Elias Jabbour, MD
	Associate Professor Leukemia Department The University of Texas MD Anderson Cancer Center Houston, Texas

I have not seen it happen that disease truly resistant to ruxolitinib subsequently had a meaningful clinical response to another JAK inhibitor. I cannot state that if a patient’s disease fails to respond to one JAK1 or JAK2 inhibitor, it will not respond to another.

	John O Mascarenhas, MD
	Myeloproliferative Disorders Program Tisch Cancer Institute Division of Hematology/Oncology Mount Sinai School of Medicine New York, New York

Emerging data from several of the ongoing trials, including trials of the new drug momelotinib (CYT387), indicate that if a patient’s disease doesn’t respond to ruxolitinib, it doesn’t necessarily mean that it won’t respond to some of the other JAK inhibitors, probably because there’s promiscuity in their target. So it’s not universal that responding or lack of response to one means that you’re not going to respond to others.

	Ruben A Mesa, MD
	Chair, Division of Hematology and Medical Oncology Deputy Director, Mayo Clinic Cancer Center Professor of Medicine Mayo Clinic in Arizona Scottsdale, Arizona

An article published by Ross Levine’s group (Bhagwat 2013) speculated that it is possible that a dose interruption of JAK2 inhibition followed by a rechallenge might help to overcome resistance. They did not observe traditional resistance in terms of a mutation affecting binding, but rather that the cell’s signaling pathways were able to compensate around the JAK2 inhibition. In their preclinical work in the laboratory they found that they were able to restore sensitivity to the drug. This is clearly experimental, but their paper raised the question, for a patient who responded and then lost response, is it possible that rechallenging with a JAK2 inhibitor after a break may have benefit?

As we have moved people from one clinical trial of a JAK2 inhibitor to another, we have in a sense replicated this scenario of having an off period in between treatment with JAK2 inhibitors. We have seen disease that either didn’t respond or stopped responding to a JAK2 inhibitor such as ruxolitinib and then gained benefit from another JAK2 inhibitor administered on a new trial.

Multiple JAK inhibitors that have slightly different activities and benefits may bring results. Although all of them inhibit JAK2, they may all not be interchangeable. Ruxolitinib and momelotinib both inhibit JAK1 and 2 kinases, whereas others, such as SAR302503 and pacritinib, predominantly inhibit JAK2 and FLT3.

	Jerry L Spivak, MD
	Professor of Medicine and Oncology Director, The Johns Hopkins Center for the Chronic Myeloproliferative Disorders Johns Hopkins University School of Medicine Baltimore, Maryland

I personally have not stopped ruxolitinib for anyone yet to be able to answer whether disease that is resistant to this agent will also be resistant to other JAK2 inhibitors. I have had patients for whom treatment with a different tyrosine kinase inhibitor failed who subsequently responded to ruxolitinib.

	David P Steensma, MD
	Attending Physician Dana-Farber Cancer Institute Associate Professor of Medicine Harvard Medical School Boston, Massachusetts

I don’t know if there has been a publication on this issue, but our clinical trial experience has been that there are cases where one JAK2 inhibitor works well for the patient and another doesn’t. I have one patient whom we just sent to transplant this past week and who is a good example. This patient had polycythemia vera diagnosed in 1991, and 3 years ago the disease progressed to MF. I placed him on a clinical trial we had with pacritinib (SB1518). He was faring well with that agent — his spleen shrunk, his counts were good and his symptoms went away. Last year the pharmaceutical company discontinued the clinical trial. At that point, I administered ruxolitinib off study and almost immediately the patient’s condition began to worsen. I increased the dose from the initial 20 mg to 25 mg BID then to 30 mg BID and could not get the disease to respond again. I had to switch therapies completely. We tried pegylated interferon alpha 2a and then cladribine, which helped him a little. Now he is getting a stem cell transplant. This is a case of a patient who had a great experience on one JAK2 inhibitor and then we couldn’t continue that benefit with another JAK2 inhibitor.

I believe this is in part because the profiles of these JAK2 inhibitors are distinct. They all have slightly different kinase inhibitory patterns. Some inhibit JAK1 to a greater extent than JAK2. Some have inhibitory activity also on JAK3, FLT3, TIK2 and PDGFR. They are all a little different from one another, so I believe that definitely some patients will respond to one and not another. To date, most of the clinical trials have enrolled patients who have only received other therapies, such as hydroxyurea, androgens and thalidomide, because the JAK2 inhibitors have not been around for long. Most trials have excluded patients who’ve received prior JAK2 inhibitors. It has been my clinical experience and that of my colleagues, however, that there are distinctions.

	Moshe Talpaz, MD
	Alexander J Trotman Professor of Leukemia Research Associate Director of Translational Research UM Comprehensive Cancer Center Associate Chief, Division of Hematology/Oncology Director, Hematologic Malignancies University of Michigan Medical Center Ann Arbor, Michigan

We are conducting prospective studies asking whether patients whose disease is resistant to ruxolitinib can subsequently respond to other JAK2 inhibitors. We have just started these trials, so I don’t know the answer to that question.

With ruxolitinib therapy, almost every case will become resistant. We have observed 2 patterns of “resistance” to ruxolitinib. The first is not necessarily resistance. It can be described as a mixture of intolerance and resistance. The patient’s disease never responds to ruxolitinib in a significant manner in terms of the spleen. This occurs in half of the patients. The second pattern can be described as “true resistance,” in which the disease stops responding to ruxolitinib. The published data and our own clinical experiences tell us that all or almost all patients will have some kind of response, but the truth is that if the patient experiences a minimal response it will be fleeting. We see the disease stop responding and the symptoms return. The spleen starts to enlarge and the white cell count starts to increase. You cannot treat optimally in these situations because each time you treat, either the anemia or the thrombocytopenia gets worse, even with a tiny dose, so you stop treatment. I have patients who have experienced 4 years of response to ruxolitinib, then their disease stopped responding.