Science & Medicine

Special Report: Jakafi and the evolution of deadly mutations

 

Does Jakafi contribute to deadly mutations?
Kate J, Newberry et al, Blood, 2017  “Clonal evolution and outcomes in myelofibrosis after ruxolitinib discontinuation.”

There is a smoking gun. But no fingerprints.  Yet.

Nevertheless, among a group of patients who discontinued Jakafi during its 2007-2011 pre-approval clinical trial stages, there were deaths, transformation to acute myeloid leukemia and the emergence of high risk mutations.

The raw numbers themselves are chilling.

Kate Newberry, PhD

Kate Newberry and her colleagues at MD Anderson undertook a retrospective review of the 107 patients enrolled in the Phase 1/2 clinical trial of ruxolitinib (later to be called Jakafi) at its Houston site during the 2007-2011 period.  Almost all — 95 patients — discontinued treatment and of that group  86 patients were available for follow-up analysis.

For Newberry, a young research scientist these were all data points derived from a study that ended years before she joined MD Anderson.

Her boss, Srdan Verstovsek, and several colleagues however had been  deeply involved in the years of Jakafi clinical trials and the clinical and educational processes that followed after FDA approval in 2011. For them, these were 86 people they saw in the halls and clinics and a project closely associated with their professional careers.

30 patients on that trial died while on therapy and were excluded from the post-discontinuation analysis.  As a result we don’t know what new mutations they may have harbored. That left 56 patients for the MD Anderson group to follow… but not for very long.  The median survival after discontinuing Jakafi was only 14 months.

The MD Anderson group took a deep dive into the data to get a clearer idea of what was going on. They had molecular data for 62 patients both when they entered the clinical trial and when they quit.

The comparison revealed roughly one-third of them had acquired new mutations while taking ruxolitinib. Worse, a whopping 61% of those mutations were in ASXL1, a High Molecular Risk (HMR) gene with awful survival prospects.

The gain in mutations, called clonal evolution, could be ominous. Overall survival for patients experiencing clonal evolution was only six months versus 16 months for others who discontinued Jakafi therapy while trial.

The question is: Did Jakafi cause these new mutations, this clonal evolution?

 To get the answer, here’s the required background, the evidence, and the witnesses.

Jakafi (ruxolitinib) is the standard therapy for intermediate and high risk myelofibrosis. Since its FDA approval in 2011 it has changed pretty much everything. .

Jakafi inhibits the interaction between a mutated JAK2 protein—the clone — an enzyme active in, among other things, blood production, and the STAT, the Signal Transducer and Activator of Transcription proteins. Essentially, the Jak2 mutation flips the  blood production switch into the ON position and the STAT enables the message to get to the cell nucleus where the production order is carried out.

One frequent result is increased fibrosis of the bone marrow marrow, literally myelofibrosis.  Blood production may then be forced out of its blood-bone marrow niche to more hospitable quarters, notably the spleen. This produces swelling of the spleen causing pain and impacting movement, digestion, quality of life.

Jakafi interrupts that process.

When good news may be bad.

When Jakafi works – which, in the beginning, for most patients, is most of the time – it causes rapid reduction of splenomegaly and a vastly improved quality of life.  That’s very good news short term.  But the Jakafi effect doesn’t last forever – usually less than three years.  And during all this time, the patient feels better while the underlying disease continues to progress and the JAK2 clones thrive.

That’s bad news since simply feeling better is all the reason most patients need to avoid the rigors of the only curative therapy for MF: stem cell transplant. Too often that mean delayed entry to transplant and reduced odds of success.  

“At present, the only curative therapeutic option for MF is HCT [hematooietic cell transplant]. The expert guidelines recommend the option of HCT in intermediate-2/high-risk disease and selected patients with intermediate-1 disease. However, physicians as well as patients face a dilemma on the optimal timing of transplant,  especially for patients who are responding well to JAK1/2 inhibitor therapy. There is equipoise among physicians as to whether to proceed to HCT in such patients or consider HCT at the failure of JAK1/2 inhibitor therapy.”  -Jay Spiegel, Vikas Gupta et al., “Impact of genomic alterations on outcomes in myelofibrosis patients undergoing JAK1/2 inhibitor therapy” Blood Advances 2017

There may be a much more lethal aspect to Jakafi therapy.

The study by Kate Newberry, Srdan Verstovsek and their MD Anderson colleagues revealed about one-third of the patients who discontinued Jakafi for one reason or another had acquired High Molecular Risk mutations in other genes.  And over 60% of those mutations were in the dreaded ASLX-1 gene. Overall life expectancy for this group was under 14 months.

Now we can call on expert witnesses to testify on what may have caused this deadly surge in mutations.

The chief investigator who should know – Dr. Srdan Verstovsek, a leading and long-term researcher into ruxolitinib,  professor in the MD Anderson Department of Leukemia, Director of the Clinical Research Center for MPNs at MD Anderson and co-author of the latest piece of evidence  –doesn’t believe Jakafi is guilty.  Neither does his co-author colleague, Kate Newberry – now up in Boston working on a lymphoma project with her new crew at Epizyme.

But others aren’t so sure.  Dr. Alessandro M. Vannucchi, for example, professor of hematology at the

Dr. Alessandro Vannucchi

University of Florence and on the board of International Working Group for Myelofibrosis Research and Treatment, noted in a comment in Blood that transfusion dependence among those patients who discontinued Jakafi had  increased from 29% TO 43% and both hemoglobin and platelet counts had significantly reduced compared with the start of their Jakafi therapy.

 He wrote: “These findings are compatible with disease progress and hematologic toxicity resulting from ruxolitinib “

Both Verstovsek and Newberry agree. Yes, those are signs of disease progress and hematologic toxicity.

“It depends on timing of the observation,” said Verstovsek.

Srdan Verstovsek, MD, PhD

“There are two phases here. Anemia and thrombocytopenia happen during the first six months of Jakafi treatment. It’s a period during which we have to adjust dosage for 75% of patients. Then once you have a stable patient the appearance of anemia and thrombocytopenia are indications of progressing disease.

“Acquiring new mutations is normal.  The same happens in AML and in MDS.  It is very well know that these diseases are not static. There is clonal evolution, bone marrow growth in malignant cells.  I don’t believe ruxolitinib is causing clonal evolution. I can’t prove it, but that is what I believe.”

Newberry concurs:  “As the disease progresses, it’s just a natural process.  These mutations are seen in MPN disorders and leukemia in general. You see them in patients who have never taken ruxolitinib.

“I think ruxolitinib is innocent. I actually do. If I recall, the patients who have clonal evolution may have been worse off when they started the therapy, more prone to anemia, more likely to become transfusion dependent. My sense is they suffered a more aggressive disease.

‘But ruxolitinib can exacerbate some of the symptoms of the disease, that’s for sure. I agree with that. It’s hard to say what the mechanism is. Nobody has looked directly at what ruxolitinib is doing to these cells. That’s hard to do with the patient data.

“I have a different perspective,” concluded Newberry. ” Others have lots of clinical experience. My point of view, the way I look at the mechanism of how drugs cause resistance and mutation, this just didn’t look like the typical pattern of acquired drug resistance in which a drug puts selective pressure on the clone to induce mutation at other sites in the protein the drug is targeting.   In our study, we did not see acquired mutations in the JAK2 itself.  Still, ruxolitinib could contribute to genomic instability.  We just don’t know.”

Even professor Vannucchi isn’t certain.  “One concerning aspect that could not be dissected in the Newberry et al study is whether the acquisition of additional mutations results from …pressure exerted by ruxolitiib on the founding clone…permitting overgrowth of pre-existing mutated clones. Or does it represent true acquisition of novel mutations as a result of clonal genetic instability exacerbated by ruxolitinib? Or is it intrinsically related to the progression of disease and has nothing to do with ruxolitinib.”

In summary

Jakafi is an invaluable, life enhancing drug.  It has been proven safe for short term use in preparing patients for stem cell transplant. It is not a totally benign drug and its use and potential effectiveness need to be established not only through clinical criteria but mutational analysis,

Regardless of the process, whether Jakafi accelerated, exacerbated, or promoted the natural emergence of high risk mutations it appears likely Jakafi contributed to the development of clonal evolution in the group of patients studied by the MD Anderson group.

The evidence is circumstantial and far from decisive but compelling.  These high molecular risk mutations may indeed eventually appear in the MPN patient population but the relatively short time span in which they arose in this patient population and the acquisition of these mutations by a large percentage of the cohort — with nearly two-thirds of those mutations in ASXL-1 — argues for the possibility of clonal evolution acceleration due to the drug.

Beyond that, Jakafi is non-specific. It is active in multiple processes involving cells that rapidly divide and present mutational opportunities.  Jakafi  not only inhibits the JAKv617v clone but the human JAK2 protein is involved in  cell growth and development, differentiation and histone modifications. It mediates essential immune system signaling events.

The fact that patients reject Jakafi due to intolerance and the high rate of discontinuation on the COMFORT trials (50% over three years) suggests a likely toxicity. And the inability of Jakafi to be effective over time indicates incremental somatic rejection of the drug and its inability to continue enabling JAK2 recruitment and phosphorylation of STAT5 to transcribe genes.

For now, Jakafi is the best we have, and in some cases the only option beside stem cell transplant. Intermediate-2 and high risk MF patients will continue the rely on it even as its use stretches into applications for polycythemia vera  and lower risk MF patients.

We can profitably use mutation analysis to direct Jakafi  MPN therapy, particularly in PV and early stages of myelofibrosis.

Alessandro Vannucchi: “Because survival after discontinuation was significantly shorter among patients who presented evidence of clonal evolution,” wrote Vannucchi, ” one might anticipate that the early detection of newly acquired mutations represents a decision node in favor of alternative therapies or stem cell transplantation when feasible.  Unfortunately, the complexity and cost of genetic tests, uncertainties about when to obtain them during ruxolitinib treatment and the fact that only one third of the patients who discontinued ruxolitinib in the study actually had evidence of clonal progression, mark the boundary between theory and clinical practice.”

[Editor’s Note: The incidence of clonal evolution is likely much higher than one-third since that figure is based on a reduced dataset, discounting the 30 patients who died on trial. The pricing consideration referred to by Vannucchi is answered both by the falling costs of genetic analysis and the cost effectiveness of avoiding the $10,000/monthly price of Jakafi if the mutational landscape is not promising.]

Patel et al. in a group including Kate Newberry and Srdan Verstovsek concluded in their 2015 Blood study correlating mutation profiles in MF patients treated with ruxolitinib, “Patients with 3 or more mutations had the worst outcomes, suggesting that multigene profiling maybe useful for therapeutic planning for MF.” Their  study of 95 patients treated with ruxolitinib using a panel of 29 genes, excluding SRSF2, reported that mutations in any of the HMR genes studied as well as a total of ≥3 mutations were associated with decreased spleen response and a shorter time to discontinuation of therapy.  (Blood, PATEL et al., 2015)

Ayalew Tefferi,  the MPN dean at Mayo Clinic Rochester  also favors mutational testing. On observing CALR and ASXL1 mutations as the most significant risk factor for survival he concludes “These observations signify immediate clinical relevance and warrant CALR and ASXL1 mutation determination in all patients with PMF …. ” Leukemia 2014

Newberry told MPNforum:  “I agree that simply putting myelofibrosis patients on Jakafi without watching for early signs of disease progression or looking for evidence of clonal evolution isn’t the answer because eventually the disease will progress.  And I strongly agree that looking at mutations earlier would be a very good approach.”

Mutation screening by the numbers.

The major reasons for prior mutation testing before Jakafi therapy:  Mutations in high molecular risk (HMR) genes ASXL1, EZH2, IDH1/w and SRSF2 are associated with: (1) inferior prognosis,  (2) decreased spleen response, (3)  shorter time to discontinuation,  (4) greater likelihood of clonal evolution and have both (5) a negative impact on overall survival while (6) increasing the likelihood of  leukemic transformation in MF.   The presence of any of these HMR genes as well as any three or more mutations reduces the odds that Jakafi would be effective.

Stem cell transplant

While Jakafi controls the symptoms and signs of myelofibrosis in the great majority of patients  — and with that may prolong life expectancy — it does not prevent diseased cells from acquiring new mutations nor becoming resistant to ruxolitinib. This resistance leads to a loss of a control and poor overall outcome. Consideration of Stem cell transplant, the only potentially curative MPN option, needs to be on the table particularly when the patient is still doing well on ruxolitinib.

 

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