Treatment of Acute Lymphoblastic Leukemia Beyond the First Remission

Treatment of Acute Lymphoblastic Leukemia Beyond the First Remission Fes, Morocco May 2005 Relapsed Pediatric ALL • The fourth most common childhood cancer – ALL (30.9 cases/106 children/yr) – Relapsed ALL (9.3 cases/106 children/yr) Gaynon et al. Cancer 1998; 82, 1387 • In spite of the improved survival rate for the newly diagnosed ALL, relapsed ALL continues to have poor prognosis Timing and Site of Relapse n=505 Years <1 2 3 4 5 >6 Total BM 78 59 66 41 17 25 286 BM/CNS BM/Test 3 1 3 2 25 8 4 9 3 2 2 2 40 24 CNS 21 33 17 4 1 2 78 Test 3 6 25 14 2 1 51 Chessells et al. Brit J Haematol 123, 396–405, 2003 Incidence of Hematologic Relapse in Total Therapy Studies Study 11 (1984–88) 12 (1988–91) 13A (1991–94) No. 358 188 165 % Cumulative Risk 17.9 18.7 13.0 Total = 106 Rivera GK et al Cancer 2005;103:368–76 Survival after First Marrow Relapse 1 0.9 0.8 0.7 CR rate: 71.7% 21.4% ± 7.2% Probability 0.6 0.5 0.4 0.3 0.2 0.1 0 0 2 4 6 n = 106 8 10 12 14 16 Years After First Marrow Relapse Rivera GK et al Cancer 2005;103:368–76 Outcome in Patients with hematological Relapse Rivera GK et al Cancer 2005;103:368–76 EFS by Length of First Remission 0.8 0.7 P < 0.0001 0.6 Probability 0.5 0.4 0.3 0.2 0.1 0 0 2 4 39.0% ± 15.2% >36 months, n = 43 11.0% ± 5.2% <36 months, n = 73 6 8 10 12 14 16 Years After First Marrow Relapse Survival by Immunophenotype 1 0.9 0.8 0.7 P < 0.001 Probability 0.6 0.5 0.4 0.3 0.2 0.1 0 0 2 4 6 8 10 12 14 26.2% ± 9.2% B-lineage, n = 91 4.0% ± 0.8% T-lineage, n = 25 Years After First Marrow Relapse Survival by Site of Relapse 1 0.9 0.8 0.7 Probability 0.6 0.5 0.4 0.3 0.2 0.1 0 0 2 4 6 8 10 12 14 40.7% ± 9.9% Combined, n = 27 18.2% ± 4.2% Isolated marrow, n = 77 Marrow after extramedullary, n = 12 } } 16 P = 0.049 P = 0.075 Years After First Marrow Relapse Survival After Relapse Chemotherapy vs. Transplantation 1 0.9 0.8 0.7 P = 0.111* Probability 0.6 0.5 0.4 0.3 0.2 0.1 0 0 2 4 6 8 10 12 14 31.1% ± 19.0% Chemotherapy n = 41 26.0% ± 9.0% Transplantation n = 36 Years After First Marrow Relapse *Modified Mantel-Byar test Comparison of Treatment Results Transplant vs. Chemotherapy Study IBMTR 1983-91 POG 1983-91 ALL-REZ BFM 1983-90 Treatment Transplant Chemotherapy Transplant Chemotherapy Chemotherapy Transplant Chemotherapy No. Patients % 5-yr DFS 255 255 51 165 115 57 230 75 150 40% 17% 52% 41%* 22%† 41% 22% 40% 23% AIEOP 1980-90 Nordic Countries Transplant 1981-95 Chemotherapy *late relapse †early relapse Treatment Strategies for Hematologic Relapse • Intensive Remission induction • Intrathecal therapy • Post remission therapy − Chemotherapy including epipodophyllotoxins x 2 years − Transplantation for very early or early relapse or T-cell ALL Treatment for Isolated CNS Relapse • Remission induction therapy • Triple IT weekly (induction); monthly postremission (until completion of CNS irradiation) • Postremission therapy − Chemotherapy including dexamethasone ± high-dose methotrexate x 1 year − CNS irradiation cranial vs. craniospinal early vs. late 18 Gy vs. 24 Gy ? Elimination of radiation Treatment for Isolated Testicular Relapse • Intensive remission induction therapy • Intrathecal chemotherapy • Postremission therapy − Chemotherapy x at least 1 year − Irradiation Bilateral involvement: 24 Gy Unilateral involvement: orchiectomy plus 15 Gy to the other testes ? High-dose methotrexate (12gm/m2) to replace irradiation Van den Berg, et al. Cancer 1997;79:2257-62. Innovative treatment strategies are necessary of children with relapse acute lymphoblastic leukemia New Agents Under Investigation • Clofarabine (Clofarex™) − 3 CR in 7 patients with relapsed ALL (Phase I study)1 • FLT3 inhibitors − Effective in cell lines and mouse model2 1. Jeha et al. Proc Am Soc Clin Oncol. 2002;21:397a. Abstract 1585. 2. Levis et al. Blood. 2002;99:3885-3891. New Agents Under Investigation (cont’d) • Imatinib mesylate (GleevecTM) − 20% to 30% CR in Ph ALL in relapse (Phase I/II studies)1,2 • 506U78 (Pro-drug of guanine arabinoside) − 40% CR in relapsed T-Cell ALL (Phase I studies)3,4 1. Druker et al. N Engl J Med. 2001;344:1038-1042. 2. Ottmann et al. Blood. 2002;100:1965-1971. 3. Kurtzberg et al. Blood. 1996;88(suppl):669a. 4. Gandhi et al. J Clin Oncol. 1998;16:3607-3615. Second EFS After Isolated CNS Relapse According to Time of Relapse: ALL-REZ BFM 8395 Second EFS According to Risk Stratification ALL-REZ BFM 83-95 EFS After Secondary Treatment by MRD Second EFS According to Time of Relapse ALL-REZ BFM 83-95 > Interim Results of High-Risk Relapsed ALL in ALL-REZ BFM 96 Study Treatment No. 3 yr-EFS P-value Chemotherapy Transplant 33 75 0 41%±6% <0.001 Interim Results of Intermediate-Risk Relapsed ALL in ALL-REZ BFM 96 Study Treatment Chemotherapy MRD transplant MUD transplant No. 222 22 26 3 yr-EFS P-value 48%±4% 92%±7% 32%±12% <0.001