36th EBMT & 9th Data Management Group Annual Meeting Vienna, 23 March 2010 Jordi Esteve Hospital Clínic (Barcelona) Acute Leukemia Working Party The European Group for Blood and Marrow Transplantation
AML + ALL: current perspective Basic concepts Classification: AML/ALL, heterogeneous diseases Diagnosis of AML/ALL: an integrated process Prognosis: reflecting biological diversity Therapy: risk-adapted therapies Future therapeutic: molecularly-targeted therapy
Acute leukemia: main subtypes Acute Myeloid Leukemia (AML) Acute Lymphoblastic Leukemia (ALL) Acute Leukemia of ambigous lineage WHO Classification, 2008
Maturation arrest
Maturation arrest
Incidence of AML according to Swedish Acute Leukemia Registry (1997-2005) New cases per 100 000 inhabitants, based on the Swedish population in 2005 Juliusson G, et al. Blood 2009
Incidence of ALL
Current approach of acute leukaemia: the hematologist s view Initial diagnosis Clinical & biological features Prognosis Therapy: (a) Front-line tx: induction CT ± TKIs (b) Post-remission tx (I): intensification CT (c) Post-remission tx (II): transplant (d) Maintenance after allo? (d) Salvage therapy: second-line CT, SCT
Natural history of AL according to MED-B forms: the EBMT data manager s view Initial diagnosis: disease classification, hematological & biological features (cytogenetics, molecular biology) Pre-transplant life : first line therapy, disease history HSCT: type, SC collection, status of disease, donor, conditioning Response to transplant Follow-up: complications & disease status
Acute Myeloid Leukemia (AML): WHO classification (I) I. AML with recurrent cytogenetic abnormalities II. AML with myelodysplasia-related changes III. Therapy-related AML/MDS IV. AML, not otherwise specified V. Myeloid sarcoma VI. Myeloid proliferations related to Down syndrome VII. Blastic plasmacytoid dendritic cell neoplasms WHO Classification, 2008
WHO classification of AML (II): towards molecularly-defined entities I. AML with recurring genetic abnormalities AML with t(8;21)(q22;q22)/runx1-runxt1 AML with inv(16) or t(16;16)(p13;q22)/cbf -MYH11 Acute promyelocytic leukemia [t(15;17) & PML-RAR- ] AML with t(9;11)(p22;q23)/af9(mllt3)-mll AML with t(6;9)(p23;q34)/dek-can(nup214) AML with inv(3) or t(3;3)(q21;q26)/rpn1-evi1 Megakaryoblastic AML with t(1;22)(p13;q13)/rbm15-mkl1 AML with mutated NPM AML with normal karyotype and CEBPA mutation WHO Classification, 2008
WHO-2008 classification of AML (III): the remaining link with FAB classification IV. AML, not otherwise specified AML with minimal differentiation AML without maturation AML with maturation Acute myelomonocytic leukemia Acute monoblastic & monocytic leukemia Acute erythroid leukemia Acute megakaryoblastic leukemia Acute basophilic leukemia Acute panmyelosis with myelofibrosis M0 M1 M2 M4 M5a+b M6 M7
Precursor Lymphoid Neoplasms (ALL): WHO classification (2008) I. B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities B-ALL with t(9;22)(q34;11.2); BCR-ABL1 B-ALL with t(v;11q23); MLL-rearranged B-ALL with t(12;21)(p13;q22); TEL-AML1 (ETV6-RUNX1) B-ALL with hyperdiploidy B-ALL with hypodiploidy B-ALL with t(5;14); IL3-IGH B-ALL with t(1;19)(q23;p13.3); E2A-PBX1 (TCF3-PBX1) II. B-lymphoblastic leukemia/lymphoma, NOS III. T-lymphoblastic leukemia/lymphoma
Diagnosis of AML: combining multiple tools Cytology: PB slide, BM (BM aspirate ± BM biopsy) Cytochemistry: MPO & Sudan Black B (myeloid); -naphthyl acetate & -naphthyl butyrate (monocytic) Inmunophenotype: multiparameter flow cytometry based Cytogenetics Conventional cytogenetics FISH; other (CGH, SKY, painting,...) Molecular biology Fusion transcripts (RT-PCR): PML/RAR-, AML1/ETO, CBF- /MYH11, MLL/..., BCR/ABL, DEK/CAN,... Gene mutations: flt-3-itd, CEBPalfa, NPM,
AML diagnosis Cytochemistry MPO Naphtol-As-D-acetate esterase -naphthyl acetate esterase
Neutrophils Monocytes LymphocytesBlasts CD45 dim CD34+ CD19+ CD10++ CD20- CD24+ CD79a+ CD66 dim CD13 dim MPO- Tdt+ CD38++
AML diagnosis Cytogenetics
APL: paradigm of integrated diagnosis FISH: PML/RARA fusion signal bcr1 bcr3 Anti-PGM3 pattern staining RT-PCR PML/RAR-alpha
AML + ALL: current perspective Basic concepts Classification: AML/ALL, heterogeneous diseases Diagnosis of AML/ALL: an integrated process Prognosis: reflecting biological diversity Therapy: risk-adapted therapies Future therapeutic: molecularly-targeted therapy
Prognostic impact of WHO classification in younger patients Grimwade D, et al. Hematology 2009
Relevant molecular and cytogenetic subgroups of AML arising in younger adults Grimwade D, et al. Hematology 2009
Survival according to combined cytogenetics and molecular categories p< 0.001 Low mol risk High mol risk Adverse cytogenetics
Outcome of SCT in AML: variables Phase CR1 Advanced disease Good prognosis cytogenetics APL CBF-r AML Intermediate-risk Normal Karyotype Other High-risk Procedure variables (Conditioning, Donor) Host variables (Age, Comorbidity Index)
General therapeutic plan in AML Induccion CT Refractory Salvage therapy Relapse Anthracycline + Ara-C CR~75% Post-remission tx Intensification CT Ara-C HD-based AlloSCT AutoSCT CT Long-term OS~35-40% (<60)
Risk-adapted therapy in AML: proposed strategy according to molecularly defined subgroups CBF-AML Risk group Proposed postcr strategy HiDAC-based chemotherapy Normal karyotype with fav markers (NPMmut/FLT3(-), CEBPAmut, ) HiDAC AutoHSCT Unfavorable markers (FLT3-ITD, MLL-PTD, ) Adverse-risk cytogenetics AlloHCT Experimental (FLT3inh, ) AlloHCT Experimental therapy (demethylating, )
ALL: current therapeutic approach Induction Antr. / VCR / PDN L-ASA, ARA-C, CFM Post-remission CR: 83% Consolidation CT AlloSCT AutoSCT CT (reinduction & maintenance) Surv * : 80% (children) 35% (adults)
Therapy of AML: state of the art Mild progress during last years: chemotherapy (anthracyclines & ara-c) and stem-cell transplantation Best risk/prognosis assignment Higher availability of transplant strategies Alternative donors Reduced-intensity conditioning procedures Improvement in supportive care
Therapy in adult ALL: state of the art High response rate after induction therapy (>80%) But high relapse rate ( 50%) Uncertain role of allohsct in CR1: High risk ALL? Urgent need of new agents
Acute leukemia: your questions Why specify therapy with tyrosine kinase inhibitors as primary treatment (in Ph(+) ALL? NRM in patients with disease? How should it be labelled?
Imatinib: mechanism of action IMATINIB de Labarthe et al,, Blood 2007;109:1408-1413
Outcome of Ph+ ALL in the pre-imatinib era according to post-remission therapy Fielding et al. Blood 2009
Therapy in Ph+ ALL: comparative improved outcome in the imatinib era de Labarthe A, et al. Blood 2007
Improved outcome after allo in the era of tyrosine kinase inhibitors (TKIs): possible reasons Better response quality / deeper cytoreduction pre-allohsct: lower relapse risk after allo? Lower cumulated toxicity before transplant = lower NRM after allo? Easier control of MRD relapse after allo
Non-relapse mortality in patients with active disease? Grey zones in patients allografted not in CR Patients achieving CR after allohsct who die of a transplantrelated toxicity: NRM Early death, before day +30, due to a clearly conditioningrelated toxicity (VOD, agvhd): no time to response to transplant And after that time-point, how long does the response to transplant takes? How do we know the disease status if the patient dies of a clearly transplant-related event (for instance, severe GvHD)? Who is responsible for that death? Disease No clear solution: end-points & definitions should be preestablished
Sometimes I feel so uninsp ired