Journal of Hematology - Supplements - Haematologica

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10 On the other hand international studies recently demonstrated that TEL-AML 1 expression in leukemic blast cells at diagnosis is a powerful favorable prognostic factor that provides clinically useful information independent of age, leukocyte count and other parameters at the onset of the leukemia. 16-18 In synthesis clinical, biological, genetic and immunologic features can serve as useful markers for formulating a prognosis for very high risk ALL patients and must be taken into consideration when the clinician plans to apply a treatment. Value of transplantation strategy for very high risk childhood ALL in 1 st CR The role of allogeneic hematopoietic stem cell transplantation in the treatment of very high risk ALL in 1 st CR is still debatable as very few studies have so far tried to establish a comparative evaluation of alloBMT versus chemotherapy. While single center studies, such as those of Brochstein 1 and Sanders 2 and the multicenter trial of Bordigoni 3 showed promising results for alloBMT patients, in 1992 Chessels, 4 on behalf of the MRC, did not find a statistically significant difference between prospectively studied patients managed with alloBMT or chemotherapy for high risk childhood ALL in 1 st CR. In 1996 Saarinen demonstrated, in a NOPMO case-control study (22 alloBMT patients versus 44 matched controls), a superior outcome for the alloBMT procedure (10 year DFS of 73% vs 50%): however the eligibility criteria of this study selected a group of patients without very high risk features at diagnosis. An Italian co-operative study, 5 based on homogeneous very high risk criteria (including most of the adverse prognostic factors most recently employed by international study groups) and using a matched design to control for both known very high risk prognostic factors and the time-to-transplant bias, showed no significant statistical difference between the two groups (4-year DFS of 58.5% and 47.7% for alloBMT vs. chemotherapy patients, respectively). Despite this, the alloBMT curve remained stable reaching a plateau after one year whereas the chemo therapy curve was more likely to fall since patients continued to experience relapse after 4 years. Ongoing international prospective study for very high risk childhood ALL in 1 st remission Recently The EBMT and I-BFM-SG set up a prospective randomized (by genetic chance) trial with the aim of comparing the role of alloBMT vs. chemotherapy in the treatment of very high risk childhood ALL. The homogeneous criteria adopted in defining very high risk patients were as follows: cytogenetic abnormalities such as t(9;22) or t(4;11), poor prednisone response and T-ALL or WBC more than 100,000/mm 3 , induction failure. Patients having a suitable HLA A, B, DR sibling donor underwent alloBMT as soon as they obtained the 1 st CR. At present the main goal of this ongoing cooperative study is to recruit a sufficient number of patients (72 alloBMT and 238 chemotherapy patients, respectively) in order to perform an intention-to-treat analysis which will be definitive in 1992. With an actual median follow–up of 27 months the z-year DFS by treatment performed and adjusted by waiting time to transplant is 58.4% (8.1 s.e.) and 53.4% (3.8 s.e.) for alloBMT and chemotherapy patients, respectively. In this interim analysis one should take into account not only the short follow-up but also some deviations from the study in that some patients received a match/mismatch unrelated donor BMT(MUD BMT) or alternative donor BMT (data not published). From this study and on the basis of some recent results of MUD BMT in childhood ALL in 1 st CR 19-23 one can foresee a trend in favor of this still debatable procedure at least for those particular subgroups of very high risk patients who lack a suitable sibling donor. As a matter of fact the effectiveness of chemotherapy in patients with adverse genetic features, such as MLL gene arrangements or BCR ABL fusion, especially in association with a poor prednisone response and/or a high WBC count at diagnosis (more than 100,000/mm 3 ), is dismal because these patients have a probability of EFS of no more than 20% in the long-term. 22 Patients who fail induction therapy could constitute another subgroup of patients for whom even an experimental type of BMT such as haplo BMT should be offered without delay when an HLA identical sibling or an unrelated donor is not available. Last but not least, persistent MRD within two to three months after the diagnosis of very high risk ALL has been identified as another bad prognosis factor so that it constitutes a new indication for an alloBMT. Conclusions In view of the more recent valid therapeutic options to offer to children with very high risk ALL, it is mandatory to follow the continuous progress both of alloBMT and chemotherapy reached by intergroup co-operative studies. The future challenge regards decreasing transplantrelated mortality by providing better treatment support so that a better overall survival can be haematologica vol. 85(supplement to n. 11):November 2000
11 achieved. However the relapse rate which, in the past, constituted one of the major barriers to curing childhood very high risk ALL should be overcome by new prospective clinical trials chemotherapy or alloBMT. References 1. Brochstein JA, Kernan NA, Groshen S, et al. Allogeneic bone marrow transplantation after hyperfractionated total body irradiation and Cyclophosphamide in children with acute leukemia. N Engl J Med 1987; 317: 1618-24. 2. Sanders JE, Thomas ED, Buckner CD, et al. Marrow transplantation for chldren with acute lymphoblastic leukemia in second remission. Blood 1987; 79:517- 26. 3. Bordigoni P, Vernant JP, Souillet G, et al. Allogeneic bone marrow transplantation for children with acute lymphoblastic leukemia in first remission: a cooperative study of the Group d’Etude de la Greffe de Moelle Osseuse. J Clin Oncol 1989; 7:747-53. 4. Chessels JM, Bailey, Wheeler K, et al. Bone marrow transplantation for high risk childhood lymphoblastic leukemia in first remission: experience of MRC UK ALL X. Lancet 1992; 340:565-8. 5. Uderzo C, Valsecchi MG, Balduzzi A, et al. Allogeneic bone marrow transplantation versus chemotherapy in high risk childhood acute lymphoblastic leukemia in first remission . Br J Haematol 1997; 96:387-94. 6. Saarinen UM, Mellander L, Nyson K, et al. Allogeneic bone marrow transplantation in first remission for children with very high risk acute lymphoblastic leukemia: a retrospective case control-study in Nordic Countries. (NOPHO) Bone Marrow Transplant 1996; 17:357-63. 7. Gaynon PS, Bleyer WA, Steinherz PG, et al. Day 7 marrow response and outcome for children with ALL and unfavourable presenting features. Med Ped Oncol 1990; 27:273-9. 8. Rivera GK, Pinkel D, Simone JV, et al. Treatment of ALL: 30 years’ experience at St. Jude Children’s Research Hospital. N Engl J Med 1993; 329:1289-95. 9. Conter V, Rizzari C, Aricò M, et al. Preliminary results of the AIEOP ’91 study for childhood ALL. Med Ped Oncol 1995; 17:283-9. 10. Reiter A, Schrappe M, Wolf Dieter L, et al. Chemotherapy in 998 unselected childhood ALL patients: results and conclusions of the multicenter trioal ALL BFM 86. Blood 1994; 84:3122-33. 11. Pui CH, Evans WE. Acute Lymphoblastic Leukaemia. New Engl J Med 1998; 333:605-12. 12. Behn FG, Raimondi SC, Frested JL, et al. Rearrangement of the MLL gene confers a poor-prognosis in childhood ALL,regardless of presenting age. Blood 1996; 87:2870-7. 13. Schlieben S, Borkhardt A, Reinisch I, et al. Incidence and clinical outcome of children with BCR/ABL positive ALL. A prospective RT-PCR study based on 673 patients enrolled in the German pediatric multicenter therapy trials ALL BFM-90 and CoALL-05-92. Leukemia 1996; 10:957-63. 14. Childhood ALL collaborative Group: duration of maintenance chemotherapy in ALL: overview of 42 trials involving 12.000 randomized children. Lancet 1996; 347:1783-8. 15. Steinherz PG, Gaynon PS, Breneman JC, et al. Cytoreduction and prognosis in ALL. The importance of early marrow response: report from the Childrens Cancer Group. J Clin Oncol 1996; 14:389-98. 16. Pui CH, Schell MJ, Raimondi SC, et al. Myeloid-antigen expression in childhood acute lymphoblastic leukemia. N Engl J Med 1991; 325:1378-9. 17. Mc Lean TW, Ringold S, Neuberg D et al: TEL/AML 1 dimerizes and is associated with a favorable outcome in childhood ALL. Blood 1996; 88:4252-8. 18. Liang DC, Chow TB, Chen JS, et al. High incidence of TEL/AML 1 fusion resulting from a criptic t (12; 21) in childhood B-lineage ALL in Taiwan. Leukemia 1996; 10:991-3. 19. Balduzzi A, Gooley T, Anasetti C, et al. Unrelated donor marrow transplantation in children. Blood 1995; 86:3247-55. 20. Davis S, Wagner JE, Shu Xo, et al. Unrelated donor marrow transplantation for children with acute leukemia. J Clin Oncol 1997; 15:557-65. 21. Green A, Clarke E, Hunt L, et al. Children with ALL who receive T-cell-depleted HLA mismatched marrow allografts from unrelated donors, have an increase incidence of primary graft failure but a similar overall transplant outcome. Blood 1999; 94:2236-46. 22. Biondi A, Cimino G, Pieters R, Pui CH. Biological and therapeutic aspects of infant leukemia. Blood 2000; 96:24-33. 23. Sierra J, Radich J, Hansen JA, et al. Marrow transplants from unrelated donors for treatment of Philadelphia chromosome positive acute lymphoblastic leukemia. Blood 1997; 90:1410-4. haematologica vol. 85(supplement to n. 11):November 2000
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