Should Mutation Status in PMF Guide Therapy? No! Brady L. Stein, MD MHS Assistant Professor of Medicine Division of Hematology/Oncology
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1 Should Mutation Status in PMF Guide Therapy? No! Brady L. Stein, MD MHS Assistant Professor of Medicine Division of Hematology/Oncology
2 Case presentation A 67 yo woman presents to transition care, as her hematologist retired. She was diagnosed with ET in 2001, and has been managed with anagrelide x 15 yrs. She notes fatigue, NS, and occasional LUQ ache. Her spleen is 7cm below the CM. Labs reveal a leukocyte count of 13 x 10 9 /L (1% blasts), Hgb 10.2 g/dl, (MCV 94), and a platelet count of 676 x 10 9 /L. LDH 576. BM reveals hypercellularity, clustering, atypical MKs, and G2 fibrosis, confirming post-etmf. The patient has never been tested for the JAK2 V617F mutation.
3 Question 1: The patient is counseled about a new diagnosis of post-etmf, based on constitutional sx, anemia, increased LDH, splenomegaly, and an abnormal BM. Anagrelide is discontinued. The patient has read about JAK-inhibitor therapy, and is contemplating initiation given progressive splenomegaly and NS. She is reluctant because her recently tested JAK2 V617F mutation test was negative. Which of the following is correct? A. Spleen and symptom improvement have not been shown in patients with CALR mutations. B. Only symptom response is impacted by JAK2 mutational status. C. Spleen and symptom improvements are statistically improved in patients with JAK2 mutations compared to JAK2 wild-type D. Spleen and symptom improvements are statistically similar between pts with JAK2 mutations compared to JAK2 wild-type.
4 Question 2: The patient has joined an online MPN pt support network. She has learned that many other patients have had next generation sequencing. Which of the following best characterizes your clinical practice? A. I do not send NGS testing in my MPN patients because I do not believe that this impacts therapeutic decision-making. B. I send NGS testing only in my MPN patients that are deciding whether or not to pursue transplantation. C. I send NGS testing prior to initiating ruxolitinib as I perceive that results can predict response to therapy. D. I send NGS testing in order to identify an actionable target in MPN patients that have failed ruxolitinib.
5 Myeloproliferative Syndromes Chronic Myeloid Leukemia, Essential Thrombocytosis, Polycythemia Vera, Myelofibrosis Myeloproliferation Thrombotic, hemorrhagic complications Extramedullary hematopoiesis Marrow Fibrosis Leukemic transformation.is it possible that these various conditions myeloproliferative disorders are all somewhat variable manifestations of proliferative activity of the bone marrow cells, perhaps due to a hitherto undetected stimulus? William Dameshek, 1951, Blood
6 Dameshek s Myelostimulatory Factors JAK2 JAK2 V617F MPL W 515K/L CALR type 1/2 MPL % of MF and ET ~95% of PV cases JAK2 Exon 12 mutations present in ~2-3% of PV 5-10% of ET and MF 20-25% of ET and MF Non-canonical, somatic and germ-line MPL mutations outside exon 10 in ~10% of TN ET Non-canonical germ-line JAK2 mutations in ~8% of TN ET Milosevic Feenstra JD, et al Blood 2016; Atypical MPL mutations also reported by Cabagnols et al, Blood 2016
7 Disease pathogenesis: JAK2 mutation Wild-type JAK2 JAK2 V617F JAK2 activates the 3 main myeloid cytokine receptors: -Erythropoietin receptor -Thrombopoietin receptor (MPL) -GCSF receptor Mutations can be heterozygous, or homozygous Stein and Moliterno JAMA 2010
8 Disease pathogenesis: MPL mutations TPO activates MPL, and then JAK2 MPL mutations activate receptor in absence of ligand (TPO) -Most frequent types: W515L/K located on transmembrane and cytosolic domains of MPL -Mutations typically heterozygous Modified figure: Stein and Moliterno JAMA 2010
9 Disease pathogenesis: CALR mutations Mutant CALR appears to chaperone and traffic MPL to the cell surface, activating JAK2 Heterozygous mutations Type 1 52 bp deletion Type 2 5 bp insert 2016 by American Society of Hematology Mario Cazzola Blood 2016;127:
10 Prognostic Impact of Driver mutations Age > 65 Constitutional sx Anemia Leukocytosis 1% circulating blasts + Transfusion-dependence Plts < 100 Abnormal karyotype *CALR positive (22.7%) JAK2 (65%) or MPL (4%) positive Triple Negative (8.6%) N= yrs 9.2 and 9.1 yrs 3.2 yrs Worsening Prognosis -Molecular markers not yet incorporated into validated risk score *Survival benefit may be restricted to type 1 CALR mutations Rumi et al, Blood 2014
11 Should we test for other mutations routinely in clinical practice? Pathway Mutation Prevalence Relevance Signaling DNA methylation Histone modification Transcription factors Splicing machinery CBL LNK TET2 DNMTA3 *IDH1/2 *EZH2 *ASXL1 TP53 *SRSF2 U2AF1 ~4% ~2% 10-20% MPN 5-10% MPN 1-3% MF 5-10% MF ~25% MF <5%, but prevalent in saml? Disease progression Disease initiation Disease initiation Adverse survival Adverse survival AML progression 10-15% MF Adverse survival Anemia? --Worst prognosis in CALR negative/asxl1 positive (2.3 yr OS) --Not specific to MPNs. Actionable? Mutation based trials sparse, though IDH inhibitors in trial and spliceosome trials in development (in MDS/AML) *High molecular risk markers; 2 also worsen outcome Vannucchi et al 2013; Tefferi et al Leuk 2014; Guglielmelli et al, Leuk 2014; Vainchenker Blood 2017
12 Current treatment (NCCN) based on symptoms and risk assessment, not on mutations Cytopenias Constitutional and systemic symptoms Splenomegaly Shortened survival Low Risk Int1 Risk Int2/High Risk
13 Low Risk MF: Observation, Clinical trial, or...*ifn 30 pts w/ early MF 73% OR 2 CR (7%) 9 PR (30%) 4 CI (13%) 7 SD (23%) *Mod/large spleen negatively impacted response No correlation between driver mutations and response No response in HMR pts (N=4) *Option per NCCN 2016 Improved marrow architecture Improved megakaryocyte morphology and increased normoblastic erythropoiesis Minimal reticulin fibrosis Absent collagen fibrosis Silver, RT Blood 2011; Silver et al, ASH 2016 Abstract 944
14 NCCN 2016 Management of MF-anemia Choice of agent based on: Epo level, Co-morbidities, Plt count, PS, RBC-dependence-- Not mutational status Exclude other causes of anemia (Iron/B12/folate, hemolysis) Yes ESA Response: 23-60% RBC-need response; positive impact from gender, leukocyte > 10k, and low ferritin; No impact from molecular profile Epo Level <500 U/L? No Androgens: Danazol 600mg daily: Response 30%, 5ms Duration: 14m *RBC need: response *Only predictive variable; no impact from JAK2 status Prednisone: 0.5-1mg/kg daily Response in 12/30 (40%) Duration: 12m IMIDs Thal/Lenalidomide (w/ Pred) 19-35% No impact from mutational profile (Len/Pred) Consider Clinical Trials upfront Based on Sx/Spleen/Plts/ Novel JAKi -Momelotonib -Pacritinib -NS-018 JAKi combo Non-JAKi -PRM-151 -Imetelstat *Sotatercept (*ASH 2016 abs 478) Hernandez-Boluda et al, EJH 2017; Cervantes F, et al. Ann Hematol. 2015;94: ; Hernandez-Boluda JC, et al. Leuk Lymph Mesa RA, et al. Blood. 2010;116: ; Thapaliya P, et al. Am J Hematol. 2011;86: Cervantes F, et al. Br J Hematol. 2006;134: ; Tsiara SN et al. Acta Hematol. 2007;117: ; Tefferi A, et al. Blood. 2000;95: ; Cervantes F. Blood. 2014;124: Jabbour E, et al. 14 Blood. 2011;118: Chihara, et al, Leuk research 2016
15 Int-1, Int-2, and High Risk Disease (Non-transplant approach Spleen/sx predominate) Ruxolitinib Momelotonib Pacritinib NS-018 Selectivity JAK1/JAK2 JAK1/JAK2/TYK2 JAK2/FLT3 JAK2 selective Phase Spleen response Symptom Relief AE s Unique effects *Approved (5y) Cytopenias Wt gain, Skin CA?, Infxn, lipids -Survival benefit? 3 3 Phase 2 complete X X X X X X X X Platelets Neuropathy Anemia response? GI toxicity Less myelosuppressive Cytopenias Neurological sx Possibly less myelosuppressive Candidacy based on presence of cytokine-related sx and splenomegaly *Only approved MF therapy
16 Ruxolitinib vs. Placebo (COMFORT-1) Ruxolitinib vs. BAT (COMFORT-2) Is a JAK2 mutation a prerequisite for therapy? COMFORT-2 Retrospective analysis Mutational status 73 vs. 80%, JAK2 mutated, respectively 75 vs. 67%, JAK2 mutated, respectively 29 CALR mutated pts (post-hoc) Influence on outcome No significant interaction between mutational status and spleen (p=0.07) or symptom response (p=.11) Reduced spleen volume across all subgroups, including JAK2 mutational status No significant difference in response rates in CALR+ vs. CALR- pts Mutational status not a prerequisite for JAKi response -Complements concept of universal JAK-STAT activation Verstovsek, et al, NEJM 2012; Harrison CN, et al NEJM 2012; Guglielmelli, et al; Br Journal Haematology 2016
17 Do other somatic mutations influence JAKi response? Outcomes by mutational profile in COMFORT-2 pts ASXL1 32.5%; TET2 10.7%; EZH2 7.2%; CBL 4.4%; SRSF2 3%; IDH1 0.7%; IDH2 0% Spleen Response Symptom Improvement High Molecular Risk Group Wk 24: 34.8% Wk 48: 26% Wk 24: 85.7% Wk 48: 76% Toxicity Profile Anemia: 74% TCP: 34% Survival Low Molecular Risk Group Wk 24: 35% Wk 48: 35% Wk 24 : 76.2% Wk 48: 83% Anemia: 72% TCP: 36.5% Statistical impact? No difference No difference No difference Improved Survival independent of molecular proflie *Among 95 phase 1/2 ruxolitinib-treated pts: Spleen response 9x more likely in pts w/ 2 mutations vs. 3 mutations (13% of the cohort); latter group had a shorter time to treatment discontinuation Retrospective/post-hoc analyses Guglielmelli et al Blood 2014; *Patel et al, Blood 2015
18 Accelerated or Blast Phase Disease MPN-Accelerated Phase Blasts 10-19% in peripheral blood or bone marrow *HSCT Candidate? Hypomethylating Agent or chemotherapy with hope to induce remission or control disease prior Yes If on ruxolitinib, may be continued for control of spleen/sx MPN-Blast Phase Blasts 20% in peripheral blood or bone marrow No HSCT -Clinical trial -*Hypomethylating Agent -Low intensity induction chemo -*5-Aza: No impact on ORR/OS from JAK2 status (duration longer in JAK2+ pts though) -**Decitabine: No correlation between response and genetic profile ORR overall response rate; OS: overall survival *Thepot et al, Blood 2010 **Badar et al Leuk Res 2015
19 Transplant as means of addressing survival impairment: High Reward, but High Risk Low risk and most Int-1 risk pts Int-2/High Risk Or *Int-1 w/ TCP, blasts, or complex karyotype Challenges -Splenomegaly impacting PS -Fibrosis delaying engraftment -GVHD -Relapse Impact of JAKi prior to transplant? Age, Comorbidities, Preferences, Donor, Caregiver ( 10% referred/transplanted) Use of mutational profile to identify candidates requires further, prospective validation Reward Possibility for cure Scoring systems that incorporate molecular genetics not yet validated/published No prospective transplant studies stratified by mutational profile (eg CALR-, ASXL1+) Useful in Int-1 pts? CALR-/ASXL+ (N=9 in retrospective study)
20 Summary, part 1 Driving and other somatic mutations impact diagnostic capabilities, inform disease pathogenesis, and influence prognosis Mutational profile yet to be formally incorporated into risk classification In 2017, therapeutic options remain limited, and decisionmaking (consensus > evidence-base) driven by symptoms and conventional risk score, not mutational status Mutational status does not impact response to conventional therapy (1 approved agent) Outcomes based more on clinical factors We need *prospective studies with upfront stratification based on mutational profile to determine impact on decision-making Ideally, mutational profile will inform conduct of rational clinical trials based on precise, targeted therapies *See next slide
21 Summary, part 2: Clinical trials Early MF: Novel Peg-IFN JAK2 V617F, CALR, MPL mutations Anti-fibrosing agents: PRM-151 Early MF w/ increased molecular risk: Ruxolitinib vs. Placebo JAK-STAT dysregulation Pacritinib Momelotonib NS-018 Selected, potential JAKi partners address: Telomerase overexpression Imetelstat No ASXL1+ or JAK2- pts responded; 38% CR in SF3B1 or U2AF1 mutated **Immunotherapy CALR?? mtor/pi3k/akt pathway Hh inhibition Epigenetic dysregulation RAS/RAF/MEK pathway HSP90 **Abnormal Megs Aurora Kinase A inhibition **Northwestern Investigator Initiated Studies, open now
22 Thank you for your
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