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

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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 of 0.3 Triple 0.2 negative 0.1 CumulativeProbability 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 % Patients, of 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, % 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 HR (95% CI) vs <10% Reductiona Time, mo 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. 1. Vannucchi AM et al. Haematologica. 2015;100:1139-1145. COMFORT-I: Mean Platelet Count and Hemoglobin Over Time1

Platelet Count Hemoglobin

370 115

Ruxolitinib Placebo Ruxolitinib Placebo

/L

9 110 320

105 270 100

220 g/L Hemoglobin, Platelets, 10 x Platelets,

95 Mean Mean

Mean Mean 170 90

120 85 0 12 24 36 48 60 72 84 96 108 120 132 144 0 12 24 36 48 60 72 84 96 108 120 132 144 Time, wk Time, wk No. of Patients No. of Patients Ruxolitinib 155 144 143 136 124 112 110 107 104 100 94 88 79 155 145 143 136 124 113 110 107 104 100 94 88 79 Placebo 151 128 112 82 37 151 132 113 83 37

1. Verstovsek S et al. Haematologica. 2015;100:479-488. Development of Anemia in First 12 Weeks of Therapy Does NOT Impact Survival1

OS in Patients With or Without an Hb Decrease of 30 g/L at Week 12

1.01 0.9 0.8 Ruxolitinib (drop in Hb ≤30 g/L) Ruxolitinib (drop in Hb >30 g/L)a 0.7 Control (drop in Hb ≤30 g/L) 0.6 0.5 Control (drop in Hb >30 g/L)a 0.4 0.3 0.2 0.1 Survival, Probability Survival, 0 0 50 100 150 Time, wk No. at Risk Ruxolitinib (drop in Hb ≤30 g/L) 143 118 101 62 Ruxolitinib (drop in Hb >30 g/L)a 29 18 13 4 Control (drop in Hb ≤30 g/L) 121 110 91 62 Control (drop in Hb >30 g/L)a 124 106 93 57 a Includes patients who became transfusion-dependent in the first 12 weeks of treatment but were independent at baseline. 1. Al-Ali HK et al. Leuk Lymphoma. 2016;57:2464-2467.

Prognosis After Ruxolitinib Discontinuation1

1.0 HR = 4.1 (95% CI, 1.8-9.5); P = .001 1.0 HR = 2.7 (95% CI, 1.3-5.8); P = .006 0.8 0.8 PLT ≥100 No clonal evolution at follow-up

Survival Clonal evolution at follow-up 0.6 PLT <100 Survival 0.6 Censored Censored 0.4 0.4

0.2 0.2 Cumulative 0.0 Cumulative 0.0 0 12 24 36 48 60 72 0 12 24 36 48 60 72 Survival After Discontinuation, mo Survival After Discontinuation, mo Platelets <100 median survival: 11/12 Clonal evolution median survival: 6/12

No. at risk No. at risk PLT ≥100 23 12 7 4 3 1 0 No CE 28 16 4 4 2 1 0 PLT <100 33 10 4 0 CE 14 3 3 1 0

1. Newberry KJ et al. Blood. 2017;130:1125-1131. JAKARTA: Phase 3 Study Design1

Week 24 or disease Placebo progression before week 24: Daily oral doses, • Aged ≥18 years crossover to fedratinib 4-week cycle • Diagnosis of 400 or 500 mg (1:1) – Primary MF Fedratinib 400 mg – Post-PV MF R Daily oral doses, – Post-ET MF 4-week cycle Week 24 • Intermediate-2 or EOT (EOC6) high-risk status Fedratinib 500 mg • Splenomegaly Daily oral doses, 4-week cycle

1 cycle = 4 weeks

1. Pardanani A et al. JAMA Oncol. 2015;1:643-651. JAKARTA: Efficacy1

Spleen Response (Primary Endpoint) Change in Total Symptom Score

20 45 40.2 40 36.5 35 0

% Reduction % 30 -20

Volume, % Volume, 25 >35

20 % Baseline, -40 15 Placebo 10 From From -60 Fedratinib 400 mg 5 Median Change Median in Change TSS Fedratinib 500 mg

in Spleen Spleen in 1 0 -80 Fedratinib Fedratinib Placebo 0 4 8 12 16 20 24

Patients With With Patients 400 mg 500 mg (n = 96) Time, wk (n = 96) (n = 97)

1. Pardanani A et al. JAMA Oncol. 2015;1:643-651. JAKARTA: Hematologic and Nonhematologic Events1

Adverse Events, Fedratinib 400 mg (n = 96) Fedratinib 500 mg (n = 97) Placebo n (%) All Grades Grade 3 or 4 All Grades Grade 3 or 4 All Grades Grade 3 or 4

Nonhematologic

Diarrhea 63 (66) 5 (5) 54 (56) 5 (5) 15 (16) 0

Vomiting 40 (42) 3 (3) 53 (55) 9 (9) 5 (5) 0

Nausea 61 (64) 0 49 (51) 6 (6) 14 (15) 0

Constipation 10 (10) 2 (2) 17 (18) 0 7 (7) 0

Asthenia 9 (9) 2 (2) 15 (16) 4 (4) 6 (6) 1 (1)

Abdominal pain 14 (15) 0 12 (12) 1 (1) 15 (16) 1 (1)

Fatigue 15 (16) 6 (6) 10 (10) 5 (5) 9 (10) 0

Dyspnea 8 (8) 0 10 (10) 1 (1) 6 (6) 2 (2)

Weight decrease 4 (4) 0 10 (10) 0 5 (5) 0

Hematologic

Anemia 95 (99) 41 (43) 94 (98) 58 (60) 86 (91) 24 (25)

Thrombocytopenia 60 (63) 16 (17) 55 (57) 26 (27) 48 (51) 9 (9)

Lymphopenia 54 (57) 20 (21) 63 (66) 26 (27) 50 (54) 19 (21)

Leukopenia 45 (47) 6 (6) 51 (53) 15 (16) 18 (19) 3 (3)

Neutropenia 27 (28) 8 (8) 42 (44) 17 (18) 14 (15) 4 (4)

1. Pardanani A et al. JAMA Oncol. 2015;1:643-651. JAKARTA-2: Open-Label Study With Fedratinib1

• Aged ≥18 years • Intermediate-2 or high-risk status Fedratinib – Primary MF Once daily, starting dose of 400 mg – Post-PV MF Consecutive 4-week cycles – Post-ET MF • Platelet count ≥50 x 109/L • Permitted dose adjustments: 200-600 mg/day • Received RUX for ≥14 days • Dose uptitration permitted if <50% reduction in • Discontinued RUX ≥14 days prior spleen volume by palpation to EOC6 to starting fedratinib • Dose titration permitted in event of toxicity • Patients who continued to benefit clinically could remain on study until the occurrence of disease RUX RUX progression or unacceptable toxicity resistant intolerant

Classification made by treating physician

1. Harrison CN et al. Lancet Haematol. 2017;4:e317-e324. JAKARTA-2: Spleen Responses1

≥35% Spleen Volume Reduction ≥35% Spleen Volume From Baseline by Reason for Reduction From Baseline Spleen Response by Subtype Ruxolitinib Discontinuationa of Ruxolitinib Resistance 100 EOC3 EOC6 100 EOC3 EOC6 90 90 ≥35% Spleen Volume Reduction From EOC3 EOC6

80 80

Baseline, n (%) 70 70 63% Insufficient 60 55% 60 52% 53% 8 (42) 10 (53) 50 47% 50 45% response (n = 19) Disease 40 40 5 (38) 5 (38)

30 30 progression (n = 13)

Patients, % Patients, Patients, % Patients, 20 20 Loss of 12 (52) 14 (61) 10 10 response (n = 23) n/N = n/N = 14/27 17/27 25/55 29/55 0 39/83 46/83 0 Per-Protocol Population Ruxolitinib Ruxolitinib (N = 83) Intolerant Resistant

• Due to the early termination, 35/83 patients had an EOC3, but no EOC6, spleen measurement; the LOCF method was used to impute missing EOC6 data with the EOC3 data (except for patients who discontinued before EOC6 due to disease progression) a One patient discontinued due to other reasons (not definable) and was therefore not classified as resistant or intolerant. 1. Harrison CN et al. Lancet Haematol. 2017;4:e317-e324. JAKARTA-2 Reanalysis at ASCO 20191

• In original JAKARTA-2 analysis, fedratinib demonstrated a 55% rate • Main findings of ≥35% SVR in pts resistant/intolerant to RUX on per protocol analysis – 79/97 enrolled patients – Reanalysis employed a more stringent definition of RUX failure (81%) met the more stringent criteria for RUX Spleen Volume and Symptom Response Rates R/R (n = 65, 82%) or intolerance (n = 14, 18%) ITT Population RUX Failure Cohort Sensitivity Cohort (N = 97) (n = 79) (n = 66) • Clinically meaningful reductions in splenomegaly Patients, % Patients, % Patients, % and symptom burden in N N N (95% CI) (95% CI) (95% CI) patients with MF who met more stringent criteria 31 30 36 SVRR 97 79 66 (22%-41%) (21%-42%) (25%-49%) – SVRR: 30% – Symptoms RR: 27% Symptoms 27 27 32 90 74 62 RR (18%-37%) (17%-39%) (21%-45%) – Safety consistent with prior reports FREEDOM-1 study also underway

1. Harrison CN et al. American Society of Clinical Oncology 2019 Annual Meeting (ASCO 2019). Abstract 7057. Review of Encephalopathy Cases1

• Across nine fedratinib trials enrolling 670 MPN or solid tumor patients – Five potential Wernicke encephalopathy (WE) 1. Fedratinib does not appear patients to increase risk for thiamine – One patient had malnutrition related to protracted deficiency beyond its potential nausea and vomiting, as well as clinical signs and to exacerbate malnutrition MRI findings consistent with WE through poor management of preventable GI events – Two patients likely experienced WE, both of whom recovered without a dose interruption, suggesting 2. Proper management of GI is fedratinib does not inhibit thiamine absorption an important component of care for patients on fedratinib – Two patients inconclusive or not supportive of WE

No clear link between WE and fedratinib

1. Harrison CN et al. Blood. 2017;130:4197. Momelotinib for Patients With MF

• Momelotinib: JAK1/2 inhibitor with potential to improve anemia, possibly via suppression of hepcidin1

Key Trial Type Key Findings

SVR ≥35% at wk 24a: momelotinib, Phase 3 RCT in MF previously treated 7%; BAT, 6% (P = .90); ≥50% TSS SIMPLIFY 22 with ruxolitinib (N = 156) reduction at wk 24: momelotinib, 26%; BAT, 6% (nominal P = .0006)

SVR ≥35% at wk 24a: momelotinib, 26.5%; ruxolitinib, 29% (P = .011; Phase 3 RCT in JAKi-naïve patients SIMPLIFY 13 noninferior); ≥50% TSS reduction at with MF (N = 432) wk 24: momelotinib, 28.4%; ruxolitinib, 42.2% (P = .98; not noninferior) a Primary endpoint(s). 1. Asshoff M et al. Blood. 2017;129:1823-1830. 2. Harrison CN. Lancet Haematol. 2018;5:e73-e81. 3. Mesa RA. J Clin Oncol. 2017;35:3844-3850. MOMENTUM Phase 3 Trial: Phase 3 Registration Trial Schema1

Primary Endpoint

Day 1 Week 24 Double-Blind Treatment Open Label/Crossover Long-Term Momelotinib 200 mg Follow-Up N = 180 daily + placebo • Previously treated with JAKi Spleen progression (momelotinib 200 mg) Momelotinib R • Symptomatic 200 mg daily (TSS ≥10) 2:1 Danazol 600 mg daily • Anemic (Hb <10 g/dL) + placebo

• 1 cycle = 4 weeks • Danazol has been selected as an appropriate treatment comparator given its use to ameliorate anemia in MF patients, as recommended by NCCN and ESMO guidelines • Global study: North America, European Union, Asia Pacific

1. https://clinicaltrials.gov/ct2/show/NCT04173494. Accessed February 19, 2020.

Pacritinib for Patients With MF

• Pacritinib: selective inhibitor of JAK2, JAK2 V617F, IRAK1, and FLT3

Key Trial Type Key Findings

Phase 3 RCT in higher-risk, a 1 SVR ≥35% at wk 24 : pacritinib, 19%; PERSIST-1 JAKi-naïve MF with any degree of BAT (no JAK2i), 5% (P = .0003) anemia/thrombocytopenia (N = 327) SVR ≥35%a: pacritinib, 18%; BAT, 3% Phase 3 RCT in MF (prior JAKi allowed) (incl RUX) (P = .001); PERSIST-22 with platelet count ≤100,000/mcL (N = 311) TSS reduced ≥50%a: pacritinib, 25%; BAT, 14% (P = .08) 200 mg BID dose most effective: Phase 2 dose-finding trial in higher-risk MF PAC2033 SVR ≥35%, 9.3%; with previous ruxolitinib (N = 164) TSS reduced ≥50%, 7.4%

a Primary endpoint(s). 1. Mesa RA et al. Lancet Haematol. 2017;4:e225-e236. 2. Mascarenhas J et al. JAMA Oncol. 2018;4:652-659. 3. Gerds AT. ASH 2019. Abstract 667. 4. Harrison CN. ASH 2019. Abstract 4175. PACIFICA Phase 3 Trial Design1

• Primary or secondary MF Pacritinib 200 mg BID 9 • Platelet count <50 x 10 /L (based on PAC203 results) • DIPSS intermediate-1, -2, or high-risk disease 1:1 R • Palpable splenomegaly ≥5 cm N = 150 • TSS ≥10 on MPN-SAF TSS 2.0 • ECOG PS 0-2 Physician’s choicea,b • Prior JAK2i for <90 days allowed

• Enrollment began third quarter 2019 • Primary endpoint: SVR at 24 weeks • Secondary endpoints: TSS at 24 weeks, overall survival, PGIC at 24 weeks a Physician’s choice includes any one of the following: low-dose ruxolitinib, corticosteroids, hydroxyurea, thalidomide, or lenalidomide. Investigators can select individual agents but cannot combine agents or give them sequentially. b Crossover not permitted. 1. https://clinicaltrials.gov/ct2/show/NCT03165734. Accessed February 19, 2020. Ruxolitinib-Based Rational Combinations

Partner Mechanism of Action Phase Azacitidine HMA 2 Accelerated/blastic phase Decitabine HMA 2 Luspatercept/sotatercept Activin receptor ligand rap 2

Treatment-related Danazol Androgen 2 cytopenia Thalidomide IMiD 2 Lenalidomide IMiD 2 Pomalidomide IMiD 1/2 PEG-IFNα-2a – 1/2 PU-H71 HSP90i 1/2

Disease Itacitinib JAK1i 2 modification/higher responses Navitoclax BCL-2/-xLi 2 Parsaclisib/umbralisib PI3Kδi 2 Ribociclib + PIM447 CDK4/6i + PIM kinase inhibitor 1b

CPI-0610 BETi 2

Moving Beyond JAK Inhibitors

Mechanism of Action Drug Class Agent • SMAC mimetic/IAPi • LCL-161 • BCL-2/-xL inhibitors Promotion of apoptosis • Navitoclax • Selective inhibitors of • Selinexor nuclear export Targeting hematopoietic stem • CD123-directed antibodies • Tagraxofusp cell/microenvironment • HSP90 inhibitors • PU-H71 • Idasanutlin Modulation of TP53 pathway • MDM2 antagonists • KRT-232 Targeting bone marrow fibrosis • Recombinant pentraxin-2 • PRM-151 Promoting megakaryocyte • Aurora kinase A inhibitors • Alisertib differentiation Telomerase inhibition – • Imetelstat • BET inhibitors • CPI-0610 Targeting epigenetic proteins • LSD1 inhibitors • Bomedemstat Therapeutic Principles, Practice, and the Convergence of JAK Inhibitors With Allogeneic HCT

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. Role of Allogeneic Transplant in 20191

1. Timing and sequencing Pretransplant Transplant of allogeneic SCT in • Age • Donor source • Comorbidities − Sib > MUD/MMUD MF can be complex • Splenectomy status • Degree of HLA-match • Disease prognostication • Conditioning and challenging • Chronic phase versus blastic − MAC • Mutational status − RIC 2. Allogeneic SCT • Treatment − Sequential − None CURE • T-cell depletion versus not remains the only − Cytoreduction 50%-55% • CMV status: recipient/donor curative approach for − JAK inhibitors • Experimental therapies transplant-eligible • ? depth of response patients 3. All available prognostic Post-transplant Relapse • Timing of IST weaning • Therapeutic DLI information and recent • MRD/chimerism monitoring • Chemotherapy +/- DLI • Preemptive DLI • Second transplant scoring systems should • ? maintenance JAK inhibitor • ? JAK inhibitor • ? splenectomy • ? role of checkpoint blockade be utilized when • Rate of fibrosis resolution • Presence of poor graft function considering alloSCT

1. McLornan DP et al. Haematologica. 2019;104:659-668. Number of MPN Transplants in the United States1

800

700 672 600 522 500 428

400 345 300 300 198 200 153 100 No. of Transplants of No. 85 100 35 50 0

1. CIBMTR database 1995 and 2018 (courtesy of Wael Saber, MD, MS). Recommendations From EBMT/ELN Regarding Patient Selection1

All patients with intermediate-2– or high-risk disease according to IPSS, 1 DIPSS, or DIPSS-plus, and age <70 y should be considered candidates for alloSCT

Patients with intermediate-1–risk disease and age <65 y should be 2 considered candidates for alloSCT if they present with refractory transfusion-dependent anemia, a percentage of blasts in peripheral blood >2%, or adverse cytogenetics

Patients with low-risk disease should not be considered candidates for 3 alloSCT; they should be monitored and evaluated for transplant when disease progression occurs

1. Kröger NM et al. Leukemia. 2015;29:2126-2133. Challenges in Referral1

Total number of MF patients N = 129

Missing n = 9 (7%)

Those referred for transplant Those referred who did not Those not referred for and went to appointment go to appointment transplant n = 41 (32%) n = 8 (6%) n = 71 (59%)

Those who will proceed with transplant n = 16 (39%)

Those who won't proceed with transplant n = 24 (60%)

1. Palmer J et al. Biol Blood Marrow Transplant. 2019;25:398-402. Considerations for HCT in MF

Post-Transplant Pretransplant Transplantation Strategies Considerations 1. Patient selection 1. Reduction of spleen size 1. Prevention of relapse 2. Which risk scoring system 2. Improve constitutional 2. Long-term outlook and should determining timing? symptoms quality of life 3. Selection of optimal donor 3. Conditioning regimen Results of Transplant vs Nontransplant, According to DIPSS After Left Truncation1

1. Kröger N et al. Blood. 2015;125:3347-3350. Results of Transplant vs Nontransplant, According to DIPSS After Left Truncation1 (Cont’d)

COX Regression: SCT vs No SCT

DIPSS Score P (Log-Rank) RR P (Wald) Low .0019 5.6 (1.7-19) .0051 Intermediate-1 .19 1.6 (0.79-3.2) .19 Intermediate-2 .0045 0.55 (0.36-0.83) .005 High .00047 0.37 (0.21-0.66) .0007

1. Kröger N et al. Blood. 2015;125:3347-3350. MIPSS Ability to Predict Transplant Outcomes1

Survival Probability Post-AlloHCT Overall Survival Based on Donor Type

With Flu/Mel Regimen

• 110 patients conditioned with Probability fludarabine/melphalan Probability • Single mutations didn’t predict Time From Transplant, mo Time From Transplant, mo

outcomes, but composite Overall Survival Based on Cytogenetic Risk Overall Survival Based on HMR Mutations

MIPSS score associated with Probability NRM and OS Probability

Time From Transplant, mo Time From Transplant, mo

Overall Survival Based on MIPSS70 Overall Survival Based on MIPSS70+ v2.0

Probability Probability

Time From Transplant, mo Time From Transplant, mo

1. Ali H et al. Blood Adv. 2019;3:83-95. Comprehensive Clinical-MTSS: MF Undergoing AlloHCT1

• Seven clinical, molecular, Variable Score and transplant-specific 9 independent factors for Leukocyte count >25 x 10 /L 1 survival Platelet count <150 x 109/L 1

• Four-level system predictive Performance status <90% 1 of survival and nonrelapse mortality Absent CALR or MPL 2 • Applicable to primary and Age >57 y 1 secondary MF HLA-mismatched unrelated 2

ASXL1 1

1. Gagelmann N et al. Blood. 2019;133:2233-2242. Comprehensive Clinical-MTSS: MF Undergoing Stem Cell Transplantation1

Proportion Alive at 5 y Prognostic Median Points After Category Survival Transplant, % Not Low 0-2 90 reported Not Intermediate 3-4 77 reported Not High 5 50 reported Not Very high 6-9 34 reported

Platelets Leukocytes Karnofsky Non-CALR/MPL Driver ASXL1 HLA-Mismatched Age ≥57 y <150 x 109/L >25 x 109/L PS Mutation Genotype Mutation Unrelated Donor

HR 1.6 1.57 1.50 1.65 2.40 1.42 2.08

Score 1 1 1 1 2 1 2

1. Gagelmann N et al. Blood. 2019;133:2233-2242. Comparison of the Performance of Prognostic Systems in Primary MF for 5-Year Survival1

C-Index Bootstrap C-Index System Components N (95% CI) (95% CI)

Hb <10 g/dL, leukocytes >25 x 109/L, circulating DIPSS 260 0.573 (0.664-0.582) 0.566 (0.557-0.575) blasts ≥1%, age >65 y, constitutional symptoms

DIPSS, transfusion dependence, unfavorable DIPSS-plus 149 0.557 (0.546-0.568) 0.542 (0.531-0.553) karyotype, platelets <100 x 109/L

Hb <10 g/dL, leukocytes >25 x 109/L, platelets <100 x 109/L, circulating blasts ≥2%, fibrosis grade ≥2, MIPSS70 260 0.587 (0.578-0.596) 0.581 (0.572-0.590) constitutional symptoms, absence of CALR type 1– like mutation, HMR category, ≥2 HMR mutations Severity of anemia, circulating blasts ≥2%, MIPSS70-plus constitutional symptoms, absence of CALR type 1– 149 0.566 (0.558-0.574) 0.560 (0.551-0.569) version 2.0 like mutation, HMR category (+ U2AF1), ≥2 HMR mutations, 3-tiered cytogenetic risk

Absence of CALR type 1–like mutation; presence of GIPSS 149 0.544 (0.532-0.556) 0.532 (0.521-0.543) ASXL1, SRSF2, or U2AF1; 3-tiered cytogenetic risk

Platelets <150 x 109/L, leukocytes >25 x 109/L, KPS <90%, age ≥57 y, HLA-mismatched unrelated donor, MTSS 260 0.718 (0.710-0.726) 0.710 (0.701-0.719) non-CALR/MPL driver mutation genotype, ASXL1 mutation

1. Gagelmann N et al. Blood. 2019;133:2233-2242.

Spleen Management Pretransplant1

• 85 patients underwent transplant

for MF

Free Survival, Free % Survival, of Relapse of – 39 underwent splenectomy -

P = .06 Cumulative Incidence Cumulative – All patients who had splenectomy Event P = .1 had spleen >20 cm Time, mo – Of patients without splenectomy, Time, mo

30% had spleen >20 cm

• Half of the splenectomized patients had a significant complication

• No significant difference in NRM, NRM of P = .62 P = .07

relapse, or OS, however trend towards % Survival, Overall Cumulative Incidence Cumulative improved EFS and OS Time, mo Time, mo 1. Robin M et al. Biol Blood Marrow Transplant. 2017;23:958-964.

Role of HCT and JAK Inhibitors (NCCN)1

Int-2 or high-risk MF • Bridging therapy can be used to decrease Transplant marrow blast prior to alloHCT candidates

AlloHCT MF accelerated phase recommended based (blasts 10%-19%) • Induce remission with HMA or low-intensity on age, PS, major induction chemotherapy followed by comorbid conditions, MF blast phase/AML alloHCT psychosocial status, and availability of (blasts ≥20% caregiver Ruxolitinib or fedratinib may be continued near to the start of conditioning therapy for the improvement of splenomegaly and other disease-related symptoms

1. NCCN Clinical Practice Guidelines in Oncology: Myeloproliferative Neoplasms. V3.2019. https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf. Using JAK Inhibitors in Conjunction With HCT

• Ruxolitinib pretreatment does not appear to negatively influence outcome after allogeneic HCT in MF1

Post-HCT Outcome, % Ruxolitinib Non Ruxolitinib aGVHD (II-IV) 19 28 2-y DFS 68 60 2-y OS 73 70 2-y NRM 22.9 23 Trend for lower risk of relapse in the ruxolitinib group (9% vs 17%; P = .2)

1. Kadir SSSA et al. Eur J Haematol. 2018;101:305-317. JAK Inhibition Prior to AlloSCT for MF

Spleen Stop of Graft GVHD Conditioning N TRM Response Ruxolitinib Failure II-IV Tapering, off at MAC/RIC NMA1 14 64% 7% 14% 7% conditioning 45% (>50%) 14% RIC2 22 At conditioning None 36% 24% (<50%) (at 14) RIC3 11 72% Different None 45% NR n = 16; Tapering, off at 2 deaths RIC4 23 NR NR 50% conditioning (GVHD) Tapering, off at RIC/MAC5 6 NR None 48% 16% conditioning Tapering off at RIC/MAC6 28 NR None 78% 7% conditioning 1. Jaekel et al. Bone Marrow Transplant. 2014;49:179-184. 2. Stübig T et al. Leukemia. 2014;28:1736-1738. 3. Lebon et al. 55th American Society of Hematology Annual Meeting (ASH 2013). Abstract 2111. 4. Robin M et al. ASH 2013. Abstract 306. 5. Shanavas M et al. Bone Marrow Transplant. 2014;49:1162-1169. 6. Salit RB et al. Bone Marrow Transplant. 2020;55:70-76. N. R. not reported Peri-Transplantation Ruxolitinib in MF

N = 12 Patients With MF N = 12 Patients With MF (Median Age of HCT, 53 y; Range, 25-66) (Median Age, 63 y; Range, 43-71 y) DL1 = 5 mg BID; DL2 = 10 mg BID Treated With Ruxolitinib → AlloHCT1 Treated With Ruxolitinib → AlloHCT Rux: From Day -3 → Day +302

• Ruxolitinib was continued • All received flu-mel conditioning (2 × 5 mg daily) until stable engraftment • For all patients • No graft failure, engraftment median of 12 • 1-y OS: 80% (95% CI, 39-95) d (11-18 d) • PFS: 68% (95%CI, 30-89) • NRM: 21% (95%CI, 3-50) • All patients engrafted • Grade III-IV aGVHD seen in 1 patient, grade I aGVHD seen in 4 patients • 1 CMV infection

1. Kröger N et al. Biol Blood Marrow Transplant. 2018;24:2152-2156. 2. Ali H et al. Blood. 2019;134:669. Conditioning Regimen Prior to Transplantation1

• EBMT study: 2,224 patients • 781 (35%) underwent MAC; 1,443 (65%) underwent RIC • No difference in OS between groups • No clear superior regimen

1 1 1

0.8 0.8 0.8

NRM

0.6 0.6 0.6 MAC RIC RIC RIC 0.4 0.4 0.4

Cumulative OS Cumulative MAC MAC 5-y OS estimates

0.2 0.2 0.2 Cumulative Incidence of Relapse of Incidence Cumulative

MAC: 53.0% (95% CI, 49.1-56.9) of Incidence Cumulative P = .08 P = NS RIC: 51.0% (95% CI, 48.3-53.7) P = .78 0 0 0 0 2 4 6 8 10 0 2 4 6 8 10 0 2 4 6 8 10 Time Post Allo-SCT, y Time Post Allo-SCT, y Time Post Allo-SCT, y

1. McLornan D et al. Biol Blood Marrow Transplant. 2019;25:2167-2171. Age and Transplant1

1

• 45 patients; median age, 0.8

67 years (65-74) 0.6 • RIC regimen 0.4

Probability of OS of Probability 0.2

• Median 4 years follow-up 0 0 2 4 6 8 10 12 Time Since SCT, y 1 • 14 patients died, 12 from 0.9 0.8 TRM 0.7 0.6 0.5 • Acceptable rates of GVHD 0.4 0.3 0.2 0.1 0

Cumulative Incidence of NRM of Incidence Cumulative 0 1 2 3 4 5 6 7 8 9 10 No. at Risk Time Since SCT, y 46 33 22 22 16 16 16 16 16 16 16 1. Daghia G et al. Eur J Haematol. 2019;103:370-378. Donor Selection

Reference N NRM OS 103 PMF, post-ET MF, At 1 y At 5 y post-PV MF MRD: 10% MRD/MUD: 74% Kroger et al. Blood. 20091 HLA matched: 82 MUD 13% MMUD: 38% HLA mismatched: 21 MMUD 38% P = .03 66 PMF, post-ET MF, post-PV MF Rondelli et al. Blood. MRD: 30 MRD: 22% MRD: 75% 20142 Haplo: 2 MUD: 59% MUD: 32% MUD: 25 MMUD: 9 At 1 y: 18% Adjusted OS at 5 y 233 PMF At 5 y: 24% MRD: 56% Gupta et al. Biol Blood MRD: 79 RR: MUD: 48% Marrow Transplant. 20143 MUD: 104 MUD: 3.92 MMUD: 34% MMUD: 50 MMUD: 9.37 (P = .002) (P < .0001)

1. Kröger N et al. Blood. 2009;114:5264-5270. 2. Rondelli D et al. Blood. 2014;124:1183-1191. 3. Gupta V et al. Biol Blood Marrow Transplant. 2014;20:89-97. Alternative Donors: Haploidentical1

• EBMT registry study evaluating 56 patients with PMF or SMF who OS PFS received haploidentical transplant • Median age: 57 years (38-72) • Primary graft failure at 2 years: 9% (1%- 16%); secondary graft failure: 13% (4%- 22%) • Grade II-IV GVHD: 28% (CI, 16%-40%) GFRF at day 100 • OS at 12 mo: 61% (CI, 48-75%); at 24 mo: 56% (CI, 41%-70%)

1. Raj K et al. Biol Blood Marrow Transplant. 2019;25:522-528.

Alternative Donors: Cord Blood1

• 35 patients, 24 received 2-y OS: 44% RIC regimen

• 54 years (range, 28 to 63)

NeutrophilRecovery Probability of Survival of Probability • Median follow-up: 24 mo of Incidence Cumulative • Neutrophil engraftment at Time, d Time, mo

2-y EFS: 30%

day 60: 80% • 14 experienced graft

failure EFS of Probability Probability of EFS of Probability

Time, mo Time, mo 1. Robin M et al. Biol Blood Marrow Transplant. 2014;20:1841-1846. EBMT/ELN Recommendation1

“…JAK inhibitor therapy (ruxolitinib or others) is indicated in patients with a symptomatic spleen or with constitutional symptoms…

…The drug should be initiated at least 2 months before transplantation and should be titrated to the maximum tolerated dose. A careful wean starting 5 to 7 days prior to conditioning should occur in an attempt to avoid rebound phenomenon, with the drug stopping just the day before conditioning…”

1. Kröger NM et al. Leukemia. 2015;29:2126-2133. Leukemia 2015 online Case Snapshot 1: To Transplant or Not to Transplant?

• A 47-year-old female patient is recently diagnosed with primary MF, no JAK-2, CALR, MPL mutation (triple negative) • Hb of 11, WBC of 10 with 1% blasts, no constitutional symptoms, mild splenomegaly (3 cm below the costal margin) • BM biopsy: MF2-3/3, no increase in blasts, normal cytogenetics

• No constitutional symptoms; NGS shows a SRSF2 mutation; she has an 10/10 MUD OPTIONS: Start a JAK inhibitor? Proceed to HCT—or is it too early? Or just observe? Case Snapshot 2: An Older Patient With MF and a CALR Mutation

• A 66-year-old gentleman presents with post-ET MF that exhibits a CALR mutation; he has well-controlled HTN, but no other medical problems • Anemia present with Hb of 9 g/dL; no constitutional symptoms or splenomegaly; WBC is 10 and he has 2% blasts • No additional mutations; NGS shows ASXL1 • He has only a 9/10 donor OPTIONS: Offer HCT or not? Consider JAK inhibitor therapy? Or observe? DIPSS/MIPSS/MTSS

Case 1 Case 2

• DIPSS: low risk • DIPSS: intermediate-2 • MIPSS: 4 points • MIPSS: 4 points (intermediate risk) (intermediate risk) – Median survival: 6-7 y – Median survival: 6-7 y – 5-y survival: 67% – 5-y survival: 67% • MTSS: 2 points • MTSS: 4 points – 5-y survival after BMT: – 5-y survival: 77% 90% Relapse1,2

• Relapse occurs in 10%-18% of patients following MAC and 29%-43% after RIC • Donor lymphocyte infusion – Preemptive vs salvage (ie, with molecular relapse vs clinical relapse): CR in 68% patients (100% in preemptive group and 44% in salvage group) – In 30 relapsed patients, DLI given in 27 patients  39% achieved a CR  15 nonresponders underwent second transplant  For whole group: 2-y PFS/OS was 67%/70%, respectively

1. Kröger N et al. Blood. 20019;113:1866-1868. 2. Klyuchnikov E et al. Br J Haematol. 2012;159:172-181.

Retrospective Study on Relapsed Patients1

• 251 relapses recorded in the EBMT – Many approaches: DLI alone, chemotherapy + DLI, second transplant, DLI + second transplant

Median OS

DLI + second allo • 76 months for the DLI DLI-alone cohort Second allo • 54 months for the

DLI + second Cumulative Survival Cumulative Cumulative Survival Cumulative alloHCT cohort • 27 months for the Time Postrelapse, mo 0 12 24 36 48 60 DLI 46 30 20 17 13 8 second alloHCT No. at Risk 202 117 81 65 52 33 DLI/ 26 22 17 13 12 7 second allo

Second allo 51 33 24 20 18 10 1. McLornan DP et al. Br J Haematol. 2018;182:418-422. What Happens to Quality of Life Following Transplant?1

• Prospective study evaluating patients who underwent allogeneic stem cell transplant • PRO: FACT-BMT, MPN-SAF (symptom score validated for MF) measured at baseline, d 30, d 100, and 1 y • Quality of life as measured by these scores did not significantly worsen • MF-specific symptoms were significantly improved after transplant (ie, pruritus, fevers, spleen symptoms)

At 1 year, 61% of the patients reported feeling better than they did prior to transplant

1. Palmer J et al. Biol Blood Marrow Transplant. 2019;25:398-402. Outlook for Patients Who Have Received a Transplant1

OS HR DFS Relapse Variables P P P • EBMT registry study (95% CI) HR (95% CI) HR (95% CI) Age (per decade) 1.45 (1.19-1.76) < .001 1.18 (1.01-1.37) .033 1.16 (0.96-1.42) .131 • 2,459 patients who received first allo transplant between Patient sex 1995-2014 Male 1 .004 1 .003 1 .205 Female 0.58 (0.4-0.84) 0.65 (0.49-0.87) 0.79 (0.55-1.14)

• 1,055 alive at 2 years—landmark study MF classification PMF 1 .01 1 .071 1 .78 • 10-y OS and DFS for 2-y survivors were 74% (71%-78%) SMF 1.66 (1.13-2.44) 1.35 (0.97-1.88) 1.07 (0.67-1.7) and 64% (60%-68%), respectively Source of stem cells Marrow 1 .442 1 .178 1 .107 • In those aged <45 years, 10-y survival was 86% PB 0.83 (0.51-1.34) 0.77 (0.52-1.13) 0.67 (0.41-1.09) Conditioning regimen intensity • Late relapse was leading cause of death .434 .017 .042 MAC 1 1 1 RIC 1.17 (0.79-1.73) 1.48 (1.07-2.04) 1.54 (1.02-2.35)

Conditioning regimen with .322 .18 .305 Chemo only 1 1 1

TBI 1.25 (0.81-1.93) 1.28 (0.89-1.82) 1.28 (0.8-2.06)

Type of donor Matched sibling 1 .669 1 .011 1 .008

Unrelated 1.08 (0.77-1.51) 1.43 (1.09-1.89) 1.65 (1.14-2.39) Survival Any previous GVHD 0.67 (0.48-0.94) .02 0.62 (0.47-0.81) .001 0.42 (0.3-0.6) < .001

Time Since Tx, mo Time Since Tx, mo Cumulative Incidence Cumulative Higher Risk of Mortality Variables that are significantly No. at 1,055 734 474 257 141 No. at 1,055 692 423 215 112 • Older age (P < .001) associated with the Risk Risk • Secondary MF (P = .01) risk are in bold. • Male sex (P = .004) • No GVHD before landmark (P = .02) 1. Robin M et al. Haematologica. 2019;104:1782-1788. Survival Compared With That of the General Population1

• Survival worse than that of age-matched general population • However, the 10-y survival is much better than would be expected otherwise

Age Sex 100% 100% Overall <45 y Male 100% 45-54 y Female 55-64 y 75% ≥65 y 75%

75%

50% 50%

50%

Incidence

Incidence Incidence 25% 25% 25%

0% 0% 0% 24 48 72 96 120 24 48 72 96 120 24 48 72 96 120 Time Since Tx, mo Time Since Tx, mo Time Since Tx, mo

1. Robin M et al. Haematologica. 2019;104:1782-1788. Role of Newer JAK Inhibitors in HCT Settings

• Not well-studied; new agents approved will need to capitalize on their role in the peri-transplant setting

Fedratinib: Pacritinib: Momelotinb: currently approved for patients with for patients with in int-2/high-risk low platelets anemia MF (NCT03645824) Modern Algorithm for Transplant Decisions in MF1

MF diagnosis <70 y

PMF SMF

NGS not available NGS available MYSEC-PM model

DIPSS model MIPSS70 model

ASXL1 if int-1

PMF short-term (<5 y) survivors SMF short-term (<5 y) survivors Intermediate-2/high-risk High risk ASXL1-pos intermediate-1 Intermediate-2/high-risk

Apply to selected patients the MTSS and discuss survival expected and rate of mortality after SCT with patients Low risk Intermediate risk High risk Very high risk 5-y OS/TRM: 90%/10% 5-y OS/TRM: 77%/22% 5-y OS/TRM: 50%/36% 5-y OS/TRM: 34%/57%

Decision Go Go Slow go No on SCT

1. Passamonti F. Blood. 2019;133:2118-2120. HCT Scenarios in MF

Pretransplant Strategies Transplantation Strategies Post-Transplant Strategies 1. Patient selection according 1. Reduction of spleen size 1. Prevention of relapse by to DIPSS and MIPSS with JAK inhibitors, splenic monitoring for evidence of scoring system irradiation or splenectomy molecular markers and 2. DIPSS/MIPSS/MTSS all 2. Improve constitutional withdrawal of may be considered symptoms with JAK immunosuppression dependent on patient inhibitors 2. Long-term outlook and characteristics 3. Conditioning regimen MAC quality of life shows patient 3. Selection of optimal donor: vs RIC reported improvement at 1 MRD/MUD/alternative year in 61% of patients donor MF Study (RuxoAllo Study)1

MF (primary or post-ET/PV; age 18-70 y)

IPSS/DIPSS intermediate-2/high/intermediate-1 + HR CGN or transfusion dependence

Ruxolitinib

Donor search (HLA-identified sibling or 10/10 MUD or 9/10 DQB1)

Donor available (within 3 mo) No donor (within 3 mo available)

(FLAMSA) Bu 10 mg, fludarabine Continue with JAK2 inhibitor

DLI if molecularly positive and/or <95 % chimerism after withdrawal of immunosuppression

1. https://www.cto-im3.de/gsgmpn/Studien.html. Accessed February 18, 2020. Clinical Take-Homes

• Transplant is a curative option for MF with good long-term outcomes • Timing of transplant is a challenge – Shared decision-making • Patient/donor selection is important • Use of JAK inhibitors to reduce spleen size not harmful and may be beneficial • Though small numbers, peri-transplant JAK inhibitors look promising • New JAK inhibitors with different toxicity profiles may provide a benefit in the transplant setting

Symposium Summary and Audience Q&A

Prithviraj Bose, MD Jeanne M. Palmer, MD Associate Professor, Associate Professor, Department of Leukemia, Division of Hematology and Oncology Division of Cancer Medicine Vice Chair and Section Lead, The University of Texas Division of Hematology MD Anderson Cancer Center Program Director, Blood and Marrow Houston, Texas Transplant Program Mayo Clinic Phoenix, Arizona

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Thank you and good day. Abbreviations

AML: acute myeloid leukemia CE: clonal evolution alloSCT: allogeneic hematopoietic stem cell transplantation CIR: cumulative incidence of relapse ASXL1: additional sex comb-like 1 CMV: cytomegalovirus BAT: best available therapy CR: complete remission BCL-2: B-cell lymphoma 2 DFS: disease-free survival BCL-xL: B-cell lymphoma-extra large DIPSS: Dynamic International Prognostic Scoring System BET: bromodomain and extra-terminal domain DIPSS-plus: Dynamic International Prognostic Scoring System-plus BETi: bromodomain and extra-terminal domain inhibitor DL: dose level BID: twice a day DLI: donor lymphocyte infusion BMS: Bristol-Myers Squibb EBMT: European Society for Blood and Marrow Transplantation BMT: bone marrow transplant ECOG PS: Eastern Cooperative Oncology Group Performance Status bp: base pair ELN: European LeukemiaNet CALR: calreticulin EOC: end of cycle CBL: Casitas B‐lineage lymphoma proto‐oncogene EOT: end of treatment CD: cluster of differentiation Abbreviations

EPO: erythropoietin HMA: hypomethylating agent ESMO: European Society for Medical Oncology HMR: high molecular risk ET: essential thrombocythemia HR-CGN: high-risk cytogenetics EZH2: enhancer of zeste homolog 2 HSP90: heat shock protein 90 FACT-BMT: Functional Assessment of Cancer Therapy-Bone HTN: hypertension Marrow Transplant IAPi: inhibitors of apoptosis proteins (IAP) inhibitor FLT3: FMS-like tyrosine kinase 3 IDH1: isocitrate dehydrogenase 1 FU: follow-up IDH2: isocitrate dehydrogenase 2 GFRF: growth factor–rich fibrin IMiD: immunomodulatory imide drugs GIPSS: Genetically Inspired Prognostic Scoring System int: intermediate aGVHD: acute graft-versus-host disease IPSS: International Prognostic Scoring System GVHD: graft-versus-host disease IRAK1: interleukin-1 receptor-associated kinase haplo: haploidentical IST: investigator-sponsored trial HCT: hematopoietic stem cell transplantation JAK: Janus kinase HLA: human leukocyte antigen JAKi: Janus kinase inhibitor Abbreviations

KPS: Karnofsky performance status MMUD: mismatched unrelated donor LSD1: lysine-specific demethylase 1 MYSEC-PM: myelofibrosis secondary to PV and ET-prognostic model MAC: myeloablative conditioning NCCN: National Comprehensive Cancer Network MDM2: Mouse double minute 2 homolog NGS: next-generation sequencing MF: myelofibrosis NE: not evaluable MF-SAF: Myelofibrosis Symptom Assessment Form NMA: nonmyeloablative MIPSS: Mutation-Enhanced International Prognostic Score System NR: not reached MK: megakaryocyte NRM: nonrelapse mortality MPL: myeloproliferative leukemia PB: peripheral blood MPN: myeloproliferative neoplasm PEG-IFNα-2a: peginterferon alfa-2a MPN-SAF: Myeloproliferative Neoplasm Symptom Assessment Form PGIC: Patient Global Impression of Change MRD: marrow-related donor PI3Kδi: phosphatidylinositol 3-kinase delta inhibitor MTSS: Molecular Transplant Scoring System PLT: platelet MUD: marrow-unrelated donor PMF: primary myelofibrosis Abbreviations

PRO: patient-reported outcomes TBI: total body irradiation PS: performance status TP53: tumor protein p53 PV: polycythemia vera TRM: transplant-related mortality RIC: reduced intensity conditioning TSS: total symptom score RR: response rate U2AF1: U2 small nuclear RNA auxiliary factor 1 RUX: ruxolitinib WE: Wernicke encephalopathy SCT: stem cell transplantation WT: wild-type SF3B1: splicing factor 3B subunit 1 SH2B3: SH2B adapter protein 3 Sib: sibling SMAC: second mitochondrial-derived activator of caspases SMF: secondary myelofibrosis SRSF2: serine/arginine-rich splicing factor 2 SVR: spleen volume reduction