SAN FRANCISCO-In 2005, researchers discovered a mutation in the JAK2 gene that is present in the majority of polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis neoplasms. Within two years, clinical researchers had JAK2 inhibitors in clinical trials. Early results show that the drugs are active but are not likely to be a home run, according to a presentation here at the Oncology Congress.
Audience members, however, were uniformly convinced of the need to enroll their patients on future trials testing the drugs.
"There is good reason to be excited about these drugs," said Stephen Oh, MD, PhD, Assistant Professor in the Hematology Division at Washington University School of Medicine in St. Louis, who presented the overview on JAK/STAT inhibitors. "However, when you look at these data so far, the biggest benefits have been in terms of symptomatic relief. In terms of cytopenias, improvements have not been seen in a large number of patients."
Current treatment options are limited for all three subtypes of chronic myeloproliferative neoplasms, but particularly for myelofibrosis. "While many of the patients with PV or ET can manage with either phlebotomy or cytoreductive agents, like hydroxyurea, we clearly need other therapies for myelofibrosis," Dr. Oh said.
Majority of Patients Have the Mutation
The most common somatic JAK2 mutation is a single amino acid change, V617F, which occurs in 95% of PV patients and 50 to 60% of patients with ET and primary myelofibrosis. Some patients who lack the V617F mutation have an alternate JAK2 mutation in exon 12.
Both mutations cause the JAK2 tyrosine kinase receptor to be constantly active, regardless of the presence or a-bsence of cytokines, like erythropoietin, that are normally required to activate the receptor. Once active, JAK2 stimulates the STAT protein-hence the pathway is often referred to as JAK/STAT-and leads to cell proliferation and survival.
Given the extraordinarily high frequency of JAK2 mutations in PV patients, some people have thought that every patient with PV must have some mutation in the gene, Dr. Oh said. "We are beginning to understand that that may not be the case, but, by and large, the vast majority do."
Recently, Dr. Oh and others have discovered that patients with myeloproliferative neoplasms who have wild-type JAK2 may carry mutations in other genes within the JAK/STAT pathway. These alternate mutations also activate the pathway and lead to unregulated proliferation and survival.
The presence of mutations at other steps in the pathway, however, may complicate drug development and it is not clear whether the JAK2 inhibitors will work in these patients, although Dr. Oh said he suspects they will.
Clinical Trials
There are seven JAK2 inhibitors in clinical trials for the treatment of myeloproliferative neoplasms. The inhibitors are in varying stages of development and have different degrees of specificity for JAK2 over related kinases. Additionally, it is important to note that the inhibitors are not specific for mutant JAK2 but also inhibit the wild-type enzyme.
INCB018424, which inhibits both JAK1 and JAK2, is furthest along in development and is now in Phase III trials for the treatment of myelofibrosis.
Phase I/II data, published in the September 16th issue of the New England Journal of Medicine, show that NCB018424 induced durable responses in 40 to 50 percent of patients depending on the treatment dose. Additionally, 70 to 80 percent of patients had a 25 percent or greater reduction in splenomegaly, and the majority of patients reported symptomatic or functional improvements.
"You will hear a classic story 'My spleen shrunk, my night sweats went away, I gained weight'," Dr. Oh said. "And that, for a patient with myelofibrosis, is really significant."
The drug was not without side effects, though. Hematologic malignancies were the major problem and Grade 3/4 thrombocytopenia, which occurred in 20 percent of patient, was dose limiting.
"JAK2 is absolutely essential for normal hematopoiesis, so it is really no surprise that when you inhibit JAK2 you could get cytopenias," Dr. Oh said.
"The problem, of course, is that for myelofibrosis patients, they are already anemic. So the question is then, are they going to see an improvement in the anemia. We know that in the case of imatinib, which hits ABL, an important enzyme, patients can have cytopenias but they, by and large, resolve over time.
"Unfortunately there was no consistent improvement in anemia and some patients even saw worsening of their anemia with the JAK2 inhibitor."
Inconsistent Lab Results
Interestingly, the laboratory results were not consistent in the trial. Cytokine markers, including inflammatory markers, went down with treatment and the drop correlated with improvements in constitutional symptoms.
However, even patients who showed symptomatic improvements did not have a substantial reduction in their mutant allele burden, suggesting that the tumor clone persisted in the presence of the drug.
"This was really a red flag for some people," Dr. Oh said. "Patients are feeling symptomatically better, but their mutant allele burden is not going down-We can draw an analogy to BCR/ABL monitoring we do in CML-If that is the case, then is this drug really hitting the bad clone? We don't really know at this point."
Meanwhile researchers have tested a different JAK2 inhibitor, TG101348, in a Phase I/II trial with a similar population of patients, most of whom had primary myelofibrosis. The majority of patients showed improvements in splenomegaly, particularly at the highest dose tested. Leukocytosis resolved in patients with elevated white counts, as did thrombocytosis in patients with elevated baseline platelet counts.
TG101348 is more specific for JAK2 over JAK1 than INCB018424, and thus it had less impact on inflammatory cytokines. However, the drug still induced constitutional symptoms, including a reduction in night sweats. Therefore, it is unclear whether the cytokine reduction is a vital component of therapy, Dr. Oh said.
Another difference between the two trials was the drugs' impact on allele burden. A larger proportion of patients treated with TG101348 compound had a reduction in their mutant allele burden, suggesting that the drug was controlling the malignant clone.
As with the INCB018424 trial, some patients treated with TG101348 developed cytopenias. The most common were Grade 3/4 thrombocytopenia, and the majority of patients who were transfusion--independent at baseline required transfusions while on study due to worsened anemia.
Additionally, there was a fair amount of low-grade gastrointestinal toxicity in this trial, but it was generally manageable.
Conclusions, Audience Participation
At the start of Dr. Oh's presentation, the audience was divided on how they would treat a 62-year-old patient with primary myelofibrosis who was transfusion--dependent and had painful splenomegaly and other constitutional symptoms. Seventeen percent said they would refer the patient for a bone marrow transplant, 7% would rely on supportive care, 23% would use thalidomide and prednisone, and 53% would recommend that the patient enroll in a JAK2 inhibitor trial.
At the conclusion of the talk, however, the vote was unanimous in favor of enrolling the patient in a clinical trial. In fact, with the other three options receiving zero votes, Dr. Oh jokingly reminded the audience that he has no financial ties to the drugs in development. He then said, in a more serious tone, that there was no right answer at this time and that a lot of questions remain unanswered with regard to the JAK2 inhibitors.
"Is this going to be the next imatinib? These results would suggest no, for these patients at least, in that we are not seeing complete restoration of normal blood counts," he said.
"We will have to see what comes out of follow up studies, but it is a little bit of a disappointment in terms of not seeing these patients have improvements in anemia, which is the primary issue for many of them."