Risk Adapted Therapy for ALL

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(Pui CH et al, N Engl J Med 1998;339:605)

St. Jude Children’s Research Hospital, 2255 children with ALL, 1962-1997

Event-free survival Overall survival

(Pui CH et al, N Engl J Med 1998;339:605)

St. Jude Children’s Research Hospital, 1984-1997

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)

•51-65 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•33-44 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)

Group Year Pt. No. Age CR(%) LFS(%)

GMALL 02/84 1993 562 28 75 39 (7-y)

FGTALL 2000 572 33 76 30 (10-y)

MRC-UKALL XA 1997 618 >15 82 28 (5-y)

MRC/ECOG 1999 920 - 89 -

GMALL 05/93 2001 1163 35 83 -

GIMEMA 2002 794 28 82 29 (9-y)

• Induction chemotherapy– CR: at least 80%– Good remission quality: MRD below 10-3 to 10 -4 after induction – Dexamethasone (vs. prednisone), cyclophosphamide, anthracycline (do

se 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)

SubgroupClinical/laboratory

characteristicsRelapse kinetics and

localization

Pro-B-ALL

  - t(4;11)/ALL1-AF4 (70%)

- High WBC (> 100,000/μL) (26%)

- Myeloid co-expression

(CD13, 33) (>50%)

- Mainly BM (>90%)

c-ALL/pre-B-ALL

- Incidence increasing with age (59% < 55 yrs vs. 75% > 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 1-1.5 yrs

Immunophenotypic Subgroup of Adult ALL

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

SubgroupClinical/laboratory

characteristicsRelapse 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 features High 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 1st year

- < 10-4 after induction - < 10-4 or negative

- > 10-3 after induction - > 10-4 or increasing

• Risk adapted therapy– Risk adapted therapy in adult ALL has already resulted in major improv

ements 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