Li et al. Biomarker Research (2019) 7:15 https://doi.org/10.1186/s40364-019-0166-y REVIEW Open Access Targeted therapies for myeloproliferative neoplasms Bing Li1,2, Raajit K. Rampal3 and Zhijian Xiao1,2* Abstract The discovery of JAK2V617F and the demonstration that BCR-ABL-negative myeloproliferative neoplasms (MPNs) are driven by abnormal JAK2 activation have led to advances in diagnostic algorithms, prognosis and ultimately also treatment strategies. The JAK 1/2 inhibitor ruxolitinib was a pivotal moment in the treatment of MPNs, representing the first targeted treatment in this field. Despite a weak effect on the cause of the disease itself in MPNs, ruxolitinib improves the clinical state of patients and increases survival in myelofibrosis. In parallel, other JAK inhibitors with potential for pathologic and molecular remissions, less myelosuppression, and with greater selectivity for JAK1 or JAK2, and the ability to overcome JAK inhibitor persistence are in various stages of development. Moreover, many novel classes of targeted agents continue to be investigated in efforts to build on the progress made with ruxolitinib. This article will discuss some of the advances in the targeted therapy in this field in recent years and explore in greater detail some of the most advanced emerging agents as well as those with greatest potential. Keywords: Targeting therapy, Myeloproliferative neoplasms Background which is affected by mutations leading to a + 1 frame- The classic BCR-ABL1–negative MPNs include three shift in the exon 9. As with MPL mutations, CALR mu- different disorders, essential thrombocythemia (ET), tations are associated with ET and PMF but with a polycythemia vera (PV), and primary myelofibrosis higher frequency (25–35%). CALR is not a molecule (PMF), and are caused by constitutive activation of the directly involved in activation of JAK2, but the new C- cytokine receptor/JAK2 pathway due to acquired som- terminus common to all mutants allows the CALR mu- atic mutations in three major genes [1]. JAK2V617F is tants to tightly bind and activate MPL and JAK2 [2–5]. the most prevalent mutation in MPNs associated with With greater understanding of the key role of JAK-STAT the three disorders (65–70%) and is present in 95% of pathway in MPN pathogenesis, the development of PVs.Mutationsinexon12ofJAK2arefoundinaround the JAK 1/2 inhibitor ruxolitinib was a pivotal mo- 2% of PV, which are negative for the JAK2V617F muta- ment in the treatment of MPN, representing the first tion. Mutations in the thrombopoietin receptor (MPL) targeted treatment in this field. Although ruxolitinib gene are mainly present in 5–10% ET and PMF. The is known to have striking impacts on reduction in most frequent are substitutions of the Trpyto- spleen size and reduction in symptom burden, there phan(W)515 residue to several other amino acids, are still many clinical challenges encountered during mostly Leucine(L) or Lysine (K). The third gene found the use of ruxolitinib. Therefore, novel drugs and tar- frequently mutated in MPNs is calreticulin (CALR), gets are being explored as mono-or combination- therapy in this field. This article will discuss some of the advances in the targeted therapy in this field in * Correspondence: [email protected] 1MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, recent years and explore in greater detail some of the Chinese Academy of Medical Sciences & Peking Union Medical College, 288 most advanced emerging agents as well as those with Nanjing Road, Tianjin 300020, China greatest potential. 2State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Li et al. Biomarker Research (2019) 7:15 Page 2 of 8 JAK inhibitors anemia status or transfusion requirements at week 24. Type I inhibitors But progression to leukemia was not significantly dif- Type I inhibitors target the ATP-binding site of the JAKs ferent [11, 12]. It is possible that most pro-survival under the active conformation of the kinase domain [6]. effects derive from its palliative anti-inflammatory ef- Most clinically tested inhibitors are type I. They differ in fects. Further analyses will be important for exploring their specificity for JAK2. Many inhibitors target both JAK2 ruxolitinib earlier in the disease course to assess the and JAK1 (ruxolitinib and momelotinib). Less frequently, effect on the natural history of MF. they target only JAK2 (NS-018, pacritinib and fedratinib). The RESPONSE study evaluated the efficacy of ruxoli- tinib in PV patients who were either refractory or in- Ruxolitinib The oral JAK1/2 inhibitor, ruxolitinib was tolerant to hydroxyurea, and had ongoing venesection the first approved targeted treatment for intermediate- requirement and splenomegaly. Patients were random- or high-risk myelofibrosis (MF) on the basis of the re- ized on a 1:1 basis between ruxolitinib and BAT with sults of the Controlled Myelofibrosis Study with Oral 22.7% of patients in the ruxolitinib group meeting the JAK Inhibitor Treatment-I (COMFORT-I) [7] and composite end points of HCT control and > 35% splenic COMFORT-II [8] clinical trials and for patients with PV volume reduction at 32 weeks, compared with 0.9% in who are refractory to or intolerant of hydroxyurea on the BAT group. In RESPONSE-2 [13], 173 PV patients the basis of the results of the Randomized Study of again resistant or intolerant to hydroxycarbamide, but Efficacy and Safety in Polycythemia Vera With JAK without splenomegaly, were randomized between ruxoli- Inhibitor INCB018424 Versus Best Supportive Care tinib and BAT, with the primary end point of HCT con- (RESPONSE) [9] clinical trial. trol achieved in 62% in the ruxolitinib group compared In COMFORT-I, 309 patients were randomized to with 19% treated with BAT. either ruxolitinib or placebo, with a ≥ 35% reduction In refractory or hydroxyurea-resistant ET patients, in spleen volume seen in 41.9% treated with ruxoliti- ruxolitinib offered no advantage compared with other nib vs. 0.7% in the placebo group. In COMFORT-II, therapies in the control of the thrombocytosis and dis- ruxolitinib was compared with best available therapy ease complications but did alleviate general symptoms (BAT) in 219 patients, randomized in a 2:1 ratio. and pruritus [14]. In the other [15], which was an open- Similarly, the primary end point of a reduction in label phase 2 trial, ruxolitinib induced a meaningful re- spleen size ≥35% by week 48 was seen in 28.5% of duction in platelet levels and attenuated ET-related patients treated with ruxolitinib compared with 0% in symptoms. These preliminary results seemed superior to the BAT group. The EORTC-QLQ-C30 scores for historically observed results, but this study was done in symptoms relevant to patients with MF showed an the absence of a comparison with another treatment. improvement from baseline by week 8 and continued Overall, ruxolitinib is a well-tolerated oral treatment through to week 48, indicating significant improve- with approximately 25–33% of adverse effects. The ment in quality of life. main toxicities are hematological, moderate anemia Following COMFORT studies, the JUMP (JAK In- that may correct with time, and thrombocytopenia, hibitor RUxolitinib in Myelofibrosis Patients) study which can be very severe in high-risk MF. Middle- [10] was initiated. JUMP was a phase 3b expanded- term toxicity is an immune suppression that may be access trial for patients in countries without access to responsible for reactivation of viral infections, particu- ruxolitinib outside of a clinical study and included larly herpes zoster and HIV1 and bacterial infections those classified as intermediate-1 risk, a population such as pneumonia, tuberculosis reactivation and that was not included in COMFORT studies. This urinary tract infections [16]. Long-term monitoring study further confirmed the safety and efficacy find- will be important because ruxolitinib decreases nat- ings from an analysis of 1144 patients with intermedi- ural killer cell functions with a potential risk of solid ate- or high-risk MF, including for those patients with tumor and lymphoma development [17, 18]. intermediate-1-risk disease. Furthermore, JUMP was a Despite these clinical benefits, chronic therapy with global study conducted in a setting that resembles ruxolitinib has not led to molecular or pathologic remis- routine clinical practice. Findings from this study help sions in the majority of MPN patients [7, 8] in contrast guide clinicians in the management of their patients to ABL kinase inhibitors in chronic myeloid leukemia with MF. (CML). Moreover, hematological toxicity, which is gen- Based on COMFORT-I and COMFORT-II clinical erally ruxolitinib-dose dependent and reversible, is an trials, analysis of patients treated for several years issue for many patients. As such there is a significant with ruxolitinb indicated a significant increase in sur- population of PMF patients who are excluded from vival in Int-2 and high-risk MF, The survival benefit treatment with ruxolitinib, with most avoiding its use in with ruxolitinib was observed irrespective of baseline patients with a platelet count of < 50 × 109/l. Li et al. Biomarker Research (2019) 7:15 Page 3 of 8 Momelotinib Momelotinib (CYT38) is a JAK1/JAK2 in- placebo for at least 6 consecutive 4-week cycles.