Newly diagnosed childhood acute lymphoblastic leukemia: Update on prognostic factors and treatment

Current Opinion in Hematology

Volumn 10, Issue 4, 2003, Pages 290-296

  Silverman, Lewis B ^a   Sallan, Stephen E ^b  

^a DANA FARBER CANCER INSTITUTE   (United States)

^b BOSTON CHILDREN S HOSPITAL   (United States)

Author keywords

Childhood acute lymphoblastic leukemia; Gene expression profiling; Late effects; Minimal residual disease; Pharmacogenomics

Indexed keywords

ANTHRACYCLINE; ANTINEOPLASTIC AGENT; ASPARAGINASE; CORTICOSTEROID; DOXORUBICIN; ENALAPRIL; EPIPODOPHYLLOTOXIN; GROWTH HORMONE; IMATINIB; METHOTREXATE; PREDNISONE; VINCRISTINE;

ACUTE LYMPHOBLASTIC LEUKEMIA; ADOLESCENCE; ADULTHOOD; AGE DISTRIBUTION; BONE NECROSIS; CANCER CHEMOTHERAPY; CANCER DIAGNOSIS; CANCER GENETICS; CANCER RADIOTHERAPY; CANCER RISK; CANCER SURVIVAL; CARDIOTOXICITY; CENTRAL NERVOUS SYSTEM; CHILD; CHILDHOOD LEUKEMIA; CLINICAL TRIAL; COGNITIVE DEFECT; DISEASE CLASSIFICATION; GENE EXPRESSION; HIGH RISK PATIENT; HORMONE SUBSTITUTION; HUMAN; LEUKOCYTE COUNT; LYMPHOBLAST; MINIMAL RESIDUAL DISEASE; MOTOR DYSFUNCTION; NEUROTOXICITY; OBESITY; PHARMACOGENETICS; PHARMACOGENOMICS; PHILADELPHIA 1 CHROMOSOME; PRIORITY JOURNAL; PROGNOSIS; REVIEW; SEIZURE; SHORT STATURE; TREATMENT OUTCOME;

CENTRAL NERVOUS SYSTEM NEOPLASMS; CHILD; CYTOGENETICS; HUMANS; LEUKEMIA, LYMPHOCYTIC, ACUTE, L1; NEOPLASM, RESIDUAL; PHARMACOGENETICS; PROGNOSIS; TREATMENT OUTCOME;

EID: 0037631926     PISSN: 10656251     EISSN: None     Source Type: Journal    
DOI: 10.1097/00062752-200307000-00007     Document Type: Review

References (83)

1. Smith M, Arthur D, Camitta B, et al.: Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia. J Clin Oncol 1996, 14:18-24.
2. Silverman LB, Gelber RD, Dalton VK, et al.: Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. Blood 2001, 97:1211-1218.
3. Gaynon PS, Desai AA, Bostrom BC, et al.: Early response to therapy and outcome in childhood acute lymphoblastic leukemia: a review. Cancer 1997, 80:1717-1726.
4. Schrappe M, Reiter A, Zimmermann M, et al.: Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Berlin-Frankfurt-Munster. Leukemia 2000, 14:2205-2222.
5. Sandlund JT, Harrison PL, Rivera G, et al.: Persistence of lymphoblasts in bone marrow on day 15 and days 22 to 25 of remission induction predicts a dismal treatment outcome in children with acute lymphoblastic leukemia. Blood 2002, 100:43-47.
6. 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 2002, 100:52-58. This study confirms the prognostic importance of minimal residual disease levels during and at the end of remission induction therapy. It is one of the first studies to demonstrate that MRD is superior to morphology at detecting prognostically significant residual disease at these time points.
7. Nyvold C, Madsen HO, Ryder LP, et al.: Precise quantification of minimal residual disease at day 29 allows identification of children with acute lymphoblastic leukemia and an excellent outcome. Blood 2002, 99:1253-1258.
8. van der Velden VH, Jacobs DC, Wijkhuijs AJ, et al.: Minimal residual disease levels in bone marrow and peripheral blood are comparable in children with T cell acute lymphoblastic leukemia (ALL), but not in precursor-B-ALL. Leukemia 2002, 16:1432-1436. The results from this study suggest that bone marrow sampling may be necessary to adequately assess minimal residual disease in B-precursor ALL, but that it may be replaced by peripheral blood sampling in T-ALL, thus reducing the need for this painful procedure in that subset of patients.
9. Cave H: van der Werff ten Bosch J, Suciu S, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. European Organization for Research and Treatment of Cancer-Childhood Leukemia Cooperative Group. N Engl J Med 1998, 339:591-598.
10. van Dongen JJ, Seriu T, Panzer-Grumayer ER, et al.: Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet 1998, 352:1731-1738.
11. Coustan-Smith E, Sancho J, Hancock ML, et al.: Clinical importance of minimal residual disease in childhood acute lymphoblastic leukemia. Blood 2000, 96:2691-2696.
12. Panzer-Grumayer ER, Schneider M, Panzer S, et al.: Rapid molecular response during early induction chemotherapy predicts a good outcome in childhood acute lymphoblastic leukemia. Blood 2000, 95:790-794.
13. Coustan-Smith E, Sancho J, Hancock ML, et al.: Use of peripheral blood instead of bone marrow to monitor residual disease in children with acute lymphoblastic leukemia. Blood 2002, 100:2399-2402. Like van der Velden [8•], the authors demonstrate that low levels of minimal residual disease are more likely to be detected in the marrow than in the peripheral blood in B-precursor ALL, but also present data suggesting that peripheral blood measurement may provide sufficient prognostic information to identify those patients at highest risk of relapse.
14. Gale KB, Ford AM, Repp R, et al.: Backtracking leukemia to birth: identification of clonotypic gene fusion sequences in neonatal blood spots. Proc Natl Acad Sci U S A 1997, 94:13950-13954.
15. Wiemels JL, Cazzaniga G, Daniotti M, et al.: Prenatal origin of acute lymphoblastic leukaemia in children. Lancet 1999, 354:1499-1503.
16. Yagi T, Hibi S, Tabata Y, et al.: Detection of clonotypic IGH and TCR rearrangements in the neonatal blood spots of infants and children with B-cell precursor acute lymphoblastic leukemia. Blood 2000, 96:264-268.
17. 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 2002, 99:2992-2996. This study confirms that pre-leukemic clones can be found at birth in patients who develop ALL much later in childhood. By including patients with molecularly distinctive subtypes of B-precursor ALL, the authors demonstrate that the prenatal origin of ALL is not limited to a specific subset.
18. Harris MB, Shuster JJ, Carroll A, et al.: Trisomy of leukemic cell chromosomes 4 and 10 identifies children with B-progenitor cell acute lymphoblastic leukemia with a very low risk of treatment failure: a Pediatric Oncology Group study. Blood 1992, 79:3316-3324.
19. Heerema NA, Sather HN, Sensel MG, et al.: Prognostic impact of trisomies of chromosomes 10, 17, and 5 among children with acute lymphoblastic leukemia and high hyperdiploidy (> 50 chromosomes). J Clin Oncol 2000, 18:1876-1887.
20. Heerema NA, Nachman JB, Sather HN, et al.: Hypodiploidy with less than 45 chromosomes confers adverse risk in childhood acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood 1999, 94:4036-4045.
21. Loh ML, Rubnitz JE: TEL/AML1-positive pediatric leukemia: prognostic significance and therapeutic approaches. Curr Opin Hematol 2002, 9:345-352.
22. Uckun FM, Nachman JB, Sather HN, et al.: Clinical significance of Philadelphia chromosome positive pediatric acute lymphoblastic leukemia in the context of contemporary intensive therapies: a report from the Children's Cancer Group. Cancer 1998, 83:2030-2039.
23. Arico M, Valsecchi MG, Camitta B, et al.: Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia. N Engl J Med 2000, 342:998-1006.
24. Sierra J, Radich J, Hansen JA, et al.: Marrow transplants from unrelated donors for treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 1997, 90:1410-1414.
25. Marks DI, Bird JM, Cornish JM, et al.: Unrelated donor bone marrow transplantation for children and adolescents with Philadelphia-positive acute lymphoblastic leukemia. J Clin Oncol 1998, 16:931-936.
26. Ottmann OG, Druker BJ, Sawyers CL, et al.: A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 2002, 100:1965-1971. One of the first published trials of imatinib in Philadelphia choromosome positive ALL, this study demonstrates that this agent has activity, although responses appear less durable in ALL than in CML.
27. Hofmann WK, Jones LC, Lemp NA, et al.: Ph(+) acute lymphoblastic leukemia resistant to the tyrosine kinase inhibitor STI571 has a unique BCR-ABL gene mutation. Blood 2002, 99:1860-1862.
28. Behm FG, Raimondi SC, Frestedt JL, et al.: Rearrangement of the MLL gene confers a poor prognosis in childhood acute lymphoblastic leukemia, regardless of presenting age. Blood 1996, 87:2870-2877.
29. Biondi A, Cimino G, Pieters R, et al.: Biological and therapeutic aspects of infant leukemia. Blood 2000, 96:24-33.
30. Gu Y, Nakamura T, Alder H, et al.: The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene. Cell 1992, 71:701-708.
31. Pui CH, Gaynon PS, Boyett JM, et al.: Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region. Lancet 2002, 359:1909-1915. The authors include outcome data from 11 study groups, making this the largest published series of pediatric patients with chromosome 11q23 abnormalities. With these large numbers, the authors were able to demonstrate the poor prognosis of infants and older children with specific translocations, and they present compelling data that transplantation in first remission does not improve outcome for those with t(4;11).
32. Chessells JM, Harrison CJ, Watson SL, et al.: Treatment of infants with lymphoblastic leukaemia: results of the UK Infant Protocols 1987-1999. Br J Haematol 2002, 117:306-314.
33. Isoyama K, Eguchi M, Hibi S, et al.: Risk-directed treatment of infant acute lymphoblastic leukaemia based on early assessment of MLL gene status: results of the Japan Infant Leukaemia Study (MLL96). Br J Haematol 2002, 118:999-1010.
34. Armstrong SA, Staunton JE, Silverman LB, et al.: MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet 2002, 30:41-47. Utilizing microarray gene analyses, the authors demonstrate that MLL-rearranged ALL has a distinctive gene expression profile, suggesting that it is a biologically distinctive entity whose gene expression patterns may identify unique leukemogenic events and potential targets for more leukemia-specific therapy.
35. Gilliland DG, Griffin JD: The roles of FLT3 in hematopoiesis and leukemia. Blood 2002, 100:1532-1542.
36. Kottaridis PD, Gale RE, Frew ME, et al.: The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 2001, 98:1752-1759.
37. Meshinchi S, Woods WG, Stirewalt DL, et al.: Prevalence and prognostic significance of Flt3 internal tandem duplication in pediatric acute myeloid leukemia. Blood 2001, 97:89-94.
38. Weisberg E, Boulton C, Kelly LM, et al.: Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell 2002, 1:433-443.
39. Stone RM, Klimek V: D.J. DA, et al. PKC412, an oral FLT3 inhibitor, has activity in mutant FLT3 acute myeloid leukemia (AML): a phase II clinical trial. Blood 2002, 100:86a.
40. Ferrando AA, Neuberg DS, Staunton J, et al.: Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell 2002, 1:75-87. Using molecular techniques including gene expression profiling, the authors convincingly present evidence that there are severally biologically distinctive, prognostically significant subtypes of T-ALL.
41. Balterini P, Blaise A, Busson-Le Coniat M: et al. HOX11L2 expression defines a clinical subtype of pediatric T-ALL associated with poor prognosis. Blood 2002, 100:991-997. The data presented in this study also suggest that T-ALL may be subdivided in prognostically significant subtypes based on levels of expression of various transcription factors, with HOX11-overexpression associated with a favorable outcome and HOX11L2 with poor prognosis.
42. Mauvieux L, Leymarie V, Helias C, et al.: High incidence of HOX11L2 expression in children with T-ALL. Leukemia 2002, 16:2417-2422.
43. 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 2002, 1:133-143. This study is one of the first to demonstrate, with a large sample size, how gene expression profiling may be useful in diagnosing and categorizing subtypes of ALL, as well as providing insights into leukemogenic events and potential targets for therapy. The authors also present intriguing data suggesting that gene expression profiles may be used, at least in some ALL subtypes, to predict relapse and the development of therapy-induced AML.
44. McLeod HL, Krynetski EY, Relling MV, et al.: Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukemia 2000, 14:567-572.
45. Stanulla M, Schrappe M, Brechlin AM, et al.: Polymorphisms within glutathione S-transferase genes (GSTM1, GSTT1, GSTP1) and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia: a case-control study. Blood 2000,95: 1222-1228.
46. Davies SM, Bhatia S, Ross JA, et al.: Glutathione S-transferase genotypes, genetic susceptibility, and outcome of therapy in childhood acute lymphoblastic leukemia. Blood 2002, 100:67-71.
47. Evans WE, Relling MV, Rodman JH, et al.: Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia. N Engl J Med 1998, 338:499-505.
48. Handin RI, Lux Se, Stossel TP, eds. Blood: Principles and Practice of Hematology. Philadelphia: Lippincott Williams & Wilkins; 2003.
49. LeClerc JM, Billett AL, Gelber RD, et al.: Treatment of childhood acute lymphoblastic leukemia: results of Dana- Farber ALL Consortium Protocol 87-01. J Clin Oncol 2002, 20:237-246.
50. Silverman LB, Declerck L, Gelber RD, et al.: Results of Dana-Farber Cancer Institute Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1981-1995). Leukemia 2000, 14:2247-2256.
51. Gaynon PS, Trigg ME, Heerema NA, et al.: Children's Cancer Group trials in childhood acute lymphoblastic leukemia: 1983-1995. Leukemia 2000, 14:2223-2233.
52. 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 1998, 338:1663-1671.
53. Lange BJ, Bostrom BC, Cherlow JM, et al.: Double-delayed intensification improves event-free survival for children with intermediate-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood 2002, 99:825-833.
54. Arico M, Valsecchi MG, Conter V, et al.: Improved outcome in high-risk childhood acute lymphoblastic leukemia defined by prednisone-poor response treated with double Berlin- Frankfurt-Muenster protocol II. Blood 2002, 100:420-426. The authors present the results of a clinical trial in which intensification of therapy improved the outcome of patients considered high risk because of high peripheral blood lymphoblast counts after an initial week of prednisone. This is the first study to demonstrate that augmentation of therapy can improve the prognosis of this subset of patients.
55. Conter V, Arico M, Valsecchi MG, et al.: Extended intrathecal methotrexate may replace cranial irradiation for prevention of CNS relapse in children with intermediate-risk acute lymphoblastic leukemia treated with Berlin-Frankfurt-Munster-based intensive chemotherapy. The Associazione Italiana di Ematologia ed Oncologia Pediatrica.. J Clin Oncol 1995, 13:2497-2502.
56. Pui CH, Mahmoud HH, Rivera GK, et al.: Early intensification of intrathecal chemotherapy virtually eliminates central nervous system relapse in children with acute lymphoblastic leukemia. Blood 1998, 92:411-415.
57. Kamps WA, Bokkerink JP, Hakvoort-Cammel FG, et al.: BFM-oriented treatment for children with acute lymphoblastic leukemia without cranial irradiation and treatment reduction for standard risk patients: results of DCLSG protocol ALL-8 (1991-1996). Leukemia 2002, 16:1099-1111.
58. Waber DP, Shapiro BL, Carpentieri SC, et al.: Excellent therapeutic efficacy and minimal late neurotoxicity in children treated with 18 grays of cranial radiation therapy for high- risk acute lymphoblastic leukemia: a 7-year follow-up study of the Dana- Farber Cancer Institute Consortium Protocol 87-01. Cancer 2001, 92:15-22.
59. Waber DP, Tarbell NJ, Fairclough D, et al.: Cognitive sequelae of treatment in childhood acute lymphoblastic leukemia: cranial radiation requires an accomplice. J Clin Oncol 1995, 13:2490-2496.
60. Langer T, Martus P, Ottensmeier H, et al.: CNS late-effects after ALL therapy in childhood. Part III: neuropsychological performance in long-term survivors of childhood ALL: impairments of concentration, attention, and memory. Med Pediatr Oncol 2002, 38:320-328.
61. Iuvone L, Mariotti P, Colosimo C, et al.: Long-term cognitive outcome, brain computed tomography scan, and magnetic resonance imaging in children cured for acute lymphoblastic leukemia. Cancer 2002, 95:2562-2570.
62. Kingma A, van Dommelen RI, Mooyaart EL, et al.: Slight cognitive impairment and magnetic resonance imaging abnormalities but normal school levels in children treated for acute lymphoblastic leukemia with chemotherapy only. J Pediatr 2001, 139:413-420.
63. Mahoney DH Jr, Shuster JJ, Nitschke R, et al.: Acute neurotoxicity in children with B-precursor acute lymphoid leukemia: an association with intermediate-dose intravenous methotrexate and intrathecal triple therapy-a Pediatric Oncology Group study. J Clin Oncol 1998, 16:1712-1722.
64. Waber DP: More good news about neuropsychological late effects in long-term survivors of acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2002, 24:86-87.
65. Lipshultz SE, Colan SD, Gelber RD, et al.: Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 1991, 324:808-815.
66. Mattano LA Jr, Sather HN, Trigg ME, et al.: Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children's Cancer Group. J Clin Oncol 2000, 18:3262-3272.
67. Strauss AJ, Su JT, Dalton VM, et al.: Bony morbidity in children treated for acute lymphoblastic leukemia. J Clin Oncol 2001, 19:3066-3072.
68. Warner JT, Evans WD, Webb DK, et al.: Body composition of long-term survivors of acute lymphoblastic leukaemia. Med Pediatr Oncol 2002, 38:165-172.
69. Sklar C, Mertens A, Walter A, et al.: Final height after treatment for childhood acute lymphoblastic leukemia: comparison of no cranial irradiation with 1800 and 2400 centigrays of cranial irradiation. J Pediatr 1993, 123:59-64.
70. Stubberfield TG, Byrne GC, Jones TW: Growth and growth hormone secretion after treatment for acute lymphoblastic leukemia in childhood. 18-Gy versus 24-Gy cranial irradiation. J Pediatr Hematol Oncol 1995, 17:167-171.
71. Lehtinen SS, Huuskonen UE, Harila-Saari AH, et al.: Motor nervous system impairment persists in long-term survivors of childhood acute lymphoblastic leukemia. Cancer 2002, 94:2466-2473.
72. Leung W, Rose SR, Zhou Y, et al.: Outcomes of growth hormone replacement therapy in survivors of childhood acute lymphoblastic leukemia. J Clin Oncol 2002, 20:2959-2964. Addressing areas of controversy in the management of long-term ALL survivors with short stature, the authors present data that growth hormone replacement can effectively treat growth impairment without increasing the risk of relapse or development of secondary malignancy.
73. Legha SS, Benjamin RS, Mackay B, et al.: Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med 1982, 96:133-139.
74. Lipshultz SE, Giantris AL, Lipsitz SR, et al.: Doxorubicin administration by continuous infusion is not cardioprotective: the Dana-Farber 91-01 Acute Lymphoblastic Leukemia protocol. J Clin Oncol 2002, 20:1677-1682. This study demonstrates that continuous infusion doxorubicin, which prevents acute cardiotoxicity in adults, is associated with the same degree of cardiac dysfunction as bolus dosing in children who received this agent as part of their ALL therapy, suggesting that alternative cardioprotective strategies need to be explored in these patients.
75. Lipshultz SE, Lipsitz SR, Sallan SE, et al.: Long-term enalapril therapy for left ventricular dysfunction in doxorubicin-treated survivors of childhood cancer. J Clin Oncol 2002, 20:4517-4522. This study suggests that enalapril, currently the standard treatment for anthracycline-induced cardiomyopathy, may not permanently prevent deterioration in cardiac function in long-term survivors, emphasizing the needs for additional treatments and more effective preventive strategies.
76. Kimball Dalton VM, Gelber RD, Li F: et al. Second malignancies in patients treated for childhood acute lymphoblastic leukemia. J Clin Oncol 1998, 16:2848-2853.
77. Loning L, Zimmermann M, Reiter A, et al.: Secondary neoplasms subsequent to Berlin-Frankfurt-Munster therapy of acute lymphoblastic leukemia in childhood: significantly lower risk without cranial radiotherapy. Blood 2000, 95:2770-2775.
78. Bhatia S, Sather HN, Pabustan OB, et al.: Low incidence of second neoplasms among children diagnosed with acute lymphoblastic leukemia after 1983. Blood 2002, 99:4257-4264. This study includes a large sample size and confirms that survivors of childhood ALL have an increased risk of second malignancy compared with the general population, although the overall cumulative incidence (1.18% at 10 years) is relatively low.
79. Pui CH, Behm FG, Raimondi SC, et al.: Secondary acute myeloid leukemia in children treated for acute lymphoid leukemia. N Engl J Med 1989, 321:136-142.
80. Winick NJ, McKenna RW, Shuster JJ, et al.: Secondary acute myeloid leukemia in children with acute lymphoblastic leukemia treated with etoposide. J Clin Oncol 1993, 11:209-217.
81. Schrappe M, Reiter A, Ludwig WD, et al.: Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood 2000, 95:3310-3322.
82. Maloney KW, Shuster JJ, Murphy S, et al.: Long-term results of treatment studies for childhood acute lymphoblastic leukemia: Pediatric Oncology Group studies from 1986-1994. Leukemia 2000, 14:2276-2285.
83. Pui CH, Boyett JM, Rivera GK, et al.: Long-term results of Total Therapy studies 11, 12 and 13A for childhood acute lymphoblastic leukemia at St Jude Children's Research Hospital. Leukemia 2000, 14:2286-2294.