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Erschienen in: Current Hematologic Malignancy Reports 5/2022

06.08.2022 | Myeloproliferative Neoplasms (P Bose, Section Editor)

Advances in Risk Stratification and Treatment of Polycythemia Vera and Essential Thrombocythemia

verfasst von: Ivan Krecak, Marko Lucijanic, Srdan Verstovsek

Erschienen in: Current Hematologic Malignancy Reports | Ausgabe 5/2022

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Abstract

Purpose of Review

Estimating and modifying thrombotic risk is currently the mainstay of care for patients with polycythemia vera (PV) and essential thrombocythemia (ET). In recent years, however, increased attention has shifted towards quality of life and disease modification. In this review, we discuss recent advances in risk stratification, present updated results for ruxolitinib and interferon randomized clinical trials, discuss new approaches in antiplatelet and anticoagulant treatment, and summarize early phase trials of novel agents and emerging therapeutic concepts for the treatment of PV and ET.

Recent Findings

International collaborations and novel technologies, i.e., next-generation sequencing and machine learning techniques, have demonstrated excellent abilities to improve thrombotic risk stratification in PV and ET. Updated results from ruxolitinib and interferon randomized clinical trials have confirmed excellent efficacy and safety of these agents, both as first- and second-line treatments. Early trials of novel agents (histone deacetylase inhibitors, telomerase inhibitors, lysine-specific demethylase-1 inhibitors, human double-minute 2 inhibitors, and hepcidin mimetics) have shown encouraging efficacy and safety in blood count control, reduction of splenomegaly, and alleviation of disease-related symptoms. Finally, accumulating evidence suggested that direct oral anticoagulants may be a valid therapeutic alternative to warfarin for prolonged thromboprophylaxis.

Summary

International collaborations (“big data”) with the help of new technologies represent an exciting new approach to analyze rare outcomes in rare diseases, especially for identifying novel prognostic biomarkers in PV and ET. Randomized clinical trials are also needed to fully elucidate whether novel agents may establish new standards of care.
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Zurück zum Zitat Gisslinger H, Buxhofer-Ausch V, Thaler J, Forjan W, Willenbacher E, Wolf D, et al. Long-term efficacy and safety of ropeginterferon alfa-2b in patients with polycythemia vera — final phase I/II Peginvera study results. Blood. 2018;132(Supplement 1):3030. CrossRef Gisslinger H, Buxhofer-Ausch V, Thaler J, Forjan W, Willenbacher E, Wolf D, et al. Long-term efficacy and safety of ropeginterferon alfa-2b in patients with polycythemia vera — final phase I/II Peginvera study results. Blood. 2018;132(Supplement 1):3030. CrossRef
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Zurück zum Zitat •• Gisslinger GH, Klade C, Georgiev P, Krochmalczyk D, Gercheva-Kyuchukova L, Egyed M, PROUD-PV Study Group, et al. Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study. Lancet Haematol. 2020;7(3):e196–208. This was a randomized study assessing ropeginterferon vs. hydroxyurea in PV patients who were either newly diagnosed or already on hydroxyurea but not optimally managed. After 1 year, non-inferiority of ropeginterferon with respect to hematological and spleen responses was not shown; however, after 24–36 months, more ropeginterferon-treated patients achieved complete hematological and molecular responses. PubMedCrossRef •• Gisslinger GH, Klade C, Georgiev P, Krochmalczyk D, Gercheva-Kyuchukova L, Egyed M, PROUD-PV Study Group, et al. Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study. Lancet Haematol. 2020;7(3):e196–208. This was a randomized study assessing ropeginterferon vs. hydroxyurea in PV patients who were either newly diagnosed or already on hydroxyurea but not optimally managed. After 1 year, non-inferiority of ropeginterferon with respect to hematological and spleen responses was not shown; however, after 24–36 months, more ropeginterferon-treated patients achieved complete hematological and molecular responses. PubMedCrossRef
85.
Zurück zum Zitat • Kiladjian JJ, Klade C, Georgiev P, Krochmalczyk D, Gercheva-Kyuchukova L, Egyed M, et al. PROUD-PV Study Group. Long-term outcomes of polycythemia vera patients treated with ropeginterferon Alfa-2b. Leukemia. 2022. https://​doi.​org/​10.​1038/​s41375-022-01528-x. This study reports the 5-year follow-up of the PROUD-PV trial. Ropeginterferon continued to effectively control the hematocrit, achieve durable molecular responses, and minimize the occurrence of thromboembolic events in patients with PV. • Kiladjian JJ, Klade C, Georgiev P, Krochmalczyk D, Gercheva-Kyuchukova L, Egyed M, et al. PROUD-PV Study Group. Long-term outcomes of polycythemia vera patients treated with ropeginterferon Alfa-2b. Leukemia. 2022. https://​doi.​org/​10.​1038/​s41375-022-01528-x. This study reports the 5-year follow-up of the PROUD-PV trial. Ropeginterferon continued to effectively control the hematocrit, achieve durable molecular responses, and minimize the occurrence of thromboembolic events in patients with PV.
86.
Zurück zum Zitat Gisslinger H, Klade C, Georgiev P, Krochmalczyk D, Gercheva-Kyuchukova L, Egyed M, et al. S196: ropeginterferon alfa-2B achieves patient-specific treatment goals in polycythemia vera: final results from the PROUD-PV/CONTINUATION-PV studies. HemaSphere. 2022;6:97–8. CrossRef Gisslinger H, Klade C, Georgiev P, Krochmalczyk D, Gercheva-Kyuchukova L, Egyed M, et al. S196: ropeginterferon alfa-2B achieves patient-specific treatment goals in polycythemia vera: final results from the PROUD-PV/CONTINUATION-PV studies. HemaSphere. 2022;6:97–8. CrossRef
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Zurück zum Zitat •• Barbui T, Vannucchi AM, De Stefano V, Masciulli A, Carobbio A, Ferrari A, et al. Ropeginterferon alfa-2b versus phlebotomy in low-risk patients with polycythaemia vera (Low-PV study): a multicentre, randomised phase 2 trial. Lancet Haematol. 2021;8(3):e175–84. The results of this randomized trial indicated that the addition of ropeginterferon to phlebotomy is more efficacious than the current standard therapy of phlebotomy alone in low-risk PV patients with respect to hematocrit control and the number of phlebotomies needed to achieve this goal. These results challenge phlebotomy-only as a standard of care in low-risk PV patients. PubMedCrossRef •• Barbui T, Vannucchi AM, De Stefano V, Masciulli A, Carobbio A, Ferrari A, et al. Ropeginterferon alfa-2b versus phlebotomy in low-risk patients with polycythaemia vera (Low-PV study): a multicentre, randomised phase 2 trial. Lancet Haematol. 2021;8(3):e175–84. The results of this randomized trial indicated that the addition of ropeginterferon to phlebotomy is more efficacious than the current standard therapy of phlebotomy alone in low-risk PV patients with respect to hematocrit control and the number of phlebotomies needed to achieve this goal. These results challenge phlebotomy-only as a standard of care in low-risk PV patients. PubMedCrossRef
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Zurück zum Zitat Mesa RA, Komatsu N, Gill H, Jin J, Lee S-E, Hou H-A, et al. Surpass-ET trial: a phase 3, open-label, multicenter, randomized, active-controlled study to assess pharmacokinetics and compare the efficacy, safety, and tolerability of P1101 vs anagrelide as second line therapy for essential thrombocythemia. Blood. 2021;138(Supplement 1):1491. CrossRef Mesa RA, Komatsu N, Gill H, Jin J, Lee S-E, Hou H-A, et al. Surpass-ET trial: a phase 3, open-label, multicenter, randomized, active-controlled study to assess pharmacokinetics and compare the efficacy, safety, and tolerability of P1101 vs anagrelide as second line therapy for essential thrombocythemia. Blood. 2021;138(Supplement 1):1491. CrossRef
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Zurück zum Zitat •• Vannucchi AM, Kiladjian JJ, Griesshammer M, Masszi T, Durrant S, Passamonti F, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372(5):426–35. This randomized clinical trial placed ruxolitinib as a first-line treatment option for PV patients with splenomegaly who are resistant or intolerant to hydroxyurea because it showed superiority of ruxolitinib over standard therapy in the achievement of composite endpoint of both hematocrit control and spleen volume reduction at 32 weeks. PubMedPubMedCentralCrossRef •• Vannucchi AM, Kiladjian JJ, Griesshammer M, Masszi T, Durrant S, Passamonti F, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372(5):426–35. This randomized clinical trial placed ruxolitinib as a first-line treatment option for PV patients with splenomegaly who are resistant or intolerant to hydroxyurea because it showed superiority of ruxolitinib over standard therapy in the achievement of composite endpoint of both hematocrit control and spleen volume reduction at 32 weeks. PubMedPubMedCentralCrossRef
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Zurück zum Zitat Verstovsek S, Harrison CN, Kiladjian JJ, Miller C, Naim AB, Paranagama DC, et al. Markers of iron deficiency in patients with polycythemia vera receiving ruxolitinib or best available therapy. Leuk Res. 2017;56:52–9. PubMedCrossRef Verstovsek S, Harrison CN, Kiladjian JJ, Miller C, Naim AB, Paranagama DC, et al. Markers of iron deficiency in patients with polycythemia vera receiving ruxolitinib or best available therapy. Leuk Res. 2017;56:52–9. PubMedCrossRef
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Zurück zum Zitat •• Passamonti F, Griesshammer M, Palandri F, Egyed M, Benevolo G, Devos T, et al. Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study. Lancet Oncol. 2017;18(1):88–99. This randomized trial was similarly designed to RESPONSE but included PV patients without splenomegaly. Similarly to the RESPONSE trial, it demonstrated superiority of ruxolitinib over standard therapy in terms of hematocrit control at 28 weeks. PubMedCrossRef •• Passamonti F, Griesshammer M, Palandri F, Egyed M, Benevolo G, Devos T, et al. Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study. Lancet Oncol. 2017;18(1):88–99. This randomized trial was similarly designed to RESPONSE but included PV patients without splenomegaly. Similarly to the RESPONSE trial, it demonstrated superiority of ruxolitinib over standard therapy in terms of hematocrit control at 28 weeks. PubMedCrossRef
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Zurück zum Zitat Passamonti F, Palandri F, Saydam G, Callum J, Devos T, Guglielmelli P, et al. Ruxolitinib versus best available therapy in inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): 5-year follow up of a randomised, phase 3b study. Lancet Haematol. 2022;9(7):e480–92. PubMedCrossRef Passamonti F, Palandri F, Saydam G, Callum J, Devos T, Guglielmelli P, et al. Ruxolitinib versus best available therapy in inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): 5-year follow up of a randomised, phase 3b study. Lancet Haematol. 2022;9(7):e480–92. PubMedCrossRef
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Zurück zum Zitat Masciulli A, Ferrari A, Carobbio A, Ghirardi A, Barbui T. Ruxolitinib for the prevention of thrombosis in polycythemia vera: a systematic review and meta-analysis. Blood Adv. 2020;4(2):380–6. PubMedPubMedCentralCrossRef Masciulli A, Ferrari A, Carobbio A, Ghirardi A, Barbui T. Ruxolitinib for the prevention of thrombosis in polycythemia vera: a systematic review and meta-analysis. Blood Adv. 2020;4(2):380–6. PubMedPubMedCentralCrossRef
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Zurück zum Zitat Mesa R, Vannucchi AM, Yacoub A, Zachee P, Garg M, Lyons R, et al. The efficacy and safety of continued hydroxycarbamide therapy versus switching to ruxolitinib in patients with polycythaemia vera: a randomized, double-blind, double-dummy, symptom study (RELIEF). Br J Haematol. 2017;176(1):76–85. PubMedCrossRef Mesa R, Vannucchi AM, Yacoub A, Zachee P, Garg M, Lyons R, et al. The efficacy and safety of continued hydroxycarbamide therapy versus switching to ruxolitinib in patients with polycythaemia vera: a randomized, double-blind, double-dummy, symptom study (RELIEF). Br J Haematol. 2017;176(1):76–85. PubMedCrossRef
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Zurück zum Zitat • Harrison CN, Mead AJ, Panchal A, Fox S, Yap C, Gbandi E, et al. Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide. Blood. 2017;130(17):1889–97. This randomized trial suggested that ruxolitinib may not be superior to current second-line treatments for ET. PubMedPubMedCentralCrossRef • Harrison CN, Mead AJ, Panchal A, Fox S, Yap C, Gbandi E, et al. Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide. Blood. 2017;130(17):1889–97. This randomized trial suggested that ruxolitinib may not be superior to current second-line treatments for ET. PubMedPubMedCentralCrossRef
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Zurück zum Zitat Verstovsek S, Amoloja T, Scherber RM, Yu J. Real-world patient characteristics and treatment patterns of ruxolitinib among patients with advanced essential thrombocythemia at community clinical practice. Leuk Res. 2021;110: 106711. PubMedCrossRef Verstovsek S, Amoloja T, Scherber RM, Yu J. Real-world patient characteristics and treatment patterns of ruxolitinib among patients with advanced essential thrombocythemia at community clinical practice. Leuk Res. 2021;110: 106711. PubMedCrossRef
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Zurück zum Zitat •• Sørensen AL, Mikkelsen SU, Knudsen TA, Bjørn ME, Andersen CL, Bjerrum OW, et al. Ruxolitinib and interferon-α2 combination therapy for patients with polycythemia vera or myelofibrosis: a phase II study. Haematologica. 2020;105(9):2262–72. This “proof of concept” study of ruxolitinib and interferon combination has shown excellent efficacy and safety for the treatment of patients with PV who were resistant or refractory to pegylated interferon. PubMedPubMedCentralCrossRef •• Sørensen AL, Mikkelsen SU, Knudsen TA, Bjørn ME, Andersen CL, Bjerrum OW, et al. Ruxolitinib and interferon-α2 combination therapy for patients with polycythemia vera or myelofibrosis: a phase II study. Haematologica. 2020;105(9):2262–72. This “proof of concept” study of ruxolitinib and interferon combination has shown excellent efficacy and safety for the treatment of patients with PV who were resistant or refractory to pegylated interferon. PubMedPubMedCentralCrossRef
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Zurück zum Zitat Chifotides HT, Bose P, Verstovsek S. Givinostat: an emerging treatment for polycythemia vera. Expert Opinion Investig Drugs. 2020;29(6):525–36. CrossRef Chifotides HT, Bose P, Verstovsek S. Givinostat: an emerging treatment for polycythemia vera. Expert Opinion Investig Drugs. 2020;29(6):525–36. CrossRef
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Zurück zum Zitat Rambaldi A, Iurlo A, Vannucchi AM, Noble R, von Bubnoff N, Guarini A, et al. Safety and efficacy of the maximum tolerated dose of givinostat in polycythemia vera: a two-part phase Ib/II study. Leukemia. 2020;34(8):2234–7. PubMedPubMedCentralCrossRef Rambaldi A, Iurlo A, Vannucchi AM, Noble R, von Bubnoff N, Guarini A, et al. Safety and efficacy of the maximum tolerated dose of givinostat in polycythemia vera: a two-part phase Ib/II study. Leukemia. 2020;34(8):2234–7. PubMedPubMedCentralCrossRef
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Zurück zum Zitat • Finazzi G, Vannucchi AM, Martinelli V, Ruggeri M, Nobile F, Specchia G, et al. A phase II study of givinostat in combination with hydroxycarbamide in patients with polycythaemia vera unresponsive to hydroxycarbamide monotherapy. Br J Haematol. 2013;161(5):688–94. This phase 2 study demonstrated favorable efficacy and safety of a combination therapy with givinostat and hydroxyurea for the treatment of hydroxyurea-resistant PV. PubMedCrossRef • Finazzi G, Vannucchi AM, Martinelli V, Ruggeri M, Nobile F, Specchia G, et al. A phase II study of givinostat in combination with hydroxycarbamide in patients with polycythaemia vera unresponsive to hydroxycarbamide monotherapy. Br J Haematol. 2013;161(5):688–94. This phase 2 study demonstrated favorable efficacy and safety of a combination therapy with givinostat and hydroxyurea for the treatment of hydroxyurea-resistant PV. PubMedCrossRef
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Zurück zum Zitat Jutzi JS, Kleppe M, Dias J, Staehle HF, Shank K, Teruya-Feldstein J, et al. LSD1 inhibition prolongs survival in mouse models of MPN by selectively targeting the disease clone. Hemasphere. 2018;2(3): e54. PubMedPubMedCentralCrossRef Jutzi JS, Kleppe M, Dias J, Staehle HF, Shank K, Teruya-Feldstein J, et al. LSD1 inhibition prolongs survival in mouse models of MPN by selectively targeting the disease clone. Hemasphere. 2018;2(3): e54. PubMedPubMedCentralCrossRef
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Zurück zum Zitat Palandri F, Vianelli N, Ross DM, Cochrane T, Lane SW, Larsen SR, et al. A phase 2 study of the LSD1 inhibitor Img-7289 (bomedemstat) for the treatment of essential thrombocythemia (ET). Blood. 2021;138(Supplement 1):38693. Palandri F, Vianelli N, Ross DM, Cochrane T, Lane SW, Larsen SR, et al. A phase 2 study of the LSD1 inhibitor Img-7289 (bomedemstat) for the treatment of essential thrombocythemia (ET). Blood. 2021;138(Supplement 1):38693.
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Zurück zum Zitat •• Palandri F, Ross DM, Cochrane T, Tate C, Lane SW, Larsen SR, et al. P1033: a phase 2 study of the LSD1 inhibitor IMG-7289 (bomedemstat) for the treatment of essential thrombocythemia (ET). HemaSphere. 2022;6:923–4. This phase 2 study demonstrated the favorable efficacy and safety of bomedemstat for the treatment of hydroxyurea-resistant ET patients. PubMedCentralCrossRef •• Palandri F, Ross DM, Cochrane T, Tate C, Lane SW, Larsen SR, et al. P1033: a phase 2 study of the LSD1 inhibitor IMG-7289 (bomedemstat) for the treatment of essential thrombocythemia (ET). HemaSphere. 2022;6:923–4. This phase 2 study demonstrated the favorable efficacy and safety of bomedemstat for the treatment of hydroxyurea-resistant ET patients. PubMedCentralCrossRef
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Zurück zum Zitat Mascarenhas J, Passamonti F, Burbury K, El-Galaly TC, Gerds A, Gupta V, et al. The MDM2 antagonist idasanutlin in patients with polycythemia vera: results from a single-arm phase 2 study. Blood Adv. 2022;6(4):1162–74. PubMedPubMedCentralCrossRef Mascarenhas J, Passamonti F, Burbury K, El-Galaly TC, Gerds A, Gupta V, et al. The MDM2 antagonist idasanutlin in patients with polycythemia vera: results from a single-arm phase 2 study. Blood Adv. 2022;6(4):1162–74. PubMedPubMedCentralCrossRef
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Zurück zum Zitat Mosoyan G, Kraus T, Ye F, Eng K, Crispino JD, Hoffman R, et al. Imetelstat, a telomerase inhibitor, differentially affects normal and malignant megakaryopoiesis. Leukemia. 2017;31(11):2458–67. PubMedPubMedCentralCrossRef Mosoyan G, Kraus T, Ye F, Eng K, Crispino JD, Hoffman R, et al. Imetelstat, a telomerase inhibitor, differentially affects normal and malignant megakaryopoiesis. Leukemia. 2017;31(11):2458–67. PubMedPubMedCentralCrossRef
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Zurück zum Zitat •• Hoffman R, Kremyanskaya M, Ginzburng Y, Kuykendall AT, Pemmarayu N, Yacoub A, et al. Rusfertide (PTG-300) controls hematocrit levels and essentially eliminates phlebotomy requirement in polycythemia vera patients. Abstract #388. Presented at the 2021 American Society of Hematology Annual Meeting, December 12, 2021. This study demonstrated excellent safety and efficacy of rusfertide, a hepcidin mimetic, in controlling hematocrit <45% without the need for phlebotomies. •• Hoffman R, Kremyanskaya M, Ginzburng Y, Kuykendall AT, Pemmarayu N, Yacoub A, et al. Rusfertide (PTG-300) controls hematocrit levels and essentially eliminates phlebotomy requirement in polycythemia vera patients. Abstract #388. Presented at the 2021 American Society of Hematology Annual Meeting, December 12, 2021. This study demonstrated excellent safety and efficacy of rusfertide, a hepcidin mimetic, in controlling hematocrit <45% without the need for phlebotomies.
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Zurück zum Zitat Yelena Ginzburg, Kamini Kirubamoorthy, Sinari Salleh, Lee S-E, Lee JH, Selvaratnam V, et al. Rusfertide (PTG-300) Induction therapy rapidly achieves hematocrit control in polycythemia vera patients without the need for therapeutic phlebotomy. Abstract #390. Presented at the 2021 American Society of Hematology Annual Meeting, December 12, 2021. Yelena Ginzburg, Kamini Kirubamoorthy, Sinari Salleh, Lee S-E, Lee JH, Selvaratnam V, et al. Rusfertide (PTG-300) Induction therapy rapidly achieves hematocrit control in polycythemia vera patients without the need for therapeutic phlebotomy. Abstract #390. Presented at the 2021 American Society of Hematology Annual Meeting, December 12, 2021.
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Zurück zum Zitat Hoffman R, Ginzburg Y, Kremyanskaya M, Khanna S, Modi N, Valone FH, et al. Rusfertide (PTG-300) treatment in phlebotomy-dependent polycythemia vera patients. J Clin Oncol. 2022;40(16_suppl):7003–7003. CrossRef Hoffman R, Ginzburg Y, Kremyanskaya M, Khanna S, Modi N, Valone FH, et al. Rusfertide (PTG-300) treatment in phlebotomy-dependent polycythemia vera patients. J Clin Oncol. 2022;40(16_suppl):7003–7003. CrossRef
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Zurück zum Zitat Verstovsek S, Kuykendall AT, Hoffman R, Ginzburg Y, Pemmaraju N, Valone F, et al. A phase 3 study of the hepcidin mimetic rusfertide (PTG-300) in patients with polycythemia vera. Blood. 2021;138(Supplement 1):1504. CrossRef Verstovsek S, Kuykendall AT, Hoffman R, Ginzburg Y, Pemmaraju N, Valone F, et al. A phase 3 study of the hepcidin mimetic rusfertide (PTG-300) in patients with polycythemia vera. Blood. 2021;138(Supplement 1):1504. CrossRef
Metadaten
Titel
Advances in Risk Stratification and Treatment of Polycythemia Vera and Essential Thrombocythemia
verfasst von
Ivan Krecak
Marko Lucijanic
Srdan Verstovsek
Publikationsdatum
06.08.2022
Verlag
Springer US
Erschienen in
Current Hematologic Malignancy Reports / Ausgabe 5/2022
Print ISSN: 1558-8211
Elektronische ISSN: 1558-822X
DOI
https://doi.org/10.1007/s11899-022-00670-8

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