JAK Inhibitors: Life is Good, Stable is Good

As we opened the first three clinical trials of JAK inhibitors in the summer of 2007 at MD Anderson Cancer Center, there was palpable enthusiasm and much anticipation among both physicians and patients. I vividly remember my first patient who enrolled in the phase I/II trial of ruxolitinib (the very first person in the world to be treated with a JAK inhibitor, in fact). He was an older man with massive splenomegaly and hepatomegaly resulting is ascites and swelling of the legs, severely compromising his ambulation and quality of life. In addition to worsening anemia, he developed substantial weight loss, cachexia, night sweats, low-grade fevers, and overwhelming fatigue—classic features of progressive myelofibrosis. He was refractory to standard therapies and was very anxious to start on this new therapy – so much so that he spent one month in a hotel in Houston (he was from Florida) waiting for the trial to begin. In short, this trial was his only hope. None of us knew what would happen. We were cautiously optimistic. JAK inhibitors were the first targeted therapies to be tested in myelofibrosis (MF), but would the drug be tolerable? What would be its effects? We didn’t know.That first month-- during which we enrolled the first three patients in the first dose cohort-- was quite amazing. Within one month of starting ruxolitinib, the first patient’s splenomegaly disappeared, and his hepatomegaly was reduced. His ascites and leg swelling markedly improved, as did his systemic symptoms. His energy level significantly improved. It was an unbelievable transformation. He was able to return to his daily activities, and several months later, upon return to Florida, resumed playing golf – his favorite pastime that he had given up more than a year prior, owing to progressive disease. He went on to live another three years with a very good quality of life before eventually succumbing to MF.The third patient we enrolled was a patient of Dr. Hagop Kantarjian, Chairman of our Leukemia Department. She was a woman in her late 50s with a spleen so large, she looked as though she were nine months pregnant. Within two weeks of taking ruxolitinib, her spleen began shrinking, and after one month, her spleen was 50 percent smaller. Her energy level improved, and she began to gain weight. Her improvements were so dramatic that I called Dr. Kantarjian to come to my clinic so he could see for himself her transformation. Amazingly, to date, this patient is still enrolled in the same trial and has been taking ruxolitinib now for 7½ years – the longest anyone in the world has been treated with a JAK inhibitor.We were awe-struck by the dramatic transformations of these first few patients. These patients were very sick and were unable to participate in most of their normal daily activities. The JAK inhibitor gave them their lives back. Along with the large reductions in splenomegaly, their symptoms also began to lessen. Patients regained their appetites and started gaining weight. Life was good again. Of course, along with triumph comes disappointment. By the traditional criteria with which we would evaluate a response in hematologic malignancies, these patients would have been considered “failures” as none of them achieved complete or partial remissions. However, the improvements in symptoms and quality of life could not be denied.This marked a turning point in the way we think about and treat myeloproliferative neoplasms (MPNs). We began to question how we define clinical benefit. The development of the MF symptom assessment form (MF-SAF)

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 has allowed us to measure and quantify symptoms and quality of life, fundamentally transforming the way we assess therapeutic responses in MPNs. The change in the MPN symptom assessment form (MPN-SAF) was accepted by the U.S. Food and Drug Administration as a secondary end point in their evaluation of ruxolitinib. This was the first time in malignant hematology that symptom improvement was used as a secondary end point in a phase III approval study (the COMFORT-I study).

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 A 50-percent reduction in the MPN-SAF is now included as a response in the revised response criteria for MF published in 2013 and is included as a primary or secondary end point in all clinical studies of new therapies in MF.

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 Furthermore, we now know, after a series of long-term follow-up analyses, that in addition to improving symptoms and quality of life, ruxolitinib also prolongs patients’ lives, altering the natural course of the disease.

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 So, although JAK inhibitors are not curative and do not eradicate the disease (exceptions exist), it has given people their quality of life back for much longer than expected. I recently saw another patient who has been on a JAK inhibitor since fall 2007 when she came to see us. At that time, she was using a wheelchair and had advanced MF. At this most recent clinic visit, she took out a photo of her family that displayed four young children, all less than five years of age. Then she said, “If it was not for this therapy, I would not have seen my four grandkids. Life is good. Stable is good.” I cannot agree more, as I have learned to value “stable.” It is not always about achieving a response by traditional response criteria, but rather helping patients live longer with a good quality of life.During the past 10 years, we have also learned that the story is much more complicated than we had initially realized. We now know that there are other mutations other than JAK2 V617F driving upregulated JAK-STAT signaling (e.g. MPL, CALR, and potentially others). Recurrent mutations in genes involved in epigenetic regulation (ASXL1, IDH 1/2, EZH2), splicing (SRSF2), and other cellular functions have been identified, and these likely contribute to the heterogeneity in the clinical presentation of patients with MF and other MPNs.

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 Ten years since the discovery of JAK2 V617F, we are now combining novel therapies that target other pathways (e.g., epigenetic inhibitors, Hedgehog pathway inhibitors, PI3K inhibitors, and others) with JAK inhibitors to bring added benefits to patients-- such as improving anemia, reducing bone marrow fibrosis, and always trying to extend the duration and quality of life. Additionally, drugs targeting cellular functions other than cell signaling and epigenetic regulation (e.g., imetelstat, which targets telomerase, and the anti-fibrotic agent PRM-151) are exciting areas of clinical development in MF. There is so much more to do, and JAK inhibitors are only the beginning.