MRD assessment are a matter of debate. Basso et al,6 in a group-wide study involving 815 patients with ALL, showed that MRD levels measured by flow cytometry on day 15 of remission induction were a powerful prognostic factor that retained independent significance in a model including MRD levels determined by polymerase chain reaction (PCR) amplification of antigen-receptor genes on days 33 and 78 from the start of remission induction. While MRD levels at any time point during treatment have prognostic value, those at an early time point (eg, day 15 of remission induction) are particularly useful for identifying patients at low risk of relapse. Indeed, in the study of Basso et al, the 5-year cumulative risk of relapse among the 187 patients with a negative (< 0.01%) MRD test (23% of all 815 patients) on day 15 of induction was only 6.4% (SE, 1.9%). Likewise, in a study at St Jude Children's Research Hospital, the 5-year cumulative risk of relapse was 6.0% (SE, 3.4%) for 51 patients without detectable MRD (46% of 110 patients tested) on day 19 of remission induction.17 Thus, the findings of Basso et al corroborate the notion that MRD testing early in the treatment course can identify patients who are likely to have a superior treatment outcome and therefore can be spared from intensive chemotherapy—a decided advantage in resource-poor countries.18 Flow cytometry–based measurements are more rapid than those made with PCR techniques, and they can be performed in virtually all patients. Basso et al6 successfully studied 98% of 830 patients at 35 centers, while in a recent Children's Oncology Group study, satisfactory results (with a sensitivity of at least 0.01%) were obtained in 92% of 2,143 patients from more than 100 centers.19 Studies of MRD at early time points such as day 15 can be performed proficiently in patients with simple and inexpensive combinations of antibodies.18 Moreover, the flow cytometric data can be easily transferred via Internet to a central site for uniform analysis.20 In our center, flow cytometric assays are now used primarily for 98% of the patients, with PCR methods reserved for the remaining patients, who lack suitable immunophenotypes for MRD detection.
MRD assays were not only more sensitive but also more specific than morphologic examination, as shown in the patients studied by Basso et al.6 For example, seven patients with an MRD level less than 0.1% were classified as having an M3 marrow ( Further refinement of risk-directed therapy will undoubtedly push the cure rates in ALL even higher. Ultimately, we can look forward to a new era of more effective and less toxic targeted therapy ushered in by advances in understanding both the genetic and epigenetic changes in leukemic cells, host pharmacogenetics, and the interactions between leukemic and other cell types. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Ching-Hon Pui, EUSA Pharma Research Funding: None Expert Testimony: None Other Remuneration: None
NOTES See accompanying articles on pages 5168, 5175, and 5189 REFERENCES
1. Möricke A, Reiter A, Zimmermann M, et al: Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: Treatment results of 2,169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 111:4477–4489, 2008. 2. Moghrabi A, Levy DE, Asselin B, et al: Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia. Blood 109:896–904, 2007. 3. Pui CH, Campana D, Pei D, et al: Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 360:2730–2741, 2009. 4. Schultz KR, Bowman WP, Aledo A, et al: Improved early event-free survival with imatinib in Philadelphia chromosome–positive acute lymphoblastic leukemia: A Children's Oncology Group study. J Clin Oncol 27:5175–5181, 2009. 5. Nachman JB, La MK, Hunger SP, et al: Young adults with acute lymphoblastic leukemia have an excellent outcome with chemotherapy alone and benefit from intensive postinduction treatment: A report from the Children's Oncology Group. J Clin Oncol 27:5189–5194, 2009. 6. Basso G, Veltroni M, Valsecchi MG, et al: Risk of relapse of childhood acute lymphoblastic leukemia is predicted by flow cytometric measurement of residual disease on day 15 bone marrow. J Clin Oncol 27:5168–5174, 2009. 7. Aricò M, Valsecchi MG, Camitta B, et al: Outcome of treatment in children with Philadelphia chromosome–positive acute lymphoblastic leukemia. N Engl J Med 342:998–1006, 2000. 8. Moorman AV, Harrison CJ, Buck GA, 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 109:3189–3197, 2007. 9. Yanada M, Takeuchi J, Sugiura I, et al: High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL–positive acute lymphoblastic leukemia: A phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol 24:460–466, 2006. 10. 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. 11. Barry E, DeAngelo DJ, Neuberg D, et al: Favorable outcome for adolescents with acute lymphoblastic leukemia treated on Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium protocols. J Clin Oncol 25:813–819, 2007. 12. Storring JM, Minden MD, Kao S, et al: Treatment of adults with BCR-ABL–negative acute lymphoblastic leukaemia with a modified paediatric regimen. Br J Haematol 146:76–85, 2009.[CrossRef][Medline] 13. Seibel NL, Steinherz PG, Sather HN, et al: Early postinduction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukemia: A report from the Children's Oncology Group. Blood 111:2548–2555, 2008. 14. Schmiegelow K, Al-Modhwahi I, Andersen MK, et al: Methotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia: Results from the NOPHO ALL-92 study. Blood 113:6077–6084, 2009. 15. Pui CH, Robison LL, Look AT: Acute lymphoblastic leukemia. Lancet 371:1030–1043, 2008.[CrossRef][Medline] 16. Campana D: Minimal residual disease in acute lymphoblastic leukemia. Semin Hematol 46:100–106, 2009.[CrossRef][Medline] 17. Coustan-Smith E, Sancho J, Behm FG, et al: Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia. Blood 100:52–58, 2002. 18. Coustan-Smith E, Ribeiro RC, Stow P, et al: A simplified flow cytometric assay identifies children with acute lymphoblastic leukemia who have a superior clinical outcome. Blood 108:97–102, 2006. 19. Borowitz MJ, Devidas M, Hunger SP, et al: Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: A Children's Oncology Group study. Blood 111:5477–5485, 2008. 20. Lorenzana R, Coustan-Smith E, Antillon F, Ribeiro RC, Campana D: Simple methods for the rapid exchange of flow cytometric data between remote centers. Leukemia 14:336–337, 2000.[CrossRef][Medline]
Related Articles
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
0.01% v 75.9% [SE, 14.1%] for the 26 with higher levels), suggesting that the increased intensification of therapy with the addition of imatinib can abolish the prognostic strengths of this typically strong marker of drug resistance. 
25% blasts by morphology), with five remaining in remission. Conversely, 19 patients with an MRD level 
