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Blood Res 2022; 57(1):
Published online March 31, 2022
https://doi.org/10.5045/br.2021.2021209
© The Korean Society of Hematology
Myelofibrotic and leukemic transformation in 2016 WHO-defined Philadelphia-negative myeloproliferative neoplasm
Correspondence to : Deog-Yeon Jo, M.D., Ph.D.
Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University Hospital, 282 Munhwa-ro, Jung-gu, Daejeon 35015, Korea
E-mail: deogyeon@cnu.ac.kr
*This study was supported by Chungnam National University Hospital Research Fund (2021).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background
Information on myelofibrotic and leukemic transformations in Korean Philadelphia chromosome- negative myeloproliferative neoplasms (Ph‒ MPNs) is limited.
Methods
This study retrospectively analyzed transformations in patients diagnosed with essential thrombocythemia (ET), polycythemia vera (PV) prefibrotic/early primary myelofibrosis (pre-PMF), or overt primary myelofibrosis (PMF) based on the 2016 World Health Organization criteria between January 1996 and December 2020 at Chungam National University Hospital, Daejeon, Korea.
Results
A total of 351 patients (144 with ET, 131 with PV, 45 with pre-PMF, and 31 with PMF; 204 men and 147 women) with a median age of 64 years (range, 15‒91 years) were followed for a median of 4.6 years (range, 0.2‒24.8 years). The 10-year incidence of overt myelofibrosis was higher in pre-PMF than in ET (31.3% and 13.7%, respectively; P =0.031) and PV (12.2%; P =0.003). The 10-year incidence of leukemic transformation was significantly higher in PMF than in ET (40.0% and 7.9%, respectively; P =0.046), pre-PMF (4.7%; P =0.048), and PV (3.2%; P =0.031). The 5-year incidence of leukemic transformation was higher in patients with secondary myelofibrosis (SMF) than in those with PMF (19.0% and 11.4%, respectively; P =0.040). The 5-year overall survival of patients with SMF was significantly worse than that of patients with pre-PMF (74% and 93%, respectively; P=0.027) but did not differ from that of patients with PMF (57%; P=0.744).
Conclusion
The rates and clinical courses of myelofibrotic and leukemic transformations in Korean patients with Ph‒ MPN did not differ from those in Western populations.
Keywords Myeloproliferative neoplasm, Essential thrombocythemia, Polycythemia vera, Primary myelofibrosis, Secondary myelofibrosis, Leukemia
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Original Article
Blood Res 2022; 57(1): 59-68
Published online March 31, 2022 https://doi.org/10.5045/br.2021.2021209
Copyright © The Korean Society of Hematology.
Myelofibrotic and leukemic transformation in 2016 WHO-defined Philadelphia-negative myeloproliferative neoplasm
Ik-Chan Song1, Sang Hoon Yeon1, Myung-Won Lee1, Hyewon Ryu1, Hyo-Jin Lee1, Hwan-Jung Yun1, Seon Young Kim2, Deog-Yeon Jo1
1Division of Hematology/Oncology, Department of Internal Medicine, 2Department of Laboratory Medicine, Chungnam National University College of Medicine, Daejeon, Korea
Correspondence to:Deog-Yeon Jo, M.D., Ph.D.
Division of Hematology/Oncology, Department of Internal Medicine, Chungnam National University Hospital, 282 Munhwa-ro, Jung-gu, Daejeon 35015, Korea
E-mail: deogyeon@cnu.ac.kr
*This study was supported by Chungnam National University Hospital Research Fund (2021).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background
Information on myelofibrotic and leukemic transformations in Korean Philadelphia chromosome- negative myeloproliferative neoplasms (Ph‒ MPNs) is limited.
Methods
This study retrospectively analyzed transformations in patients diagnosed with essential thrombocythemia (ET), polycythemia vera (PV) prefibrotic/early primary myelofibrosis (pre-PMF), or overt primary myelofibrosis (PMF) based on the 2016 World Health Organization criteria between January 1996 and December 2020 at Chungam National University Hospital, Daejeon, Korea.
Results
A total of 351 patients (144 with ET, 131 with PV, 45 with pre-PMF, and 31 with PMF; 204 men and 147 women) with a median age of 64 years (range, 15‒91 years) were followed for a median of 4.6 years (range, 0.2‒24.8 years). The 10-year incidence of overt myelofibrosis was higher in pre-PMF than in ET (31.3% and 13.7%, respectively; P =0.031) and PV (12.2%; P =0.003). The 10-year incidence of leukemic transformation was significantly higher in PMF than in ET (40.0% and 7.9%, respectively; P =0.046), pre-PMF (4.7%; P =0.048), and PV (3.2%; P =0.031). The 5-year incidence of leukemic transformation was higher in patients with secondary myelofibrosis (SMF) than in those with PMF (19.0% and 11.4%, respectively; P =0.040). The 5-year overall survival of patients with SMF was significantly worse than that of patients with pre-PMF (74% and 93%, respectively; P=0.027) but did not differ from that of patients with PMF (57%; P=0.744).
Conclusion
The rates and clinical courses of myelofibrotic and leukemic transformations in Korean patients with Ph‒ MPN did not differ from those in Western populations.
Keywords: Myeloproliferative neoplasm, Essential thrombocythemia, Polycythemia vera, Primary myelofibrosis, Secondary myelofibrosis, Leukemia
Fig 1.
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Abbreviations: AML, acute myeloid leukemia; ET, essential thrombo-cythemia; PMF, overt primary myelofibrosis; pre-PMF, prefibrotic/early primary myelofibrosis; PV, polycythemia vera.
Fig 2.
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Abbreviations: ET, essential thrombocythemia; pre-PMF, prefibrotic/early primary myelofibrosis; PV, polycythemia vera.
Fig 3.
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Abbreviations: ET, essential thrombocythemia; PMF, overt primary myelofibrosis; pre-PMF, prefibrotic/early primary myelofibrosis; PV, polycythemia vera; SMF, secondary myelofibrosis.
Fig 4.
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Abbreviations: OS, overall survival; PMF, overt primary myelofibrosis; pre-PMF, prefibrotic/early primary myelofibrosis; SMF, secondary myelofibrosis.
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Table 1 . Patient characteristics (N=351)..
ET (N=144) PV (N=131) Pre-PMF (N=45) PMF (N=31) Age (yr), median (range) 62 (15–88) 64 (18–91) 63.5 (22–88) 68.5 (40–88) Female, N (%) 70 (48.6) 48 (36.6) 19 (42.2) 10 (32.3) Palpable splenomegaly, N (%) 0 (0.0) 11 (8.4) 4 (8.9) 16 (51.6) Laboratory findings WBC, ×109/L 11.0±4.5 14.7±6.2 14.5±10.2a) 13.7±11.0 Monocyte, ×109/L 0.6±0.4 0.7±0.4 0.8±0.4a) 1.0±0.8 Hemoglobin, g/dL 13.6±2.2 18.3±2.5 13.0±2.8 10.3±2.5 Platelet, ×109/L 946.5±244.9 510.9±288.4 1,093.9±461.1a) 424.8±327.5 LDH, ×UNL 1.1±0.4 1.3±0.5 1.6±0.7a) 2.0±1.5 Abnormal cytogenetics, N (%) 0 (0.0) 3 (2.3) 3 (6.7) 3 (9.7) Driver gene mutation, N (%)b) JAK2 V617F83/122 (68.0) 100/114 (87.7) 24/38 (63.2) 15/23 (65.3) CALR 14/122 (11.5) - 5/38 (13.2) 5/23 (21.7) MPL 0/12 (0.0) - 0/3 (0.0) 0/3 (0.0) JAK2 exon 12- 6/114 (5.3) - - IPSET, N (%) Low 46 (31.9) - - - Intermediate 42 (29.2) - - - High 56 (38.9) - - - IPSS, N (%) Low - - 24 (53.3) 5 (16.1) Intermediate-1 - - 17 (37.8) 8 (25.8) Intermediate-2 - - 3 (6.7) 12 (38.7) High - - 1 (2.2) 6 (19.4) Comorbidity, N (%) Hypertension 51 (35.4) 78 (59.5) 23 (51.1) 11 (35.5) Diabetes mellitus 19 (13.2) 33 (25.2) 9 (20.0) 7 (22.6) Chronic kidney disease 21 (14.6) 29 (22.1) 10 (22.2) 4 (12.9) Smoking 29 (20.1) 53 (40.5) 14 (31.1) 4 (12.9) Treatments, N (%) Cytoreductive treatment 109 (75.7) 108 (82.4) 34 (75.6) 17 (29.0) Hydroxyurea 93 (64.6) 107 (81.7) 28 (62.2) 8 (25.8) Anagrelide 13 (9.0) 0 (0.0) 4 (8.9) 1 (3.2) Both 3 (2.1) 1 (0.7) 2 (4.4) 0 (0.0) Ruxolitinib 0 (0.0) 0 (0.0) 0 (0.0) 8 (25.8) Aspirin 128 (88.9) 123 (93.9) 38 (84.4) 12 (38.7) Thrombosis, N (%)c) 37 (25.7) 39 (29.8) 13 (28.9) 1 (3.2) FU (yr), median (range) 6.5 (0.6–24.8) 6.2 (0.6–20.3) 4.0 (0.5–16.4) 3.2 (0.2–14.7) a)
P <0.05 compared to ET. b)A subpopulation of the patients enrolledunderwent gene mutation tests. c)Thrombosis before and at the time of diagnosis..Abbreviations: FU, follow-up; ET, essential thrombocythemia; IPSET, International Prognostic Score for Essential Thrombocythemia; IPSS, International Prognostic Scoring System; LDH, lactate dehydrogenase; pre-PMF, prefibrotic/early primary myelofibrosis; PV, polycythemia vera; UNL, upper normal limit..
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Table 2 . Clinical features of patients with essential thrombocythemia and polycythemia vera who developed myelofibrosis..
ET (N=10) PV (N=11) At ET diagnosis At SMF diagnosis P a)At PV diagnosis At SMF diagnosis P a)Age (yr), median (range) 62 (51–75) 70 (63–83) 61 (36–75) 73 (52–85) Palpable splenomegaly, N (%) 0 (0.0) 6 (60.0) <0.001 4 (36.4) 5 (45.5) 1.000 Laboratory findings WBC, ×109/L 7.0±6.0 8.6±6.1 0.101 15.1±7.7 20.9±21.7 0.384 Monocyte, ×109/L 0.8±0.4 0.4±0.5 0.118 1.1±0.6 1.6±2.3 0.598 Hemoglobin, g/dL 12.9±2.5 8.9±1.5 0.001 17.3±3.1 10.6±1.4 0.001 Platelet, ×109/L 667.0±845.7 527.8±486.8 0.033 626.7±426.3 399.3±401.2 0.154 Leukoerythroblastosis, N (%) 0 (0.0) 8 (80.0) <0.001 0 (0.0) 10 (90.9) <0.001 LDH, ×UNL 1.3±0.6 2.8±1.2 0.004 1.1±1.1 2.2±0.6 0.037 Abnormal karyotype, N (%) 0 (0.0) 3 (30.0) <0.001 2 (18.2) 6 (54.5) 0.076 a)Data presented as mean±SD were analyzed using Student’s
t -test for paired samples; data presented as percentages were analyzed using the chi-square test..Abbreviations: ET, essential thrombocythemia; LDH, lactate dehydrogenase; SMF, secondary myelofibrosis; UNL, upper normal limit..
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Table 3 . Clinical features of patients with prefibrotic/early myelofibrosis who progressed to overt myelofibrosis (N=10)..
At pre-PMF diagnosis At overt PMF diagnosis P a)Age (yr), median (range) 62 (16–72) 69.5 (34–79) Palpable splenomegaly, N (%) 2 (20.0) 7 (70.0) 0.025 Laboratory findings WBC, ×109/L 12.6±5.3 12.6±10.9 0.987 Monocyte, ×109/L 0.8±0.3 0.5±0.4 0.119 Hemoglobin, g/dL 13.2±2.4 9.2±2.5 0.004 Platelet, ×109/L 1,186.3±567.7 450.7±196.5 0.003 LDH, ×UNL 1.5±0.4 2.8±0.5 0.005 Leukoerythrolastosis, N (%) 2 (20.0) 9 (90.0) 0.002 Abnormal karyotype, N (%) 1 (10.0) 7 (70.0) 0.006 IPSS, N (%) 0.004 Low 7 (70.0) 1 (10.0) Intermediate-1 3 (30.0) 1 (10.0) Intermediate-2 0 (0.0) 3 (30.0) High 0 (0.0) 5 (50.0) a)Data presented as mean±SD were analyzed using Student’s
t -test for paired samples; data presented as percentages were analyzed using the chi-square test..Abbreviations: LDH, lactate dehydrogenase; IPSS, International Prognostic Scoring System; pre-PMF, prefibrotic/early primary myelofibrosis; UNL, upper normal limit..
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Table 4 . Clinical features of patients with secondary and overt primary myelofibrosis..
SMF (N=21) PMF (N=31) P Age (yr), median (range) 70.5 (52–85) 68 (32–86) 0.118 Male, N (%) 11 (52.4) 21 (67.7) 0.358 Palpable splenomegaly, N (%) 11 (52.4) 14 (45.2) 0.382 Laboratory findings WBC, ×109/L 14.9±14.6 13.7±10.1 0.741 Monocyte, ×109/L 0.8±1.3 1.0±0.8 0.488 Hemoglobin, g/dL 9.6±1.7 10.3±2.6 0.282 Platelet, ×109/L 458.1±408.0 424.8±327.5 0.749 LDH, ×UNL 2.6±1.0 2.1±1.6 0.252 Bone marrow fibrosis, N (%) MF-1 0 (0.0) 0 (0.0) 1.000 MF-2/3 21 (100.0) 31 (100.0) 1.000 Abnormal karyotype, N (%) 9 (42.9) 3 (9.7) 0.002 Diver gene mutation, N (%) JAK2 V617F12/17 (70.6) 15/23 (65.2) 0.615 CALR 3/17 (17.6) 5/23 (21.7) 0.604 JAK2 exon 121/17 (5.9) - - IPSS, N (%) Low 0 (0.0) 5 (16.1) 0.038 Intermediate-1 2 (9.5) 8 (25.8) Intermediate-2 9 (42.9) 12 (38.7) High 10 (47.6) 6 (19.4) Treatment, N (%) Hydroxyurea 12 (57.1) 9 (29.0) 0.028 Ruxolitinib 8 (38.1) 9 (29.0) 0.417 Leukemic transformation, N (%) 3 (14.3) 2 (6.5) 0.316 FU (yr), median (range) 1.5 (0.1–5.9) 2.5 (0.1–14.7) 0.145 Abbreviations: FU, follow-up; IPSS, International Prognostic Scoring System; LDH, lactate dehydrogenase; PMF, overt primary myelofibrosis; SMF, secondary myelofibrosis; UNL, upper normal limit..
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Table 5 . Fine and Gray regression analysis to determine risk factors for developing myelofibrosis in patients with essential thrombocythemia (N=144)..
Univariate analysis Multivariate analysis HR 95% CI P HR 95% CI P Factors at diagnosis Age >60 yr 1.89 0.59–6.05 0.286 - - - Male 1.82 0.49–6.74 0.367 - - - IPSET high 0.83 0.24–2.83 0.768 - - - WBC >11.0×109/L 0.82 0.27–2.49 0.721 - - - Monocyte >1.0×109/L 2.79 1.23–9.12 0.045 3.57 1.17–10.91 0.026 Platelet >1,000×109/L 0.92 0.30–2.85 0.890 - - - LDH >1.5×UNL 0.58 0.15–2.27 0.432 - - - Positive JAK2 V617F0.72 0.21–2.50 0.602 - - - Positive CALR mutation3.26 1.01–10.47 0.048 4.42 1.20–16.37 0.026 Thrombosis before or at diagnosis 1.86 0.52–6.66 0.342 - - - Hydroxyurea treatment 1.27 0.27–5.94 0.766 - - - Abbreviations: CI, confidence interval; HR, hazard ratio; IPSET, International prognostic scoring for essential thrombocythemia; LDH, lactate dehydrogenase; UNL, upper normal limit..
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Table 6 . Fine and Gray regression analysis to determine risk factors for developing myelofibrosis in patients with polycythemia vera (N=131)..
Univariate analysis Multivariate analysis HR 95% CI P HR 95% CI P Factors at diagnosis Age >60 yr 0.84 0.27–2.63 0.765 - - - Female 2.92 0.99–8.57 0.051 - - - Palpable splenomegaly 3.19 0.97–10.44 0.056 - - - WBC >11.0×109/L 1.44 0.38–5.44 0.588 - - Monocyte >1.0×109/L 3.17 0.89–11.35 0.076 - - - Platelet >1,000×109/L 2.01 0.30–13.68 0.473 - - - LDH >1.5×UNL 4.01 1.04–15.59 0.044 2.39 0.31–18.60 0.405 Positive JAK2 V617F2.72 0.30–24.40 0.386 - - - Positive JAK2 exon 12 mutation2.67 0.35–20.16 0.341 - - - Abnormal karyotype 21.44 5.71–80.91 <0.001 18.20 2.0–165.95 0.010 Thrombosis before or at diagnosis 0.31 0.04–2.63 0.284 - - - Hydroxyurea treatment 2.20 0.27–17.74 0.458 - - - Abbreviations: CI, confidence interval; HR, hazard ratio; LDH, lactate dehydrogenase; UNL, upper normal limit..
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Table 7 . Fine and Gray regression analysis to determine risk factors for leukemic transformation in patients with myeloproliferative neoplasm (N=351)..
Univariate analysis Multivariate analysis HR 95% CI P HR 95% CI P Factors at diagnosis Age >60 yr 2.90 0.75–11.30 0.125 - - - Female 1.98 0.62–6.34 0.247 - - - Palpable splenomegaly 2.79 0.80–9.87 0.140 - - - WBC >11.0×109/L 1.86 0.57–6.06 0.304 - - - Monocyte >1.0×109/L 4.05 1.23–13.39 0.022 3.22 0.69–14.68 0.135 Platelet >1,000×109/L 2.44 0.77–7.73 0.128 - - - LDH >1.5×UNL 2.74 0.81–9.26 0.105 - - - Positive JAK2 V617F3.40 0.41–28.40 0.258 - - - Positive CALR mutation0.99 0.26–2.11 0.579 - - - PMF 3.51 0.80–15.44 0.096 - - - Abnormal karyotype 5.60 1.10–28.59 0.038 3.62 0.41–31.14 0.241 Thrombosis before or at diagnosis 1.26 0.34–4.66 0.730 - - - Hydroxyurea treatment 1.98 0.43–9.11 0.381 - - - Abbreviations: CI, confidence interval; HR, hazard ratio; LDH, lactate dehydrogenase; PMF, overt primary myelofibrosis; UNL, upper normal limit..
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