Keywords
MPN; Polycythemia vera; Interferon; JAK inhibitors.
How to Cite
Musso, A. (2021). The Treatment of BCR-ABL1 Negative Myeloprolipherative Neoplasms (MPN). Personal Experience with Interferon and Comments on New Drugs. Journal of Hematology, 25(2), 75–84. Retrieved from https://revistahematologia.com.ar/index.php/Revista/article/view/369
Abstract
Encouraged by the benefits of interferon on CML and by the absence of leukemogenic effect on PV, we started using it in the late 1980s. Eight patients with PV were treated with conventional IFN-alpha2b and, although effective to induce remissions with very few vascular events, the side effects and the high cost made its use inconvenient. A 64 years old female patient with PV presented with stroke, was treated with IFN and died in hematologic remission ten years later due to MI. Pegylated interferon proved to be highly effective and was very well tolerated by five patients (three PV, one ET/MF, and one preMF).
These patients were followed up for a period of 6-16 years, a total of 62 years altogether, and never suffered from any vascular event. A female patient with PV in complete molecular remission developed MF after 14 years of treatment. She is currently doing extremely well three years later receiving IFN + Epo. A patient with PV in clinical and hematologic remission developed a rectal carcinoma nine years after starting treatment. One PV patient in remission for five years and another one with ET/MF in remission for six years are on treatment without complications.
An elderly female patient with preMF discontinued IFN after five years due to depression. New agents are being used to improve the conditions of patients with MPN. Ropeginterferon is the only one that can induce complete molecular response in PV and ET. Some other are JAK inhibitors, like ruxolitinib (approved for MF and PV), fedratinib, pacritinib, momelotinib (active in MF against constitutional symptoms, splenomegaly and anemia), Itacitinib.
Some erythopoiesis stimulating agents like luspatercept, sotatercept, roxadustat, can be useful in MF.
References
1. Barbui T, Thiele J, Gisslinger H, et al. The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer J. 2018; 8:15.
2. Musso AM. Significación Clínica de las Mutaciones en Neoplasias Mieloproliferativas BCR-ABL1 Negativas (NMP). Hematología. 2015;19:54.
3. Silver RT. Recombinant alfa-interferon for treatment of polycythemia vera. Lancet. 1988; 2:403 (letter).
4. Musso AM, Santos MI, Alcón Alvarez M. Tratamiento de la Policitemia Proliferativa Primaria (PPP) con interferón. Hematología. 1999; 3:187 (Resumen P118).
5. Musso AM. Las Policitemias en el Año 2001. Hematología. 2001; 5:1.
6. Musso AM. Adultos Mayores con Neoplasia Mieloproliferativa BCR-ABL Negativa (NMP) Tratados con
interferón. Hematología. 2013; 17(NE):213 (Resumen PA177).
7. Musso AM. Tratamiento de la Policitemia Vera (PV). ¿Se utilizan oportunamente los recursos terapéuticos disponibles?". Hematología. 2013; 17:147.
8. Musso AM. Anagrelide y Anemia. Hematología. 2013; 17:46.
9. Kiladjian J-J, Cassinat B, Chevret S et al. Pegylated interferón-alfa-2a induces complete hematologic and
molecular responses with low toxicity in polycythemia vera. Blood. 2008; 112:3065.
10. Quintas-Cardama A, Kantarjian H, Manshouri T et al. Pegylated interferón alfa-2a yields high rates of hematological and molecular responses in patients with advanced essential thrombocytemia and polycythemia vera. J Clin Oncol. 2009; 27:5418.
11. Silver RT, Vandris K, Goldman JJ. Recombinant interferón-alfa may retard progression of early primary myelofibrosis: a preliminary report. Blood. 2011; 117:6669.
12. Verstovsek S. Comunicación personal.
13. Emanuel RM, Duek AC, Geyer HL et al. “Myeloproliferative Neoplasm (MPN) Symptom Assessment Form
Total Symptom Score: Prospective International Assessment of an Abbreviated Symptom Burden Scoring
System Among Patients With MPNs. J Clin Oncol. 2012; 33:4098.
14. Yacoub A, Mascarenhas J, Kosiorek H et al. Pegylated interferón alfa-2a for polycythemia vera or essential thrombocythemia resistant or intolerant to hydroxyurea. Bood. 2019; 134:1498.
15. Gilreath JA, Tashi T, Kim SJ et al. Compassionate Use of Ropeginterferon-Alfa-2b/P1101 for Treatment of High Risk Polycythemia Vera and Essential Thrombocythemia Patients Previously Controlled on Pegylated Interferon-Alfa-2a/Pegasys. Blood. 2018; 132:5459.
16. Kiladjian J-J, Klade C, Georgiev P et al. Thromboembolic Risk Reduction and High Rate of Complete Molecular
Response with Long-Term Use of Ropeginterferon Alhpa-2b in Polycythemia Vera: Results from a Randomized Controlled Study. Blood. 2019; 134(Supp_1):553.
17. Gisslinger H, Klade C, Georgiev P et al. Evidence for Superior Efficacy and Disease Modification after Three Years of Prospective Randomized Controlled Treatment of Plycythemia Vera Patients with Ropeginterferon Alpha-2b vs. HU/BAT. Blood. 2018; 132(Supp_1):579.
18. Palmer J, Kosiorek HE, Zimmerman C et al. Clinical
Benefit of Ropeginterferon Alfa 2b (P1101) in Patients with Myelofibrosis. Bood. 2018; 132(Suppl 1):5475.
19. Abel GA and Klepin HD. Frailty and the management of hematologic malignancies. Blood. 2018; 131:515.
20. Internullo M, Giannelli V, Sardo L et al. Hydroxyurea-induced interstitial pneumonitis: case report and review of the literature. Eur Rev Med Pharmacol Sci. 2014; 18:190.
21. Crisci S, Amitrano F, Saggese M et al. “Overview of Targeted Anti-Cancer Drugs for Therapy in Onco-Hematology. Medicina. 2019; 55:414.
22. Verstovsek S, Mesa RA, Gotlib J et al. Long-Term Outcome of Ruxolitinib Treatment in Patients with Myelofibrosis. Durable Reductions in Spleen Volume, Improvements in Quality of Life, and Overall Survival Advantage in COMFORT-I. 54th Annual Meeting of the American Society of Hematology (ASH). Blood. 2012; Vol 120(21), Abstract 800.
23. Cervantes E, Kiladjian J-J, Niederwieser D et al. LongTerm Safety, Efficacy, and Survival Findings From
Comfort-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy (BAT) for the Treatment of Myelofibrosis (MF). 54th Annual Meeting of the American Society of Hematology (ASH). Blood. 2012; Vol
120(21), Abstract 801.
24. Verstovsek S, Passamonti F, Rambaldi A et al. Long-Term Efficacy and Safety Results From a Phase IIStudy of Ruxolitinib in Patients with Polycythemia Vera. 54th Annual
Meeting of the American Society of Hematology (ASH). Blood. 2012; Vol 120(21), Abstract 804.
25. Verstovsek S, Passamonti F, Rambaldi A et al. A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant to hydroxyurea. Cancer. 2014; 120:513.
26. Kiladjian J-J, Zachee P, Hino M et al. Long-term efficacy
and safety of ruxolitinib versus best available therapy in polycythemia vera (RESPONSE): 5-year follow up of a phase 3 study. Lancet Haematol. 2020; 7:e226.
27. Bose P and Verstovsek S. JAK2 inhibitors for myeloproliferative neoplasms: what is next?. Blood. 2017;
130:115.
28. Geyer HL and Mesa RA. Therapy for myeloproliferative neoplasms: when, which agent, and how?. Blood. 2014; 124,3529.
29. Asshoff M, Petzer V, Warr MR et al. Momelotinib inhibits ACVR1/ALK2, decreases hepcidin production, and
ameliorates anemia of chronic disease in rodents. Bood. 2017; 129:1823.
30. Mascarenhas JO. Comunicación personal.
31. Kremyanskaya M, Ginzburg Y, Kuykendall AT et al.
PTG-300 eliminates the need for therapeutic phlebotomy in both low and high-risk polycythemia vera patients. 62nd ASH Annual Meeting, Dec 6, 2020. Abstract 482.
32. De Oliveira RD, Soret-Dulphy J, Zhao L-P et al. “Interferon-Alpha (IFN) Therapy Discontinuation is Feasible
in Myelproliferative Neoplasm (MPN) Patients with
Complete Hematological Remission. Blood. 2020; 136 (Supplement 1):35.
33. Tefferi A, Lasho TL, Jimma T et al. One thousand patients with primary mielofibrosis: the Mayo Clinic experience. Mayo Clinic Proc. 2012; 87:25.
34. Zhou Li, Nguyen AN, Sohal D et al. Inhibition of the TGF-beta receptor I kinase promotes hematopoiesis in MDS. Blood. 2008; 112:3434.
35. Suragani RNVS, Cadena SM, Cawley SM et al. Transforming growth factor-β superfamily ligand trap ACE536 corrects anemia by promoting late-stage erythropoiesis. Nat Med. 2014; 20:408.
36. Gerds AT, Vannucchi A, Passamonti F et al. Duration of Response to Luspatercept in Patients (Pts) Requiring Red Blood Cell (RBC) Transfusions with Myelofibrosis (MF) – Updated Data from the Phase 2 ACE-536-
MF-001 Study. 62nd ASH Annual Meeting, Dec 6, 2020. Poster 2992.
37. Abu-Zeinah G, Krichevsky S, Cruz T et al. Interferon in Polycythemia Vera (PV) Yields Improved Myelofibrosis-Free and Overall Survival. Blood. 2020; 136 (Suppl 1):31.
38. Bose P, Pemmaraju N, Masarova L et al. Sotatercept (ACE-011) for Anemia of Myelofibrosis: A Phase 2 Study. Blood. 2020; 136 (Suppl 1):10.
39. Hasselbalch HC, Holmström MO. Perspectives on Interpheron-alpha in the treatment of polycythemia vera
and related myeloproliferative neoplasms: minimal residual disease and cure? Semin Immunopathol. 2019; 41:5.
40. Provenzano R, Besarab A, Sun CH et al. Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat (FG-4592) for the Treatment of Anemia in Patients with CKD. Clin J Am Soc Nephrol. 2016; 11:982.
41. Henry DH, Glaspy J, Harrup RA et al. Roxadustat (FG4592; ASP1517; AZD9941) in the Treatment of Anemia in Patients with Lower Risk Myelodysplastic Syndrome (LR-MDS) and Low Red Blood Cell (RBC) Transfusion Burden (LTB). Blood. 2019; 134 (Suppl 1):843.
42. Verstovsek S, Egyed M, Lech-Maranda E et al. Robust
overall survival and sustained efficacy outcomes during long term exposure to momelotinib in JAK inhibitor naive and previously JAK inhibitor treated intermediate/high risk mielofibrosis patients. 62nd ASH Annual Meeting, December 5-8, 2020. Abstract 54.
43. Mascarenhas J, Komrokji RS, Cavo M et al. Imetelstat is Effective Treatment for Patients with Intermediate-2 or High-Risk Myelofibrosis Who Have Relapsed on or Are Refractory to Janus Kinase Inhibitor Therapy: Results of a Phase 2 Randomized Study of Two Dose Levels. Blood. 2018; 132 (Suppl 1):685.
44. Gisslinger H, Klade C, Georgiev P et al. Ropeginterferon alfa-2b versus standard therapy for polycythemia vera (PROUD-PV and CONTINUATION-PV) a randomised, non-inferiority, phase 3 trial and its extensión study. Lancet Haematol. 2020; 7:e196.
45. Aguilar Vera R, Bendek G, Barzallo M y col. Neoplasias mieloproliferativas crónicas BCR-ABL negativas, manifestación clínica y evolución. Experiencia en el Hospital Italiano de Buenos Aires. Hematología. 2020; 24:20.
46. Kiladjian J-J, Soret-Dulphy J, Resche-Rigon M et al. Ruxopeg, a Multi-Center Bayesian Phase 1/2 Adaptative Randomized Trial of the Combination of Ruxolitinib and Pegylated Interferon Alpha-2a in Patients with Myeloproliferative Neoplasm (MPN)-Associated Myelofibrosis. Blood. 132 (Suppl 1):581.
2. Musso AM. Significación Clínica de las Mutaciones en Neoplasias Mieloproliferativas BCR-ABL1 Negativas (NMP). Hematología. 2015;19:54.
3. Silver RT. Recombinant alfa-interferon for treatment of polycythemia vera. Lancet. 1988; 2:403 (letter).
4. Musso AM, Santos MI, Alcón Alvarez M. Tratamiento de la Policitemia Proliferativa Primaria (PPP) con interferón. Hematología. 1999; 3:187 (Resumen P118).
5. Musso AM. Las Policitemias en el Año 2001. Hematología. 2001; 5:1.
6. Musso AM. Adultos Mayores con Neoplasia Mieloproliferativa BCR-ABL Negativa (NMP) Tratados con
interferón. Hematología. 2013; 17(NE):213 (Resumen PA177).
7. Musso AM. Tratamiento de la Policitemia Vera (PV). ¿Se utilizan oportunamente los recursos terapéuticos disponibles?". Hematología. 2013; 17:147.
8. Musso AM. Anagrelide y Anemia. Hematología. 2013; 17:46.
9. Kiladjian J-J, Cassinat B, Chevret S et al. Pegylated interferón-alfa-2a induces complete hematologic and
molecular responses with low toxicity in polycythemia vera. Blood. 2008; 112:3065.
10. Quintas-Cardama A, Kantarjian H, Manshouri T et al. Pegylated interferón alfa-2a yields high rates of hematological and molecular responses in patients with advanced essential thrombocytemia and polycythemia vera. J Clin Oncol. 2009; 27:5418.
11. Silver RT, Vandris K, Goldman JJ. Recombinant interferón-alfa may retard progression of early primary myelofibrosis: a preliminary report. Blood. 2011; 117:6669.
12. Verstovsek S. Comunicación personal.
13. Emanuel RM, Duek AC, Geyer HL et al. “Myeloproliferative Neoplasm (MPN) Symptom Assessment Form
Total Symptom Score: Prospective International Assessment of an Abbreviated Symptom Burden Scoring
System Among Patients With MPNs. J Clin Oncol. 2012; 33:4098.
14. Yacoub A, Mascarenhas J, Kosiorek H et al. Pegylated interferón alfa-2a for polycythemia vera or essential thrombocythemia resistant or intolerant to hydroxyurea. Bood. 2019; 134:1498.
15. Gilreath JA, Tashi T, Kim SJ et al. Compassionate Use of Ropeginterferon-Alfa-2b/P1101 for Treatment of High Risk Polycythemia Vera and Essential Thrombocythemia Patients Previously Controlled on Pegylated Interferon-Alfa-2a/Pegasys. Blood. 2018; 132:5459.
16. Kiladjian J-J, Klade C, Georgiev P et al. Thromboembolic Risk Reduction and High Rate of Complete Molecular
Response with Long-Term Use of Ropeginterferon Alhpa-2b in Polycythemia Vera: Results from a Randomized Controlled Study. Blood. 2019; 134(Supp_1):553.
17. Gisslinger H, Klade C, Georgiev P et al. Evidence for Superior Efficacy and Disease Modification after Three Years of Prospective Randomized Controlled Treatment of Plycythemia Vera Patients with Ropeginterferon Alpha-2b vs. HU/BAT. Blood. 2018; 132(Supp_1):579.
18. Palmer J, Kosiorek HE, Zimmerman C et al. Clinical
Benefit of Ropeginterferon Alfa 2b (P1101) in Patients with Myelofibrosis. Bood. 2018; 132(Suppl 1):5475.
19. Abel GA and Klepin HD. Frailty and the management of hematologic malignancies. Blood. 2018; 131:515.
20. Internullo M, Giannelli V, Sardo L et al. Hydroxyurea-induced interstitial pneumonitis: case report and review of the literature. Eur Rev Med Pharmacol Sci. 2014; 18:190.
21. Crisci S, Amitrano F, Saggese M et al. “Overview of Targeted Anti-Cancer Drugs for Therapy in Onco-Hematology. Medicina. 2019; 55:414.
22. Verstovsek S, Mesa RA, Gotlib J et al. Long-Term Outcome of Ruxolitinib Treatment in Patients with Myelofibrosis. Durable Reductions in Spleen Volume, Improvements in Quality of Life, and Overall Survival Advantage in COMFORT-I. 54th Annual Meeting of the American Society of Hematology (ASH). Blood. 2012; Vol 120(21), Abstract 800.
23. Cervantes E, Kiladjian J-J, Niederwieser D et al. LongTerm Safety, Efficacy, and Survival Findings From
Comfort-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy (BAT) for the Treatment of Myelofibrosis (MF). 54th Annual Meeting of the American Society of Hematology (ASH). Blood. 2012; Vol
120(21), Abstract 801.
24. Verstovsek S, Passamonti F, Rambaldi A et al. Long-Term Efficacy and Safety Results From a Phase IIStudy of Ruxolitinib in Patients with Polycythemia Vera. 54th Annual
Meeting of the American Society of Hematology (ASH). Blood. 2012; Vol 120(21), Abstract 804.
25. Verstovsek S, Passamonti F, Rambaldi A et al. A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant to hydroxyurea. Cancer. 2014; 120:513.
26. Kiladjian J-J, Zachee P, Hino M et al. Long-term efficacy
and safety of ruxolitinib versus best available therapy in polycythemia vera (RESPONSE): 5-year follow up of a phase 3 study. Lancet Haematol. 2020; 7:e226.
27. Bose P and Verstovsek S. JAK2 inhibitors for myeloproliferative neoplasms: what is next?. Blood. 2017;
130:115.
28. Geyer HL and Mesa RA. Therapy for myeloproliferative neoplasms: when, which agent, and how?. Blood. 2014; 124,3529.
29. Asshoff M, Petzer V, Warr MR et al. Momelotinib inhibits ACVR1/ALK2, decreases hepcidin production, and
ameliorates anemia of chronic disease in rodents. Bood. 2017; 129:1823.
30. Mascarenhas JO. Comunicación personal.
31. Kremyanskaya M, Ginzburg Y, Kuykendall AT et al.
PTG-300 eliminates the need for therapeutic phlebotomy in both low and high-risk polycythemia vera patients. 62nd ASH Annual Meeting, Dec 6, 2020. Abstract 482.
32. De Oliveira RD, Soret-Dulphy J, Zhao L-P et al. “Interferon-Alpha (IFN) Therapy Discontinuation is Feasible
in Myelproliferative Neoplasm (MPN) Patients with
Complete Hematological Remission. Blood. 2020; 136 (Supplement 1):35.
33. Tefferi A, Lasho TL, Jimma T et al. One thousand patients with primary mielofibrosis: the Mayo Clinic experience. Mayo Clinic Proc. 2012; 87:25.
34. Zhou Li, Nguyen AN, Sohal D et al. Inhibition of the TGF-beta receptor I kinase promotes hematopoiesis in MDS. Blood. 2008; 112:3434.
35. Suragani RNVS, Cadena SM, Cawley SM et al. Transforming growth factor-β superfamily ligand trap ACE536 corrects anemia by promoting late-stage erythropoiesis. Nat Med. 2014; 20:408.
36. Gerds AT, Vannucchi A, Passamonti F et al. Duration of Response to Luspatercept in Patients (Pts) Requiring Red Blood Cell (RBC) Transfusions with Myelofibrosis (MF) – Updated Data from the Phase 2 ACE-536-
MF-001 Study. 62nd ASH Annual Meeting, Dec 6, 2020. Poster 2992.
37. Abu-Zeinah G, Krichevsky S, Cruz T et al. Interferon in Polycythemia Vera (PV) Yields Improved Myelofibrosis-Free and Overall Survival. Blood. 2020; 136 (Suppl 1):31.
38. Bose P, Pemmaraju N, Masarova L et al. Sotatercept (ACE-011) for Anemia of Myelofibrosis: A Phase 2 Study. Blood. 2020; 136 (Suppl 1):10.
39. Hasselbalch HC, Holmström MO. Perspectives on Interpheron-alpha in the treatment of polycythemia vera
and related myeloproliferative neoplasms: minimal residual disease and cure? Semin Immunopathol. 2019; 41:5.
40. Provenzano R, Besarab A, Sun CH et al. Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat (FG-4592) for the Treatment of Anemia in Patients with CKD. Clin J Am Soc Nephrol. 2016; 11:982.
41. Henry DH, Glaspy J, Harrup RA et al. Roxadustat (FG4592; ASP1517; AZD9941) in the Treatment of Anemia in Patients with Lower Risk Myelodysplastic Syndrome (LR-MDS) and Low Red Blood Cell (RBC) Transfusion Burden (LTB). Blood. 2019; 134 (Suppl 1):843.
42. Verstovsek S, Egyed M, Lech-Maranda E et al. Robust
overall survival and sustained efficacy outcomes during long term exposure to momelotinib in JAK inhibitor naive and previously JAK inhibitor treated intermediate/high risk mielofibrosis patients. 62nd ASH Annual Meeting, December 5-8, 2020. Abstract 54.
43. Mascarenhas J, Komrokji RS, Cavo M et al. Imetelstat is Effective Treatment for Patients with Intermediate-2 or High-Risk Myelofibrosis Who Have Relapsed on or Are Refractory to Janus Kinase Inhibitor Therapy: Results of a Phase 2 Randomized Study of Two Dose Levels. Blood. 2018; 132 (Suppl 1):685.
44. Gisslinger H, Klade C, Georgiev P et al. Ropeginterferon alfa-2b versus standard therapy for polycythemia vera (PROUD-PV and CONTINUATION-PV) a randomised, non-inferiority, phase 3 trial and its extensión study. Lancet Haematol. 2020; 7:e196.
45. Aguilar Vera R, Bendek G, Barzallo M y col. Neoplasias mieloproliferativas crónicas BCR-ABL negativas, manifestación clínica y evolución. Experiencia en el Hospital Italiano de Buenos Aires. Hematología. 2020; 24:20.
46. Kiladjian J-J, Soret-Dulphy J, Resche-Rigon M et al. Ruxopeg, a Multi-Center Bayesian Phase 1/2 Adaptative Randomized Trial of the Combination of Ruxolitinib and Pegylated Interferon Alpha-2a in Patients with Myeloproliferative Neoplasm (MPN)-Associated Myelofibrosis. Blood. 132 (Suppl 1):581.
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