The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before
sharing sensitive information, make sure you’re on a federal
government site.
The
https://
ensures that you are connecting to the
official website and that any information you provide is encrypted
and transmitted securely.
As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with,
the contents by NLM or the National Institutes of Health.
Learn more:
PMC Disclaimer
中国医学科学院血液病医院（中国医学科学院血液学研究所），实验血液学国家重点实验室，国家血液系统疾病临床医学研究中心，天津医学健康研究院，细胞生态海河实验室，天津 300020,
State Key Laboratory of Experimental Hematology, National Clinical Research Centre for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin Institutes of Health Science, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300020, China
95%
CI
P
值
95%
CI
P
值男性1.400.77~2.540.256年龄>65岁1.330.66~2.680.417HGB<90 g/L2.381.14~4.960.0151.550.64~3.780.331WBC≥25×10
9
/L1.070.54~2.080.850PLT≤350×10
9
/L3.211.24~8.350.0101.980.74~5.300.172白蛋白<35 g/L1.390.74~2.600.292诊断为原发性骨髓纤维化1.790.86~3.740.106脾脏肿大2.771.16~6.600.0151.650.57~4.790.355输血依赖1.250.67~2.320.473复杂染色体核型4.401.97~9.80<0.0012.531.06~6.050.036外周血原始细胞比例≥10％1.230.61~2.510.544骨髓原始细胞比例≥10％2.650.92~7.620.055有体质性症状1.050.58~1.910.858骨髓网状纤维≥2级4.091.24~13.490.0112.480.55~11.160.237动态国际预后积分系统 中危-2组0.840.33~2.120.705 高危组1.210.40~3.630.737 中危-1组（对照）JAK2V617F突变0.920.49~1.720.7881型CALR突变0.650.29~1.490.300驱动基因突变阴性1.320.55~3.170.519TP53突变2.180.94~5.040.057ASXL1突变0.880.47~1.670.697SRSF2突变1.180.58~2.380.646SETBP1突变0.970.46~2.040.928RUNX1突变0.840.39~1.840.659TET2突变1.560.76~3.220.214EZH2突变0.510.16~1.680.254
58例患者有进展为AP/BP后治疗情况随访结果。其中12例患者接受支持治疗
[6]
，包括输血、口服降细胞和缩脾药物（美法仑、羟基脲和芦可替尼）；42例患者接受包括IA（去甲氧柔红霉素+阿糖胞苷）/DA（柔红霉素+阿糖胞苷）方案化疗和去甲基化药物（HMA）等白血病样化疗
[6]
；4例患者接受allo-HSCT。支持治疗组的中位OS期为3.0（95％
CI
2.3～3.7）个月，白血病样化疗组的中位OS期为13.0（95％
CI
8.3～17.7）个月，差异有统计学意义（
P
＝0.011）。allo-HSCT组的中位OS期为21.3（95％
CI
10.2～32.3）个月，优于支持治疗组（
P
＝0.05），与白血病样化疗组比较差异无统计学意义（
P
＝0.357）。为进一步分析MPN-AP/BP患者中影响预后的临床特征（复杂染色体核型）与不同治疗方案对预后的相互作用，采用Cox回归风险模型进一步分析，结果显示复杂染色体核型仍是影响MPN-AP/BP患者OS的独立不良预后因素（
HR
＝4.58，95％
CI
1.96～10.70，
P
<0.001）；allo-HSCT和白血病样化疗（
HR
＝0.25，95％
CI
0.11～0.57，
P
＝0.001）仍是影响MPN-AP/BP患者OS的独立良好预后因素。
讨论
Ph染色体阴性MPN是一组起源于造血干细胞的恶性克隆性疾病，其特征为一系或多系成熟细胞过度增殖伴有向急性髓系白血病转化风险增高，是严重影响患者长期生存的主要危险因素之一
[1]
。既往国外多个回顾性研究表明，MPN-AP患者中位OS期短于2年，MPN-BP患者中位OS期短于6个月
[15]
。既往关于MPN-AP/BP患者的研究
[2]
–
[5]
,
[16]
–
[18]
多为国外的小样本临床报道，为阐释我国MPN-AP/BP患者的临床特征及预后，我们总结分析了在我中心诊治的67例MPN-AP/BP患者的临床和分子生物学特征及其预后影响因素，以期进一步指导临床实践。
既往国外研究表明，由不同亚型MPN进展的MPN-AP/BP患者在临床特征上有差异
[6]
。本研究结果显示PMF-AP/BP较其他MPN-AP/BP患者LDH水平更高，脾肿大、MF≥2级患者占比更高；表明MPN患者进展到AP/BP期后，临床特征仍与其慢性期的疾病类型密切相关。ASXL1突变是PMF患者最常见非驱动基因突变，其检出率为21.7％～38.9％
[19]
–
[20]
，高于PV（12％）和ET（11％）患者
[21]
。本研究中PMF-AP/BP患者ASXL1突变检出率亦显著高于其他MPN-AP/BP患者，与Venton等
[18]
研究结果一致，可能与ASXL1突变在慢性期PMF患者中检出率较高有关。我们既往研究
[13]
表明，与PMF相比，PV/ET后骨髓纤维化患者中极少出现剪接体复合物相关基因突变（如U2AF1、SRSF2等）。本研究中PMF-AP/BP组SRSF2基因突变中位VAF值高于其他MPN-AP/BP组，提示作为亚克隆的SRSF2突变可能在其他MPN-AP/BP患者中获得时间晚于PMF-AP/BP患者，但目前尚不明确是慢性期存在的SRSF2突变还是AP/BP期新增的SRSF2突变最终促进了疾病进展。SRSF2突变获得时机对不同亚型MPN患者进展为AP/BP的影响仍需在大样本量序贯患者中进一步研究。
国外有研究表明，接受芦可替尼治疗的PMF患者中，JAK2V617F突变VAF增高或出现高分子风险突变（HMR）是导致芦可替尼缩脾疗效丧失比例增高的因素之一；出现克隆进展的患者中位生存时间明显缩短
[22]
。同样有研究表明，非驱动基因克隆演变是促使慢性期MPN向急变期转化的重要因素，其中ASXL1、EZH2、TP53等是常见的新增非驱动基因突变
[16]
–
[18]
。在本研究中，仅15例患者可序贯比较慢性期和AP/BP期驱动基因VAF和非驱动基因突变结果，结果显示疾病转化过程中伴有JAK2V617F突变VAF增高和新增非驱动基因突变。上述研究结果亦表明在MPN慢性期进行驱动基因检测和非驱动基因突变检测的重要性。我们既往的研究
[20]
表明，包含HMR突变的MIPSS70-plus预后积分系统对PMF患者预后评估的价值优于DIPSS。因此建议慢性期MPN患者应定期行二代测序基因突变检测，既可作出更准确的预后评估，又可及时预判疾病进展的风险。
国外的回顾性研究结果显示，MPN-AP/BP患者独立的不良预后因素包括PLT<100×10
9
/L、输血依赖、年龄>65岁、低白蛋白水平、基因突变数目≥4个、复杂染色体核型和TP53、RUNX1、PTPN11、SRSF2、TET2基因突变等
[5]
–
[6]
,
[16]
–
[18]
。本研究中我们仅证实复杂染色体核型为MPN-AP/BP患者独立不良预后因素，可能与本研究样本量较小有关。期望通过开展多中心大样本量研究建立适用于我个MPN-AP/BP患者的预后积分系统。
国外的回顾性研究表明，不同治疗方案亦是影响MPN-AP/BP患者的生存因素之一，其中接受支持治疗的患者中位生存期仅为1.1～3个月
[3]
–
[6]
，接受白血病样化疗的患者中位OS期为9～11.8个月
[4]
–
[5]
,
[23]
–
[24]
；接受allo-HSCT和白血病样化疗的患者OS期无明显差异
[5]
–
[6]
,
[17]
，表明allo-HSCT较白血病样化疗并不能显著改善MPN-AP/BP患者长期生存。这可能与接受allo-HSCT的MPN-AP/BP患者移植前诱导化疗难以达到完全缓解以及移植后高复发率相关
[15]
。我们的研究亦表明不同的治疗方案是影响MPN-AP/BP患者的独立预后因素，接受allo-HSCT或白血病样化疗的患者OS期差异无统计学意义，但均优于接受支持治疗患者。因此，不推荐MPN患者进入AP/BP后再行allo-HSCT治疗，而应在有进展为AP/BP高危因素时尽早行allo-HSCT治疗；对于MPN-AP/BP患者应尽可能接受白血病样化疗。
本研究结果初步揭示了我国Ph染色体阴性MPN-AP/BP患者的临床特征及预后因素，PMF-AP/BP患者与其他MPN-AP/BP患者比较，具有较高的脾大和MF≥2级发生率，LDH水平较高，进展为AP/BP较快；复杂染色体核型是MPN-AP/BP患者独立不良预后因素，而白血病样化疗和allo-HSCT较支持治疗可延长MPN-AP/BP患者OS期。本研究为单中心回顾性研究，纳入病例数量较少，上述结论尚需多中心、大样本量的研究进一步验证。
Funding Statement
基金项目：国家自然科学基金（82170139、82070134、81530008）；中国医学科学院医学与健康科技创新工程项目（2022-I2M-1-022）；细胞生态海河实验室创新基金（22HHXBSS00033）；国家血液系统疾病临床医学研究中心第一批临床研究基金（2023NCRCA0117、2023NCRCA0103）
Fund Program: National Natural Science Foundation of China（82170139, 82070134, and 81530008）; Innovation project of medical and health science and technology of Chinese Academy of Medical Sciences（2022-I2M-1-022;）Haihe Laboratory of Cell Ecosystem Innovation Fund（22HHXBSS00033）; Clinical research fund from National Clinical Research Center for Blood Diseases（2023NCRCA0117, 2023NCRCA0103）
Footnotes
利益冲突
所有作者声明不存在利益冲突
作者贡献声明
严欣：病例资料收集，数据分析，文章撰写；肖志坚：研究设计及实施；徐泽峰：研究设计及实施，数据分析，文章审核；其他作者：参与或协助研究
References
1.
Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia[J]
Blood.
2016;
127
(20):2391–2405. doi: 10.1182/blood-2016-03-643544.
[
PubMed
] [
CrossRef
]
[
Google Scholar
]
2.
Mesa RA, Li CY, Ketterling RP, et al. Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases[J]
Blood.
2005;
105
(3):973–977. doi: 10.1182/blood-2004-07-2864.
[
PubMed
] [
CrossRef
]
[
Google Scholar
]
3.
Kennedy JA, Atenafu EG, Messner HA, et al. Treatment outcomes following leukemic transformation in Philadelphia-negative myeloproliferative neoplasms[J]
Blood.
2013;
121
(14):2725–2733. doi: 10.1182/blood-2012-10-464248.
[
PubMed
] [
CrossRef
]
[
Google Scholar
]
4.
Mollard LM, Chauveau A, Boyer-Perrard F, et al. Outcome of Ph negative myeloproliferative neoplasms transforming to accelerated or leukemic phase[J]
Leu Lymph.
2018;
59
(12):2812–2820. doi: 10.1080/10428194.2018.1441408.
[
PubMed
] [
CrossRef
]
[
Google Scholar
]
5.
Lancman G, Brunner A, Hoffman R, et al. Outcomes and predictors of survival in blast phase myeloproliferative neoplasms[J]
Leu Res.
2018;
70
:49–55. doi: 10.1016/j.leukres.2018.05.004.
[
PubMed
] [
CrossRef
]
[
Google Scholar
]
6.
Tefferi A, Mudireddy M, Mannelli F, et al. Blast phase myeloproliferative neoplasm: Mayo-AGIMM study of 410 patients from two separate cohorts[J]
Leukemia.
2018;
32
(5):1200–1210. doi: 10.1038/s41375-018-0019-y.
[
PMC free article
]
[
PubMed
] [
CrossRef
]
[
Google Scholar
]
7.
Cahu X, Chevallier P, Clavert A, et al. Allo-SCT for Philadelphia-negative myeloproliferative neoplasms in blast phase: a study from the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC)[J]
Bone Marrow Transplant.
2014;
49
(6):756–760. doi: 10.1038/bmt.2014.31.
[
PubMed
] [
CrossRef
]
[
Google Scholar
]
8.
Badar T, Kantarjian HM, Ravandi F, et al. Therapeutic benefit of decitabine, a hypomethylating agent, in patients with high-risk primary myelofibrosis and myeloproliferative neoplasm in accelerated or blastic/acute myeloid leukemia phase[J]
Leu Res.
2015;
39
(9):950–956. doi: 10.1016/j.leukres.2015.06.001.
[
PMC free article
]
[
PubMed
] [
CrossRef
]
[
Google Scholar
]
9.
Bose P, Verstovsek s, Cortes JE, et al. A phase 1/2 study of ruxolitinib and decitabine in patients with post-myeloproliferative neoplasm acute myeloid leukemia[J]
Leukemia.
2020;
34
(9):2489–2492. doi: 10.1038/s41375-020-0778-0.
[
PubMed
] [
CrossRef
]
[
Google Scholar
]
10.
Masarova L, Verstovsek S, Hidalgo-Lopez JE, et al. A phase 2 study of ruxolitinib in combination with azacitidine in patients with myelofibrosis[J]
Blood.
2018;
132
(16):1664–1674. doi: 10.1182/blood-2018-04-846626.
[
PMC free article
]
[
PubMed
] [
CrossRef
]
[
Google Scholar
]
11.
Gangat N, Morsia E, Foran JM, et al. Venetoclax plus hypomethylating agent in blast-phase myeloproliferative neoplasm: preliminary experience with 12 patients[J]
Br J Haematol.
2020;
191
(5):e120–e124. doi: 10.1111/bjh.17084.
[
PubMed
] [
CrossRef
]
[
Google Scholar
]
12.
Tremblay D, Feld J, Dougherty M, et al. Venetoclax and hypomethylating agent combination therapy in acute myeloid leukemia secondary to a myeloproliferative neoplasm[J]
Leu Res.
2020;
98
:106456. doi: 10.1016/j.leukres.2020.106456.
[
PubMed
] [
CrossRef
]
[
Google Scholar
]
13.
Li B, Gale RP, Xu Z, et al. Non-driver mutations in myeloproliferative neoplasm-associated myelofibrosis[J]
J Hematol Oncol.
2017;
10
(1):99. doi: 10.1186/s13045-017-0472-5.
[
PMC free article
]
[
PubMed
] [
CrossRef
]
[
Google Scholar
]
14.
Passamonti F, Cervantes E, Vannucchi AM, et al. 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)[J]
Blood.
2010;
115
(5):1703–1708. doi: 10.1182/blood-2009-09-245837.
[
PubMed
] [
CrossRef
]
[
Google Scholar
]
15.
Tania Jain, Rampal R.K. Accelerated and Blast Phase Myeloproliferative Neoplasms[J]
Hematol Oncol Clin North Am.
2021;
35
(2):325–335. doi: 10.1016/j.hoc.2020.12.008.
[
PubMed
] [
CrossRef
]
[
Google Scholar
]
16.
McNamara CJ, Panzarella T, Kennedy JA, et al. The mutational landscape of accelerated- and blast-phase myeloproliferative neoplasms impacts patient outcomes[J]
Blood Adv.
2018;
2
(20):2658–2671. doi: 10.1182/bloodadvances.2018021469.
[
PMC free article
]
[
PubMed
] [
CrossRef
]
[
Google Scholar
]
17.
Lasho TL, Mudireddy M, Finke CM, et al. Targeted next-generation sequencing in blast phase myeloproliferative neoplasms[J]
Blood Adv.
2018;
2
(4):370–380. doi: 10.1182/bloodadvances.2018015875.
[
PMC free article
]
[
PubMed
] [
CrossRef
]
[
Google Scholar
]
18.
Venton C, Courtier F, Charbonnier A, et al. Impact of gene mutations on treatment response and prognosis of acute myeloid leukemia secondary to myeloproliferative neoplasms[J]
Am J Hematol.
2018;
93
(3):330–338. doi: 10.1002/ajh.24973.
[
PubMed
] [
CrossRef
]
[
Google Scholar
]
19.
Vannucchi AM, Lasho TL, Guglielmelli P, et al. Mutations and prognosis in primary myelofifibrosis[J]
Leukemia.
2013;
27
(9):1861–1869. doi: 10.1038/leu.2013.119.
[
PubMed
] [
CrossRef
]
[
Google Scholar
]
20.
严 欣, 李 冰, 秦 铁军, et al. MIPSS70-plus预后积分系统评估中国原发性骨髓纤维化患者预后的评价[J]
中华血液学杂志
2021;
42
(1):15–20. doi: 10.3760/cma.j.issn.0253-2727.2021.01.004.
[
CrossRef
]
[
Google Scholar
]
21.
Tefferi A, Lasho TL, Guglielmelli P, et al. Targeted deep sequencing in polycythemia vera and essential thrombocythemia[J]
Blood adv.
2016;
1
(1):21–30. doi: 10.1182/bloodadvances.2016000216.
[
PMC free article
]
[
PubMed
] [
CrossRef
]
[
Google Scholar
]
22.
Pacilli A, Rotunno G, Mannarelli C, et al. Mutation landscape in patients with myelofibrosis receiving ruxolitinib or hydroxyurea[J]
Blood Cancer J.
2018;
8
(12):122. doi: 10.1038/s41408-018-0152-x.
[
PMC free article
]
[
PubMed
] [
CrossRef
]
[
Google Scholar
]
23.
Thepot S, Itzykson R, Seegers V, et al. Treatment of progression of Philadelphia-negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid leukemia by azacitidine: a report on 54 cases on the behalf of the Groupe Francophone des Myelodysplasies (GFM)[J]
Blood.
2010;
116
(19):3735–3742. doi: 10.1182/blood-2010-03-274811.
[
PubMed
] [
CrossRef
]
[
Google Scholar
]
24.
Badar T, Kantarjian HM, Ravandi F, et al. Therapeutic benefit of decitabine, a hypomethylating agent, in patients with high-risk primary myelofibrosis and myeloproliferative neoplasm in accelerated or blastic/acute myeloid leukemia phase[J]
Leuk Res.
2015;
39
(9):950–956. doi: 10.1016/j.leukres.2015.06.001.
[
PMC free article
]
[
PubMed
] [
CrossRef
]
[
Google Scholar
]
Articles from
Chinese Journal of Hematology
are provided here courtesy of
Editorial Office of Chinese Journal of Hematology
