JAK inhibitors in Phmyeloproliferative

Transcription

1 Disclosures for A Pardanani Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Scientific Advisory Board TargeGen, Cytopia/YM BioSciences, PharmaMar None None None None None Presentation includes discussion of the following off-label use of a drug or medical device. Hydroxyurea, interferon-alpha, imatinib mesylate, 2-CdA, busulfan, anagrelide, thalidomide, lenalidomide, pomalidomide, prednisone, androgens, erythropoiesis stimulating agents, alemtuzumab, INCB18424, TG11348, CYT387, RAD1, PKC412, Panobinostat, Givinostat JAK inhibitors in Phmyeloproliferative neoplasms: survival benefit or palliation? A. Pardanani, MBBS, PhD Mayo Clinic 1

2 "If you believe that, I've got a bridge to sell you." brooklyn bridge Chronic phase Accel./blast phase JAK2, MPL, TET2, ASXL1, CBL, IDH1/2, IKZF4, LNK, EZH2, DNMT3A?? Disease-initiatinginitiating mutations Phenotype-modifying mutations Disease-transforming mutations Polyclonal stem cells harboring disease-susceptibilitysusceptibility alleles such as JAK2 46/1 haplotype? BCR-ABL1 negative MPN BCR-ABL1 * * * * * * * * * * * * ** * * PV ET PMF?? * * * * * * * * * JAK2(-) AML JAK2(+) AML? Tefferi A. Leukemia 24: , 21 CML Blast phase CML 2

3 Mutations galore in BCR-ABL1-negative myeloid neoplasms MPL JAK2 LNK CBL PV ET PMF CMML RARS-T MDS AML IDH TET2 EZH2 IKZF1 ASXL1 A. Figure 1 Wild-Type Clonal hierarchy in a patient with PMF and two distinct LNK mutations, JAK2V617F and IDH2 R14Q C. LNK _delGGCCCCG wild-type LNK 955_delA heterozygous LNK 955_delA IDH2 R14Q LNK _del GGCCCCG JAK2 V617F heterozygous homozygous JAK2 V617F wild-type IDH2 R14Q wild-type heterozygous heterozygous B. Wild-Type LNK _del GGCCCCG Wild-Type LNK _del GGCCCCG LNK _del GGCCCCG Homozygous LNK _del GGCCCCG Homozygous LNK _del GGCCCCG LNK 955_delA LNK 955_delA LNK 955_delA LNK 955_delA LNK 955_delA Wild-Type JAK2 V617F Wild-Type IDH2 R14Q n=1 5% Wild-Type JAK2 V617F IDH2 R14Q n=3 15% JAK2 V617F IDH2 R14Q n=4 2% Wild-Type JAK2 V617F IDH2 R14Q n=7 35% JAK2 V617F IDH2 R14Q n=7 35% LNK Mutation Studies In Chronic- and Blast-Phase Myeloproliferative Neoplasms and JAK2 Mutation-Negative Erythrocytosis ASH 21, abstract #415 3

4 Targeted therapy in MPN What mutant molecule should we target? MPL <1% LNK <3% CBL <3% JAK2 >95% IDH <5% TET2 <2% EZH2 <5% IKZF1 <1% ASXL1 <1% DIPSS-plus (Dynamic International Prognostic Scoring System + karyotype + platelet count + transfusion status) risk stratification in 793 patients with primary myelofibrosis seen at Mayo Clinic Rochester Survival Low risk ( adverse points) n=66; median survival ~ 185 months Intermediate-1 risk (1 adverse point) n=174; median survival ~ 78 months Intermediate-2 risk (2 or 3 adverse points) n=36; median survival ~ 35 months High risk (4 or more adverse points) n=193; median survival ~ 16 months P<.1 Adverse points 1. Hgb < 1 g/dl 2. Circulating blasts 1% 3. WBC > 25k 4. Constitutional symptoms 5. Age > 65 years 6. Transfusion need 7. Platelets < 1k 8. Unfavorable karyotype IPSS/DIPSS DIPSS-plus Monosomal karyotype Complex karyotype Trisomy 8-7/del(7q) Del(5q) Inv(3) isochromosome 17q/17p- 12p- 11q23 abnormality Gangat et al. ASH 21 abstract #414 Months Gangat et al., J Clin Oncol. 211 Feb 1;29(4):

5 Primary end point for Phase III JAK inhibitor trials in myelofibrosis 35% decrease in spleen volume by MRI/CT OS PFS JAK inhibitor ATP mimetics in clinical trials for myelofibrosis Anti-JAK2 IC5 (JAK1/JAK3 selectivity) INCB nm (Phase 1/2 study) (x1./x98) N=153 TG nm (Phase 1/2 study) (x35/x332) N=59 CYT nm (Phase 1/2 study) (x.6/x8.6) N=6 CEP-71 1 nm (Phase 2 study) (x?/x3) SB1518 (Phase 1/2 study) AZD148 (Phase 1/2 study) LY (Phase 1/2 study) 22 nm (x58/x24).26 nm (x5/x15) Scant literature Non-JAK kinase targets None of ~28 kinases evaluated FLT3 RET JNK1 CDK2 FLT3 TrkA FLT3 TrkA Aurora A FGFR1 Scant literature 5

6 Safety and Efficacy of INCB18424, a JAK1 and JAK2 Inhibitor, in Myelofibrosis JAK-1/JAK-2 Verstovsek S et al. N Engl J Med 21;363: % 49% INCB18424 Phase 1/2 study N=153 Median f/u=14.7 months DLT=Gr 3/4 thrombocytopenia MTD=25 mg BID or 1 mg QD Verstovsek S et al. N Engl J Med 21;363:

7 Study discontinuation rate=25% Verstovsek S et al. N Engl J Med 21;363: Longer-Term Follow up with TG11348 Therapy In Myelofibrosis Confirms Sustained Improvement In Splenomegaly, Disease-Related Symptoms, and JAK2V617F Allele Burden JAK-2 J Clin Oncol. 211 Mar 1;29(7):

8 39% 39% 47% 47% Cycle 6 Cycle 12 Early satiety 1 9 Night sweats 8 Percentage of Subjects TG Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Resolved From Mild Resolved From Moderate or Severe Phase 1 study N=59 Median f/u=38 days Normalization of Leukocyte count = 56% Normalization of platelet count = 88% DLT=Gr 3/4 elevated amylase/lipase MTD=68 mg QD Adverse Event Grade 1/2 All subjects N=59 TG11348: safety and tolerability Grade 3/4 study discontinuation rate = 44% MTD cohort N=4 Grade 1/2 Grade 3/4 Nausea 66% 3% 78% 5% Vomiting 54% 3% 68% 3% Diarrhea 6% % 1% % Lipase increased 17% 1% 23% 15% ALT increased 19% 7% 23% 8% AST increased 25% 2% 33% 3% Creatinine increased 24% % 28% % Alkaline phosphatase increased 17% % 23% % Subjects Number of MTD cohort: 7% required dose reduction Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle Anorexia 14% % 15% % Peripheral edema 1% % 1% % Skin exfoliation 14% % 2% % Adverse Event All N= Subjects 59 MTD N= Cohort 4 Grade 1/2 Grade 3/4 Grade 1/2 Grade 3/4 Anemia (N=37) 8% 35% 8% 54% Thrombocytopenia 17% 24% 2% 28% Neutropenia 63% 1% 5% 1% 8

9 A Phase I/II Study of CYT387, An Oral JAK-1/2 Inhibitor, In Myelofibrosis: Significant Response Rates In Anemia, Splenomegaly, and Constitutional Symptoms ASH 21, Abstract #46 JAK-1/JAK % All 1mg/d 15mg/d 2mg/d 3mg/d 4mg/d subjects (n=3) (n=19) (n=3) (n=24) (n=4) (n=53) Spleen response (IWG) Night sweats (n=26) Bone Pruritus pain (n=13) (n=25) Fever (n=5) All 15 mg/d 3 mg/d 1 CYT387 Phase 1/2 study N=6 Median f/u 4.9 months %/43% 58%/69% Anemia evaluable Transfusion-dep DLT Gr 3 elevated lipase/headache MTD 3 mg QD mg/d (n=2/1) 15mg/d (n=17/14) 3mg/d (n=19/16) 4mg/d (n=4/2) 9

10 CYT387: safety and tolerability study discontinuation rate = 5% Adverse events Grade 1 Grade 2 Grade 3 Grade 4 Nausea 15% Diarrhea 12% Abdominal pain 7% Vomiting 3% Increased transaminases 2% 3% Increased bilirubin 16% Increased lipase 7% 5% Increased amylase 5% 5% Increased Alk Pase 7% 3% Increased creatinine 5% All patients (n=6) Starting dose 15 mg/day Starting dose 3 mg/day Transient Lightheadedness Systolic BP decrease >2 mm Hg 43% 52% 19% 33% 59% 63% Numbness 5% Headache 1% 3% Prolonged QTc 3% Dry mouth 3% Adverse events Grades 1/2 Grade 3 Grade 4 Anemia 7% 7% Thrombocytopenia 42% 18% 8% Neutropenia 2% 5% Platelet inclusion criteria: INCB18424: 1k ; TG11348: 5K; CYT387: 5k The two pathogenetic faces of myelofibrosis Secondary inflammatory state (cytokine-mediated) JAK-STAT-driven clonal myeloproliferation Abnormal cytokine milieu Bone marrow stromal reaction AML Survival Leukocytosis Thrombocytosis Ineffective hematopoiesis (anemia) Extramedullary hematopoiesis (splenomegaly) Hypercatabolic symptoms, pruritus and cachexia 1

11 Units JAK2V617F allele burden C1D1 C7D1 C13D Interleukin-6 Absolute Change (pg/ml) TNF-α 5 5 Baseline Cycle 6 Cycle 12 6% 31% 32% (23-1%) (4-1%) (7-1%) p <.1 Absolute Change (pg/ml) Interleukin-8 Absolute Change (pg/ml) Interleukin-2 TG11348 JAK1 JAK1/2 JAK2 JAK2V617F J Clin Oncol. 211 Mar 1;29(7): Verstovsek S et al. N Engl J Med 21;363:1117 INCB18424 JAK1 JAK1/2 JAK2 JAK2V617F Verstovsek S et al. N Engl J Med 21;363:

12 Can targeting cytokines favorably impact survival in MF? Plasma cytokines in primary myelofibrosis are abnormally increased and correlate with phenotype and prognosis IL-8, IL-2R, IL-12, IL-15 and CXCL1 were independently associated with poor survival 1 9 treatment-naive patients with PMF Plasma IL-8 and IL-2R in the normal range (n=6) Median survival ~8 months One or both cytokines elevated (n=3) Median survival ~17 months Only intermediate-1 risk patients considered; N = 27 Plasma IL-8 and IL-2R in the normal range (n=21) Median survival not reached One or both cytokines elevated (n=6) Median survival ~17 months val Surviv P< Months J Clin Oncol. 211 Apr 1;29(1):

13 The fallacy of retrospective comparisons Mature survival data for 288 young patients (age 65 years) with primary myelofibrosis stratified by year of diagnosis P=.3 Years N= Years N=127 Before 199 N= Updated data from Vaidya et al. Mayo Clin Proc 29;84:

14 What can we expect from JAK inhibitor therapy in PV or ET? Survival and risk of leukemic transformation in ET are significantly influenced by accurate morphologic diagnosis: An international study of 1,14 patients. Barbui et al. Blood 21; 21 ASH abstract #457 ET and pre-fibrotic MF vs Europe* Age- and sex-adjusted actuarial survival curves 1,9,8,7 Survival,6,5 4,4,3,2 Europe ET Pre-fibrotic MF, Years Fibrotic progression was significantly less in the presence of JAK2V617F 14

15 What is the prognosis for JAK inhibitors in Ph- myeloproliferative neoplasms? Myelofibrosis Well tolerated, significant palliation Disease modifying? Combination with other agents Polycythemia vera / Essential thrombocythemia limited niche (eg. refractory pruritus) Unproven benefit wrt clinically relevant end points 15