JAK2 components play an important role in hematopoiesis, cell proliferation, and differentiation. Abnormal activation of JAK pathway by gene mutations or rearrangements is common in Philadelphia-negative myeloproliferative neoplasm (MPN). About 75% of typical Philadelphia-negative MPN, including essential thrombocytosis (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), carry a specific V617F somatic mutation in JAK2 gene (1, 2). In contrast, chromosomal translocations involving JAK2 gene are rare and have been reported in various hematological malignancies. Among them, the PCM1-JAK2 fusion gene derived from t(8;9)(p22;p24) is the most frequent (3–7). MPN with PCM1-JAK2 rearrangement is accompanied by varying degrees of eosinophilia, lymphadenopathy/hepatosplenomegaly, and myelofibrosis (8). Based on share characteristics, myeloid/lymphoid neoplasms (MLNs) with PCM1-JAK2 rearrangement has been added as a provisional entity in the 2016 World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia (9).

MLN with PCM1-JAK2 rearrangement is a rare disease with poor prognosis and lacks unified treatment guidelines. Up to now, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only way that can cure the disease. Ruxolitinib, a JAK2 inhibitor, has been approved by the United States Food and Drug Administration for the treatment of intermediate- and high-risk PMF according to the findings of two randomized controlled trials (10, 11). However, ruxolitinib is not yet approved for MPN with PCM1-JAK2 rearrangement, although it has been shown to be effective. Here, we report two patients with MPN with PCM1-JAK2 fusion who received ruxolitinib-based regimen, one of which is the first report of ruxolitinib combined with pegylated interferon (Peg-IFN) at home and abroad.

So far, 68 cases of PCM1-JAK2 fusion have been reported in hematological malignancies, most commonly in myelodysplastic syndrome (MDS)/MPN and MPN. The median age is 50 years (12–86 years), the male to female ratio is 3.17:1, 83.61% of patients have varying degrees of eosinophilia, and 50% of patients have myelofibrosis ( Table 1 and Figure 2 ). Thirteen patients were treated with ruxolitinib ± HSCT, of which 11 were myeloid neoplasms and two were lymphatic neoplasms. Twelve were responsive to ruxolitinib, and one was of uncertain efficacy; however, the duration of response varied widely ( Table 2 ). The 2021 National Comprehensive Cancer Network (NCCN) guidelines for MLN-Eo with PCM1-JAK2 fusion recommend that clinical trial is the preferred treatment option for patients with chronic phase disease, and patients with chronic phase disease can be treated with tyrosine kinase inhibitor (TKI) monotherapy in the absence of a clinical trial. However, early referral to allo-HSCT should be considered for eligible patients, since TKI therapy alone does not result in durable remissions. We report two male cases diagnosed as MLN-Eo with PCM1-JAK2 fusion. Patient 1 was initially treated with ruxolitinib and HU to obtain instant CHR but later experienced progressive increase of white blood cells and eosinophils, which indicated treatment failure. The effect was regained after the addition of Peg-IFN, and PCM1-JAK2 fusion transcript decreased significantly, suggesting that molecular response was obtained. As far as we know, this is the first report of MLN-Eo and PCM1-JAK2 fusion receiving ruxolitinib combined with Peg-IFN at home and abroad. Unfortunately, limited by short follow-up time, we have not observed patients obtained complete molecular response (CMR). Patient 2 initially responded to treatment with ruxolitinib and HU, but it was discontinued due to intolerant hematological toxicity. Both cases indicated the effectiveness of ruxolitinib in MLN-Eo with PCM1-JAK2 fusion, despite different durations of response and toxicity, and both patients will undergo HSCT.

PCM1-JAK2 rearrangement has been reported in a variety of hematological neoplasms (3–7), which indicates that the PCM1-JAK2 rearrangement lacks lineage specificity. Because of the abnormality of the JAK2 signaling pathway in these diseases, treatment with ruxolitinib may be effective. Previous documents confirmed that ruxolitinib can inhibit the growth of PCM1-JAK2 transformed Ba/F3 mouse cells in vitro and the phosphorylation of JAK-STAT5 pathway (18). Lierman (18) and colleagues reported the first case of ruxolitinib in myeloproliferative disease with PCM1-JAK2 rearrangement. A 72-year-old male diagnosed with chronic eosinophilic leukemia (CEL) of PCM1-JAK2 rearrangement received ruxolitinib alone 10–20 mg twice daily, achieved complete cytogenetic response (CCyR) after 15 months, and was recurrence-free after 36 months (31). Subsequently, Rumi et al. (21) reported a second similar case. A 31-year-old woman was diagnosed with CEL with PCM1-JAK2 rearrangement. She was treated with ruxolitinib 15 mg twice, acquired complete clinical remission 1 year later, and attained CCyR 46 months later, with a significant decrease in the fusion transcript (31). These cases indicated that ruxolitinib is valuable for MPN with PCM1-JAK2 rearrangement and could induce long-term remission. Schwaab et al. (23) identically confirmed that ruxolitinib was valuable in myeloid neoplasms with PCM1-JAK2 fusion, but the patient relapsed after 24 months on ruxolitinib. Recently, Schwaab et al. (28) reported a series of nine myeloid malignancy cases treated with ruxolitinib alone as first-line treatment, including eight cases of PCM1-JCK2 rearrangement and one case of BCR-JAK2 rearrangement. With a median time of 4 months (range 2–18 months), five patients achieved CHR. CCyR or CMR was observed in one patient. Their data showed that all the patients did not have long-term beneficial effects with ruxolitinib. In brief, the efficacy of ruxolitinib in MPN with PCM1-JAK2 fusion is inconsistent, with some patients surviving for a long time after ruxolitinib treatment and others relapsing early. There are also differences in the efficacy of ruxolitinib in lymphoid neoplasms with abnormal JAK2 pathway. Recent data (29) reported that an elderly woman diagnosed with B-cell acute lymphoblastic leukemia (B-ALL) with PCM1-JAK2 rearrangement failed to obtain complete cytogenetic and molecular biological response after receiving traditional chemotherapy and immunotherapy. Within 1 year after ruxolitinib 10 mg bid treatment, the PCM1-JAK2 fusion transcript and abnormal metaphase were significantly reduced, but none of them disappeared completely. Another young female patient with relapsed and refractory B-ALL with RNPC3-JAK2 fusion did not respond to chemotherapy combined with immunotherapy and ruxolitinib (32). Mayfield et al. (33) documented that a 17-year-old B-ALL patient with JAK2 F694L mutation persisted with minimal residual disease (MRD) after standard chemotherapy, while the MRD turned out to be negative after the integration of ruxolitinib 20 mg bid for 2 weeks. The research of Ding (34) and his coworkers found that high-dose ruxolitinib combined with multidrug chemotherapy was safe and effective for children with BCR-ABL1-like ALL, and whether the combination therapy is suitable for MPN with PCM1-JAK2 fusion is worth exploring. In summary, there have been considerable evidences that ruxolitinib is effective in hematological malignancies with abnormal JAK2 signaling pathways, although the efficacy is highly heterogeneous. The heterogeneity may be partially attributed to different somatic mutations or blastic crisis of MPN (8).

No somatic mutations were detected in both of our patients. Due to the rarity of hematological neoplasms with PCM1-JAK2 rearrangement, it is difficult to conduct large-scale clinical studies. Thus, there are no large cohort data on the molecular characterization of PCM1-JAK2-rearranged hematologic neoplasms. Baer et al. (25) found that mutation rates were 14% (1/7) for hematologic neoplasms with PCM1-JAK2 rearrangement, and the patient had TET2 somatic mutations. We speculate that somatic mutations of epigenetic regulators may be present in hematologic neoplasms with PCM1-JAK2 fusion, so hypomethylating-agent-based programs may be effective. Dargent et al. (16) described the diagnosis and treatment of a patient with MDS/MPN with PCM1-JAK2 fusion. The initial analysis of bone marrow karyotype was normal, but t(8;9) was detected by fluorescence in situ hybridization analysis in peripheral blood. The author suggested that t(8;9)(p22;p24) was not easy to detect in the study of G-banding and was easy to be ignored, especially in poor specimens. Tang (8) and his colleagues also noted that because t(9p24.1;V) only involved small segments of the 9p chromosome, such rearrangements were cryptic and therefore missed by routine chromosome analysis. These explain the reason for the normal karyotype of patient 2.

MLN-Eo with PCM1-JAK2 rearrangement is rare and has a poor prognosis. Existing data have shown that ruxolitinib is effective for the disease, but allo-HSCT is still the only way to cure the disease. Ruxolitinib can be used as a bridging treatment before allo-HSCT. Here, we reported the efficacy and safety of ruxolitinib in MPN with PCM1-JAK2 rearrangement. For patients with low efficacy of ruxolitinib monotherapy or rapid disease progression, the treatment options to obtain cytogenetics or molecular response prior to HSCT warrant further study. Ruxolitinib combined with Peg-IFN could be one of the candidates.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by the Research Ethics Committee of the First Affiliated Hospital of Soochow University. The patients/participants provided their written informed consent to participate in this study.

YS wrote the manuscript. SC guided the treatment of cases. YC, JC, JNC, MZ, and JP performed the research and analyzed the data. All authors contributed to the article and approved the submitted version.

This study was supported by grants from the National Key R&D Program of China (2019YFA0111000), the National Natural Science Foundation of China (81700140, 81873449, 81900130, 81970136, 81970142, 81970142, 82000132, and 82000158), the Natural Science Foundation of the Jiangsu Higher Education Institution of China (18KJA320005), the Natural Science Foundation of Jiangsu Province (BK20190180), priority academic program development of Jiangsu Higher Education Institution, the Innovation Capability Development Project of Jiangsu Province (BM215004), the Translational Research Grant of NCRCH (2020WSB03, 2020WSB11, and 2020WSB13), the Open Project of Jiangsu Biobank of Clinical Resources (SBK202003001 and SBK202003003), Jiangsu Provincial Key Medical Center (YXZXA2016002), and National Science and Technology Major Project (2017ZX09304021).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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