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Editorial theme | The management of relapsed/refractory myelofibrosis: Part 3 – treatment options beyond JAK inhibition

Mar 10, 2021

There is an ongoing effort to develop novel approaches with different modes of action to fulfil an unmet need when Janus kinase (JAK) inhibitors (JAKi) are not enough or fail to halt disease progression. As part of the new editorial theme on the management of relapsed or refractory myelofibrosis (R/R MF), our third article reviews new treatment options that are independent of JAK inhibition including allogeneic hematopoietic stem cell transplantation (allo-HSCT). These novel agents described below are currently under investigation at phase II level, and here, we summarize the available safety and efficacy data in patients with MF who were JAKi-naïve or who failed on JAK inhibition.

In case you have missed it, here is the link to our first editorial article summarizing the challenges of treating patients whose disease has failed to respond to ruxolitinib, and our second editorial article, that focuses on new JAKi.


LCL161 is a second mitochondrial-derived activator of caspases (SMAC) mimetic that shows activity through promoting apoptosis by regulating the expansion of abnormal cells, particularly in tumors with high tumor necrosis factor (TNF)-alpha expression. TNF-α levels have been shown to be significantly elevated in patients with MF.1

LCL161 is currently under investigation as a novel therapeutic option for patients with MF who fail on or who are ineligible for JAK inhibition. As summarized on the MPN hub, phase II results have shown that LCL161 produced an overall response rate of 30% with low rates of Grade 3–4 hematologic (thrombocytopenia and anemia), and nonhematologic (syncope and nausea/vomiting), treatment-emergent adverse events (TEAEs). The median overall survival (OS) was not reached at a median follow-up of 22 months. LCL161 plus other targeted options including ruxolitinib are under consideration.


Bomedemstat is an inhibitor of lysine-specific demethylase-1 (LSD1), an enzyme involved in the maturation of blood cells, and neoplastic stem and progenitor bone marrow (BM) cells. It has been shown to be overexpressed in myeloproliferative neoplasms (MPN). LSD1 and growth factor independent 1B (GFI1b) promote maturation of progenitors to normal-functioning megakaryoctyes.2 The MPN Hub reported on the phase II results of the IMG-7289 study (NCT03136185), which were presented during the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition; bomedemstat demonstrated good tolerability with a manageable safety profile and improved symptom scores, as well as reduction in spleen volume and BM fibrosis.

Bomedemstat holds the U.S. Food and Drug Administration (FDA) orphan drug and fast track designations for the treatment of MF and essential thrombocythemia (ET), and has been granted access to the Priority Medicines (PRIME) scheme of the European Medicines Agency (EMA) for the treatment of MF.

It is also currently under investigation for ET and polycythemia vera (PV) in several studies.


Imetelstat inhibits the enzymatic activity of telomerase, a protein complex which is temporarily activated in MF/cancer stem and progenitor cells but not in normal/progenitor cells, by binding to the template region of the RNA component. It was associated with the restoration of normal BM after fibrosis, and morphologic and molecular remissions in patients with MF in a pilot study, suggesting a possible disease-modifying activity.3

The phase II IMbark trial (NCT02426086) evaluated the efficacy of imetelstat in patients with MF who relapsed following, or became refractory to, JAK inhibition. The key results of the IMbark trial, presented at the 62nd ASH Annual Meeting and Exhibition, have been recently summarized on the MPN Hub.

Treatment with imetelstat was associated with dose-dependent responses in spleen volume and symptoms, and OS. The reduction in telomerase activity (TA) and human telomerase reverse transcriptase (hTERT) gene expression were dependent of dose and exposure, and a correlation between clinical response with shorter telomerase length (TL) and higher hTERT expression supported an on-target mechanism of action. Imetelstat will be further investigated in patients with MF who failed to respond to a JAK inhibitor in the phase III IMpactMF trial (NCT04576156).


KRT-232 is an oral, first-in-class, potent, selective, small molecule murine double minute 2 (MDM2) inhibitor targeting the malignant MF stem and progenitor cells. MDM2 is a negative modulator of p53 and is overexpressed in circulating CD34+ cells that are found in elevated levels in patients with MF. As reported on the MPN Hub, it is currently under investigation as monotherapy in patients with primary or secondary MF who have R/R MF following JAK inhibition, in the phase IIa/IIb KRT-232-101 trial (NCT03662126). It is also being assessed in another study in combination with ruxolitinib in patients with MF with suboptimal responses to ruxolitinib.

The results of the KRT-232-101 study have demonstrated dose-dependent responses since a spleen volume reduction of ≥35% was reported in 16% of patients receiving 240 mg. However, not having a mandatory washout period for ruxolitinib was acknowledged as a contributing factor in spleen response due to induction of spleen flare following discontinuation. Patients who were on ruxolitinib had a 3% increase in spleen volume compared with a mean reduction of 21% in those who were off ruxolitinib at baseline. There was also a rapid and dose-dependent reduction in the levels of CD34+ from baseline. Safety profile was also manageable. KRT-232 will be further investigated in a randomized phase III trial conducted in patients with R/R MF who have failed on JAK inhibition.

For a video interview with Haifa Kathrin Al-Ali on why MDM2 should be targeted in MF, click here.


CPI-0610 is a small molecule, inhibitor of the bromodomain and extraterminal (BET) proteins, currently investigated with or without ruxolitinib, in patients with myelofibrosis. The phase II MANIFEST trial included three different patient cohorts; one arm evaluated CPI-0610 monotherapy in patients who were resistant/intolerant or ineligible for JAKi, while the other two arms focused on the combination with ruxolitinib. Patients were stratified based on being transfusion-dependent (TD) or transfusion-independent (TI). Outcomes with the CPI-0610 monotherapy demonstrated that:

  • The proportion of patients with a ≥35% spleen volume reduction and 50% improvement in the total symptom score was higher in the TI group (23.8% and 47.4%, respectively) compared with the TD group (0% and 8.3%, respectively)
  • In the TD group, 57.9% of patients had a ≥1.5 g/dL mean increase in hemoglobin
  • Conversion to TI occurred in 21.4% of TD patients, suggesting a possible disease-modifying effect of CPI-0610
  • The most common Grade 3 TEAEs were thrombocytopenia (14%), and anemia (9.3%), followed by diarrhea (4.7%), and respiratory tract infections (2.3%). No Grade 4 or 5 TEAEs were reported

Click here for a summary of the data presented at the 25th Congress of the European Hematology Association (EHA-2020).


Transplantation is considered the only curative option for patients with MF; however, there is a concern of high rate of morbidity and mortality associated with this approach, with non-relapse mortality (NRM) due to graft failure, regimen-related toxicities, and graft-versus-host-disease (GvHD) being the main challenges.4,5 As summarized by Nicolaus Kroeger at the 46th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT), the number of patients with R/R MF who received allo-HSCT have doubled in Europe since 2006 and cure rates in younger patients can reach up to 70%. However, some data indicate that transplants may be associated with worse outcomes after JAK failure.5

In a study by Shanavas et al.,5 the outcomes of allo-HSCT in patients who failed, or who had clinical improvement, on a JAK inhibitor were investigated. The 2-year OS after transplant in patients who lost symptom response (anemia requiring transfusion) or who became intolerant was 54%, while it was 60% in those who progressed or lost spleen response, and 32% in those who had leukemic transformation. The worse OS in the group with leukemic transformation was attributed to the higher relapse rate compared with other groups. Of note, the OS in patients who were transplanted while still showing clinical improvement under ruxolitinib was 91%.

The risk scoring systems such as the Dynamic International Prognostic Scoring System (DIPSS) or Myelofibrosis Transplant Scoring System (MTSS) may be helpful to identify eligible patients for transplant, and to predict outcomes such as OS or NRM. For more information on the outcome predictors, click here.


There is an unmet clinical need in treating patients with R/R MF, and there is a continuous effort to improve outcomes and modify disease progression in several studies. Novel drug candidates with different mechanisms of action show very encouraging activity in pretreated patients and some of them may even have disease-modifying potential. In the next article, the MPN Hub will cover combination approaches that are under evaluation in clinical trials.

  1. Pemmeraju N, Carter BZ, Kantarjian HM, et al. Results for phase II clinical trial of LCL161, a SMAC mimetic, in patients with primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF) or post-essential thrombocytosis myelofibrosis (post-ET MF). Blood. 2016;128(22):3105. DOI: 1182/blood.V128.22.3105.3105
  2. Pettit K, Gerds AT, Yacoub A, et al. A phase 2a study of the LSD1 inhibitor Img-7289 (bomedemstat) for the treatment of myelofibrosis. Blood. 2019;134(Supplement 1):556. DOI: 1182/blood-2019-123244
  3. Wang X, Siang Hu C, Petersen B, et al. Imetelstat, a telomerase inhibitor, is capable of depleting myelofibrosis stem and progenitor cells. Blood Adv. 2018;2(18):2378-2388. DOI: 1182/bloodadvances.2018022012
  4. Harrison CN, Schaap N, and Mesa RA. Management of myelofibrosis after ruxolitinib failure. Ann Hematol. 2020;99(6):1177-1191. DOI: 1007/s00277-020-04002-9
  5. Shanavas M, Popat U, Michaelis LC, et al. Outcomes of allogeneic hematopoietic cell transplantation in patients with myelofibrosis with prior exposure to Janus Kinase 1/2 inhibitors. Biol Blood Marrow Transplant. 2016;22(3):432-440. DOI: 1016/j.bbmt.2015.10.005