Ruxolitinib use in myelofibrosis patients: the single center experience and the relationship between JAK-2 allele burden and Ruxolitinib response
Yıl 2021,
, 322 - 329, 01.04.2021
Mesut Göçer
,
Erdal Kurtoğlu
Öz
Purpose: Ruxolitinib is an oral JAK-1/2 inhibitor approved for the treatment of splenomegaly and/or constitutional symptoms in intermediate and high-risk myelofibrosis patients. The aim of our study is to evaluate the efficacy and safety of ruxolitinib in primary MF, post-ET MF and post-PV MF patients, to evaluate the relationship between response and JAK-2 mutation rate and to compare them with literature data.
Materials and Methods: In our single centered and retrospective study, we investigated the data of 30 MF patients diagnosed in our clinic between May 2015 and December 2019. We reported demographic features, laboratory values, and spleen sizes.
Results: 18 patients (60%) with a median age of 67.5 (45-78) had primary myelofibrosis. Spleen sizes decreased significantly 3 and 6 months after treatment. Constitutional symptoms have disappeared in 28 patients (93.3%). No association was found between JAK-2 mutation rate and treatment response success.
Conclusion: Ruxolitinib MF is very safe and effective to relieve constitutional symptoms and decrease spleen size. Despite JAK-2 inhibition, no linear relationship was found between JAK-2 mutation rate and treatment efficacy.
Kaynakça
- References:
[1] A. M. Vannucchi and P. Guglielmelli, “Advances in understanding and management of polycythemia vera,” Curr. Opin. Oncol., vol. 22, no. 6, pp. 636–641, 2010.
- [2] Amriah Buang, “WHO Klassifikation 2016,” Blood, vol. 2, no. 20, pp. 58–71, 2006.
- [3] R. A. Mesa, A. Green, G. Barosi, S. Verstovsek, J. Vardiman, and R. P. Gale, “MPN-associated myelofibrosis (MPN-MF),” Leuk. Res., vol. 35, no. 1, pp. 12–13, 2011.
- [4] G. Barosi et al., “Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: A consensus statement from the international working group for myelofibrosis research and treatment [6],” Leukemia, vol. 22, no. 2, pp. 437–438, 2008.
- [5] R. A. Mesa et al., “The burden of fatigue and quality of life in myeloproliferative disorders (MPDs): An international internet-based survey of 1179 MPD patients,” Cancer, vol. 109, no. 1, pp. 68–76, 2007.
- [6] F. Cervantes et al., “New prognostic scoring system for primary myelofibrosis based on a study of the International working group for myelofibrosis research and treatment,” Blood, vol. 113, no. 13, pp. 2895–2901, 2009.
- [7] W. Vainchenker and S. N. Constantinescu, “JAK/STAT signaling in hematological malignancies,” Oncogene, vol. 32, no. 21, pp. 2601–2613, 2013.
- [8] R. Rampal et al., “Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis,” Blood, vol. 123, no. 22, 2014.
- [9] A. Tefferi et al., “U2AF1 mutations in primary myelofibrosis are strongly associated with anemia and thrombocytopenia despite clustering with JAK2V617F and normal karyotype,” Leukemia, vol. 28, no. 2, pp. 431–433, 2014.
- [10] A. Quintás-Cardama et al., “Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: Therapeutic implications for the treatment of myeloproliferative neoplasms,” Blood, vol. 115, no. 15, pp. 3109–3117, 2010.
- [11] A. M. Vannucchi et al., “Ruxolitinib reduces JAK2 p.V617F allele burden in patients with polycythemia vera enrolled in the RESPONSE study,” Ann. Hematol., vol. 96, no. 7, pp. 1113–1120, 2017.
- [12] S. Verstovsek et al., “Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial,” J. Hematol. Oncol., vol. 10, no. 1, pp. 1–14, 2017.
- [13] P. Guglielmelli et al., “Impact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORT-II study,” Blood, vol. 123, no. 14, pp. 2157–2160, 2014.
- [14] H. K. Al-Ali et al., “Safety and efficacy of ruxolitinib in an open-label, multicenter, single-arm phase 3b expanded-access study in patients with myelofibrosis: A snapshot of 1144 patients in the JUMP trial,” Haematologica, vol. 101, no. 9, pp. 1065–1073, 2016.
- [15] N. Kröger et al., “Rapid regression of bone marrow fibrosis after dose-reduced allogeneic stem cell transplantation in patients with primary myelofibrosis,” Exp. Hematol., vol. 35, no. 11, pp. 1719–1722, 2007.
- [16] V. Gupta, P. Hari, and R. Hoffman, “Allogeneic hematopoietic cell transplantation for myelofibrosis in the era of JAK inhibitors,” Blood, vol. 120, no. 7, pp. 1367–1379, 2012.
- [17] N. Gangat et al., “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., vol. 29, no. 4, pp. 392–397, 2011.
- [18] A. Tefferi et al., “Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report,” Blood, vol. 122, no. 8, pp. 1395–1398, 2013.
- [19] S. Verstovsek et al., “A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis,” N. Engl. J. Med., vol. 366, no. 9, pp. 799–807, 2012.
- [20] C. N. Harrison et al., “Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis,” Leukemia, vol. 30, no. 8, pp. 1701–1707, 2016.
- [21] S. Verstovsek, “Ruxolitinib: An oral Janus kinase 1 and Janus kinase 2 inhibitor in the management of myelofbrosis,” Postgrad. Med., vol. 125, no. 1, pp. 128–135, Jan. 2013.
- [22] H. M. Kvasnicka et al., “Long-term effects of ruxolitinib versus best available therapy on bone marrow fibrosis in patients with myelofibrosis,” J. Hematol. Oncol., vol. 11, no. 1, pp. 1–10, 2018.
- [23] R. A. Mesa and J. Cortes, “Optimizing management of ruxolitinib in patients with myelofibrosis: The need for individualized dosing,” J. Hematol. Oncol., vol. 6, no. 1, p. 1, 2013.
- [24] M. Breccia et al., “Efficacy and safety of ruxolitinib and hydroxyurea combination in patients with hyperproliferative myelofibrosis,” Ann. Hematol., vol. 98, no. 8, pp. 1933–1936, 2019.
- [25] M. Griesshammer et al., “Ruxolitinib for the treatment of inadequately controlled polycythemia vera without splenomegaly: 80-week follow-up from the RESPONSE-2 trial,” Ann. Hematol., vol. 97, no. 9, pp. 1591–1600, 2018.
- [26] A. M. Vannucchi et al., “A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis,” Haematologica, vol. 100, no. 9, pp. 1139–1145, 2015.
- [27] B. S. Wilkins, D. Radia, C. Woodley, S. El Farhi, C. Keohane, and C. N. Harrison, “Resolution of bone marrow fibrosis in a patient receiving JAK1/JAK2 inhibitor treatment with ruxolitinib,” Haematologica, vol. 98, no. 12, pp. 1872–1876, 2013.
Myelofibrozis hastalarında Ruxolitinib kullanımı: tek merkez deneyimi ve JAK-2 allel yükü ile Ruxolitinib yanıtı arasındaki ilişki
Yıl 2021,
, 322 - 329, 01.04.2021
Mesut Göçer
,
Erdal Kurtoğlu
Öz
Abstract:
Purpose: Ruxolitinib is an oral JAK-1/2 inhibitor approved for the treatment of splenomegaly and/or constitutional symptoms in intermediate and high-risk myelofibrosis patients. The aim of our study is to evaluate the efficacy and safety of ruxolitinib in primary MF, post-ET MF and post-PV MF patients, to evaluate the relationship between response and JAK-2 mutation rate and to compare them with literature data.
Materials and Methods: In our single centered and retrospective study, we investigated the data of 30 MF patients diagnosed in our clinic between May 2015 and December 2019. We reported demographic features, laboratory values, and spleen sizes.
Results: 18 patients (60%) with a median age of 67.5 (45-78) had primary myelofibrosis. Spleen sizes decreased significantly 3 and 6 months after treatment. Constitutional symptoms have disappeared in 28 patients (93.3%). No association was found between JAK-2 mutation rate and treatment response success.
Conclusion: Ruxolitinib MF is very safe and effective to relieve constitutional symptoms and decrease spleen size. Despite JAK-2 inhibition, no linear relationship was found between JAK-2 mutation rate and treatment efficacy.
Kaynakça
- References:
[1] A. M. Vannucchi and P. Guglielmelli, “Advances in understanding and management of polycythemia vera,” Curr. Opin. Oncol., vol. 22, no. 6, pp. 636–641, 2010.
- [2] Amriah Buang, “WHO Klassifikation 2016,” Blood, vol. 2, no. 20, pp. 58–71, 2006.
- [3] R. A. Mesa, A. Green, G. Barosi, S. Verstovsek, J. Vardiman, and R. P. Gale, “MPN-associated myelofibrosis (MPN-MF),” Leuk. Res., vol. 35, no. 1, pp. 12–13, 2011.
- [4] G. Barosi et al., “Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: A consensus statement from the international working group for myelofibrosis research and treatment [6],” Leukemia, vol. 22, no. 2, pp. 437–438, 2008.
- [5] R. A. Mesa et al., “The burden of fatigue and quality of life in myeloproliferative disorders (MPDs): An international internet-based survey of 1179 MPD patients,” Cancer, vol. 109, no. 1, pp. 68–76, 2007.
- [6] F. Cervantes et al., “New prognostic scoring system for primary myelofibrosis based on a study of the International working group for myelofibrosis research and treatment,” Blood, vol. 113, no. 13, pp. 2895–2901, 2009.
- [7] W. Vainchenker and S. N. Constantinescu, “JAK/STAT signaling in hematological malignancies,” Oncogene, vol. 32, no. 21, pp. 2601–2613, 2013.
- [8] R. Rampal et al., “Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis,” Blood, vol. 123, no. 22, 2014.
- [9] A. Tefferi et al., “U2AF1 mutations in primary myelofibrosis are strongly associated with anemia and thrombocytopenia despite clustering with JAK2V617F and normal karyotype,” Leukemia, vol. 28, no. 2, pp. 431–433, 2014.
- [10] A. Quintás-Cardama et al., “Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: Therapeutic implications for the treatment of myeloproliferative neoplasms,” Blood, vol. 115, no. 15, pp. 3109–3117, 2010.
- [11] A. M. Vannucchi et al., “Ruxolitinib reduces JAK2 p.V617F allele burden in patients with polycythemia vera enrolled in the RESPONSE study,” Ann. Hematol., vol. 96, no. 7, pp. 1113–1120, 2017.
- [12] S. Verstovsek et al., “Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial,” J. Hematol. Oncol., vol. 10, no. 1, pp. 1–14, 2017.
- [13] P. Guglielmelli et al., “Impact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORT-II study,” Blood, vol. 123, no. 14, pp. 2157–2160, 2014.
- [14] H. K. Al-Ali et al., “Safety and efficacy of ruxolitinib in an open-label, multicenter, single-arm phase 3b expanded-access study in patients with myelofibrosis: A snapshot of 1144 patients in the JUMP trial,” Haematologica, vol. 101, no. 9, pp. 1065–1073, 2016.
- [15] N. Kröger et al., “Rapid regression of bone marrow fibrosis after dose-reduced allogeneic stem cell transplantation in patients with primary myelofibrosis,” Exp. Hematol., vol. 35, no. 11, pp. 1719–1722, 2007.
- [16] V. Gupta, P. Hari, and R. Hoffman, “Allogeneic hematopoietic cell transplantation for myelofibrosis in the era of JAK inhibitors,” Blood, vol. 120, no. 7, pp. 1367–1379, 2012.
- [17] N. Gangat et al., “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., vol. 29, no. 4, pp. 392–397, 2011.
- [18] A. Tefferi et al., “Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report,” Blood, vol. 122, no. 8, pp. 1395–1398, 2013.
- [19] S. Verstovsek et al., “A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis,” N. Engl. J. Med., vol. 366, no. 9, pp. 799–807, 2012.
- [20] C. N. Harrison et al., “Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis,” Leukemia, vol. 30, no. 8, pp. 1701–1707, 2016.
- [21] S. Verstovsek, “Ruxolitinib: An oral Janus kinase 1 and Janus kinase 2 inhibitor in the management of myelofbrosis,” Postgrad. Med., vol. 125, no. 1, pp. 128–135, Jan. 2013.
- [22] H. M. Kvasnicka et al., “Long-term effects of ruxolitinib versus best available therapy on bone marrow fibrosis in patients with myelofibrosis,” J. Hematol. Oncol., vol. 11, no. 1, pp. 1–10, 2018.
- [23] R. A. Mesa and J. Cortes, “Optimizing management of ruxolitinib in patients with myelofibrosis: The need for individualized dosing,” J. Hematol. Oncol., vol. 6, no. 1, p. 1, 2013.
- [24] M. Breccia et al., “Efficacy and safety of ruxolitinib and hydroxyurea combination in patients with hyperproliferative myelofibrosis,” Ann. Hematol., vol. 98, no. 8, pp. 1933–1936, 2019.
- [25] M. Griesshammer et al., “Ruxolitinib for the treatment of inadequately controlled polycythemia vera without splenomegaly: 80-week follow-up from the RESPONSE-2 trial,” Ann. Hematol., vol. 97, no. 9, pp. 1591–1600, 2018.
- [26] A. M. Vannucchi et al., “A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis,” Haematologica, vol. 100, no. 9, pp. 1139–1145, 2015.
- [27] B. S. Wilkins, D. Radia, C. Woodley, S. El Farhi, C. Keohane, and C. N. Harrison, “Resolution of bone marrow fibrosis in a patient receiving JAK1/JAK2 inhibitor treatment with ruxolitinib,” Haematologica, vol. 98, no. 12, pp. 1872–1876, 2013.