Prof. Dr. İbrahim C. Haznedaroğlu Hacettepe Üniversitesi Tıp Fakültesi İç Hastalıkları Anabilim Dalı Hematoloji Bilim Dalı, Ankara

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1 MYELOPROLİFERATİF HASTALIKLAR: Klinik Hematologlar Patologlardan ne bekler? Prof. Dr. İbrahim C. Haznedaroğlu Hacettepe Üniversitesi Tıp Fakültesi İç Hastalıkları Anabilim Dalı Hematoloji Bilim Dalı, Ankara

2 HASTAYA KLİNİK YAKLAŞIM İnvazif girişim ÖN TANI AYIRICI TANI İleri lab Hasta FM Genel Analiz Genel Analiz TANI TEDAVİ & İZLEM HASTALIK BİLGİLERİ (KLİNİK BİLİMLER) B İ L İ M S E L T E M E L (TEMEL BİLİMLER)

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4 Myelofibrozis kök hücreleri Primer myelofibrozis patogenezinde defektif stem hücre niş

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6 HASTALIK EVRELERİ LÖSEMİ ye DÖNÜŞÜM YAKLAŞIK %10. BAŞTA GELEN ÖLÜM NEDENİ DEĞİLDİR. HASTALIĞIN DOĞAL SEYRİ (VE ONU DEĞİŞTİRMEK) NE DEMEKTİR? ASEMPTOMATİK TROMBOZLARLA İLGİLİ SEMPTOMLAR ANEMİ SEMPTOMALARI SPLENOMEGALİ SEMPTOMLARI KONSTİTÜSYONEL SEMPTOMLAR: ATEŞ, TERLEME, ZAYIFLAMA KAŞINTI İLİK YETMEZLİĞİ SEMPTOMLARI PORTAL HİPERTANSİYON ile İLGİLİ SEMPTOMALR DİĞER EM HEMATOPOEZ ile İLGİLİ SEMPTOLAR KEMİK AĞRILARI PM PV ET HU ihtiyacının kaybolması, dalak, LDH, konstitüsyonel semptomlar, dakrositler ve lökoeritroblastozis

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10 Priorities for MPN treatment, perceptions of physicians and patients. Alessandro M. Vannucchi, and Claire N. Harrison Blood 2017;129: by American Society of Hematology

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13 Thiele J, Best Pract Res Clin Haematol 2006; 19:413.

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18 Original Article Ruxolitinib versus Standard Therapy for the Treatment of Polycythemia Vera Alessandro M. Vannucchi, M.D., Jean Jacques Kiladjian, M.D., Ph.D., Martin Griesshammer, M.D., Tamas Masszi, M.D., Ph.D., Simon Durrant, M.D., Francesco Passamonti, M.D., Claire N. Harrison, D.M., Fabrizio Pane, M.D., Pierre Zachee, M.D., Ph.D., Ruben Mesa, M.D., Shui He, Ph.D., Mark M. Jones, M.D., William Garrett, M.B.A., Jingjin Li, Ph.D., Ulrich Pirron, Ph.D., Dany Habr, M.D., and Srdan Verstovsek, M.D., Ph.D. N Engl J Med Volume 372(5): January 29, 2015

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20 Primary Response and Duration of Response. Vannucchi AM et al. N Engl J Med 2015;372:

21 Symptom Assessments. Vannucchi AM et al. N Engl J Med 2015;372:

22 Ruxolitinib in PV has been evaluated in 3 phase 3 studies, RESPONSE, RESPONSE2, and RELIEF, showing that in the second line after HC failure/intolerance, ruxolitinib effectively controls blood count, spleen size, and symptoms, and interestingly, there may be molecular responses in some patients. In RESPONSE, there was a reduction in thrombotic events (6 vs 1), although not a preplanned endpoint, which thus cannot be overinterpreted; transformation to PPV-MF and AML occurred on both arms of the study. Selection of patients resistant to HC is important because those patients with cytopenias in particular have an increased risk for death (hazard ratio, 3.5; 95% confidence interval, ; P =.003). Cytopenia at the lowest dose required to achieve a response was also an independent risk factor for transformation to acute leukemia (hazard ratio, 20.3; 95% confidence interval, ; P <.001). Problems with these studies is the selection of the endpoints: control of hematocrit, reduction of spleen size, and as a result of restricted alternative therapies, the comparison of ruxolitinib against drugs the patient already failed. Nonetheless, ruxolitinib presents a valuable treatment of PV resistant and/or intolerant of HC and could be tested earlier in disease to assess the effect on major manifestations and disease course. No new safety signals emerged here, but an excess of herpes zoster reactivation and nonmelanoma skin cancers were observed.

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29 TYPICAL MPN CASE FOR HYPOTHESES JAK2(+) PV 64y fenale Splenectomised due to gastric cancer surgery Hyperproliferative BM with hyperleukocytosis Failure of hydrea and interferon Controlling the cellular proliferation with PEG-intron+Ruxolutinib Real-life MPN patient

30 PM TEDAVİ YÖNTEMLERİ BEKLE-İZLE YAKLAŞIMI İLAÇ TEDAVİLERİ SPLENEKTOMİ RADYOTERAPİ PALYATİF YAKLAŞIMLAR ALLOJENEİK TRANSPLANT Tek küratif tedavidir. Az hastaya uygulanabilir.

31 SEMPTOM YÖNETİMİ: SPLENOMEGALİ SEMPTOMATİK SPLENOMEGALİ Ruxolitinib ve/veya Hidroksiüre Int-2 ve yüksek riskli hastalıkta sağkalım avantajı Daha kalıcı yanıt Daha yüksek dalak/ semptom yanıt oranı?? SPLENEKTOMİ* * Eğer splenektomi uygun değilse öz. infarkt gibi acil hallerde radyoterapi düşünülebilir.

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34 Ortanca yaş: 64,8 Endikasyonlar: Transfüzyon bağımlı anemi % 45,3 Symptomatik splenomegali % 39 Portal hipertansiyon % 10,8 Ağır trombositopeni % 4,9 Kalıcı düzelme olasılıkları: Konstitüsyonel semptomlar % 67 Portal HT % 50 Anemi % 23 Trombositopeni % 0 Subklinik DİK (D-dimer yüksekliği ± diğer lab bozuklukları) varsa splenektomi ertele (artmış periop kanama riski) Postop tromboz riskine karşı proflaksi unutma! Postop hepatik ekstramedüller hematopoez ve sitozlar için sitoredüktif tedavi

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36 KİME NAKİL YAPALIM? AZALTILMIŞ YOĞUNLUKTA HAZIRLAMA REJİMİ ÇALIŞMASI

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38 In MF, MPN disease-propagating stem cells aberrantly mobilize from the bone marrow to the spleen. Lane S W, and Mullally A Blood 2014;124: by American Society of Hematology

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41 MYELOFIBROSIS 1. Shortened survival Leukemic transformation Fibrotic transformation 2. Poor quality of life Thrombosis/bleeding Splenomegaly Anemia Cachexia Constitutional symptoms Pruritus

42 Survival and prognosis in primary myelofibrosis: A Mayo Clinic study of 884 patients Based on 8 risk factors: Karyotype, Transfusion-dependency, Hgb <10, Plt <100, WBC >25, Circulating blasts 1%, constitutional symptoms, Age >65 Survival DIPSS-plus low risk; n=84 median survival ~ 200 months; 2-year mortality 3% DIPSS-plus intermediate-1 risk; n=128 median survival ~ 94 months; 2-year mortality 11% DIPSS-plus intermediate-2 risk; n=322 median survival ~ 44 months; 2-year mortality 26% DIPSS-plus high risk; n=298 median survival ~ 23 months; 2-year mortality 53% Very high risk category;* n=52 median survival ~ 9 months; 2-year mortality 82% P< Inv(3)/i(17q) Monosomal karyotype Two of the following: WBC>40k, circulating blasts >9%, unfavorable karyotype Months Tefferi et al. Blood 2012

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45 European study: Vannucchi et al. 879 PMF patients At time of: Diagnosis (n=483) Referral (n=396) ASXL1 tested 279: mutated 85 (30.5%) SRSF2 tested 358: mutated 52 (14.5%) EZH2 tested 270: mutated 15 (5.6%) IDH2 tested 374: mutated 10 (2.7%) IDH1 tested 374: mutated 7 (1.9%) Mayo Clinic study: Tefferi et al.

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47 Myelofibrosis Extramedullary hematopoiesis Spleen enlergement

48 Study 251 Spleen Size Reduction in Patient Treated with INC424 MF Patient Pre-Therapy Patient After 2 Months of Therapy Photos used with permission from M. D. Anderson Cancer Center.

49 COMFORT trials COMFORT-I Patients with MF N = 309 Randomized 1:1 Ruxolitinib 15 or 20 mg BID Placebo BID Primary endpoint Proportion of patients achieving 35% reduction in spleen volume from baseline to Week 24 measured by MRI or CT Secondary endpoints Duration of the reduction in spleen volume Proportion of patients with a reduction in the total symptom score of 50% or more from baseline to Week 24, as assessed with MS-SAF (v2.0) Overall survival COMFORT-II Patients with MF N = 219 BAT, best available therapy. Randomized 2:1 Ruxolitinib 15 or 20 mg BID BAT Primary endpoints Proportion of patients with 35% reduction in spleen volume from baseline at Week 48, measured by MRI or CT Secondary endpoints Key: Achievement of 35% reduction in spleen volume from baseline at Week 24 Duration 35% reduction in spleen volume Time to achieve 35% reduction in spleen volume Progression-free survival Leukemia-free survival Overall survival Change in bone marrow histomorphology Verstovsek S, et al. N Engl J Med. 2012;366: ; Harrison C, et al. N Engl J Med. 2012;366:

50 COMFORT-I Design and dosing 1:1 randomization Ruxolitinib (n=155) 15 mg bid if platelets x10 9 /L 20 mg bid if platelets >200x10 9 /L Patients with MF (N=309) Placebo (n=154) Oral bid The dose was adjusted for lack of efficacy or excess toxicity as specified in the protocol Crossover Criteria Unblinding of the study-drug assignments and crossover from placebo to ruxolitinib were permitted for protocol defined worsening splenomegaly Verstovsek S, et al. N Engl J Med. 2012;366:

51 COMFORT-I Ruxolitinib was associated with a greater reduction in splenomegaly vs placebo Spleen volume was reduced by 35% in a significantly greater proportion of patients in the ruxolitinib compared with the placebo group at Week 24 The one patient receiving placebo who had 35% reduction in spleen volume experienced splenic infarct and later died Patients with 35% spleen volume reduction (%) % Ruxolitinib (n = 155) p<0.001 Odds ratio (95% CI) ( ) 0.7% Placebo (n = 153) Patients who discontinued prior to week 24 or crossed over prior to week 24 were counted as nonresponders Verstovsek S, et al. N Engl J Med. 2012;366:

52 COMFORT-I Reduction in spleen volume from baseline At Week 24, spleen volume had decreased in most patients treated with ruxolitinib, whereas it increased in most patients treated with placebo Ruxolitinib-treated patients had a median 33.0% decrease in spleen volume; in contrast, placebo-treated patients had a median 8.5% increase Change in spleen volume from baseline (%) Ruxolitinib (n = 155) Placebo (n = 153) = 106) Corresponding to 50% reduction in palpable spleen length 35% reduction (primary endpoint) Verstovsek S, et al. N Engl J Med. 2012;366:

53 COMFORT-II Design and dosing 2:1 randomization Ruxolitinib (n=146) 15 mg bid if platelets 200x10 9 /L 20 mg bid if platelets >200x10 9 /L Patients with MF (N=219) Best available therapy* (n=73) Dose regimen could be adjusted based on safety and efficacy so that each patient was titrated to their most appropriate dose; doses were not to exceed 25 mg bid Crossover Criteria At any time, patients who met protocol-specified criteria (underwent splenectomy or had an increase in spleen volume of >25% from the nadir during the study period, which could include the baseline volume) discontinued the randomized treatment phase of the study and could enter an extension phase. In the extension phase, patients who had been randomly assigned to the best available therapy could receive ruxolitinib if they met protocol-specified safety criteria, and patients who had been randomly assigned to ruxolitinib could continue to receive ruxolitinib if they were still deriving a clinical benefit. Patients who had leukemic transformation or underwent splenic irradiation were withdrawn from the study. *Any commercially available agents (as monotherapy or in combination) or no therapy at all and which could be changed during the treatment phase. Harrison C, et al. N Engl J Med. 2012;366:

54 COMFORT-II Ruxolitinib was associated with a greater reduction in splenomegaly vs BAT 28% of patients achieved 35% reduction in spleen volume at Week 48 compared with 0% of patients receiving BAT (p<0.001) Patients with 35% Spleen Volume Reduction (%) % Ruxolitinb (n=144) p < % BAT (n=72) Similarly, only patients in the ruxolitinib group met the criterion for the key secondary end point: a reduction of at least 35% in spleen volume at 24 weeks (32%, vs. 0% in the group receiving the best available therapy; p<0.001) Harrison C, et al. N Engl J Med. 2012;366:

55 COMFORT-II Reduction in spleen volume from baseline The mean percentage change in spleen volume from baseline in ruxolitinib vs. BAT was 29.2% vs. 2.7% (p<0.001) at Week 24 and 30.1% vs. 7.3% (p<0.001) at Week 48 During the 48-week period, almost all patients who were treated with ruxolitinib (97%), as compared with 56% given BAT, had a measurable reduction in spleen volume Reductions in spleen volume with ruxolitinib were seen across all patient subgroups, including subgroups defined according to sex, MF subtype, IPSS, and JAK2 V617F mutation status Harrison C, et al. N Engl J Med. 2012;366:

56 COMFORT-II Best percentage change in spleen volume on 5 year follow-up 60 Ruxolitinib randomized a (n = 136) After crossover a (n = 39) Best Change From Baseline in Spleen Volume, % % decrease % of patients (132/136) experienced some degree of spleen volume reduction 78 patients (53.4%) in the ruxolitinib arm achieved a 35% reduction in spleen volume at any time on treatment 75.6% (34/45) of patients who crossed over experienced spleen volume reductions from the time of crossover, and 42.2% (19/45) had a 35% reduction At 5 years, 88% of patients (45/51) who remained on treatment had improvements from baseline in spleen volume, and 67% (34/51) achieved 35% reductions a Only patients with baseline and postbaseline spleen volume assessments are included; for crossover patients, the spleen volume at the time of crossover was used as the new baseline value. Harrison CN, et al. ASH 2015; abstract 59.

57 COMFORT-II Duration of spleen response on 5 year follow-up Loss of response: no longer a 35% reduction that is also a >25% increase over nadir Events Censored Ruxolitinib a n = (43.6%) 44 (56.4%) BAT a n = (100%) Ruxolitinib, n = BAT, n = Median duration of response: ruxolitinib, 3.2 years The Kaplan-Meier estimated probability of maintaining response 3 years, 0.51 (95% CI, ) 5 years, 0.48 (95% CI, ) a For patients who achieved a 35% reduction at any time during randomized treatment; crossover patients are not summarized. Harrison CN, et al. ASH 2015; abstract 59.

58 COMFORT-II Overall survival on 5 year follow-up Median Overall Survival Ruxolitinib (ITT) = not reached BAT (ITT) = 4.1 years BAT (RPSFT) = 2.7 years Probability Ruxolitinib BAT (ITT) BAT (RPSFT) n = Time, years Median OS was not yet reached in the ruxolitinib arm (ie, > 5 years) ITT: HR, 0.67 (95% CI, ); P =.06 RPSFT: HR, 0.44 (95% CI, ) in favor of ruxolitinib vs BAT HR, hazard ratio; ITT, intent-to-treat; RPSFT, Rank-Preserving Structural Failure Time. Harrison CN, et al. ASH 2015; abstract 59.

59 COMFORT-II Ruxolitinib may modify the natural history of PMF Survival from diagnosis of 100 PMF patients receiving ruxolitinib within COMFORT-II was compared with that of 350 matched patients of the DIPSS study Data showed that the risk of death might be reduced by 40% to 50% by introducing ruxolitinib into the treatment of PMF patients Patients receiving ruxolitinib had longer survival (5 years, 95% CI: vs 3.5 years, 95% CI: ) with a hazard ratio of 0.61 (95% CI: ; p=0.0148) Passamonti F, et al. Blood. 2014;123:

60 Ruxolutinib, Anti-sitokin etkiler, MPN kök hücreleri

61 PM PATOBİYOLOJİSİ: SİTOKİNLERİN ROLLERİNE DİKKAT! Klonal miyeloproliferasyon % 60 JAK2V617F, % 3-8 MPL ve kalanların yarısında CALR mutasyonları Disregüle kinaz sinyalizasyonu Anormal sitokin salınımı Salınan sitokin ve büyüme faktörlerine bağlı ilikte fibrozis ve stroma değişiklikleri Anormal hücrelerin ekstramedüller dokulara yerleşmeleri Salınan sitokinlere bağlı sistemik semptomlar ve performans bozukluğu

62 HEMATOLOJİK NEOPLAZİLERDE SİTOKİNLERİN PATOGENEZ/SEMPTOMATOLOJİ ile İLİŞKİSİ? PM de SİTOKİNEMİ KONTROLÜ SEMPTOMLARI ve SAĞKALIMI DÜZELTİR IL-6 MİYELOM, POEMS ve CASTLEMAN PATOBİYOLOJİLERİNDE ÖNEMLİDİR HEMOFAGOSİTİK SENDROM KONTROLSÜZ SİTOKİNEMİYE BAĞLIDIR LENFOMADA B SEMPTOMLARININ OLMASI DAHA KÖTÜ PROGNOZLA İLGİLİ OLABİLİR. B SEMPTOMLARI SİTOKİNLERLE İLGİLİDİR PERFORMANS SKORU BÜTÜN NEOPLAZİLERDE EN ÖNEMLİ PROGNOSTİK BELİRTEÇ PERFORMANS SKORU NEDEN BOZULUR? SADECE İLİK YETMEZLİĞİ/ ORGAN BOZUKLUĞU/ KOMPLİKASYONLAR? SİTOKİNEMİNİN ROLÜ? HEMOFAGOSİTİK SENDROM EBV T ya da NK lenfosit Makrofaj MULTİORGAN YETMEZLİK SENDROMU

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64 Grading of BM Fibrosis According to WHO-defined 4-point scoring system (0-3) 1 Grade-0 Grade-1 Grade-2 Grade-3 Changes at 24 and 48 mo (vs BL) were characterized as Improvement, Stabilization, and Worsening. 1 Thiele J, Kvasnicka HM, et al. Haematologica. 2005;90:

65 Patients Phase I/II*, single-arm, open-label study of ruxolitinib, a JAK1/JAK2 inhibitor. 1,2 158 patients with PMF, Post-PV MF and Post-ET MF; median study follow-up period 32 mo. 107 of the 158 study patients were enrolled at a single center (MDACC). Inclusion criteria: PMF, Post-ET MF or Post-PV MF requiring therapy Intermediate or high-risk status (Lille scoring) Splenomegaly 1 Verstovsek S, et al. N Engl J Med. 2010;363: Verstovsek S, et al. Blood. 2012;120: * Study INCB ; NCT

66 Baseline Characteristics of Patients Characteristic Value 95% CI Age (yrs), mean Gender (F/M), % 44% / 56% IPSS risk status, % high risk intermediate-2 intermediate-1 59% 28% 13% Spleen size* (cm), mean Hemoglobin (g/dl), mean Platelets (x10 9 /L), mean WBC (x10 9 /L), mean Peripheral blasts (%), mean Total Symptom Score, mean * Palpable spleen length below costal margin

67 Change in WHO-Defined BM Fibrosis Grade at 24 and 48 mo Following Ruxolitinib Distribution of Direction of Changes Versus Baseline 24 mo 48 mo 39/68 10/18 Percentage of patients 10/68 19/51* Percentage of patients 4/18 4/16* 15% 57% 37% 22% 56% 25% * Excludes patients with Grade-3 WHO-defined BM fibrosis at baseline (since progression cannot be demonstrated)

68 Baseline biopsy Grade-3 24 mo post Rux Grade-2 48 mo post Rux Grade-0

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70 Ruxolitinib: Approved Indications of Use FDA (Jakafi): Treatment of patients with intermediate or high-risk myelofibrosis (November 16, 2011) EMA (Jakavi): Treatment of diseaserelated splenomegaly or symptoms in adult patients with myelofibrosis (August 28, 2012)

71 A PHARMACOBIOLOGICAL APPROACH FOR THE CLINICAL DEVELOPMENT OF RUXOLUTINIB, IN MPN Ruxolutinib is a JAK-STAT signaling patway inhibitor drug The function of JAK-STAT signaling patway is cellular proliferation in health and disease Ruxolutinib is an anti-proliferative drug in health and disease Ruxolutinib has the potential to inhibit neoplastic cellular proliferation of MPN Ruxolutinib can cause cytopenias due to its antiproliferative effects at any lineage (good in disease; bad in health)

72 CURRENT CLINICAL CHALLENGES FOR RUXOLUTINIB IN MPN (VERY) LOW-RISK MPN Survival is long and may even not different from the healthy population in some in low-risk MPNs like ET and PV. Competitors of Ruxolutinib is observation only, low-dose aspirin, phlebotomy, hydroxyurea, anagrelide. All of them are cheaper and safer in most cases. There is no data that long-term Ruxolutinib may affect disease course via the prevention of BM fibrosis in low-risk MPN. (VERY) HIGH-RISK MPN Profound deep (pan)cytopenias already in the high-risk MPN could become worse after the addition of Ruxolutinib-induced cytopenias. Inability of Ruxolutinib administration in optimal dosage and duration due to cytopenias of high-risk MPN. Interruption and discontinuation of the drug. ( Ruxolutinib cessation syndrome ) Ruxolutinib may not improve already very shortened survival, morbidity, and comorbidities due to advanced/terminal MPN. Ruxolutinib may not improve irreversible severe organ damage due to advanced/terminal MPN (hepatic failure, portal hypertension bone marrow failure, huge spleen, etc.)

73 What is the ideal subpopulation of MPN for the long-term Ruxolutinib administration at the proper therapeutic dosage and duration to let the drug modifying the MPN disease course and/or bone marrow architecture?