Myelofibrosis: new treatment strategies Jeanne Palmer Mayo Clinic - PowerPoint PPT Presentation

Myelofibrosis: new treatment strategies Jeanne Palmer Mayo Clinic Arizona

Evolution of Myelofibrosis PV/ET Terminal stage Early MF Overt MF/secondary MF EARLY DEATH Symptoms/Splenomegaly 18% BM Years after diagnosis insufficiency Thrombocytopenia/Anemia 31% Acute Leukoerythroblastosis Leukemia Peripheral blasts 13%Thrombosis Marrow fibrosis grade 11% Infections MF0 MF1 MF2 MF3 17% Second RETICULUM COLLAGEN FIBROSIS OSTEOSCLEROSIS neoplasia 5% Bleedings Barbui T, et al. J Clin Oncol. 2011 Feb 20;29(6):761-70. Caramazza D, et al. Leukemia. 2011 Jan;25(1):82-8.Tefferi A, et al. Leukemia. 2012 Jun;26(6):1439-41. Passamonti F, et al. Blood. 2010 Oct 14;116(15):2857-8. Cervantes F. Blood. 2009 Mar 26;113(13):2895-901. Arber et al. Blood. 2016; 127(20):2391-405. . Thiele J, et al. Haematologica. 2005;90:1128-1132; Thiele J, Kvasnicka HM, et al . Ann Hematol . 2006;85(4):226-232, Vener C, et al. Blood. 2008

WHO Diagnostic Criteria: Prefibrotic MF vs Overt MF Primary MF Diagnosis Requirement for diagnosis All 3 major criteria AND ≥ 1 minor criteria • Major criteria 1. Megakaryocytic proliferation and atypia, without reticulin fibrosis > grade 1 (prefibrotic PMF) or with reticulin and/or collagen fibrosis grade 2/3 (overt fibrotic PMF) 2. JAK2 , CALR , or MPL mutation, presence of other clonal markers* OR absence of reactive MF 3. Not meeting WHO criteria for other myeloid malignancies Minor criteria 1. Anemia not attributed to a comorbid condition 3. Palpable splenomegaly 2. Leukocytosis ≥ 11 × 10 9 /L 4. LDH increased above ULN 5. Leukoerythroblastosis (overt fibrotic PMF) * eg, ASXL1 , EZH2 , TET2 , IDH1/IDH2 , SRSF2 , SF3B1 . Arber DA, et al. Blood . 2016;127:2391-2405.

4 Finazzi Blood Cancer J 2018; 8:104

5 Finazzi Blood Cancer J 2018; 8:104

Diagnosing PPV- or PET-MF PV ET 10% transformation rate per 10 years 2 <4% transformation rate per 10 years 2 Post-PV or Post-ET Myelofibrosis 1 IWG IWG Diagnostic Criteria for Post-PV Myelofibrosis Diagnostic Criteria for Post-PV Myelofibrosis REQUIRED CRITERIA Documentation of previous diagnosis of PV or ET as defined by WHO criteria Grade 2 or 3 bone marrow fibrosis (0-3 scale) or grade 3 or 4 bone marrow fibrosis (0-4 scale) Additional Criteria (2 Required) Additional Criteria (2 Required) Anemia and a decrease of ≥2 mg/mL from Anemia or sustained loss of need for either baseline hemoglobin level phlebotomy or cytoreductive therapy Leukoerythroblastosis Leukoerythroblastosis ≥5 cm increase in palpable splenomegaly or ≥5 cm increase in palpable splenomegaly or new splenomegaly new splenomegaly Increased serum LDH level Development of ≥1 of 3 constitutional symptoms 3 Development of ≥1 of 3 constitutional symptoms 3 ET = essential thrombocythemia; IWG – International Working Group; LDH = lactate dehydrogenase; PET-MF – post-essential thrombocythemia myelofibrosis; PPV-MF = post-polycythemia vera myelofibrosis; PV = polycythemia vera; WHO = World Health Organization. 3 Constitutional symptoms include > 10% weight loss in 6 months, night sweats and unexplained fever (>37.5°C). 1. Barosi G et al. Leukemia. 2008;22:437-438; 2. Tefferi A. Am J Hematol. 2008;83:491-497

NCCN Guideline for Treatment of MF: Based on Risk and Symptoms/Signs Observation or ruxolitinib (if symptomatic) or clinical Low Risk trial Observation or ruxolitinib (if symptomatic) or clinical trial Intermediate-1 or allogeneic HSCT (selected pts) Intermediate-2 Transplant candidate Allogeneic HSCT Or or High Risk Transplant ineligible/symptomatic ruxolitinib or clinical trial AND/or Transplant ineligible/anemia anemia rx or clinical trial Adapted from National Comprehensive Cancer Network (NCCN). Myeloproliferative Neoplasms (Version Low risk = 0 on IPSS, DIPSS-Plus, or DIPSS 2.2017, https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf. INT-1 risk = IPSS = 1, DIPSS-Plus = 1, DIPSS = 1 or 2 INT-2 risk = IPSS = 2, DIPSS-Plus =2 or 3, DIPSS = 3 or 4 High risk = IPSS = 3, DIPSS-Plus = 4 to 6, DIPSS = 5 or 6

HOW DO WE DEFINE RISK?

Dynamic International Prognostic Scoring System DIPSS scores/risk: DIPSS plus (2 scores/risk pts) • 0 pts: low risk • 0 pts: low risk • 1-2 pts: Intermediate – 1 • 1 pt: intermediate-1 • 3-4 pts: Intermediate – 2 • 2-3 pts: intermediate-2 • 5-6 pts: High risk

Clarification of risks • Anemia–low red blood cell count. Hemoglobin (hgb) is consistently less than 10 • Thrombocytopenia- low platelet (plt) count, less than 100. • Leukocytosis – high white blood cell count (WBC), consistently greater than 25 • Blasts – immature white blood cells • Note this does not mean you have leukemia unless blast % greater than 20%

Other factors that contribute to risk • Driver mutation • Cytogenetics • Molecular mutations

Driver mutation • Mutations that CAUSE the disease • JAK-2 • MPL • CAL-R • CAL-R is GOOD • No mutations is unfavorable

Cytogenetics • Cytogenetics (abnormal chromosomes found in your bone marrow) • complex karyotype (3 or more abnormalities) or sole or 2 abnormalities that include +8, −7/7q−, i(17q), inv(3), −5/5q−, 12p−, or 11q23 rearrangement These are not inherited… they are changes that occur only in disease cells

Molecular mutations “next generation sequencing”

TREATMENT

EARLY FRONT LINE TREATMENT

IFN for First-Line MF Treatment: Consideration in Early Hyperproliferative Stage • Consider IFN use in selected pts Impact of Use • With preserved performance status Blood count control • and limited comorbidities Early • Address splenomegaly, when modest • Who are earlier in disease course Reduction in thrombosis risk • When splenomegaly modest • • Without additional non- JAK2 mutations (?) Anticlonal activity • • Limitations: Late Potential for regression of histologic • • Potential for short-term negative changes and delayed transformation? impact on QoL 17 • Tolerable in the long term? Foucar CE, et al. Curr Hematol Malig Rep . 2017.

Approach to the Treatment of Anemia in MF EPO (erythropoietin) level ADEQUATE INADEQUATE ≥ 500 mIU/mL < 500 mIU/mL ESA x 3 mos Danazol, No response Response Thalidomide, lenalidomide NCCN guidelines, 2017

Approach to symptomatic disease • Ruxolitinib-- JAK2 inhibitor • Works even if you DON’T have a JAK2 mutation • Approved in 2011

MF: What does ruxolitinib do? Patient Pre-Ruxolitinib Therapy After 2 Months of Therapy It is good for spleen and symptoms

Early-Stage MF May Have a Significant Clinical Burden DIPSS low-risk MF patients are moderately to highly symptomatic in 44% of the cases • The reduction of quality of life and social/working activity is similar in low and high risk • categories Harrison C, et al. Ann Hematol . 2017:5; Mesa RA, et al. BMC Cancer . 2016:27;16:167; Scherber R, et al. Blood 2011;118:401-408; Scherber R, et al. EHA 2016 [abstract 2250]; Marchetti M, et al. Leukemia. 2016;1-7.

OK, these medications don’t work, now what? • Anemia associated with MF • Ruxolitinib failure

How to approach this • Add agents to ruxolitinib • Newer JAK inhibitors • Anti-fibrotic agents • Novel agents/pathway

How to approach this • Add agents to ruxolitinib • Newer JAK inhibitors • Anti-fibrotic agents • Novel agents/pathway

Resurrecting response to ruxolitinib: A Phase I study of ruxolitinib and umbralisib (TGR-1202) in ruxolitinib-experienced myelofibrosis Tamara K. Moyo, Jeanne Palmer, Yi Huang, Olalekan Oluwole, Sanjay R. Mohan, Rebekah Caza, Gregory D. Ayers, Lynne Berry, Channing Dudley, Laura Dugger, Hari P. Miskin, Amy Cavers, Peter Sportelli, Brandon McMahon, Stephen A. Strickland, Ruben Mesa, Laura C. Michaelis, and Michael R. Savona June 15, 2018 23 rd Congress of EHA

Study design and patient populations EXPANSION COHORT 1 Ruxolitinib-experienced MF Ruxolitinib-experienced MF Ruxolitinib-experienced MF Ruxolitinib-experienced ESCALATION STAGE 1 ESCALATION STAGE 2 Myelofibrosis (MF) EXPANSION COHORT 2 •PMF, post-PV MF or Treatment-naïve MF post-ET MF •Grade ≥1 fibrosis EXPANSION COHORT 3 •Lost, suboptimal or no Polycythemia vera response on a stable EXPANSION COHORT 4 dose of ruxolitinib for ≥ 8 CMML weeks EXPANSION COHORT 5 Other MDS/MPNs Stable Escalating Stable ruxolitinib 23 patients in ruxolitinib ruxolitinib (cleared ES2) this analysis + + + Escalating Umbralisib Umbralisib MTD umbralisib MTD from ES1 from ES1

IWG-MRT & ELN responses to umbralisib + ruxolitinib DLT Best IWG-MRT & ELN Response* Not Assessed DLT Stable Disease MC Clinical Benefit MC Complete Remission PD Status MC Off-study MC Continues on Treatment MC Off Study Reason PD DLT Dose-limiting Toxicity (n=2) MC PD AE Adverse Event (n=1) AE PD Progressive Disease (n=3) SCT MC Physician or Patient Decision SCT (n=6) -30 20 70 120 Weeks on Study Transplant (n=1) * Tefferi A, et al. Blood 2013

Two subjects achieved complete remission Case 1 Case 2 Baseline Follow-up Baseline Follow-up Marrow Marrow Reticulin

Newer JAK inhibitors • Pacritinib • Momolotenib • Fedratinib