Welcome to Master Class for Oncologists Session 3: 2: PM 3:3 PM Pasadena, CA May 1, 21 Myeloproliferative Neoplasms 21 Speaker: Ayalew Tefferi Mayo Clinic, Rochester, MN Presenter Disclosure Information The following relationships exist related to this presentation: Dr Tefferi has no relationships to disclose. Myeloproliferative Neoplasms 21 Ayalew Tefferi Mayo Clinic, Rochester, MN Off Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. ET 1
MDS/ CMML JMML a MDS/-U e.g. RARS-T JAK2 V617F BCR-ABL AML 28 WHO Classification of Myeloid Malignancies ET Classic JAK2 Exon 12 MPL W1 Non-classic CNL CEL SM -U MDS -eos X KIT D816V X HES PDGFR rearranged FGFR1 rearranged Which of the following statements is correct 1. A JAK2 mutation is specific to whereas a PDGFR mutation excludes the possibility of reactive eosinophilia. 2. A JAK2 mutation is expected in whereas a PDGFR mutation is specific to HES. 3. A JAK2 mutation is not specific to and clonal T cells are sometimes seen in HES. 4. A JAK2 mutation is specific to clonal myeloproliferation and a PDGFR mutation is not consistent with a diagnosis of HES.. A JAK2 mutation can be seen in, ET, or whereas HES is sometimes associated with a PDGFR mutation. Suspected ET HES SM Which one of the following statements is correct Blood BCR-ABL1 screen (+) Blood JAK2V617F and Epo screen (+) VF Epo low Screen for JAK2 exon 12 mutation (-) VF (+) VF Epo not low Not sure Blood JAK2V617F screen (-) VF possible (+) (+) V617F or del(13q) or trisomy 9 Blood PDGFR mutation screen (-) CEL vs Lymphocytic variant hypereosinophilia vs HES (+) tryptase (+) CD (+) KIT mut. SM 1. A JAK2 mutation is specific to whereas a PDGFR mutation excludes the possibility of reactive eosinophilia. 2. A JAK2 mutation is expected in whereas a PDGFR mutation is specific to HES. 3. A JAK2 mutation is not specific to and clonal T cells are sometimes seen in HES. 4. A JAK2 mutation is specific to clonal myeloproliferation and a PDGFR mutation is not consistent with a diagnosis of HES.. A JAK2 mutation can be seen in, ET or whereas HES is sometimes associated with a PDGFR mutation Tefferi A. et al. Nat Rev Clin Oncol. 29;6(11):627-637. 2
What is the correct interpretation of recent treatment results in and ET with JAK2 inhibitors or IFN-alpha 1. Demonstration of drug-induced reduction in JAK2 mutant allele burden is a reasonable starting point towards a potential to improve survival in ET or. 2. Drug-induced complete remission in or ET has been associated with improved survival. 3. Neither IFN-alpha nor JAK2 inhibitors have been shown to be superior to hydroxyurea in reducing the risk of thrombosis in or ET. 4. There is controlled evidence to suggest that IFN-alpha is better than hydroxyurea for the treatment of young patients with.. JAK2 inhibitors are effective in the treatment of -associated pruritus and have been shown to induce cytogenetic remission in some cases. ET Response Response Criteria II - European LeukemiaNet 1: CR: Platelet count < 4 x1 9 /L, WBC < 1 x1 9 /L, normal spleen, no disease-related symptoms PR: Platelet count < 6 x1 9 /L OR decrease > % from baseline 1 Barosi G, et al. Blood. 29;113:4829-4833. 13% CR By comparison: Busulfan 1% CR and no leukemia in patients > 6 years of age after a median f/u of 72 months: Shvidel L, et al. Leukemia. 27;21:271-272. Pegylated interferon 76% CR plus some molecular remission: Quintás- Cardama A, et al. J Clin Oncol. 29;27:418-424. Results 4% CR By comparison: Pegylated interferon 7% CR plus some molecular remission: Quintás-Cardama A, et al. J Clin Oncol. 29;27:418-424. Pipobroman 94% CR: Najman A, et al. Blood.1982;9:89-894. Busulfan > 7% CR: Messinezy M, et al. Br J Haematol. 198;61:67-666; D Emilio A, et al. Br J Haematol.1987;6:121-122. 1% achieved phlebotomy independence % reduction in palpable length in most patients Alleviation of pruritus in most patients 46% 43% 39% 37% 39% 17 Verstovsek, et al. Blood. 29;114:Abstract 311 18 Verstovsek, et al. Blood. 29;114:Abstract 311 3
What is the correct interpretation of recent treatment results in and ET with JAK2 inhibitors or IFN-alpha 1. Demonstration of drug-induced reduction in JAK2 mutant allele burden is a reasonable starting point towards a potential to improve survival in ET or. 2. Drug-induced complete remission in or ET has been associated with improved survival. 3. Neither IFN-alpha nor JAK2 inhibitors have been shown to be superior to hydroxyurea in reducing the risk of thrombosis in or ET. 4. There is controlled evidence to suggest that IFN-alpha is better than hydroxyurea for the treatment of young patients with.. JAK2 inhibitors are effective in the treatment of -associated pruritus and have been shown to induce cytogenetic remission in some cases. Cervantes F, et al. Blood. 29;113(13):289-291. Dynamic IPSS (DIPSS) in : Hgb < 1 = 2 points, others = 1 point Survival curves of 4 patients with stratified by transfusion status at diagnosis or in the 1 st year of diagnosis Zero points Median survival not reached Transfusion need in the 1 st year post-diagnosis Transfusion Independent for at least 1 year post-diagnosis 1 or 2 points Median survival=14.2 years Transfusion need at diagnosis Survival curves in 71 int-1 risk patients Survival curves in 18 int-2 or high risk patients Transfusion independent Median survival=4 years or 6 points 3 or 4 points Median survival=1. years Transfusion dependent Passamonti et al. Blood in press Tefferi A et al. Am J Hematol. 21;8(1):14-17. 4
Cytogenetic Risk Categorization in All patients considered N = 2 Favorable (n =12); IPSS-1 patients N = 64 Favorable (n = 49); Myelofibrosis Treatment Algorithm Median survival 82 months Unfavorable (n = 48); Median survival 42 months Median survival 81 months Unfavorable (n = 1); Median survival 33 months Yes Is q- or +13 present No P =.7 P =.8 Survival S Lenalidomide (In the presence of symptoms) IPSS/DIPSS prognostic category months Complex +8 Others NN +9 13q- 2q- High risk or Int-2 risk or Int-1 risk with unfavorable karyotype or Transfusion-dependent < 4 yr. Consider CIC allo-hct 4-6 yr. Consider RIC allo-hct* > 6 yr. Low-risk or Int-1 risk without transfusions or unfavorable karyotype Symptomatic Asymptomatic Observation Hussein K. et al. Blood. 21;11(3):496-499. Tefferi. T in press Investigational drug therapy conventional drug therapy Tefferi A., et al. J Clin Oncol 29;27(27):463-469. Anemia % Splenomegaly % Disease-initiatinginitiating mutations Phenotype-modifying mutations JAK2 or MPL mutations TET2 ASXL1 CBL IDH1/2 Disease-transforming mutations Compound TG11348 JAK Inhibitor ATP Mimetics Primary Target JAK2 IC (nm) 3nM JAK Family Selectivity Profile (X-fold selectivity) JAK2 vs JAK3 JAK2 vs JAK1 JAK2 vs TYK2 332x 3x 13x Polyclonal stem cells harboring disease-susceptibilitysusceptibility alleles such as JAK2 46/1 haplotype BCR-ABL1 * * * * * * * * * * * * * * * * BCR-ABL1 negative ET * * * * * * * * * JAK2(-) AML JAK2(+) AML INCB18424 XL19 CEP71 CYT387 4.nM 2nM 1nM 18nM 72x 1x 3x 8.6x.6x 6x.6x 4x 17x AZD148 Blast phase SB118 Tefferi A. in press *HIDAC inhibitors including ITF237, MK683 and LBH89 are also being evaluated
Majority of subjects receiving 1 to mg BID show % improvement of individual MF symptoms on therapy Proportion of Subjects Exh hibiting % Improvement in MFSA AF Score 1 7 1 Month 6 Months Night Sweats Itching Abdominal Bone/Muscle Pain/Discomfort Pain N=21 N=16 N=27 N=24 INCB18424 Response analysis based on % spleen reduction (last on-therapy value) Proportion Of Subjects in Respon nse Group 1 7 BID, ITT -24% -49% -99% 1% 1 BID, ITT INCB18424 11 patients with JAK2V617F data following 3 months of treatment Median allele burden 7% Impact of INCB18424 therapy Average decrease of 11% at 1 year (n = 81, P <.1) Average decrease of 18% at 2 year (n = 12, P =.) Greater than % reduction in JAK2V617F in 19 patients (1%) Greater than % reduction in JAK2V617F in 8 patients (6%) Percent of baseline 1 8 6 4 2 Patients with > % reduction in V617F 84 168 2 336 42 4 88 672 76 Verstovsek, et al. Blood. 29;114:Abstract 76. Verstovsek, et al. Blood. 29;114:Abstract 76. Days Decrease in Palpable Spleen Size by Cycle 68 mg/day* TG11348 (N = 37) TG11348 Effect on Leukocytosis ( WBC Count > 11 x 1 9 /L) of Subjects Percentage o 8 7 6 4 3 2 1 spleen size: Median = 18 cm Range = 6-32 cm >/=% 1% WBC Count (x1 ^9/L) 24 22 2 18 16 14 12 1 8 6 4 73% of subjects had normal WBC counts at their last follow-up visit 112 1322 1223 1624 126 1427 1628 1429 143 1633 1434 113 1237 1438 1642 164 1448 (n = 36) (n = 33) (n = 32) (n = 28) (n = 29) (n = 28) 2 Follow-Up ULN 1649 142 143 14 137 *Starting dose. Doses (mg/day) Cycle 1, 2-8; Cycles 2-6, 36-68 mg/day. 22-47% increase in 3 subjects with drug held for ~2-3 weeks immediately prior to measurement. Pardanani A, et al. Blood. 29;114:Abstract 7. Doses at follow-up range from 36 to 68 mg/day. Last visit follow-up visit ranges from 8 to 24 weeks (median 24 weeks). ULN = upper limit of normal. Pardanani A, et al. Blood. 29;114:Abstract 7. Pardanani A, et al. Blood. 29;114:Abstract 7 TG11348 Effect on V617F Allele Burden in Subjects With > 2% (N = 22) * Change From Baselin ne as a Proportion of Base eline 2 18 16 14 12 1 8 6 4 2 *Subset of JAK2V617F positive subjects in the overall population (N = 48). Doses at follow-up 36 to 68 mg/day. Last visit follow-up visit ranges from 2 to 72 weeks (median 24 weeks). Follow-Up 121 124 148 169 141 Increased (%) 1417 118 1322 1624 Stable 14 (36%) 143 1431 1237 1438 1642 144 Decreased (9%) 164 Median decrease 6% 1147 1448 142 143 14 IL-6 IL-1 IL-11 IL-22 Leukemia inhibitory factor Oncostatin-M Ciliary neutrotrophic factor JAK1 INF-α/β IL-2 IL-4 IL-7 IL-9 IL-1 IL-21 JAK3 IFN-γ G-CSF TYK2 IL-12 IL-23 JAK2 Epo Tpo IL-3 IL- GM-CSF Growth hormone Leptin Prolactin Pardanani A, et al. Blood. 29;114:Abstract 7. Tefferi A. in press 6
No Changes in Cytokine Levels With TG11348 IL-8 pg/ml pg/ml IL-6 3 3 2 1 1 Cycle 1 Cycle 3 3 3 2 1 1 Cycle 6 3 3 2 1 1 All values are medians. Cycle 1 Cycle 1 Cycle 3 Cycle 6 Cycle 3 Cycle 6 TNF-a pg/ml pg/ml IL-2 Cycle 3 Cycle 6 3 3 2 1 1 Cycle 1 Pardanani A, et al. Blood. 29;114:Abstract 7. Verstovsek, et al. Blood. 29;114:Abstract 76. Treatment Algorithm in HES or Clonal Eosinophilia FISH for CHIC2 and cytogenetic studies for q33 translocations CHIC2+ or q33+ Imatinib-insensitive Imatinibeosinophilic disorder CEL or other myeloid malignancy HES Lymphocytic variant hypereosinophilia Imatinib 1 mg/day PDGFRA-rearranged PDGFRB-rearranged Is treatment necessary Prednisone for acute therapy Verstovsek, et al. Blood. 29;114:Abstract 76. 7 Chronic therapy Low--dose prednisone Low Hydroxyurea Interferon alpha Imatinib Mepolizumab Alemtuzumab
Practical Classification of Mast Cell Disease Survival for 342 systemic mastocytosis patients classified by disease type compared with Expected the expected US age Survival and gender compared matched to WHO US Population s classification survival 1 Cutaneous mastocytosis (skin-only disease) 1 8 ISM, (n=19) ASM, (n=41) AHD, (n=138) MCL, (n=4) Expected US Survival 6 Both can manifest mast cell mediator release symptoms Sur rvival 4 2 i Indolent SM 2 Systemic mastocytosis (SM) ii Aggressive SM (cytopenia, bone disease, organomegaly, etc.) 1. SM without associated 2 nd myeloid/lymphoid neoplasm 2. SM with associated 2 nd myeloid/lymphoid neoplasm 3. Mast cell leukemia 1 2 3 Years from Dx Lim KH, et al. Blood. 29;113(23):727-736. 1Oct8 Treatment for Systemic Mastocytosis Indolent Aggressive Associated with MDS or CMML Mast cell leukemia H1 and H2 blockers Cromolyn Phototherapy Topical steroids Cladribine or IFN-α Thank you for attending Master Class for Oncologists If this fails, OK to try IFN-α or cladribine If this fails, don t count on either dasatinib or midostaurin Treat as MDS or CMML Treat as AML or with cladribine then transplant Questions & Answers 8