Abstract
The cure rate of acute lymphoblastic leukemia (ALL) in children is 80%, compared to less than half in adults. A major proportion of this cure rate drop occurs in adolescents and young adults (AYAs). The age range defining this population varies between studies, biological characteristics are different from both younger children and older adults, and AYAs are treated either by pediatric or adult oncologists, who often apply different treatment approaches to the same ALL patient population. The outcome of AYAs aged 15-21 years treated by more contemporary pediatric protocols is similar to that of younger children but is inferior when using adult regimens. This motivated studying AYA patients, including those above the age of 21 years, with pediatric or ‘pediatrics-inspired' regimens that intensified nonmyelosuppressive drugs such as vincristine, steroids and asparaginase, with very promising preliminary results. Discovering new mutations in AYA ALL will help stratify patients into risk subgroups and identify targets for novel agents. This, together with fine-tuning pediatric chemotherapy principles will hopefully finally decrease the cure rate gap between children and AYAs - and even older adults.
References
1.
Siegel R, Naishadham D, Jema A: Cancer statistics. CA Cancer J Clin 2013;63:11-30.
2.
Pui CH, Evans WE: Treatment of acute lymphoblastic leukemia. N Engl J Med 2006;354:166-178.
3.
Larson RA, Dodge RK, Burns CP, Lee EL, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, Hooberman AL, Westbrook CA, Arthur DC, George SL, Bloomfield CD, Schiffer CA: A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood 1995;85:2025-2037.
4.
Stock W, Johnson JL, Stone RM, Kolitz JE, Powell BL, Wetzler M, Westervelt P, Marcucci G, DeAngelo DJ, Vardiman JW, McDonnell D, Mrózek K, Bloomfield CD, Larson RA: Dose intensification of daunorubicin and cytarabine during treatment of adult acute lymphoblastic leukemia: results of Cancer and Leukemia Group B Study 19802. Cancer 2013;119:90-98.
5.
Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM: In adults with standard-risk acute lymphoblastic leukemia, 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/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood 2008;111:1827-1833.
6.
Linker C, Damon L, Ries C, Navarro W: Intensified and shortened cyclical chemotherapy for adult acute lymphoblastic leukemia. J Clin Oncol 2002;20:2464-2471.
7.
Kantarjian HM, O'Brien S, Smith TL, Cortes J, Giles FJ, Beran M, Pierce S, Huh Y, Andreeff M, Koller C, Ha CS, Keating MJ, Murphy S, Freireich EJ: Results of treatment with hyper-CVAD, a dose intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol 2000;18:547-561.
8.
Pulte D, Gondos A, Brenner H: Improvement in survival in younger patients with acute lymphoblastic leukemia from the 1980s to the early 21st century. Blood 2009;113:1408-1411.
9.
Douer D: Is asparaginase a critical component in the treatment of acute lymphoblastic leukemia? Best Practice Res Clin Haematol 2008;21:647-658.
10.
Harrison CJ: Cytogenetics of pediatric and adolescent acute lymphoblastic leukemia. Br J Haematol 2009;144:147-156.
11.
Hunger SP, Schafer ES: Optimal therapy for acute lymphoblastic leukemia in adolescents and young adults. Nat Rev Clin Oncol 2011;8:417-424.
12.
Wood WA, Lee SJ: Malignant hematologic diseases in adolescents and young adults. Blood 2011;117:5803-5815.
13.
Alvarnas JC, Brown PA, Aoun P, Ballen KK, Bellam N, Blum W, Boyer MW, Carraway HE, Coccia PF, Coutre SE, Cultrera J, Damon LE, Deangelo DJ, Douer D, Frangoul H, Frankfurt O, Goorha S, Millenson MM, O'Brien S, Petersdorf SH, Rao AV, Terezakis S, Uy G, Wetzler M, Zelenetz AD, Naganuma M, Gregory KM: Acute lymphoblastic leukemia. J Natl Compr Canc Netw 2012;10:858-914.
14.
Hoelzer D, Thiel E, Loffler H, Büchner T, Ganser A, Heil G, Koch P, Freund M, Diedrich H, Ruhl H, Maschmeyer H, Lipp T, Nowrousian MR, Burkert M, Gerecke D, Pralle H, Müller U, Lunsken CH, Fülle H, Ho AD, Küchler R, Busch FW, Schneider W, Görg CH, Emmerich B, Braumann D, Vaupel HA, von Paleske A, Bartels A, Neiss A, Messerer D: Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults. Blood 1988;71:123-131.
15.
Moorman AV, Harrison CJ, Buck GA, Richards SM, Secker-Walker LM, Martineau M, Vance GH, Cherry AM, Higgins RR, Fielding AK, Foroni L, Paietta E, Tallman MS, Litzow MR, Wiernik PH, Rowe JM, Goldstone AH, Dewald GW: 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.
16.
Mulligan CG: Molecular genetics of B-precursor acute lymphoblastic leukemia. J Clin Invest 2012;122:3407-3415.
17.
Paulsson K, Cazier JB, Macdougall F, Stevens J, Stasevich I, Vrcelj N, Chaplin T, Lillington DM, Lister TA, Young BD: Microdeletions are a general feature of adult and adolescent acute lymphoblastic leukemia: unexpected similarities with pediatric disease. Proc Natl Acad Sci USA 2008;105:6708-6713.
18.
Loh ML, Harvey RC, Mullighan CG, Linda SB, Devidas M, Borowitz MJ, Carroll AJ, Chen I-M, Gastier-Foster NM, Heerema NA, Kang H, Raetz EA, Roberts KG, Zhang J, Winick N, Wood BL, Larsen EC, Carroll WL, Willman CL, Hunger SP: A BCR-ABL1-like gene expression profile confers a poor prognosis in patients with high-risk acute lymphoblastic leukemia (HR-ALL): a report from Children's Oncology Group (COG) AALL0232. Blood 2011;118:743.
19.
Stock W: Adolescents and young adults with acute lymphoblastic leukemia. Am Soc Hematol Educ Program 2010;2010:21-29.
20.
Douer D: Adult lymphoblastic leukemia: a cancer with no standard of care. Acta Haematol 2013;130:196-198.
21.
Barry E, DeAngelo DJ, Neuberg D, Stevenson K, Loh ML, Asselin BL, Barr RD, Clavell LA, Hurwitz CA, Moghrabi A, Samson Y, Schorin M, Cohen HJ, Sallan SE, Silverman LB: Favorable outcome for adolescents with acute lymphoblastic leukemia treated on Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium Protocols. J Clin Oncol 2007:25:813-819.
22.
Nachman JB, La MK, Hunger SP, Heerema NA, Gaynon PS, Hastings C, Mattano LA Jr, Sather H, Devidas M, Freyer DR, Steinherz PG, Seibel NL: 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 2009;27:5189-5194.
23.
Pui CH, Pei D, Campana D, Bowman WP, Sandlund JT, Kaste SC, Ribeiro RC, Rubnitz JE, Coustan-Smith E, Jeha S, Cheng C, Metzger ML, Bhojwani D, Inaba H, Raimondi SC, Onciu M, Howard SC, Leung W, Downing JR, Evans WE, Relling MV: Improved prognosis for older adolescents with acute lymphoblastic leukemia. J Clin Oncol 2010;29:386-391.
24.
Freyer DR, Devidas M, La M, Carroll WL, Gaynon PS, Hunger SP, Seibel NL: Postrelapse survival in childhood acute lymphoblastic leukemia is independent of initial treatment intensity: a report from the Children's Oncology Group. Blood 2011;117:3010-3015.
25.
Stock W, La M, Sanford B, Bloomfield CD, Vardiman JW, Gaynon P, Larson RA, Nachman J; Children's Cancer Group; Cancer and Leukemia Group B studies: What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children's Cancer Group and Cancer and Leukemia Group B studies. Blood 2008;112:1646-1654.
26.
Schiffer CA: Differences in outcome in adolescents with acute lymphoblastic leukemia: a consequence of better regimens? Better doctors? Both? J Clin Oncol 2003;21:760-761.
27.
Usvasalo A, Räty R, Knuutila S, Vettenranta K, Harila-Saari A, Jantunen E, Kauppila M, Koistinen P, Parto K, Riikonen P, Salmi TT, Silvennoinen R, Elonen E, Saarinen-Pihkala UM: Acute lymphoblastic leukemia in adolescents and young adults in Finland. Haematologica 2008;93:1161-1168.
28.
Thomas DA, O'Brien S, Rytting M, Faderl S, Cortes J, Wierda WG, Ravandi F, Kantarjian HM: Acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) after frontline therapy with hyper-CVAD regimens. Blood 2008;112:1930.
29.
Stock W, Douer D, DeAngelo DJ, Arellano M, Advani A, Damon L, Kovacsovics T, Litzow M, Rytting M, Borthakur G, Bleyer A: Prevention and management of asparaginase/pegasparaginase-associated toxicities in adults and older adolescents: recommendations of an expert panel. Leuk Lymphoma 2011;52:2237-2253.
30.
Douer D, Yampolsky H, Cohen LJ, Watkins K, Levine AMJ, Periclou AP, Avramis VI: Pharmacodynamics and safety of intravenous pegaspargase during remission induction in adults aged 55 years or younger with newly diagnosed acute lymphoblastic leukemia. Blood 2007;109:2744-2750.
31.
Douer D, Aldoss I, Lunning MA, Ramezani L, Burke P, Mark L, Vrona J, Park JH, Tallman MS, Pullarkat V, Mohrbacher AM, Avramis VI: Pharmacokinetics-based modification of intravenous pegylated asparaginase dosing in the context of a ‘pediatric-inspired' protocol in adults with newly diagnosed acute lymphoblastic leukemia (ALL). Synapse 2012;120:1495.
32.
Burke PW, Aldoss I, Lunning MA, Avramis VI, Mohrbacher AM, Pullarkat V, Tallman MS, Douer D: High-grade pegylated asparaginase-related hepatotoxicity occurrence in a pediatric-inspired adult acute lymphoblastic leukemia regimen does not necessarily predict recurrent hepatotoxicity in subsequent cycles. Blood 2013;122:2671.
33.
Ribera JM, Oriol A, Sanz MA, Tormo M, Fernández-Abellán P, del Potro E, Abella E, Bueno J, Parody R, Bastida P, Grande C, Heras I, Bethencourt C, Feliu E, Ortega JJ: Comparison of the results of the treatment of adolescents and young adults with standard-risk acute lymphoblastic leukemia with the Programa Espanol de Tratamiento en Hematologia pediatric-based protocol ALL-96. J Clin Oncol 2008;26:1843-1849.
34.
Huguet F, Leguay T, Raffoux E, Thomas X, Beldjord K, Delabesse E, Chevallier P, Buzyn A, Delannoy A, Chalandon Y, Vernant JP, Lafage-Pochitaloff M, Chassevent A, Lhéritier V, Macintyre E, Béné MC, Ifrah N, Dombret H: Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol 2009;27:911-918.
35.
DeAngelo DJ, Dahlberg S, Silverman LB, Couban S, Amrein PC, Seftel MD, Turner AR, Leber B, Howsan-Jan K, Wadleigh M, Sirulnik LA, Supko J, Galinsky I, Sallan SE, Stone RM: A multicenter phase II study using a dose intensified pediatric regimen in adults with untreated acute lymphoblastic leukemia. Blood 2007;110:587.
36.
Goekbuget N, Beck J, Brueggemann M: 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 2010:116:494.
37.
Storring JM, Minden MD, Kao S, Gupta V, Schuh AC, Schimmer AD, Yee KW, Kamel-Reid S, Chang H, Lipton JH, Messner HA, Xu W, Brandwein JM: Treatment of adults with BCR-ABL negative acute lymphoblastic leukaemia with a modified paediatric regimen. Br J Haematol 2009;146:76-85.
38.
Douer D: What is the impact, present and future, of novel targeted agents in acute lymphoblastic leukemia? Best Pract Res Clin Hematol 2012;25:453-464.
39.
Thomas DA, O'Brien S, Faderl S, Garcia-Manero G, Ferrajoli A, Wierda W, Ravandi F, Verstovsek S, Jorgensen JL, Bueso-Ramos C, Andreeff M, Pierce S, Garris R, Keating MJ, Cortes J, Kantarjian HM: Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor B-lineage acute lymphoblastic leukemia. J Clin Oncol 2010;28:3880-3889.
40.
Brentjens RJ: CARs and cancers: questions and answers. Blood 2012;119:3872-3873.
41.
Deenik W, Beverloo HB, van der Poel-van de Luytgaarde SC, Wattel MM, van Esser JW, Valk PJ, Cornelissen JJ: Rapid complete cytogenetic remission after upfront dasatinib monotherapy in a patient with a NUP214-ABL1-positive T-cell acute lymphoblastic leukemia. Leukemia 2009;23:627-629.
© 2014 S. Karger AG, Basel
2014
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.
