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State-Of-The-Art Solutions for Myelofibrosis the Intersection of JAK Inhibitors, Allogeneic Transplant, and Other Strategies for Patient Care

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State-Of-The-Art Solutions for Myelofibrosis the Intersection of JAK Inhibitors, Allogeneic Transplant, and Other Strategies for Patient Care State-of-the-Art Solutions for Myelofibrosis The Intersection of JAK Inhibitors, Allogeneic Transplant, and Other Strategies for Patient Care This session is open only to registrants of the 2020 Transplantation and Cellular Therapy (TCT) Meetings of ASTCT and CIBMTR in Orlando, FL. Disclosures Prithviraj Bose, MD, has a financial Jeanne M. Palmer, MD, has a financial interest/relationship or affiliation in the form of: interest/relationship or affiliation in the form of: Consultant and/or Advisor for Celgene Consultant and/or Advisor for CTI BioPharma Corporation; CTI BioPharma Corp.; Incyte Corp. Corporation; and Kartos Therapeutics, Inc. Grant/Research Support from Astellas Pharma US, Inc.; Blueprint Medicines Corporation; Celgene Corporation; CTI BioPharma Corp.; Incyte Corporation; Kartos Therapeutics, Inc.; NS Pharma,Inc.; Pfizer, Inc.; Promedior, Inc. and Constellation Pharmaceuticals. This CME activity is jointly provided by The Medical College of Wisconsin and PVI, PeerView Institute for Medical Education. This activity is supported by an educational grant from Celgene Corporation. Visit us at PeerView.com/MF2020 • Watch for the onDemand version in the coming weeks • Download the slides and Practice Aids • Apply for CME credit Join the conversation on Twitter @PeerView Need more information? Send an email to [email protected] Welcome, Introduction, and Baseline Assessment Jeanne M. Palmer, MD Associate Professor, Division of Hematology and Oncology Photo Pending Vice Chair and Section Lead, Division of Hematology Program Director, Blood and Marrow Transplant Program Mayo Clinic Phoenix, Arizona Go online to access full [Certification Type] information, including faculty disclosures. Today’s Agenda Risk-adapted therapy in MF and the role established for novel JAK inhibitor–based therapy The modern role of HCT in MF and the convergence of JAK inhibition with allogeneic transplant Navigating the Treatment Landscape in MF: Risk-Adapted Therapy and the New JAK Inhibitor Era Prithviraj Bose, MD Associate Professor, Department of Leukemia, Division of Cancer Medicine Photo Pending The University of Texas MD Anderson Cancer Center Houston, Texas Go online to access full [Certification Type] information, including faculty disclosures. The Evolution of Risk Stratification Models in MF1-3 Parameter IPSS DIPSS DIPSS-Plus Age >65 y Constitutional symptoms WBC >25 x 109/L Hb <100 g/L (two points) Peripheral blasts ≥1% Platelet count <100 x 109/L – – RBC transfusion need – – Unfavorable karyotype – – 1. Cervantes F et al. Blood. 2009;113:2895-2901. 2. Passamonti F et al. Blood. 2010;115:1703-1708. 3. Gangat N et al. J Clin Oncol. 2011;29:392-397. Risk Stratification1-3 Unfavorable Karyotypes i(17q) +8 MK Complex karyotype -7/7q- inv(3) 11q23 rearrangement 5/5q- 12p- 1. Tefferi A et al. Leukemia. 2012;26:1439-1441. 2. Gangat N et al. J Clin Oncol. 2011;29:392-397. 3. Caramazza D et al. Leukemia. 2011;25:82-88. Prognostic Value of Driver Mutations1 JAK2 V617F vs CALR vs Triple Negative Highest OS 1 CALR mutant (median OS: 17.7 y) 0.9 JAK2 mutant (median OS: 9.2 y) MPL mutant (median OS: 9.1 y) 0.8 CALR Triple negative (median OS: 3.2 y) 0.7 0.6 JAK2 V617F 0.5 or MPL 0.4 of Survival 0.3 Triple 0.2 negative 0.1 Cumulative Probability 0 0 5 10 15 20 25 30 Lowest OS Time, y 1. Rumi E et al. Blood. 2014;124:1062-1069. Prognostic Value of Driver Mutations1 (Cont’d) CALR Type 1 vs Type 2 • Two types of mutations 1 CALR type 1/type 1–like – Type 1: 52 bp deletion 0.9 n = 53 0.8 Median: 26.4 (15.5-37.3) y – Type 2: 5 bp insertion 0.7 0.6 CALR type 2/type 2–like • Effect of mutation on OS 0.5 n = 21 0.4 Median: 7.4 (4.6-10.2) y – Type 1 patients: OS advantage JAK2 V617F HR = 4.9 (1.8-12.9) 0.3 n = 251 – Type 2 patients: OS 0.2 Median: 7.2 (5.7-8.6) y HR = 6.0 (2.7-13.4) P < .0001 comparable 0.1 N = 396 0 with JAK2 V617F % of Patients, Proportion 0 5 10 15 20 25 30 Follow-Up, y 1. Guglielmelli P et al. Blood Cancer J. 2015;5:e360. “Nondriver” Mutations1 Prognostically important genes other than JAK2/CALR/MPL in ET, PV, and MF PMF SRSF2 ASXL1 IDH2 EZH2 TP53 U2AF1 CBL PV ET SF3B1 SH2B3 1. Tefferi A et al. Blood Adv. 2016;1:21-30. MIPSS70 and MIPSS70-Plus1 http://mipss70score.it A B 1 1 P < .001 Key Elements P < .001 0.8 Low 0.8 Low • Hb <10 g/dL • HMR 0.6 0.6 9 0.4 0.4 • WBC >25 x 10 /L – ASXL1 Intermediate Probability, % Probability, Probability, % Probability, 9 0.2 Intermediate 0.2 • PLT <100 x 10 /L – EZH2 High High 0 0 • Blasts ≥2% – SRSF2 0 5 10 15 20 25 30 0 5 10 15 20 25 Survival, y Survival, y • Fibrosis > grade 1 – IDH1/2 No. at Risk No. at Risk Low 380 173 70 35 18 – – Low 27 21 9 5 0 – Intermediate 198 102 27 8 5 – – Intermediate 105 54 17 9 2 – • Constitutional • Two or more HMR High 54 10 3 0 0 – – High 79 23 5 0 0 – symptoms C D 1 1 P < .001 • Absence of type 1– P < .001 0.8 0.8 Low like CALR Low 0.6 0.6 Intermediate Unfavorable karyotype 0.4 0.4 Probability, % Probability, Probability, % Probability, 0.2 0.2 High High Intermediate Very high Very high 0 0 0 5 10 15 20 25 30 0 5 10 15 20 25 30 Survival, y Survival, y No. at Risk No. at Risk Low 86 67 28 17 4 – – Low 25 20 6 3 1 – – Intermediate 63 38 10 12 1 – – Intermediate 108 74 24 7 0 – – High 127 43 4 1 0 – – High 79 50 18 2 0 – – Very high 39 3 0 0 0 – – Very high 49 18 4 1 0 – – 1. Guglielmelli P et al. J Clin Oncol. 2018;36:310-318. GIPSS: Genetically Inspired Prognostic Scoring System1 GIPSS-Stratified Survival Data in 641 Patients With Primary MF • Karyotype – Very high risk = 2 points – Unfavorable = 1 point • Driver mutations – Type 1–like CALR absent = 1 point • High-risk mutations – ASXL1 mutation = 1 point – SRSF2 mutation = 1 point – U2AF1 Q157 mutation = 1 point 1. Tefferi A et al. Leukemia. 2018;32:1631-1642. The MYSEC-PM Nomogram1 Available at https://mysec.shinyapps.io/prognostic_model/ Covariate Points Hb <11 g/dL 2 PLT <150 x 109/L 1 PB blasts ≥3% 2 CALR-WT 2 Constitutional 1 symptoms 1. Put the score value assigned for non–age-prognostic variables on the vertical axis 2. Put patient’s age on horizontal axis 3. Locate the combination of non-age score and age 4. The color at the location indicates the final risk category 1. Passamonti F et al. Leukemia. 2017;31:2726-2731. MYSEC-PM Estimate of Survival in Post-PV/ET MF1 100 Low risk (n = 133), NR 80 60 Int-1 risk (n = 245), 9.3 years (95% CI, 8.1-NR) 40 Overall Survival, % Overall Int-2 risk (n = 126), 4.4 years (95% CI, 3.2-7.9) 20 High risk (n = 75), 2 years (95% CI, 1.7-3.9) 0 0 2 4 6 8 10 12 14 No. at Risk 133 105 74 48 25 16 6 Low 245 166 104 50 20 10 6 Intermediate-1 126 70 30 15 8 2 Intermediate-2 75 25 6 1 High SMF Follow-Up Time, y 1. Passamonti F et al. Leukemia. 2017;31:2726-2731. JAK Inhibitors and Status of Development in Myelofibrosis as Lead Indication Approved Derailed in earlier phase 3, now re-entering phase 3 Selective Fedratinib JAK1, Active in Ruxolitinib - combo trials combo? Active Toxicity second late phase line • Neuro Pacritinib, momelotinib Active • Pancreas Active mid phase Failed early Itacitinib phase BMS-911543 LY2784544 NS018 Lestaurtinib AZD1280 XL019 COMFORT-I and -II: Ruxolitinib for Patients With Intermediate-2–Risk/High-Risk MF1,2 • Randomized phase 3 studies in which patients with intermediate-2–risk/high-risk MF were treated with ruxolitinib (15 or 20 mg BID) vs placebo (COMFORT-I, N = 309) or best available therapy (COMFORT-II, N = 149) • Grade 3/4 anemia/thrombocytopenia/neutropenia in COMFORT-I, %: ruxolitinib, 45/13/7; placebo, 19/1/2a COMFORT-I, wk 24 COMFORT-II, wk 48 Outcome Ruxolitinib Placebo P Ruxolitinib BAT P (n = 155) (n = 154) (n = 144) (n = 73) Spleen volume reduction ≥35%,b % 41.9 0.7 < .001 28 0 < .001 ≥50% reduction in MF-SAF TSS, % 45.9 5.3 < .001 NR NR NR Discontinued for AEs 11.0 10.6 NR 8 5 NR a n = 1,151. b Primary endpoint. 1. Verstovsek S et al. N Engl J Med. 2012;366:799-807. 2. Harrison C et al. N Engl J Med. 2012;366:787-798. COMFORT Studies: Ruxolitinib and Overall Survival1 • The risk of death was reduced by 30% • Median OS: ruxolitinib, 5.3 years; control, 3.8 years; HR (ruxolitinib vs control) = 0.70; 95% CI, 0.54-0.91; P = .0065 0.0 1. Verstovsek S et al. J Hematol Oncol. 2017;10:156. Better Spleen Response to Ruxolitinib, Better Outcome1 Ruxolitinib Events HR (95% CI) ≥10% to <25% (n = 62) 15 0.36 (0.18-0.72) ≥25% to <35% (n = 49) 7 0.25 (0.18-0.61) ≥35% to <50% (n = 64) 8 0.24 (0.11-0.56) Other Evidence: OS of Patients by Degree of Spleen Length Reduction On Ruxolitinib ≥50% (n = 47) 6 0.18 (0.07-0.47) Control 1.01 0.9 ≥10% to <25% (n = 10) 0.8 3 0.7 1.02 (0.31-3.29) 0.6 ≥25% to <35% (n = 5) 2 0.5 2.79HR = 0.22(0.65 (95%-11.90) CI, 0.10 -0.51) 0.4 P = .0001 0.3 <25% reduction (n = 23) ≥35% to <50% (n = 1) 1 0.2 43.90 (4.16≥25%- but463.5) <50% reduction (n = 13) Survival, Probability Survival, 0.1 ≥50% reduction (n = 61) 0 0.01 0.1 1 10 100 0 6 12 18 24 30 36 42 48 a Time, mo HR (95% CI) vs <10% Reduction a Category includes patients with a <10% reduction from baseline in spleen volume at week 24 or no assessment (ruxolitinib, n = 64; control, n = 189); among these patients, there were 26 deaths (events) in the pooled ruxolitinib group and 63 deaths in the control group.
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