Department of Medical Oncology, Adult Leukemia Program, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
Leukemia and Myeloid Disorders Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.
Clin Lymphoma Myeloma Leuk. 2024 Jul;24(7):459-467. doi: 10.1016/j.clml.2024.03.001. Epub 2024 Mar 11.
Myelofibrosis is the most aggressive subtype among classical BCR::ABL1 negative myeloproliferative neoplasms. About 90% of cases are driven by constitutive activation of 1 of 3 genes impacting the JAK/STAT pathway: JAK2, CALR, and MPL. Triple-negative myelofibrosis (TN-MF) accounts for only 5%-10% of cases and carries the worst outcomes. Little has been described about this subset of disease. Given the marked heterogeneity surrounding disease biology, clonal architecture, clinical presentation, and poor outcomes in TN-MF, identification of features of interest and assessment of treatment response are areas in need of further investigation.
We collected and evaluated baseline clinical and molecular parameters from 626 patients with a diagnosis of myelofibrosis who presented to the H. Lee Moffitt Cancer Center in Tampa (Florida, US) between 2003 and 2021 and compared them based on presence or absence of the three classical phenotypic driver mutations.
A small proportion of patients (6%) harbored TN-MF which correlated with inferior outcomes, marked by a 4-year reduction in overall survival time compared to the non-TN cohort (mOS 37.4 months vs. 85.7 months; P = .009) and higher rates of leukemic transformation. More pronounced thrombocytopenia and anemia, lower LDH, EPO levels, as well as lower percentage of marrow blasts at baseline were more commonly seen in TN-MF (P < .05). Similarly, patients with TN-MF had higher risk disease per DIPSS+ and GIPSS. Mutations impacting RNA splicing, epigenetic modification and signaling, specifically SRSF2, SETBP1, IDH2, CBL, and GNAS, were more commonly seen among those lacking a classical phenotypic driver. The prevalence of co-mutant ASXL1/SRSF2 clones was significantly higher in TN-MF as was trisomy 8. TN patients had fewer responses (46.2% vs. 63.4%) and shorter duration of response to ruxolitinib.
TN-MF is invariably associated with significantly decreased survival and more aggressive clinical behavior with higher rates of leukemic transformation and shorter duration of response to ruxolitinib. Mutations impacting RNA splicing, epigenetic modification and signaling (SRSF2, SETBP1, IDH2, CBL, and GNAS) are more common in TN-MF, which likely drive its aggressive course and may account for suboptimal responses to JAK inhibition.
骨髓纤维化是经典 BCR::ABL1 阴性骨髓增殖性肿瘤中最具侵袭性的亚型。约 90%的病例是由影响 JAK/STAT 通路的 3 个基因中的 1 个组成性激活驱动的：JAK2、CALR 和 MPL。三阴性骨髓纤维化（TN-MF）仅占病例的 5%-10%，但其预后最差。关于这种疾病亚群的描述很少。鉴于 TN-MF 疾病生物学、克隆结构、临床表现和不良预后存在明显异质性，因此需要进一步研究确定有意义的特征和评估治疗反应。
我们收集并评估了 626 例骨髓纤维化患者的基线临床和分子参数，这些患者于 2003 年至 2021 年间在佛罗里达州坦帕市的 H. Lee Moffitt 癌症中心就诊，并根据是否存在三种经典表型驱动突变进行了比较。
一小部分患者（6%）存在 TN-MF，这与较差的预后相关，与非 TN 组相比，总生存时间缩短了 4 年（mOS 37.4 个月 vs. 85.7 个月；P =.009），白血病转化率更高。更明显的血小板减少和贫血、较低的 LDH、EPO 水平以及基线时骨髓原始细胞百分比较低在 TN-MF 中更为常见（P <.05）。同样，TN-MF 患者的 DIPSS+和 GIPSS 风险更高。影响 RNA 剪接、表观遗传修饰和信号转导的突变，特别是 SRSF2、SETBP1、IDH2、CBL 和 GNAS，在缺乏经典表型驱动突变的患者中更为常见。缺乏经典表型驱动突变的患者中，SRSF2、SETBP1、IDH2、CBL 和 GNAS 等影响 RNA 剪接、表观遗传修饰和信号转导的突变更为常见。ASXL1/SRSF2 克隆共突变的发生率在 TN-MF 中明显更高，8 三体也更高。TN 患者的反应率更低（46.2% vs. 63.4%），对鲁索利替尼的反应持续时间更短。
TN-MF 总是与生存明显下降、临床行为更具侵袭性相关，白血病转化率更高，对鲁索利替尼的反应持续时间更短。影响 RNA 剪接、表观遗传修饰和信号转导的突变（SRSF2、SETBP1、IDH2、CBL 和 GNAS）在 TN-MF 中更为常见，这可能导致其侵袭性病程，并可能导致对 JAK 抑制的反应不佳。
