ETP - Acute Lymphoblastic Leukaemia

Transcription

1 ETP - Acute Lymphoblastic Leukaemia Dr Sally Campbell - Royal Children s Hospital Melbourne 24 February 2017

2 T-ALL 12-15% of all newly diagnosed ALL cases in pediatrics are T-ALL T-ALL behaves differently from B-ALL Kinetics Risk stratification ETP is a recently described entity (2009), accounting for 15% of T-ALL cases

3 Early T Precursor ALL Subtype of T-ALL Clinically often have lower WCC, age >10 years Kinetically distinctive with higher end of MRD burdens and rates of induction failure M3 marrows on Day 29 Initial reports were of unfavorable outcomes Emerging data is of similar outcomes to T-ALL

4 COG T ALL risk group definitions Risk Standard risk Intermediate risk Definitions M1 day 29 marrow Day 29 MRD <0.01%, CNS 1, no testicular involvement, no steroid pre-treatment M1 or M2 day 29 marrow Day 29 MRD >0.01% EOC MRD <0.01% Any CNS or testicular disease, any steroid pretreatment Very high risk M3 day 29 marrow or EOC MRD >0.01%

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6 Classification of ETP Classically defined by immunophenotype Other definitions have been proposed based on array based genome wide expression profiling ETP demonstrations a similar transcriptional and mutational landscape to myeloid leukemia and hematopoietic stem cells

7 ETP Classification by FC ccd3+, scd3-, CD1a-, CD2+, CD5 dim (<75% of blasts expressing CD5) & 1 or more myeloid marker (HLA-DR, CD117, CD13, CD33, CD11b and/or CD65) on at least 25% of blasts CD5 is the marker of debate COG AALL0434 classified ETP cases as including near ETP with CD5+ staining

8 Mutational landscape of ETP More than 60% of ETP-ALL harbour mutations in Cytokine receptor (IL7R) RAS (NRAS, KRAS, FLT3) Janus kinase/signal transducer and activator of transcription (JAK/STAT) (JAK1, JAK3, SH2B3) Gene expression profiling suggest the JAK/STAT pathway may be dysregulated in some ETP-ALL regardless of the presence or absence of JAK/STAT mutations

9 RCH Cases S.L 14 y/o Female (Dx 2009) DW 17y/o Male (Dx 2012) OR 13 y/o male (Dx 2014) IA 7 y/o Female (Dx 2015) RY 10 y/o male (Dx 2015)

10 Case 1 SL Dx 2009 ETP by FC ccd3+, CD2+, CD1a-, CD8-,CD33+, HLA-DR+ t(10;11), CNS negative Rx on COG ALL0434, MRD not done in 2009 Transplanted in first CR (6 months of Rx) with UCB including TBI 12 Gy fractions Continuing complete remission since 2010

11 Case 2 DW Dx 2012 Near ETP by FC with CD5+, and remainder of immunophenotype consistent with ETP ccd3+, CD10+, CD5+, CD33+,CD79a, TdT, CD1a- FISH amplified ABL1, ABL:NUP214 by molecular Rx on COG AALL 0434 Day 15 BMA 16% blasts, Day 29 MRD <0.01%, and EOC by FC TBI & MUD at CR1 Continuing complete remission since 2013

12 Case 3 OR - ETP Dx 2014 Dx by FC (CD1a -, ccd3+, CD2+, CD5 dim, CD117+, HLA-DR+, CD13+) Cytogenetics - ABL-NUP214 fusion gene Rx on COG AALL0434 Day 29+ (33%), EOC MRD+ (5%), Intensified treatment with AML induction Transplanted with MSD with positive MRD (0.39%) Molecular marker TCRD4 Day 30 post BMT MRD FC + 0.9% immunosuppression ceased early, negative by molecular Day 60 post HSCT MRD FC + 0.1% - negative by molecular MRD Day 100 post HSCT MRD FC %, negative by molecular MRD Day 180 post HSCT MRD negative by Molecular MRD

13 Case 4 IA Dx Sept 2015 ETP by FC, CNS negative, Deletion 17q22 (30% of blasts), FLT3-ITD negative ccd3+, CD7+, CD5 dim, CD13, CD33 partial, HLA-DR partial, CD4 & 8 -, CD1a - Day 8 MRD: 24%, Day 29 MRD 6.6%, Mid consolidation MRD 6% with M1 marrow, EOC MRD 1.6% EOC VHR stratification MUD HSCT post FLAG IDA Post FLAG IDA MRD <0.057% MUD HSCT MRD Day 30, 60, 90 <0.01% Relapsed Day 172, sample sent to Foundation One (Boston) no molecular target identified Ruxolitinib 2 x courses decreased MRD from 25% to 3% - (+ sirolimus) Planning for Haplo HSCT if continues to respond

14 Case 5 RY - ETP Dx 2015, presented with mediastinal mass ETP Dx by FC (CD1a-, CD5dim, ccd3+, CD117+, HLA-DR+, CD13+, CD33+) FLT3-ITD positive, WT1+ Day 8 MRD + (0.5%), Day 29 MRD + (0.119%), EOC MRD negative (<0.01%) Currently in maintenance therapy

15 Summary 5 cases in the last 8 years - 4 went to HSCT in CR1-3 are in continued CR - 1 relapsed post HSCT & currently on JAK1/2 inhibitor - 1 is on currently on maintenance therapy

16 Summary Improved outcomes are likely attributable to the superiority of MRD based, risk adapted treatment strategies The MRD + at EOI, now results in intensification of therapy which may offset the higher risk biology of ETP Promising data continues to emerge of using JAK/STAT inhibitors in ETP - ETP appears to be addicted to the JAK/STAT pathway Further research continues in other pathways for rarer cases where JAK/STAT inhibition is less effective

17 References 1) Maude S et al. Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T cell precursor (ETP) acute lymphoblastic leukaemia. Blood (2015) 125: ) Jain N et al. Early T cell precursor lymphoblastic leukaemia/lymphoma (ETP ALL/LBL) in adolescents and adults: a high-risk subtype. Blood (2016) 127: ) Zhang J et al. The genetic basis of early T cell precursor acute lymphoblastic leukaemia. Nature (2012) 481: ) Bernt, K et Al. The functional role of PRC2 in early T cell precursor acute lymphoblastic leukaemia mechanisms and opportunities, Frontiers in Paediatrics 4:49 5) Wood Bl et al. T lymphoblastic leukaemia T ALL shows excellent outcome, lack of significance of the early thymic precursor (ETP) immunophenotype, and validation of the prognostic value of end of induction MRD in COG Study AALL0434 (abstract)blood 2014:124(21) Abstract 1 6) Vainchencker W, et al JAK/STAT signalling in haematological malignancies. Oncogene. 2013;32(21) ) Vora A et al. Treatment reduction for children and young adults with low risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial. Lancet Oncology. 2013;14(3):