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Arizona, USA ©2011 MFMER | 3133089-1 Ruben A. Mesa, MD Professor & Chairman, Division of Hematology & Medical Oncology Deputy Director, Mayo Clinic Cancer.

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Presentation on theme: "Arizona, USA ©2011 MFMER | 3133089-1 Ruben A. Mesa, MD Professor & Chairman, Division of Hematology & Medical Oncology Deputy Director, Mayo Clinic Cancer."— Presentation transcript:

1 Arizona, USA ©2011 MFMER | Ruben A. Mesa, MD Professor & Chairman, Division of Hematology & Medical Oncology Deputy Director, Mayo Clinic Cancer Center Mayo Clinic – Arizona, USA Myeloproliferative Neoplasms Hematology Highlights Las Vegas, NV, USA – February 27, 2014, 2014

2 Myeloproliferative Neoplasms Hematology Highlights 2014 Burden and Biology of MPNs JAK2 Inhibition in 2014 JAK2 Inhibition and beyond

3 The Natural History of MPNs ©2011 MFMER | Polycythemia Vera Early/ Pre-fibrotic Primary Myelofibrosis Classic Primary MF Post ET/PV MF Classic Primary MF Post ET/PV MF MPN Blast Phase WHO 2008 Essential Thrombocythemia Diagnosis

4 ©2011 MFMER |

5 Within ER - chaperone ensuring quality control of glycoprotein folding - calcium homeostasis Outside ER - found in cytoplasmic, cell surface and extracellular compartments - roles in: proliferation apoptosis phagocytosis immunogenic cell death Calreticulin (CALR)

6 CALR mutations in JAK2 negative ET and MF

7 Burden of ET/PV Microvascular Symptoms Microvascular Symptoms Macrovascular Risk MPN Associate d Symptom s Burden of Myelofibrosis Anemia/ Cytopenis Anemia/ Cytopenis Splenomegaly MF Associated Symptoms Et & PV Associated Symptoms

8 Myelofibrosis and Cytopenias (N=364) ©2011 MFMER | Emanuel et. al. JCO 2012 N.B. Varying times NL Hg Men 13.5 g/dL Women 12 g/dL

9 Myelofibrosis and Splenomegaly ©2011 MFMER | Cervantes et. al. Blood 2009 (N=1054 PMF) Emanuel et. al. JCO 2012 (N=329 MF) Why does Splenomegaly Matter in MF? Mechanical discomfort Pain Possible splenic infarction Early satiety adding to cachexia Splenic sequestration and exacerbation of cytopenias May delay engraftment in setting of allogeneic stem cell transplant Why does Splenomegaly Matter in MF? Mechanical discomfort Pain Possible splenic infarction Early satiety adding to cachexia Splenic sequestration and exacerbation of cytopenias May delay engraftment in setting of allogeneic stem cell transplant

10 Quartile 1 (Q1): 0-24% Quartile 2 (Q2): 25-49% Quartile 3 (Q3): 50-74% Quartile 4 (Q4): % Percentile MPN-SAF TSS Q1 TSS <8 Q2 TSS Q3 TSS Q4 TSS >32 ParameterP value of Comparison Age0.24 Gender F>M<0.001 MPN Diagnosis<0.001 Subtype of MF0.86 IPSET (ET Risk)0.18 PV Risk (PV)0.30 DIPSS (MF Risk)<0.001 MPN Symptom Burden by Quartiles 1858 MPN-SAF Respondents

11 ET (N=775) PV (N=654) MF (N=423) Q1 – 30%Q2 – 26% Q3 – 24%Q4 – 20% Q1 – 17%Q2 – 21% Q3 – 26% Q4 – 36% Q1 – 25%Q2 – 23% Q3 – 26%Q4 – 26%

12 New Response Criteria for MPNs ET 2 PV 2 MF 1 Complete response Partial response Clinical improvement Stable disease No response Relapse Other responsesMolecular Cytogenetic and molecular 1. Tefferi A et al. Blood. 2013;122: Barosi G et al. Blood. 2013;121:

13 New Response Criteria for MF: Complete Response 1 EMH: extramedullary hematopoiesis 1. Tefferi A et al. Blood. 2013;122: Bone marrow: Age-adjusted normocellularity; <5% blasts; Grade 1 MF; and Peripheral blood: Hemoglobin 100 g/L and

14 New Response Criteria for MF: Other Categories 1 1. Tefferi A et al. Blood. 2013;122: Clinical improvement Achievement of anemia, spleen, or symptoms response without progressive disease or increase in severity of anemia, thrombocytopenia, or neutropenia Anemia response Transfusion-independent pts: a 20 g/L increase in Hb level Transfusion-dependent pts: becoming transfusion independent Spleen response Baseline splenomegaly that is palpable at 5-10 cm, below the LCM, becomes not palpable, OR Baseline splenomegaly that is palpable at >10 cm, below the LCM, decreases by 50% Baseline splenomegaly that is palpable at <5 cm, below the LCM, is not eligible for spleen response Symptoms response A 50% reduction in the MPN-SAF TSS CI: clinical improvement; LCM: left costal margin.

15 Myeloproliferative Neoplasms Hematology Highlights 2014 Burden and Biology of MPNs JAK2 Inhibition in 2014 JAK2 Inhibition and beyond

16 JAK Inhibitors and Status of Development Myelofibrosis as lead indications ©2011 MFMER | No Longer in Development For MPNs * Now Testing in PV * * * *

17 Patient Disposition – 3 Year FU Comfort I Ruxolitinib (n = 155) Placebo (n = 151) Placebo Ruxolitinib (n=111) Median exposure, weeks Still on treatment, n (%)77 (49.7)057 (51.4) Crossed over, n (%)111 (73.5) Discontinued, n (%)78 (50.3)40 (26.5)54 (48.6) Primary reasons for discontinuation, n (%)* Death15 (19.2)7 (17.5)11 (20.4) Adverse event15 (19.2)9 (22.5)8 (14.8) Consent withdrawn12 (15.4)7 (17.5)11 (20.4) Disease progression18 (23.1)13 (32.5)15 (27.8) All patients originally randomized to placebo crossed over or discontinued within 3 months of the primary analysis Median time to crossover: 41.1 weeks 17 * Percentages are calculated based on the number of patients who discontinued within the respective treatment group. ASH 2013

18 Mean Daily Dose of Ruxolitinib Over Time 18 Approximately 70% of patients had dose adjustments during the first 12 weeks of therapy By week 24, patients originally randomized to RUX 15 mg BID and 20 mg BID were titrated to a mean dose of ~10 mg BID and mg BID, respectively Mean Daily Dose (mg, BID) ± SEM Weeks 20 mg BID starting dose 15 mg BID starting dose mg BID mg BID Number of patients ASH 2013

19 Percentage Change in Spleen Size 19 Mean reductions in spleen volume and palpable spleen length with ruxolitinib were stable over time RuxolitinibPlacebo Weeks Mean Percentage Change from Baseline n = Weeks RuxolitinibPlacebo n = Mean Percentage Change from Baseline Spleen VolumeSpleen Length ASH 2013

20 Improvements in EORTC QLQ-C30 Over Time Arrows indicate improvement RUXPBO Global Health Status/QoL Mean Change From Baseline Weeks Fatigue Mean Change From Baseline Weeks Physical Functioning Mean Change From Baseline Weeks Role Functioning Mean Change From Baseline Weeks ASH 2013

21 Overall Survival *By week 80, all patients originally randomized to placebo discontinued or crossed over to ruxolitinib therapy Placebo Ruxolitinib Number of patients at risk Randomized to Placebo Ruxolitinib Randomized to Ruxolitinib Probability Weeks HR=0.69 (95% CI: 0.46, 1.03); P=0.067 No. of deaths: Ruxolitinib=42; Placebo=54 Median follow-up: 149 weeks Percent of at-risk placebo who crossed over or discontinued * Overall survival favored patients originally randomized to ruxolitinib compared with patients originally randomized to placebo ASH 2013

22 Overall Survival: Rank-Preserving Structural Failure Time (RPSFT) Analysis Probability Weeks HR=0.36 (95% CI: 0.204, 1.035) Placebo Ruxolitinib Ruxolitinib Placebo-RPSFT 22 RPSFT is a recognized method to estimate HR after adjusting for crossover 1-5 Hazard ratio of 0.36 is consistent with the hypothesis that ITT analysis underestimates the survival benefit of ruxolitinib relative to true placebo (1) Robins J, Tsiatis A. Commun Stat Theory Methods. 1991;20: ; (2) Demetri GD, et al. Clin Cancer Res. 2012;18: ; (3) National Institute for Health and Care Excellence (NICE). NICE technology appraisal guidance Issued September 23, 2009; (4) Sternberg CN, et al. Eur J Cancer. 2013;49: ; (5) National Institute for Health and Care Excellence (NICE). NICE technology appraisal guidance Issued February ASH 2013

23 Mean Platelet Count and Hemoglobin Level Over Time Platelet CountHemoglobin Weeks Mean Hemoglobin (g/L) Weeks Mean Platelets (x10 9 /L) 12882PBO RUX Number of patients Number of patients 370 Ruxolitinib Placebo Ruxolitinib Placebo ASH 2013

24 Incidence of New Onset All Grade Non-hematologic Adverse Events Regardless of Causality 24 Incidence (%) Ruxolitinib 0–<12 months (n=155) 12–<24 months (n=130) 24–<36 months (n=103) 36 months (n=82) Fatigue Diarrhea Ecchymosis Peripheral edema Dyspnea Dizziness Pain in extremity Headache Nausea Constipation Abdominal pain Insomnia Vomiting Pyrexia Cough Arthralgia Upper respiratory tract infection There was no change in the rate, distribution, or severity of nonhematologic adverse events in the ruxolitinib group with longer-term treatment; most nonhematologic adverse events were grade 1 or 2 Percentage of patients for each event was based on the effective sample size of the time interval (number of patients at risk at the beginning of the interval minus half of the censored patients during the time interval). Adverse event is included if the incidence was >10% at any yearly interval. ASH 2013

25 Incidence of New Onset Grade 3 or 4 Non-hematologic Adverse Events Regardless of Causality 25 Incidence (%) Ruxolitinib 0–<12 months (n=155) 12–<24 months (n=130) 24–<36 months (n=103) 36 months (n=82) Fatigue Pneumonia Abdominal pain Arthralgia Diarrhea Dyspnea Pain in extremity Hyperuricemia Fall GI hemorrhage Septic shock Muscular weakness Hypoxia Sepsis Epistaxis Renal failure acute Abdominal pain upper Myocardial infarction Percentage of patients for each event was based on the effective sample size of the time interval (number of patients at risk at the beginning of the interval minus half of the censored patients during the time interval). Adverse event is included if the incidence was 2 patients at any yearly interval. ASH 2013

26 BM Morphology in a Ruxolitinib-Treated Patient: A Case Demonstrating Improvement on Ruxolitinib 26 Baseline Biopsy Grade 3 24 Mo Post Ruxolitinib Grade 2 48 Mo Post Ruxolitinib Grade 0 Kvasnicka HM, et al. ASCO (abstr 7030). Permission to use images from Kvasnicka, HM ASH 2013

27 Dynamics of BM Changes Following Ruxolitinib Treatment at 48 Mo 27 Kvasnicka, et al. ASH Abstract ASH 2013

28 JAK1 & 2 Inhibitors in MPNs – Efficacy Summary – As of ASH 2013 MyelofibrosisPolycythemia Vera Essential Thrombocythemia SpleenConst. Sympt. AnemiaSurvival Counts Const. Sympt. Vasc Events Counts Const. Sympt. Vasc Events Ruxolitinib - ApprovedP III P II SAR – PH III JAKARTA (HOLD) P III P IIP III Pacritinib- PIII Ongoing (Persist MF) P II CYT387P II LY P I NS-018 BMS PH II INCB (JAK1 Alone) P I CEP701P II ©2011 MFMER | Not Reported Yet Not Reported Yet Yes No Occasional Ongoing Trials

29 JAK1 & 2 Inhibitors in MPN – Toxicity ASH 2013 Hematological Toxicities Gastrointestinal/ Renal Toxicities Neurological Toxicities Anemia ANC PLT NauseaDiarr- hea LFTs Or CR Lipase Head- ache DizzyNeuroP/ Parathia Ruxolitinib - Approved 23%7%11%2%0.6% SAR – PIII Ongoing (MF) 41%6%11%0%5%1%W. E. % ? Pacritinib- PIII Ongoing (MF) 6%0%18%6% CYT387 PII Ongoing (MF) 10%2%20%1% INCB (JAK1) – PI/II MF 28%27%10% BMS %10% 0% LY %0%3%8% Renal ©2011 MFMER | <10% % % % % % % % % % Toxicity Color – Represents All Grades ( Grade ¾ Toxicity - Percentage in Table Above)

30 Myeloproliferative Neoplasms Hematology Highlights 2014 Burden and Biology of MPNs JAK2 Inhibition in 2014 JAK2 Inhibition and beyond

31 MPNs – Plateau vs. Decline ©2011 MFMER | ET – Possible Plateau Asymptomatic Thrombocytosis No Vascular Events ET – Possible Plateau 2 Symptomatic Thrombocytosis Sinus Venous Thrombosis Time Clinical Status PV – Possible Plateau 2 Symptomatic Erythrocytosis No Vascular Events Post PV MF 6 Months worsening Fatigue 10 kg weight loss Massive spleen MF on Successful JAK2 Rx Improving Weight Decreased Spleen Improved Survival

32 MPNs – Cumulative Benefits ©2011 MFMER | Time Clinical Status Improved Symptom Burden Improved Spleen Burden Improved Survival Ruxolitinib

33 MPNs – Cumulative Benefits Single Agent Trials JAK2 Inhibitors Compared to Ruxo ©2011 MFMER | Time Clinical Status Improved Symptom Burden Improved Spleen Burden Improved Survival ? Other Benefit -Less cytopenias -Improved activity ? Other Benefit -Less cytopenias -Improved activity STUDY (JAK2/FLT3 Inhibitor) NS-018 (PH I/II) NCT STUDY (JAK2/FLT3 Inhibitor) NS-018 (PH I/II) NCT STUDY (JAK2/FLT3 Inhibitor) Pacritinib (SB1518) (PH III vs. BAT) NCT STUDY (JAK2/FLT3 Inhibitor) Pacritinib (SB1518) (PH III vs. BAT) NCT STUDY (JAK2 Inhibitor – Also ET and PV) LY (PH I/II) NCT STUDY (JAK2 Inhibitor – Also ET and PV) LY (PH I/II) NCT STUDY (JAK2/JAK1 Inhibitor) Momelotinib (CYT387) (PH III vs. Ruxo) NCT STUDY (JAK2/JAK1 Inhibitor) Momelotinib (CYT387) (PH III vs. Ruxo) NCT

34 MPNs – Cumulative Benefits Ruxolitinib + drug X for Anemia ©2011 MFMER | Time Clinical Status Improved Symptom Burden Improved Spleen Burden Improved Survival Improved Anemia Burden STUDY COMBINATION (JAK2 PLUS Androgen) Ruxolitinib Plus Danazol Mayo Clinic (AZ) and Mt. Sinai Trial: NCT STUDY COMBINATION (JAK2 PLUS Androgen) Ruxolitinib Plus Danazol Mayo Clinic (AZ) and Mt. Sinai Trial: NCT STUDY COMBINATION(JAK2 PLUS Hypomethylation) Ruxolitinib Plus Azacitidine MDACC Trial: NCT STUDY COMBINATION(JAK2 PLUS Hypomethylation) Ruxolitinib Plus Azacitidine MDACC Trial: NCT STUDY COMBINATION (JAK2 PLUS IMID) Ruxolitinib Plus Lenalidomide NCT STUDY COMBINATION (JAK2 PLUS IMID) Ruxolitinib Plus Lenalidomide NCT STUDY COMBINATION (JAK2 PLUS IMID) Ruxolitinib Plus Pomalidomide Germany (ULM): NCT STUDY COMBINATION (JAK2 PLUS IMID) Ruxolitinib Plus Pomalidomide Germany (ULM): NCT

35 MPNs – Cumulative Benefits Ruxolitinib + drug X for Deeper Marrow Changes Impact Clinical Status Improved Symptom Burden Improved Spleen Burden Improved Survival Improved Marrow Dysfunction STUDY COMBINATION (JAK2 PLUS HDAC Inhibitors) Ruxolitinib Plus Panobinostat Mt. Sinai Trial: NCT UK Trial: NCT STUDY COMBINATION (JAK2 PLUS HDAC Inhibitors) Ruxolitinib Plus Panobinostat Mt. Sinai Trial: NCT UK Trial: NCT STUDY COMBINATION (JAK2 PLUS LOXL2 Inhibitors) Ruxolitinib Plus GS-6624 NCT STUDY COMBINATION (JAK2 PLUS LOXL2 Inhibitors) Ruxolitinib Plus GS-6624 NCT STUDY COMBINATION (JAK2 PLUS rhPTX-2 (Anti-fibrosing)) Ruxolitinib Plus PRM -151 Opening Soon STUDY COMBINATION (JAK2 PLUS rhPTX-2 (Anti-fibrosing)) Ruxolitinib Plus PRM -151 Opening Soon STUDY COMBINATION (JAK2 PLUS PI3 Kinase Inhibitor) Ruxolitinib Plus BKM120 NCT STUDY COMBINATION (JAK2 PLUS PI3 Kinase Inhibitor) Ruxolitinib Plus BKM120 NCT STUDY COMBINATION (JAK2 PLUS Hedgehog Inhibitor) Ruxolitinib Plus LDE225 NCT STUDY COMBINATION (JAK2 PLUS Hedgehog Inhibitor) Ruxolitinib Plus LDE225 NCT

36 MPNs – Cumulative Benefits Single Agent Trials Alternate Targets Time Clinical Status Improved Symptom Burden Improved Spleen Burden Improved Survival ? Other Benefit -Less cytopenias -Improved activity ? Other Benefit -Less cytopenias -Improved activity STUDY (Interferons) Peg Interferon α2b in Early MF Cornell Lead: NCT STUDY (Interferons) Peg Interferon α2b in Early MF Cornell Lead: NCT STUDY (Activin - ActRIIA-IgG1Fc) Sotatercept (ACE 011) MDACC: NCT STUDY (Activin - ActRIIA-IgG1Fc) Sotatercept (ACE 011) MDACC: NCT STUDY (Telomerase Inhibitor) Imetelstat (GRN163L) Mayo Clinic (Rochester): NCT STUDY (Telomerase Inhibitor) Imetelstat (GRN163L) Mayo Clinic (Rochester): NCT STUDY (JAK1 Inhibitor) INCB (PH II) NCT STUDY (JAK1 Inhibitor) INCB (PH II) NCT

37 Imetelstat: A Telomerase Inhibitor imetelstat binds to RNA template preventing maintenance of telomeres Telomerase enzyme: Reverse transcriptase comprised of an RNA component (hTR) and a reverse transcriptase catalytic protein subunit (hTERT) Binds to the 3 strand of DNA and adds TTAGGG nucleotide repeats to offset the loss of telomeric DNA occurring with each replication cycle Not active in somatic cells; transiently upregulated in normal hematopoietic progenitor cells to support controlled proliferation Highly upregulated in malignant progenitor cells, enabling continued and uncontrolled proliferation Imetelstat: Proprietary: 13-mer thio-phosphoramidate oligonucleotide complementary to hTR, with covalently-bound lipid tail to increase cell permeability/tissue distribution Long half-life in bone marrow, spleen, liver (estimated human t½ = 41 hr with doses 7.5 – 11.7 mg/kg); Potent competitive inhibitor of telomerase: IC50 = nM (cell-free) Target: malignant progenitor cell proliferation (hTR) – 37 – (hTERT) Tefferi et. al. ASH 2013

38 Preliminary efficacy results from Mayo Clinic investigator-sponsored trial of imetelstat in myelofibrosis – 10 – Gerons independent efficacy analysis of the first 22 MF patients enrolled in the study Tefferi et. al. ASH 2013

39 Preliminary efficacy results from Mayo Clinic investigator-sponsored trial of imetelstat in myelofibrosis – 10 – Gerons independent efficacy analysis of the first 22 MF patients enrolled in the study Tefferi et. al. ASH 2013

40 Change in Spleen Volume at Week 12 by Dose Cohort 40 Percentage Change From Baseline at Week 12 n=7 n=9 *Only patients with baseline and week 12 data were included. Median % Change in Spleen Volume* n=38 INCB ASH Mascarenhas et. al

41 Improvement in TSS at Week 12 by Dose Cohort 41 Percentage of Patients Percentage Change From Baseline at Week 12 n=9n=43 *Patients who discontinued prior to the week 12 visit were considered nonresponders; 20%-33% of patients in each group discontinued prior to week 12. Only patients with baseline and week 12 data were included. 50% Reduction in TSS*Median % Change in TSS n=10 n=6n=34n=8 INCB ASH Mascarenhas et. al

42 Mean Hemoglobin Levels Over Time by Dose Cohort 42 Weeks Mean (±SEM) Hemoglobin (g/dL) mg BID mg BID mg QD n, patients Patients entering the study without transfusion requirements* All Patients *Receipt of 2 or more units of red blood cell product transfusions in the 12 weeks prior to day mg BID200 mg BID 600 mg QD 100 mg BID 200 mg BID 600 mg QD n, patients INCB ASH Mascarenhas et. al

43 MPNs – Cumulative Benefits Difficult PV-ET Clinical Status Improved Symptom Burden Improved Spleen Burden Improved Survival Improved Marrow Dysfunction STUDY COMBINATION (PV) Ruxolitinib Vs. Hydroxyurea (RELIEF) NCT STUDY COMBINATION (PV) Ruxolitinib Vs. Hydroxyurea (RELIEF) NCT STUDY (ET and PV) MPD-RC 112 Peg Inf a2a vs. Hydroxyurea (PH III) NCT STUDY (ET and PV) MPD-RC 112 Peg Inf a2a vs. Hydroxyurea (PH III) NCT STUDY (ET and PV) MPD-RC 111 Peg Inf a2a AFTER Hydroxyurea (PH III) NCT STUDY (ET and PV) MPD-RC 111 Peg Inf a2a AFTER Hydroxyurea (PH III) NCT STUDY (PV) AOP Peg Inf a2a vs Hydroxyurea (PH III) NCT STUDY (PV) AOP Peg Inf a2a vs Hydroxyurea (PH III) NCT FUTURE STUDY COMBINATION JAK2 Inhibitor Plus PEG INF 2a/b FUTURE STUDY COMBINATION JAK2 Inhibitor Plus PEG INF 2a/b Improved Vascular Event Risk (?PV)

44 Patient Goals & Input Improving Symptom Burden /HR QOL Balancing Spleen/ Cytoses/ Cytopenias Extending Life CURE ©2011 MFMER | Individualizing MPN Pharmacotherapy

45

46 ©2011 MFMER | Acknowledgements Argentina Ana Clara Kneese, MD Federico Sackmann, MD Australia David M Ross MBBS, PhD Cecily Forsyth John Seymour, MBBS, PhD Karen Hall, MD Kate Burbury MD Tam Constantine, MD Canada Lynda Foltz, MD Vikas Gupta, MD China Hsin-An Hou, MD Huan-Chau Lin, MD Hung Chang, MD Ming-Shen Dai, MD Yuan-Bin Yu, MD Yung-Chen Su, MD Zhijian Xiao, MD Denmark Christen Lykkegaard Andersen, MD Hans Hasselbalch, MD France Brigitte Dupriez, MD Jean-Jacques Kiladjian, MD Jean-Loup Demory MD Magali Demilly, PhD Germany Heike L. Pahl, PhD Ireland Mary Francis McMullen, MD Israel Martin Ellis, MD Italy Alessandro M. Vannucchi, MD Francesco Passamonti, MD Giovanni Barosi, MD Tiziano Barbui, MD Netherlands Harry Schouten, MD, PhD Jan Jacques Michiels, MD Karin Klauke, MD Peter te Boekhorst, MD Sonja Zweegman, MD PhD Stephanie Slot, MD Suzan Commandeur, MD New Zealand Hilary Blacklock, MD Panama Francis Guerra, MD Singapore Wee Joo Chng, MB ChB Spain Ana Kerguelen Fuentes, MD Carlos Besses, MD Francisco Cervantes, MD Dolores Fernandez-Casados Sweden Andreasson Bjorn, MD Elisabeth Ejerblad, MD Gunnar Birgegard, MD Jan Samuelsson, MD Johanna Ablesson, MD Peter Johansson, MD UK Anthony Green, MD Claire N. Harrison, MD Deepti Radia, MD Uruguay Pablo Muxi, MD USA Alison Moliterno, MD Brady Stein, MD MHS Casey O'Connell Catriona Jamieson Daniel Rubin, ND Elizabth Hexner Hala Simm Jason Gotlib, MD Jeff Sloan, PhD Jessica Altman, MD Joseph Prchal, MD Kimberly Hickman Martin Tallman, MD Mike Boxer, MD Olatoyosi Odenike, MD Robert Silver, MD Ross Levine, MD Soo Jin Kim Srdan Verstovsek, MD


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