The New Era of Treating Myelofibrosis - Episode 7
Aaron Gerds, MD, MS; and Srdan Verstovsek, MD, PhD, share insights on the impact of pathways, including JAK-STAT, on myelofibrosis disease progression and discuss considerations for the use of JAK inhibitors.
Aaron Gerds, MD, MS: The JAK/STAT [Janus kinase and signal transducer and activator of transcription] pathway plays a central role in the pathogenesis of myeloproliferative neoplasms [MPNs]. It all started back in 1951, when William Dameshek postulated that there was a connection between PV [polycythemia vera], ET [essential thrombocythemia], and myelofibrosis, since they all had a similar clinical phenotype. It wasn’t until several years later when recurrent mutations in the JAK2 V617F mutation was discovered by 4 groups independently. After that, we’ve seen a rush of JAK inhibitors, which has no doubt altered the field dramatically and improved the lives of patients. After the discovery of JAK2 V617F, in most patients with MPN, there were additional discoveries identifying the current mutations in a gene called MPL, which is the thrombopoietin receptor, as well as a gene called CALR [calreticulin]. CALR is an endoplasmic reticulum chaperone protein. It helps your cells make new proteins and shuttle along in their maturation process. When all 3 of these genes become mutated, they need a constitutive JAK/STAT activation by different mechanisms, but the result is the same for all 3 mutations at the end. For JAK/STAT pathway, STAT is a transcription factor, and it basically enhances transcription of key genes in the cell, which lead to elevated cytokine levels, abnormal proliferation because, again, this is a cytokine pathway. The thrombopoietin, EPOR [erythropoietin receptor], and G-CSF [granulocyte colony-stimulating factor] pathways all feed through JAK/STAT, as well as alterations in NF [nuclear factor] kappa B, TGF [transforming growth factor]-beta, and some prosurvival signals, all ultimately leading to this proliferation and production of cytokines within the bone marrow space, leading to the clinical phenotype that we see.
After the discovery of recurrent mutations in JAK2, the JAK inhibitors were developed, and there was a whole cadre of JAK inhibitors being developed from the start. What they do is block the constitutive activation of that pathway. Normally, 2 JAK molecules must dimerize to get the pathway going, but with the mutations, they’re on all the time, and this is trying to block that. Some JAK inhibitors block only wild-type JAK molecules, whether that will be JAK1, JAK2, or JAK3. Some block mutant JAK2, as well. Nonetheless, it’s tamping down that pathway, so instead of having that cytokine signal pathway within the cell firing all the time, it can slow down the proliferation of the cells and their ultimate downstream products it’s producing, once again, loss of TGF-beta, NF kappa B, and these other signals. They aren’t curative, that’s a key piece of all this. This is not CML [chronic myeloid leukemia] where there’s a BCR-ABL mutation, we give a BCR-ABL inhibitor, the cells all die off, and we don’t see them anymore. The cells can continue to grow and persist, despite JAK inhibition. JAK inhibitors are not equally effective in all populations. Sometimes we think about JAK inhibitors being difficult to use in patients who are myelosuppressed already, so patients who have low blood counts, in particular anemic patients and thrombocytopenic patients because, again, we’re blocking not only mutant pathways but also wild-type pathways, in general. If a patient already has low blood counts, we are blocking the pathway in which the bone marrow is making more red blood cells and platelets. It’s going to lead to more and worsening myelosuppression. Thus, in those patients, JAK inhibitors may not be a good fit. We know that JAK inhibitors can be slightly immunosuppressive, particularly with respect to latent infections. Someone who has latent TB [tuberculosis], someone who has an untreated hepatitis—it would not be a great idea to use a JAK inhibitor on those patients because we know it can lead to reactivation of viral infections, as well as things like latent TB. In anyone you suspect may have a latent infection, you certainly would want to rule that out before starting a JAK inhibitor.
Srdan Verstovsek, MD, PhD: The JAK/STAT pathway is the major unifying biological abnormality in all patients with MPNs, including all the patients with myelofibrosis. But there are other pathways, particularly myelofibrosis, that may be active through other mutations that are present in about 40% to 50% of patients. It activates the PI3K [phosphoinositide 3-kinase] pathway and RAS pathway, or additional abnormalities, in terms of epigenetic control of the genetic expression in the bone marrow cells. Splicing gene mutations, for example, are present in a number of patients, that may contribute to the bone marrow failure. The pathways that are there, and multiple of them, are responsible to a large degree for the progression of the disease, and for the loss of response and having a medication, for example, the implications are obvious. That will do more than just 1 partway inhibition, it will possibly benefit patients in a different way. Inflammation, for example, is tied to the JAK/STAT pathway and inhibition of the JAK/STAT pathway is known to inhibit the inflammation, but there is also a native immune system tool, like IRAK1 [interleukin-1 receptor-associated kinase 1] pathway. That’s another inflammatory pathway that affects the cells in the bone marrow of myelofibrosis patients through NF kappa B activation and contributes to the inflammatory potential of myelofibrosis as it was recently described.
Transcript Edited for Clarity