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Variable IPSS DIPSS DIPSS-Plus Supplemental file 1: Prognostic models for myelofibrosis Prognostic models for primary myelofibrosis [1-5] Variable IPSS DIPSS DIPSS-plus Age > 65 1 1 1 Constitutional 1 1 1 Symptoms Hb < 10g/dL 1 2 1 WBC > 25 x 109/L 1 1 1 PB blasts 1% or more 1 1 1 Platelet < 100 x 109/L - - 1 RBC transfusion need - - 1 Unfavourable - - 1 karyotypeA IPSS: international prognostic scoring system; DIPSS: dynamic international prognostic scoring system; Hb: Haemoglobin; WBC: white blood cell; PB: peripheral; RBC: red blood cell. A: Unfavourable karyotype comprised +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p- and 11q23 rearrangements Overall survivals predicted by prognostic models in primary myelofibrosis [1-5] Prognostic System Risk Score Median OS (months) Lille scoreA Low 0 93 Intermediate 1 26 High 2 13 IPSS Low 0 135 Int-1 1 95 Int-2 2 48 High >3 27 DIPSS Low 0 NR Int-1 1-2 170 Int-2 3-4 48 High 5-6 18 DIPSS-plus Low 0 185 Int-1 1 78 Int-2 2-3 35 High 4-6 16 IPSS: international prognostic scoring system; DIPSS: dynamic international prognostic scoring system; OS: overall survival A: Haemoglobin <10 g/dL and leucocyte count < 4 or > 30 x 109 are the two adverse prognostic indicators with a score of 1 for each. Prognostic models integrating clinical risk variable, cytogenetics and gene mutations in PMF [6-14] Variable MIPSS70 MIPSS70+ MIPSS70+ GIPSS v2.0 Anaemia 1 (Hb 1 (Hb < 2 (Hb < <10g/dL) 10g/dL) 9g/dL in men, < 8g/dL in women) 1 (Hb 9- 10.9g/dL in men, 8- 9.9g/dL in women) WBC > 25 x 109/L 2 - - - Platelet < 100 x 109/L 2 - - - Circulating blasts ≥ 2% 1 1 1 - BM fibrosis grade ≥ 2 1 - - - Constitutional symptoms 1 1 2 - Absence of type 1/type 1-like 1 2 2 1 CALR mutations Presence of an HMR mutation 1 1 2 1 (ASXL1), 1(SRSF2), 1 (U2AF1Q157) Presence of ≥2 or more HMR 2 2 3 - mutationsA Unfavourable karyotypeB - 3 3 1 Very high risk karyotypeB - - 4 2 MIPSS: mutation-enhanced international prognostic scoring system for transplant-age patients; v2.0: Version 2.0; GIPSS: genetically inspired prognosic scoring system; Hb: haemoglobin; WBC: white blood cell; BM: bone marrow; HMR: high-molecular risk. A: HMR mutations comprise ASXL1, EZH2, IDH1/2, SRFS2 and, in addition, U2AF1Q157 for MIPSS70+ version 2.0. B: Unfavourable karyotype and very high risk karyotype was defined using the revised cytogenetic risk stratification for primary myelofibrosis [13] Overall survival predicted by prognostic models integrating gene mutations in PMF [6-14] Prognostic System Risk Score Median OS (years) MIPSS70 (3-tiered) Low 0-1 Not reached Intermediate 2-4 6.3 High ≥5 3.1 MIPSS70-plus version 2.0 Very low 0 Not reached (5-tiered) Low 1-2 16.4 Intermediate 3-4 7.7 High 5-8 4.8 Very high ≥9 1.8 GIPSS (4-tiered) Low 0 26.4 Int-1 1 8 Int-2 2 4.2 High ≥3 2 MIPSS: mutation-enhanced international prognostic scoring system for transplant-age patients; v2.0: Version 2.0; GIPSS: genetically inspired prognostic scoring system; OS: overall survival References: 1. Cervantes, F.; Dupriez, B.; Pereira, A.; Passamonti, F.; Reilly, J. T.; Morra, E.; Vannucchi, A. M.; Mesa, R. A.; Demory, J. L.; Barosi, G.; Rumi, E.; Tefferi, A., New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood 2009, 113, (13), 2895- 901. 2. Passamonti, F.; Cervantes, F.; Vannucchi, A. M.; Morra, E.; Rumi, E.; Pereira, A.; Guglielmelli, P.; Pungolino, E.; Caramella, M.; Maffioli, M.; Pascutto, C.; Lazzarino, M.; Cazzola, M.; Tefferi, A., A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood 2010, 115, (9), 1703-8. 3. Gangat, N.; Caramazza, D.; Vaidya, R.; George, G.; Begna, K.; Schwager, S.; Van Dyke, D.; Hanson, C.; Wu, W.; Pardanani, A.; Cervantes, F.; Passamonti, F.; Tefferi, A., DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol 2011, 29, (4), 392-7. 4. Morel, P.; Duhamel, A.; Hivert, B.; Stalniekiewicz, L.; Demory, J. L.; Dupriez, B., Identification during the follow-up of time-dependent prognostic factors for the competing risks of death and blast phase in primary myelofibrosis: a study of 172 patients. Blood 2010, 115, (22), 4350-5. 5. Rumi, E.; Cazzola, M., Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms. Blood 2017, 129, (6), 680-692. 6. Guglielmelli, P.; Lasho, T. L.; Rotunno, G.; Mudireddy, M.; Mannarelli, C.; Nicolosi, M.; Pacilli, A.; Pardanani, A.; Rumi, E.; Rosti, V.; Hanson, C. A.; Mannelli, F.; Ketterling, R. P.; Gangat, N.; Rambaldi, A.; Passamonti, F.; Barosi, G.; Barbui, T.; Cazzola, M.; Vannucchi, A. M.; Tefferi, A., MIPSS70: Mutation-Enhanced International Prognostic Score System for Transplantation-Age Patients With Primary Myelofibrosis. J Clin Oncol 2018, 36, (4), 310-318. 7. Guglielmelli, P.; Lasho, T. L.; Rotunno, G.; Score, J.; Mannarelli, C.; Pancrazzi, A.; Biamonte, F.; Pardanani, A.; Zoi, K.; Reiter, A.; Duncombe, A.; Fanelli, T.; Pietra, D.; Rumi, E.; Finke, C.; Gangat, N.; Ketterling, R. P.; Knudson, R. A.; Hanson, C. A.; Bosi, A.; Pereira, A.; Manfredini, R.; Cervantes, F.; Barosi, G.; Cazzola, M.; Cross, N. C.; Vannucchi, A. M.; Tefferi, A., The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients. Leukemia 2014, 28, (9), 1804-10. 8. Tefferi, A., Primary myelofibrosis: 2019 update on diagnosis, risk-stratification and management. American journal of hematology 2018, 93, (12), 1551-1560. 9. Rozovski, U.; Verstovsek, S.; Manshouri, T.; Dembitz, V.; Bozinovic, K.; Newberry, K.; Zhang, Y.; Bove, J. E. t.; Pierce, S.; Kantarjian, H.; Estrov, Z., An accurate, simple prognostic model consisting of age, JAK2, CALR, and MPL mutation status for patients with primary myelofibrosis. Haematologica 2017, 102, (1), 79-84. 10. Rumi, E.; Pietra, D.; Pascutto, C.; Guglielmelli, P.; Martinez-Trillos, A.; Casetti, I.; Colomer, D.; Pieri, L.; Pratcorona, M.; Rotunno, G.; Sant'Antonio, E.; Bellini, M.; Cavalloni, C.; Mannarelli, C.; Milanesi, C.; Boveri, E.; Ferretti, V.; Astori, C.; Rosti, V.; Cervantes, F.; Barosi, G.; Vannucchi, A. M.; Cazzola, M.; Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative, I., Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis. Blood 2014, 124, (7), 1062- 9. 11. Tefferi, A.; Guglielmelli, P.; Nicolosi, M.; Mannelli, F.; Mudireddy, M.; Bartalucci, N.; Finke, C. M.; Lasho, T. L.; Hanson, C. A.; Ketterling, R. P.; Begna, K. H.; Naseema, G.; Pardanani, A.; Vannucchi, A. M., GIPSS: genetically inspired prognostic scoring system for primary myelofibrosis. Leukemia 2018, 32, (7), 1631-1642. 12. Tefferi, A.; Guglielmelli, P.; Pardanani, A.; Vannucchi, A. M., Myelofibrosis Treatment Algorithm 2018. Blood cancer journal 2018, 8, (8), 72. 13. Tefferi, A.; Nicolosi, M.; Mudireddy, M.; Lasho, T. L.; Gangat, N.; Begna, K. H.; Hanson, C. A.; Ketterling, R. P.; Pardanani, A., Revised cytogenetic risk stratification in primary myelofibrosis: analysis based on 1002 informative patients. Leukemia 2018, 32, (5), 1189-1199. 14. Tefferi, A.; Guglielmelli, P.; Lasho, T. L.; Gangat, N.; Ketterling, R. P.; Pardanani, A.; Vannucchi, A. M., MIPSS70+ Version 2.0: Mutation and Karyotype-Enhanced International Prognostic Scoring System for Primary Myelofibrosis. J Clin Oncol 2018, 36, (17), 1769-1770. Novel Therapies in CML NOTE: Hyperactivation of WNT974 MDM2i/HDM2i:MDM2i/HDM2i: JQ-1 Smo i: LSC survival Nutlin-3a, Plasma membrane Mechanism of TKI resistance Alteration in CML LSC Hh pathway ↑ TPO receptor JAK/STAT Nutlin-3a, Increased Sonidegib/ LDE225 MI-219, DS-5272 (MPL) hyperactivity MI-219, DS-5272 expression BMS-833923 + Dasatinib PPARγ agonist: PPARα agonist: ↑BCR-ABL1 Misoprostol +/- (TKI) PORCN Rosiglitazone Clofibrate , WY-14643 ATO + Peg-IFNα-2a Upregulation IL- Hh Wnt Wnt TNF 12β NK-cell mediated Modification Release from ER IL-1 AHI-1 JAKi: IFNα Upregulation Angiogenesis cytotoxicity JAK2 BCR-ABL1 Ruxolitinib +/- JAK2 JAK2 TKR (growth factor)-TK domain IL-12β PGE1 (Nilotinib/ -12β Wnt ↑PRMT5 IFNAR2 IFNAR1 IL PGE2 PPARγ agonist: Dasatinib/Bosutinib) Pioglitazone +/- TKI: Ruxolitinib JAK1 TYK2 (Ceased STAT3/5 STAT3/5 VEGFR NKG2D-L EP4 degradation (Imatinib) Imatinib, Dasatinib compleX) Transcription factor acts on DVL3 (Inhibition of Inhibition of Grb2 Smo PTCH FZD4 (in both nucleus hOCT1 (Nuclear SHP-2 SHC transcription Cytoplasm a.a. DVL PRMT5 phosphorylation) Amino acid APC Axin and cytoplasm) translocation) Down- (Mitochondria) 3’ Death 5’ BP1001 regulation receptor Clonal PPARγ STAT3i: Grb2 Charged GSK3β CK1 Activation of aminoacyl-tRNA evolution BP-5087 +/- 1 2 STAT3 STAT5 STAT3 ATO + Peg-IFNα-2a ATO + TKI Axin 1 RXR STAT5 Gab2 In K562 Increases in Imatinib (Imatinib) SOS STAT 55S uptake STAT (Accumulation) (Inhibition of RITA Tigecycline phosphorylation) Mitoribosome 39S Binding (Nuclear PJ-68 IKKγ IRF9 translocation) Cell cycling of Overcome TKI Transcription factor Growth arrest 5’ E-site P-site A-site 3’ Gli IKKα IKKβ DNA damage, additional Triggered ↑KRas Gli3R β-Catenin Degradation (Nuclear translocation) dormant LSCs resistance acquisition of mutations in production of ROS Ras Tigecycline 28S Kif7 Proliferation ATO + TKI CaSpaSe-8 CML LSC (homologous to 30S in bacteria) Sufu Binding to BCR-ABL1 Activation of Wnt/ Ca2+/ NFAT KRas Transcription factor Increases hyperactivation Myc MAX Myc MAX BCR-ABL1 Increased mRNA and Citrate Citrate p50 (Nuclear protein content (mitochondrial Block apoptosis and induce Binding Transcription factor IκBα NF-κB translocation) dysfunction, expansion of progenitor cells (Nuclear translocation) Src downregulation C82 + Nilotinib p65 RAF PKC Myc Degradation of ETC, increases Isocitrate + Apoptosis CaSpaSe-3, -6, -7 Dissociation PP2A oxidative stress) Isocitrate NADP NADP+ Pro-apoptotic signals from NF-κB (Upregulation àTKI resistant) BCR-ABL1 (e.g.
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