Over 20,000 haematologists, scientists and trainees gathered for this year’s ASH meeting in New Orleans despite the ice storms that gripped America at this time the meeting was an invigorating and stimulating as ever..

A new gene for MPN – CALRETICULIN

The research was published in December 2013, in the New England Journal of Medicine.

In 2005 scientists identified abnormalities in the JAK2 gene in patients with MPDs. Since the discovery, blood testing for JAK2 has become a routine part of the diagnostic work up of patients with suspected MPDs. However, whilst the vast majority of patients with polycythaemia vera are positive for the JAK2 test and can be readily diagnosed, only about half of patients with essential thrombocythaemia or myelofibrosis have a positive test. Diagnosing these patients is currently time consuming and requires multiple, often invasive tests, such as a bone marrow biopsy.

In a recent study led by Professor Tony Green from the University of Cambridge, and a separate study from Professor Robert Kralovics from Vienna, researchers identifed a new gene called CALR that was found to be abnormal in 40% of MPD patients. In particular, this was found in the majority of patients with essential thrombocythaemia or myelofibrosis that were negative for the JAK2 test.

Professor Tony Green said: “Diagnosing these chronic blood cancers is currently difficult and requires multiple tests, some of which are invasive and painful. Now, most patients with a suspected myeloproliferative disorder will be able to be given a diagnosis after a simple blood test.”

Dr Jyoti Nangalia, one of the lead investigators said: “Not only will the identification of CALR lead to a new, less invasive test, we also hope that it can lead to new treatments – just as the discovery of JAK2 did. The CALR gene is involved in a cell function – aiding with the folding of proteins made by the cell – which has not implicated in these disorders before, so our research raises as many questions as it answers.”

Based on these findings a blood test is being developed which will transform the way MPDs will now be diagnosed. The test is currently a research tool but is anticipated to be available in a number of hospitals in 2014.
Recently CALRETICULIN mutations (CALR) have been shown to convey a better prognosis in both ET and MF and for ET patients a lower risk of thrombosis or blood clotting.

Otherwise at ASH..

Updates for Ruxolitinib
There were over 80 abstracts mentioning Ruxolitinib major points for digestion included even clearer evidence for safety and survival benefit. No new toxicities after over 3 years in the phase 3 studies and a 52% reduction in risk of death. Furthermore a polled analysis o the phase 3 trials showed for the first time for every 500cm3 increases in spleen volume of the phase 3 patients survival was worse. Other highlights for this drug included data for pulmonary hypertension, splanchnic vein thrombosis, peri-transplantation and also its effects on the immune system perhaps explaining some of the minor increase in risk of infection seen with this drug.

Goodbye Fedratinib

Despite completing a successful phase 3 trial JAKARTA and showing much promise for patients not responding well or developing problems on Ruxolitinib (both of which were announced at ASH 2013) the JAK inhibitor Fedratinib has been withdrawn, causing concern and withdrawing an effective therapy for many patients. Why?

No company would invest the millions required to take a drug through a phase 3 study and have the paperwork ready for approval as was the case here if it didn’t believe the drug was safe and effective. Unfortunately for Sanofi 8 cases of a disorder known as Wernicke’s encephalopathy developed in patients taking this drug worldwide. No clear cause was identifiable and due to patient risk the drug has been withdrawn.

Importantly this is not believed to be likely to be seen with all JAK inhibitors just those that cross the blood brain barrier and we should be reminded that a different drug XL019 was also withdrawn for neurological side effects.

Telomerase of interest in MF – hope or hype?

In 2012 data was presented with this drug which inhibits an enzyme which chews away at the ends of DNA (genetic material) in patients with ET. It looked interesting but a little toxic. At this year’s ASH potentially exciting data was presented for patients with MF. Many investigators were however concerned at toxicity affecting the bone marrow as some patients had major bleeding events and others abnormal liver blood tests. So hyper or hope? Perhaps watch this space.