Risk Adapted Therapy for ALL 서울아산병원 내과 이 제 환

(Pui CH et al, N Engl J Med 1998;339:605) St. Jude Children’s Research Hospital, 2255 children with ALL, Event-free survival Overall survival

(Pui CH et al, N Engl J Med 1998;339:605) St. Jude Children’s Research Hospital,

Cytogenetic Abnormalities in ALL (Faderl S et al, Cancer 2003;98:1337)

(Gökbuget N et al, Rev Clin Exp Hematol 2002;6:114)

Immunologic Classification of ALL (Ludwig WD et al, Leuk Lymphoma 1996;13:71) German Multicenter Study Group for Adult ALL (GMALL)

Cytogenetic Abnormalities in ALL (Gökbuget N et al, Rev Clin Exp Hematol 2002;6:114)

Cytogenetic Abnormalities in ALL (Gökbuget N et al, Rev Clin Exp Hematol 2002;6:114) chromosomes Chromosomes 4, 6, 10, 14, 17, 18, 21, X Low incidence in adult ALL ? Prognosis in ALL – gain in chrom 4, 6, 10, 17: good prognosis – gain in chrom 5, isochrom 17, I(17)(q10): poor prognosis

Cytogenetic Abnormalities in ALL (Gökbuget N et al, Rev Clin Exp Hematol 2002;6:114) 45 chromosomes or less 45 chromosomes (ex, monosomy 7): – most frequent, intermediate prognosis chromosomes: – rare (0.8%) – poorer outcome than 45 chromosome

Cytogenetic Abnormalities in ALL (Gökbuget N et al, Rev Clin Exp Hematol 2002;6:114) t(9;22)(q34;q11) BCR/ABL hybrid gene 20-30% of all adult ALL cases > 50% in older patients > 55 yrs Almost exclusively found in B-precursor ALL (c-ALL/pre-B-ALL) Most unfavorable prognostic subgroup

Cytogenetic Abnormalities in ALL (Gökbuget N et al, Rev Clin Exp Hematol 2002;6:114) t(4;11)(q21;q23) ALL1-AF4 (MLL-AF4) hybrid gene 5% of all adult ALL cases assoc. with pro-B-ALL (CD10 negative) > 50% in pro-B-ALL Poor prognosis

Cytogenetic Abnormalities in ALL (Gökbuget N et al, Rev Clin Exp Hematol 2002;6:114) t(10;14)(p15;q11) TCR gene on chromosome 14 t(11;14)(p15;q11), t(11;14)(p13;q11) T-ALL Better outcome

Cytogenetic Abnormalities in ALL (Gökbuget N et al, Rev Clin Exp Hematol 2002;6:114) p15, p16 genes CDK4, CDK6 40% Prognostic value: unclear

Targets for Detection of MRD (Foa R et al, Rev Clin Exp Hematol 2002;6:181)

Results of Multicenter Studies in Adult ALL (Gökbuget N et al, Rev Clin Exp Hematol 2002;6:114) GroupYearPt. No.AgeCR(%)LFS(%) GMALL 02/ (7-y) FGTALL (10-y) MRC-UKALL XA > (5-y) MRC/ECOG GMALL 05/ GIMEMA (9-y)

Induction chemotherapy –CR: at least 80% –Good remission quality: MRD below to after induction –Dexamethasone (vs. prednisone), cyclophosphamide, anthracycline (dose intensity and schedule), L-asparaginase (native E.coli, Erwinia, PEG), high-dose cytarabine –Prophylactic use of growth factors Consolidation therapy –Early and late intensification –High dose methotrexate, high dose cytarabine Maintenance therapy Hematopoietic cell transplantation –Allogeneic vs. autologous CNS prophylaxis –CNS irradiation Treatment of Adult ALL

HCT Indications in Adult ALL (Gökbuget N et al, Rev Clin Exp Hematol 2002;6:114)

Monoclonal Antibody Therapy in ALL (Hoelzer D et al, Hematology 2002;162)

Risk stratification models by prognostic factors –Identification of patients that are candidates for HCT in first CR –Characterization of biologic subgroups Improvement with subgroup adjusted therapy treatment schedules ALL is not a uniform disease. –Subtypes with distinct biologic, clinical, and prognostic features. –Clinical features: WBC, immunophenotype, cytogeneitc and molecular aberrations, time to CR, course of MRD –Leukemia-free survival according to subtypes Risk Stratification of Adult ALL

Immunophenotypic Subgroup of Adult ALL (Gökbuget N et al, Rev Clin Exp Hematol 2002;6:114) Subgroup Clinical/laboratory characteristics Relapse kinetics and localization Pro-B-ALL - t(4;11)/ALL1-AF4 (70%) - High WBC (> 100,000/ μ L) (26%) - Myeloid co-expression (CD13, 33) (>50%) - Mainly BM (>90%) c-ALL/pre- B-ALL - Incidence increasing with age (59% 55 yrs) - Ph/BCR-ABL (40-50%) - M-BCR (30%), m-BCR (70%) - Mainly BM (>90%) - Continuous relapses up to 5-7 yrs Mature B- ALL - Large tumor mass (elevated LDH in > 90% of cases) - Organ involvement (32%) - CNS involvement (13%) - Frequent CNS (10%) and extramedullary - Rapid progression at relapse - Up to yrs

Immunophenotypic Subgroup of Adult ALL (Gökbuget N et al, Rev Clin Exp Hematol 2002;6:114) Subgroup Clinical/laboratory characteristics Relapse kinetics and localization Early T-ALL - Mediastinal tumor (75%) - Higher age (24% > 50 yrs) - CNS involvement (9%) - Frequent CNS (10%) and extrameduallry (6%) - Rapid progression at relapse - Up to 3-4 yrs Thymic ALL - Mediastinal tumor (75%) Mature T-ALL - CNS involvement (7%) - High WBC (> 50/ml) (48%) - Younger age (6% > 50 yrs)

Risk Classification in Adult ALL (Gökbuget N et al, Rev Clin Exp Hematol 2002;6:114) Prognostic factors Low risk featuresHigh risk features Age - Younger age (<25, <35 yrs) - Higher age (>35, >50 yrs) Cytogenetics/ molecular genetics - TEL-AML1? - High hyperdiploid? - t(9;22)/BCR-ABL - t(4;11)/ALL1-AF4 WBC - < 30,000/  L - > 30,000/  L (B-lineage) - > 10,000/  L (T-lineage) Immuno- phenotype - Thymic (cortical) T-ALL - Pro B-ALL - Early T-ALL - Mature T-ALL Time to CR - CR < 2-4 weeks - Timely clearance of blasts - > 2-4 weeks - Persistence of blasts in PB at day 7 and BM at day 14 MRD After induction During 1 st year - < after induction - < or negative - > after induction - > or increasing

Risk adapted therapy –Risk adapted therapy in adult ALL has already resulted in major improvements in treatment outcome of B- and T-ALL. Future perspectives –Specific treatment elements T-ALL: cyclophosphamide, cytarabine, T-cell specific drugs Pro-B-ALL: high dose cytarabine B-precursor ALL: high dose cytarabine, 6-mercaptopurine Mature B-ALL: high dose methotrexate, high dose cytarabine –Post-remission therapy intensity and duration Should be adapted to risk of relapse –Hematopoietic cell transplantation Indication for allogeneic HCT in first CR Indication for matched unrelated HCT New modalities for HCT: nonmyeloablative HCT, better conditioning –Evaluation of MRD –Immunotherapy: monoclonal antibody –Targeted therapy: imatinib mesylate Summary