Elisabeth Koller 3rd Medical Dept., Center for Hematology and Oncology, Hanusch Hospital, Vienna, Austria
Incidence Diagnosis Prognostic factors Treatment Induction therapy - HSCT Indications for HSCT New drugs
DNA-damage (translocations, fusion genes, dysregulation of genes) BCR/ABL fusion p185 worse prognosis MLL/AF4 fusion - t(4;11) TEL/AML1 + hyperdiploidy - good prognosis FLT3 mutations, RAS Mutations LOH loss of heterozygosity CNA copy number abnormalities NOTCH1 FBXW7 50% T-ALL T
Basic laboratory results Morphology Immunophenotyping Cytogenetics FISH PCR
1. Acute lymphoblastic leukemia/ lymphoma: ( FAB L1/ L2) Precursor B Acute lymphoblastic leukemia/ lymphoma Cytogenetic subtypes t(12;21)(p12,q22) TEL/ AML-1 t(1;19)(q23;p13) PBX/ E2A t(9;22)(q34;q11) ABL/ BCR t(v,11)(v;q23) V/ MLL Precursor T acute lymphblastic leukemia/ lymphoma 2. Burkitt s leukemia/ lymphoma ( FAB L3) 3. Biphenotypic acute leukemia
Normal lymphoid development and different immunological subtypes in adult ALL HSC CLP Early Pro B Pro B Pre B Immature B Mature B Biphenotypic rare Common type 70% Pre B 20% B mature 3% HSC CLP Pro T Pre T TCR low TCR high CD4+ CD8 + Biphenotypic rare Pro Pre T 40% Cortical T 40% T mature 20%
At diagnosis Good Adverse B Adverse T Clinical parameters Immunophenotype Genetic markers WBC < 30 G/l WBC > 30/l Thymic T Pre B TEL-AML1? t(9;22),t(4;11) HOX11L2? WBC > 100 G/l Early, Mature T HOX11? t(1;19)/e2a/pbx? CALM-AF4 AF4? 9p-? Complex KT? Complex KT? Hyperdiploid KT? Low hypodiploid? Low hypodiploid? Near tetraploid? Near tetrapolid? Age <25,<35 >35,>55,>70 >35,>55,>70 During treatment Prednisone response Good? Time to CR Early MRD Negative Poor? Poor? Late Late Positive Positive
LALA94 Trial OS according to age Quoc-Hung Le et al, Cancer 2007
LALA94 Trial Survival curves according to the karyotype Quoc-Hung Le et al, Cancer 2007
LALA 94 Trial Quoc-Hung Le et al, Cancer 2007
MRC UKALLXII/ECOG E2993 Estimated OS by karyotypic categories Blood 2008, March 1, 111 V Pullakart et al
Study Year n CR % % Survival GMALL 5/93 2001 1163 83 35(5y) GIMEMA 0288 2002 767 82 27(9y) MD Anderson 2004 288 92 38(5y) EORTC ALL-3 2004 340 74 36(6y) LALA-94 2004 922 84 36(5y) MRCXII/ E2993 2005 1521 86 38(5y) GIMEMA 0496 2005 450 80 33(5y) Pethema ALL-93 2005 222 82 34(5y) SCT PR n.r. Ph+ PO PR PO n.r. HR PR prospective risk model, PO prospective in pts with donor HR prospective for HR pts
MRC UKALL XI I / ECOG E2993 Rowe, J. M. et al. Blood 2005;106:3760-3767
MRC UKALL XII / ECOG E2993 Standard versus high risk patients - OS rates from the time of diagnosis Rowe, J. M. et al. Blood 2005;106:3760-3767
MRC UKALL XI I / ECOG E2993 Overall Prognostic groups Risk level Low risk Ph- Intermediate risk Ph- PH+ High risk Ph- Prognostic factors < 35 y AND WBC < 100 T or 30 B < 35 y AND WBC > 100 T or 30 B > 35 y AND WBC < 100 T or 30 B > 35 y AND WBC > 100 T or 30 B Rowe, J. M. et al. Blood 2005;106:3760-3767
MRC UKALL XI I / ECOG E2993 OS from diagnosis of patients with B- versus T- lineage disease Marks, D. I. et al. Blood 2009;114:5136-5145
MRC UKALL XII / ECOG E2993 Survival of patients and donor versus no-donor analysis Goldstone, A. H. et al. Blood 2008;111:1827-1833
MRC UKALL XII / ECOG E2993 Chemotherapy versus autologous transplantation Goldstone, A. H. et al. Blood 2008;111:1827-1833
MRC UKALL XI I / ECOG E2993 Overall survival from diagnosis for donor versus no-donor for Ph-negative patients Goldstone, A. H. et al. Blood 2008;111:1827-1833
MRC UKALL XII / ECOG E2993 Overall survival by treatment for 267 unselected Ph-positive patients Fielding, A. K. et al. Blood 2009;113:4489-4496
Recommendations for HSCT in adult ALL MRD CR1 < 40y SR Yes CR1 < 40y HR Yes CR1 > 40y Yes < = CR2 Yes Refractory ALL Yes Ph+ Yes MRD-positive Yes MUD No Yes No Yes Yes Yes Possibly
MRD diagnosis is important for prospective risk stratification MRD status is highly associated with outcome Helps to induvidualize treatment in combination with other risk factors
Molecular response to treatment in childhood ALL Campana, D. Hematology 2008;2008:366-373
Inferior outcome in comparison to children due to Leukemia biology Increased therapy related toxicity (asparaginase, osteonecrosis) Relatively favorable results with pediatric regimens Age N Outcome PETHEMA 1996-2005 SR 15-30 81 6y EFS 61% 6y OS 69% Princess Margaret Hospital 18-35 42 3y RFS 77% 3y OS 83%
Retrospective analysis of adolecsents CCG vs CALGB Comparison of EFS and OS Stock, W. et al. Blood 2008;112:1646-1654
Late effects and secondary malignancy GVHD Infertility Infections Increased risk of secondary leukemia, MDS, lymphoproliferative disorders Lifetime increased risk for SMN (skin, breast)
Inferior outcome due to Leukemia biology (poor prognosis cytogenetics, drug resistance) Increased therapy related toxicity Multimorbidity Drug interactions Need for different specifically designed treatments Palliative strategies including targeted treatments can provide prolonged survival with good quality of life.
BCR/ABL p185 Imatinib, Dasatinib, Nilotinib Rituximab, Blimatumomab B-cell T-cell Purinanalogs e.g. Nelarabine
Imatinib + /-/ Chemotherapy gives high CR- rates in de novo ALL (> 90%) No larger randomized trials! Most patients relapse without HSCT (mutations) Imatinib reduces relapse rate after HSCT No increase of non-relapse mortality Ongoing trails investigating maintenance strategies (Interferon)
Phase II trials Combination with chemotherapy Tolerable toxicity High hematological and molecular remission rates Monotherapy + corticosteroids
Imatinib administration in conjunction with the GMALL protocols 06/99 and 07/03 Wassmann, B. et al. Blood 2006;108:1469-1477
Probabilities of remission and overall survival Wassmann, B. et al. Blood 2006;108:1469-1477
Infection prevention Injury prevention Education related to care of: CVC, diet, infection prevention, bleeding risk, treatment specific side effects Energy conservation Psychosocial support
At last: I hope you have time to enjoy Vienna!