PAX5-JAK2 fusion in acute lymphoblastic leukaemia. Dr Andrew Baldi Royal Children s Hospital 24 February 2017 Melbourne

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1 PAX5-JAK2 fusion in acute lymphoblastic leukaemia Dr Andrew Baldi Royal Children s Hospital 24 February 2017 Melbourne

2 Case 12-year-old girl Diagnosed with BCP ALL in November 2015 Presenting WCC 35x10 9 /L 46,XX karyotype BCR/ABL1, ETV6/RUNX1 fusions and KMT2A rearrangement not detected by FISH CRLF2 not expressed on flow cytometry PAX5/JAK2 fusion detected on molecular testing

3 Case Commenced on COG protocol AALL08B1/1131 (HR VHR) MRD by flow cytometry: End of induction 4.980% End of consolidation (control arm) 5.215%

4 Case Ruxolitinib trialled Combined with dexamethasone and vincristine tolerated well for six weeks Reduction in MRD to 0.164% Increased to 0.760% Inotuzumab ozogamicin provided on compassionate basis 0.5mg/m 2 /dose weekly for two doses MRD <0.01%

5 Case MUD HSCT (12/12) in CR1 (July 2016) TBI/VP16/ATG conditioning Neutrophil engraftment Day +10 No significant infective complications Mild chronic GVHD (skin) Off all immunosuppression

6 Case Remains in remission six months post-allogeneic HSCT Assessment day MRD (FCM) Chimerism (whole BM) Day +30 <0.010% 99.97% donor Day +60 <0.010% 99.90% donor Day +100 <0.010% 99.68% donor Day +180 <0.010% 99.20% donor

7 Ph-like BCP ALL Similar gene expression profile to Ph+ ALL (but lacking BCR/ABL1 fusion) generally related to mutations and rearrangements in cytokine receptor genes and kinase pathways that alter expression of transcription factor genes Peak in adolescents and young adults Represents around 15% of children with HR B-ALL

8 Ph-like BCP ALL More common than Ph+ ALL even in young adults (27% compared with 22%) Kinase-activating mutations in most cases many genes implicated including ABL1, ABL2, CRLF2, CSF1R, EPOR, IL7R, JAK2, NTRK3, PDGFRB, PTK2B, SH2B3, TSLP and TYK2 Generally associated with higher-risk disease

9 Ph-like BCP ALL Overall survival of patients with Ph-like ALL (25.8+/-9.9%, 65.8+/-7.1% and 72.8+/-4.8%) From Roberts KG, Targetable Kinase-Activating Lesions in Ph-like Acute Lymphoblastic Leukemia, NEJM 2014;371:1008

10 Ph-like BCP ALL Potentially targetable mutations involve either JAK or ABL pathways Tyrosine kinase inhibitors where ABL1, ABL2 or PDGFRB altered (eg dasatinib) JAK inhibitors where JAK or EPOR altered (eg ruxolitinib) JAK inhibitors have a role in patients with CRLF2 rearrangement many of whom also have mutated JAK1/2

11 PAX5 Regulator of normal lymphoid development Germline loss of PAX5 expression noted in rare autosomal dominant ALL Altered PAX5 signalling is implicated in leukaemogenesis B cell differentiation and PAX5 From Murray A, Mutagenetix, UT Southwestern Medical Center

12 JAK2 The JAK-STAT pathway From Shuai K et al, Regulation of JAK-STAT Signalling in the Immune System, Nature Reviews Immunology 2003;3:900-11

13 PAX5/JAK2 in Ph-like ALL PAX5/JAK2 protein consists of JAK2: kinase domain preserved leads to activation of JAK- STAT signalling pathway PAX5: DNA-binding domain preserved Fusion protein located near nucleus (in contrast to cytoplasmic localisation of JAK proteins may enable the protein to bind PAX5 targets)

14 Detecting Ph-like ALL GEP analysis CRLF2 expression FISH for ABL and JAK fusions RT-PCR to look for ABL and JAK fusion partners

15 Summary Gain-of-function mutations and translocations involving JAK2 are present in some paediatric cases of HR BCP ALL JAK2 activation and other Ph-like gene expression can provide targeted therapeutic options Targeted therapy can be used in upfront or relapse therapy may serve as a bridge to HSCT

16 Summary Current Phase 2 study (Children s Oncology Group) NCT

17 References Den Boer ML et al, A Subtype of Childhood Acute Lymphoblastic Leukaemia with Poor Treatment Outcome: A genomewide classification study, Lancet Oncology 2009;10(2): Fasan A et al, Three Steps to the Diagnosis of Adult Ph-like ALL, Blood 2015;126:2610 Kantarjian HM et al, Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia, NEJM 2016;375: Mullighan CG, The Genomic Landscape of Acute Lymphoblastic Leukaemia in Children and Young Adults, ASH Hematology, The Education Program, December : Roberts KG, Targetable Kinase-Activating Lesions in Ph-like Acute Lymphoblastic Leukemia, NEJM 2014;371: Schinnerl D et al, The Role of the Janus-faced Transcription Factor PAX5-JAK2 in Acute Lymphoblastic Leukemia, Blood 2015; 125(8): Shah S, A Recurrent Germline PAX5 Mutation Confers Susceptibility to Pre-B Cell Acute Lymphoblastic Leukemia, Nat Genet 2013;45(10): Shuai K et al, Regulation of JAK-STAT Signalling in the Immune System, Nature Reviews Immunology 2003;3: Steeghs EMP et al, JAK2 Aberrations in Childhood B-Cell Precursor Acute Lymphoblastic Leukemia, Blood 2016;128:583