MPNs: JAK2 inhibitors & beyond. Mohamed Abdelmooti (MD) NCI, Cairo University, Egypt

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1 MPNs: JAK2 inhibitors & beyond Mohamed Abdelmooti (MD) NCI, Cairo University, Egypt

2 Myeloproliferative Neoplasms (MPNs) AGENDA: 1. Molecular biology 2. New WHO diagnostic criteria. 3. Risk stratification 4. Management of PV and ET 5. Management of PMF Mohamed Abdelmooti (MD)

3 JAK2 mutations: t(8;9)(p22;p24) fuses Peri-centriolar Material 1 (PCM1) and JAK2 genes JAK2 mutation activation of the JAK2 tyrosine kinase. Exon 12 (codons ) (JAK2 ex12 mutation) Exon 14 (codon 617) (JAK2 V617F mutation) Vainchenker et al, EHA (2007) Vannucchi and Barbui, EHA (2008)

4 Frequency of JAK2, CALR, and MPL mutations in MPNs 3-10% 15% * 3-10% 10% * 97% * 50% 60% 1/3 1/3 * 50% 60% JAK: Janus kinase 2 MPL: Myeloproliferative leukemia virus CARL: Calreticulin (triple-negative) 10-15% Nangalia and Green. ASH Educational Book 2014

5 High molecular risk (HMR) MPNs Gene MPN (%) ASXL1 MF (10-35%) EZH2 MF (7-10%) IDH1/2 MF (5%) SRSF2 MF (5-17%) ASXL1: Addition of Sex Combs Like 1 EZH2: Enhancer of Zeste Homolog 2 IDH1/2: Isocitrate dehydrogenase 1/2 SRSF2: Serine/arginine-rich splicing factor 2 OS by Number of Mutated HMR Genes Nangalia and Green. ASH Educational Book 2014 Guglielmelli P, et al. Leukemia 2014.

6 New proposed revision for WHO diagnostic criteria for MPNs (2014) Criteria PV ET PMF Major: 1. Hb >16.5 (>16) or HCT >49% (>48%) 2. BMB: trilineage myeloproliferation with pleomorphic megakaryocyte 1. PLT > /L 2. BMB: megakaryocyte proliferation with large & mature morphology 3. JAK2 mutation 3. JAK2, CALR or MPL mutation 4. Not meeting WHO criteria for CML, PV, PMF, MDS. Minor 1. Subnormal EPO level 1. Clonal marker (e.g. abnormal karyotype) or Absence of evidence for reactive thrombocytosis Diagnosis requires 1. BMB: Megakaryocyte proliferation & atypia + either reticulin and/or collagen fibrosis 2. JAK2, CALR or MPL mutation. 3. Not meeting WHO criteria for CML, PV, ET, MDS. 1. Clonal marker (e.g. abnormal karyotype) or Absence of evidence for reactive BM fibrosis 2. Anemia or palpable SM 3. Presence of leukoerythroblastosis or Increased LDH. All three major criteria or All four major criteria or All three major criteria or The first two major criteria + one minor criterion. First three major criteria + one minor criterion First two major criteria + all three minor criteria Tefferi et al. Leukemia 2014

7 Survival in different MPNs Compared to Survival in PV Is Significantly Reduced Compared General to Control Population Population ET MPN MS (yr) ET 7-24 PV 15 PMF 6-10 PV ET PMF PMF, primary myelofibrosis Tefferi A, et al. Blood July18. [Epub ahead of print]

8 Management of PV and ET

9 Thrombotic risk stratification of PV and ET Risk factors Established High-risk PV Any of the following 1. Age >60 y High-risk ET Any of the following 2. Previous documented thrombosis Controversial 3. Erythromelagia (refractory to aspirin) 4. Previous hge related to ET 5. PLT>1500 X 10 9 /L 1. DM or HTN requiring pharmacological therapy 2. PLT >1000 X10 9 /L 3. Significant splenomegaly (i.e. > 5 cm below CM)* 4. Symptomatic splenomegaly (pain, early satiety)* *This may be an indication for treatment rather than a risk factor per se Harrison and Garcia. ASH Educational Book 2014

10 Recommendations for therapy in PV and ET in 2015 PV ET Target HCT <45% PLT <450 X 10 9 /L All patients 1. Low-dose aspirin (unless contraindicated) 2. Venesection High-risk patients* 1 st line 2 nd line < 60 y of age: HU or IFN > 60 y of age: HU > 75 y of age: Bu or 32 P. 1. IFN 2. Ruxolitinib 2. Anagrelide** alone or in combination *Evidence for low- or intermediate-risk ET or PV management is unavailable Harrison and Garcia. ASH Educational Book 2014

11 Interferon-alpha for PV/ET Current indications: 1. May be the 1 st therapy particularly in young patients + at risk of thrombosis + refuse HU (?leukemogenicity) 2. Women of childbearing age 3. During pregnancy in case of history of recurrent abortion and/or fetal loss or previous thrombosis 4. Intractable pruritus not responding to other therapies. Vannucchi and Barbui, EHA (2008)

12 Pegylated IFN: Tulure et al. 36/0 82% 12% 29% 77.4 Tulure et al, ASH, 2011

13 JAK2 inhibitors (Ruxolitinib) for refractory PV

14 Ruxolitinib vs best available therapy (BAT) in PV RESPONSE trial: Prospective, randomized, open-label phase 3 study PV patients resistant to or Intolerant of HU Ruxolitinib (JAK1/JAK2 inhibitor) (n= 110) vs BAT (n= 112) Ruxolitinib Statistically significant: Better HCT control, Greater reduction of phlebotomies, Greater reduction of enlarged spleen, Improvement of total symptom score Lower rate of thrombotic events. Verstovsek et al. ASCO, Abst. TPS203. Verstovsek et al. ASCO Abst

15 Ruxolitinib On December 4, 2014: The U.S. FDA approved ruxolitinib (Jakafi) for the treatment of patients with PV who have had an inadequate response to or are intolerant of hydroxyurea (HU). fda.gov

16 Anagrelide for management of ET 1. Second-line therapy in patients who are resistant or intolerant to HU. 2. Combined use of HU and anagrelide when the dose of HU required to maintain platelet count at the target level causes hematological or other kind of toxicities.

17 Optimal management strategy for ET: Hydroxyurea Vs. anagrelide in ET: 809 patients HU + ASA Anagrelide + ASA P Venous thrombosis 1.7% 0.4% Arterial thrombosis 2.1% 4.6%* Serious hemorrhage 1% 2.7% Transformation to MF** 0.6% 2%** 0.01 Transformation to AML 0.7% 0.5% NS *Mainly in JAK V617F -positive patients **Regular monitoring of patients for the development of fibrosis. Harrison et al, NEJM (2005)

18 Management of PMF

19 International Prognostic Scoring Systems (IPSS) for PMF Variable IPSS 1 Dynamic IPSS (DIPSS) 2 DIPSS Plus 3 Age > 65 y Constitutional symptoms Hb < 10 g/dl Leucocytic count > 25 x 10 9 /L Circulating blasts 1% Platelet count < 100 x 10 9 /L RBC transfusion need Unfavorable karyotype* 1 point each 1 point each but Hb= 2 1 point each Low-risk (MS in years) 0 p (11.2 yr) 0 p (not reached) 0 p (15.4 yr) Intermediate I-risk (MS in yr) 1 p (7.9 yr) 1-2 p (14.2 yr) 1 p (6.5 yr) Intermediate II-risk (MS in yr) 2 p (4 yr) 3-4 p (4 yr) 2-3 p (2.9 yr) High-risk (MS in years) >3 p (2.2 yr) 5-6 p (1.5 yr) >4 p (1.3 yr) Reference Cervantes et al. Blood 2009 Passamonti et al. Blood 2010 Gangat et al. JCO * Unfavorable karyotype: +8,-7/7q-, i(17q), inv(3), -5/5q, 12p-, or 11q23 rearrangements

20 Treatment of PMF in 2015 All Patients: Clinical need First line Second line 1. Anemia Corticosteroids Danazol Androgens 2. Symptomatic splenomegaly Constitutional symptoms/qol ESA Thalidomide Lenalidomid e Hydroxyurea Splenectomy RT 4. Extramedullary hematopoiesis Radiation therapy 5. Risk of thrombosis or recurrence Low dose aspirin Hydroxyurea Intermediate- to high-risk patients: 1. Ruxolitinib 2. Allogeneic SCT Vannucchi. ASH 2011

21 Conventional and new treatment modalities for PMF Allogeneic SCT: Indications Patients with high-risk disease and a good PS status should be encouraged to consider allogeneic SCT specially if they show resistance to conventional treatment. Indications of SCT Allo-SCT eligible patients whose MS is expected to be <5 years: 1. Intermediate-2 or high-risk DIPSS (MS 18, 48 m). 2. Patients with RBC transfusion need (MS= 20m) 3. Patients with unfavorable CG abnormalities (MS= 40m) Adverse factors of SCT outcome 1. Advanced age, 2. Advanced stage of disease, 3. RBC transfusion load 4. Presence of marked splenomegaly 5. Use of a non HLA-identical sibling donor, or unrelated donor who is not fully HLA matched 6. Increased allo-sct-specific comorbidity index Barbui et al. JCO. 2011

22 Conventional and new treatment modalities for PMF Allogeneic SCT: The only curative therapy for PMF. Results: Age TRM OS Relapse MAC-SCT Younger patients 20-50% 40-60% + RIC-SCT Patients 45 to 70 years old 10-30% 55-85% ++ Barosi, EHA (2008)

23 Management of PMF JAK2 inhibitors:

24 MECHANISM: JAK1/JAK2 inhibitor Inhibits cytokine induced STAT3 phosphorylation Ruxolitinib (JAKAFI) COMFORT trials: COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment Nature Review, Immunology

25 COMFORT-I: Study Design PMF or PPV-MF, or PET-MF Intermediate-2 or High Risk by IWG-MRT Palpable spleen 5 cm Platelet count 100 x10 9 /L JAK2 V617F positive or negative 1:1 R a n d o m i z e Ruxolitinib (n= 155) 15 or 20 mg BID Placebo (n= 154) Primary Endpoint: % of patients with 35% Decrease in Spleen Volume at W 24. IWG-MRT, International Working Group for Myelofibrosis Research and Treatment; PET-MF, post-essential thrombocythemia-myelofibrosis; PMF, primary myelofibrosis; PPV-MF, post-polycythemia vera-myelofibrosis. Verstovsek. EHA 2012

26 Primary Endpoint: % of Patients With 35% Decrease in Spleen Volume: P < Odds ratio (95% CI) (17.97, 1005) Ruxolitinib (n = 155) Placebo (n = 153) 64% maintained a 35% reduction for at least 2 years Verstovsek. EHA 2012

27 Mean HB Levels Over Time Mean Platelet Counts Over Time Nadirs after 8 12 weeks of therapy and Recovers to a new steady state Which remains stable with longer-term therapy Remain stable with longer-term therapy Verstovsek. EHA 2012

28 Survival Probability 2-year Overall Survival: ITT Population HR=0.58 (95% CI: 0.36, 0.95); P=0.028 No. of deaths: Ruxolitinib=27; Placebo=41 Median follow up: 102 weeks 83% 73% Ruxolitinib Placebo 0.2 Age adjusted HR * =0.61 (95% CI: 0.37, 0.99); P= No. at risk Weeks Ruxolitinib Placebo Note: For this unplanned analysis, P-values are descriptive and nominally significant. * Age was the only baseline characteristic that differed significantly between treatment groups as reported in Verstovsek S, et al. N Engl J Med 2012;366: (median age: ruxolitinib, 66 years; placebo, 70 years; P<0.05). Verstovsek. EHA 2012

29 RUX OS advantage over PCB regardless of JAK2V617F mutation status Verstovsek. ASH 2012

30 SCOMFORT-I: Most common Adverse Events Hematologic: Ruxolitinib (G3/4) PCB (G3/4) Thrombocytopenia 70% (13%) 31% (1.3%) Anemia 96% (45%) 87% (19%) Neutropenia 19% (7%) 4% (2%) Non-hematologic: Ruxolitinib (G3/4) PCB (G3/4) Bruising 23% (0.6%) 15% (0%) Dizziness 18% (0.6%) 7% (0%) Headache 15% (0%) 5% (0%) UTI 9% (0%) 5% (1%) Weight Gain 7% (0.6%) 1.3% (0.7%) H.Z. 2% (0%) 0.7% (0%) Verstovsek. ASH 2012

31 COMFORT-II: Study Design Patients with PMF, PPV-MF, or PET-MF with 2 IPSS risk factors 5 N = 219 Data cutoff: 01 Dec 2012 Open-label randomized 2:1 Ruxolitinib 15 or 20 mg bid n = 146 BAT n = 73 (n = 45) Crossover to ruxolitinib Primary endpoint Achieving 35% reduction in spleen volume from BL at w 48 as measured by MRI (at wks 12, 24, 36, 48) Vannucchi et al. ASH Abstract Harrison et al. N Engl J Med

32 COMFORT-II: 3-year follow-up 35% reduction in spleen volume In 51.4% of patients in ruxolitinib arm (Vs 0% with BAT). Higher RR in patients with PV/ET-MF compared with PMF. Sustained with continued ruxolitinib therapy. BAT patients who crossed over to ruxolitinib had reductions in spleen volume after crossover. Myelofibrosis-associated symptoms Ruxolitinib marked reductions of symptoms BAT worsening of symptoms 3-Year Update Vannucchi et al. EHA

33 Probability COMFORT-II: Overall Survival (3-year update) Ruxolitinib BAT No. of Patients Events 29 (19.9%) 22 (30.1%) Censored 117 (80.1%) 51 (69.9%) Weeks Ruxolitinib, n = BAT, n = Median follow-up, 151 weeks There was a 52% reduction in risk of death in the ruxolitinib arm compared with BAT (HR=0.48; P=.009) 81% 61% P=0.009 Vannucchi et al. EHA

34 COMFORT-II: Most common Adverse Events Hematologic: Ruxolitinib (G3/4) BAT (G3/4) Thrombocytopenia 44% (7.5%) 9.6% (4%) Anemia 40% (9.6%) 12% (4%) Anemia and thrombocytopenia rarely led to discontinuation of ruxolitinib: as only 1% of patients discontinued due to anemia 3.6% of patients discontinued due to thrombocytopenia. Rates of anemia, thrombocytopenia, bleeding events, and infections generally decreased over time. Cervantes, et al. Blood, 2013 (122):

35 COMFORT-II: Most common Adverse Events Non-hematologic (any grade): Peripheral edema Ruxolitinib BAT 37% 29% Diarrhea 36% 18% Asthenia 24% 12% Pyrexia 25% 10% Cough 25% 16% Bronchitis 25% 8% Dyspnea 24% 21% Ruxolitinib BAT Fatigue 24% 11% Nausea 20% 10% Weight gain 20% 1.4% Arthralgia 19% 10% Headache 14% 6% HZ 11% 0% Leukemia 3.3% 4.1% TB 1.4% Harrison, et al. EHA, Abstract P403.

36 Ruxolitinib (JAKAFI) in PMF INDICATIONS AND USAGE: FDA Approval (2011) Patients with intermediate or high-risk myelofibrosis, including: PMF, Post-PV-MF, Post-ET-MF.

37 Management of Intermediate to high risk MF Assess the role and timing of ALLO-SCT Donor availability Risk Candidate or not Urgent ALLO Delayed/never ALLO Proceed to ALLO (possible JAK2I before) Ruxolitinib (Unless anemia/thrombocytop enia is the main problem) Ruxolitinib failure Refractory cytopenia Ruxolitinib comb. New JAK2I Adapted from: Geyer and Mesa. ASH Educational Book 2014

38 New JAK2 inhibitors in development in MF (Phase I/II) Drug Fedratinib (SAR302503) JAKARTA trial Pacritinib (SB1518) Lestauritinib (CEP-701) Momelotinib (CYT387) Other targets FLT3, Ret Response Constit. Spleen Anemi a Hem % 60% - Anemia, Thrombocyt. Leucopenia FLT3 >50% 57% - No FLT3, TrkA JAK1, JNK1, TYK2 Withdrawn due to encephalopathy NR 32% 9% Thrombocyt. Withdrawn due to toxicities Anemia, >50% 45% 50% Thrombocyt. Side effects FLT: fms-like tyrosine kinase Ret: rearranged during transfection TrkA: Tropomyosin receptor kinase JAK: Janus kinase JNK1: Jun N-terminal kinase 1 TYK2: Tyrosine kinase 2 Cervantes, Martinez-Trillos. Expert Opin Pharmacother 2013; 14: Non-Hem. Diarrhea, + amylase Diarrhea, Nausea Diarrhea, vomiting ++ lipase, Headache

39 MPNs: JAK2 inhibitors & beyond Conclusions: It is very encouraging to witness recent developments in our understanding and treatment of MPN and to observe the benefits that these new options can provide to patients. Advances in our understanding of the molecular pathogenesis of these disorders combined with data from clinical trials support these improvements.

40 Thank You NCI, Cairo University, Egypt