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The bone marrow niche is the local tissue microenvironment that maintains and regulates stem cells for hematopoiesis. It is comprised of many different cell types that work together to create a functional network. Myeloproliferative neoplasms (MPN) result in a disruption of the balance of this network due to inherent increases in proinflammatory cytokines, skewed adaptive and innate immune responses, and ‘cross-talk’ between the normal and mutated hematopoietic stem cells (HSC), all within endosteal and vascular niches and the extracellular matrix. This contributes to disease progression and drug resistance.
The impact of MPN on the bone marrow niche, and how they can be targeted, was recently reviewed by Natalia Curto-Garcia, Donal P McLornan, and MPN Hub Steering Committee member Claire Harrison in a publication in the journal Haematologica. 1
The bone marrow niche is comprised of the endosteal niche, the vascular niche, the sympathetic nervous system, and the extracellular matrix. MPN are often associated with Janus kinase-2 (JAK2) V617F mutations in HSCs, which promote their proliferation, survival, and migration, therefore giving these cells a clonal advantage to dominate the bone marrow niche compared to non-mutated cells.
Normal function
Abnormal function in MPN
Normal function
Abnormal function in MPN
Normal function
Abnormal function in MPN
Normal function
Abnormal function in MPN
Currently, allogeneic stem cell transplantation is the only curative treatment for myelofibrosis (MF). However, many patients are ineligible because of age, co-morbidities, lack of a suitable donor, or risk profile. Therefore, treatment with therapeutics is the next best option, with ruxolitinib, a JAK1/2 inhibitor, being the only licensed agent for the treatment of myelofibrosis. Its approval was based on the COMFORT-I and -II trials, which showed an improvement in overall survival. Other agents that have been tested in clinical trials include inhibitors of histone deacetylases, telomerase, and MDM2, which have been summarized in Table 1.
Table 1. Selection of therapeutics that have been tested in clinical trials in patients with PMF 1
ET, essential thrombocythemia; HDACi, histone deacetylase inhibitor; IWG-MRT, International Working Group-Myeloproliferative Neoplasms Research and Treatment; JAKi, Janus kinase inhibitor; MF, myelofibrosis; ORR, overall response rate; OS, overall survival; PV polycythemia vera. |
|||
Inhibitor |
Drug |
Trial |
Result |
---|---|---|---|
JAKi |
Pacritinib |
PERSIST-I and -II (see more here) |
In patients with MF with thrombocytopenia, 18% had a splenic volume reduction ≥ 35%. |
|
Momelotinib |
SIMPLIFY 1 (vs ruxolitinib) (see more here) |
At Week 24, 66.5.% of patients with MF were transfusion independent
|
|
|
SIMPLIFY 2 (vs BAT) |
7% of patients had a splenic volume reduction ≥ 35%. |
|
Fedratinib |
JAKARTA-1 (see more here) |
In patients with MF who were ruxolitinib resistant/intolerant, 36% and 40% of patients had a splenic volume reduction ≥ 35% (400 mg and 500 mg dose group, respectively). |
|
|
JAKARTA-2 |
55% of patients had a splenic volume reduction ≥ 35%. |
HDACi |
Panobinostat |
NCT01298934 |
In combination with ruxolitinib in patients with MF; the ORR was 36% by IWG-MRT.
|
Telomerase inhibitor |
Imetelstat |
NCT02426086 |
In patients with MF, OS was 19.9 months and 29.9 months for low dose and high dose, respectively.
|
|
|
NCT01243073 |
In patients with ET, 89% achieved complete hematological response.
|
MDM2i |
Idasanutlin |
NCT02407080 (see more here) |
In patients with PV or ET, there was a 58% response with monotherapy and 50% response with combined therapy after six cycles. |
A number of therapeutics that target bone marrow fibrosis in MPN have been tested recently but have proven unsuccessful in clinical trials. IPI926, an oral hedgehog inhibitor, was studied as a monotherapy, with no significant improvements in fibrosis. Sonidegib (LDE225), a SMO receptor antagonist, tested in a phase Ib/II study in combination with ruxolitinib, only demonstrated spleen and symptom responses in a minority of patients. In vivo studies with the anti-fibrotic agent, pirfenidone, also showed minimal clinical benefits, and fresolimumab, a monoclonal antibody against TGF-β, demonstrated no relevant changes in MF.
The balance of the bone marrow niche is disrupted by MPN-mutated HSC, which promote a self-reinforcing environment that enhances their proliferation over normal hematopoiesis and fosters the development of myelofibrosis. These changes may eventually lead to therapeutic resistance and drive disease progression towards the blastic phase of the disease. Therapeutics against various components of the bone marrow niche have been trialed and have led to variable results. As the bone marrow niche is highly complex, it is likely that combinatorial or sequenced therapeutic strategies will be required to better treat this disease.
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