Dr. Richard T. Silver… The long view

Science & Medicine

Dr. Richard T. Silver… The long view

As snow fell outside, I met with the iconic Dr. Richard T. Silver in Atlanta at the American Society of Hematology (ASH) conference for an MPNforum interview. Charming and direct, Dr. Silver placed work in myeloproliferative neoplasms in context with other cancers and hematological diseases.
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– Marina Sampanes Peed

MPNforum: You have devoted decades to the science and treatment of myeloproliferative neoplasms. What are the most significant achievements thus far?;

Dr. Silver: First of all, we understand the molecular basis for most of the common MPNs with JAK2, MPL, and calreticulan (CALR) mutations. There are distinctions among these disorders even though there isn’t a clear chromosomal abnormality like Philadelphia-positive chromosome as in CML.

Therapeutically, we’ve been disappointed that we haven’t found the Holy Grail, as we have for CML. I had the good fortune to be involved with the early trials of imatinib for CML. It was exciting because we understood the molecular basis for the disease, the cytogenic basis, and developed a drug synthesized to take advantage of that knowledge. It marked the beginning of personalized medicine.

We had high expectations for a similar path for MPN, but that has not occurred. One of the most significant treatment advances for MPN is ruxolitinib, the JAK1/2 inhibitor. As our readers know, there have been at least ten other drugs synthesized, but they had significant toxicities and didn’t come to market, even though they had some benefits not seen with ruxolitinib. There is, however, renewed reason to pursue pacratinib and fedratinib.

CML has five FDA-approved drugs effective for patients. If one doesn’t work for a patient, there are other options.

We still need better therapy for the PH(-) MPNs. You know that I am very biased toward interferon as an early intervention for MPN patients. In the United States, we are behind Europe. Our data at Weill-Cornell are almost identical to that of Professor Hasselbach in Denmark, Professor Gisslinger in Austria, and Professor Kiladjian in France; interferon can put the diseases in clinical remission. We have such evidence, as do the French and the Danes.

We believe in the early treatment of polycythemia vera and myelofibrosis.

If you regard these as neoplastic diseases, which they are, we feel “watch and wait” for early stage disease as akin to telling a woman with a lump in her breast to wait until it’s in her bones.

We have evidence that in myelofibrosis, early treatment with interferon will cause stable decrease or better in about 70% of patients. We tried to do a randomized trial comparing early treatment to “watch and wait” but for various reasons that was not possible.

We have single-arm studies which are peer reviewed; the last was published in the journal Cancer, in May 2017. Interferon can even result in marrow remissions in some patients.

Interferon is not the final answer. It is not the best answer. We clearly need better drugs. The JAK1/2 inhibitors are also not the answer.

It’s very important to stress that the data stating ruxolitinib prolongs life are suspect. But clearly there are positive benefits in reduction of splenomegaly and other symptoms.

MPNforum: When you look into your crystal ball, where will we be in 10 to 50 years with MPN?

Dr. Silver: 10 to 50 years? Well, as a starter, I won’t be here! (laughs)

We will understand more of the molecular basis of disease and have better ways to treat the disease. MPNs are much more complex than CML, but less so than breast cancer. We feel sorry for people working in colon cancer and lung cancer. Those malignancies are very complex and will take much longer to figure out.

With the new sequencing techniques and cytogenetic techniques, and more knowledgeable researchers and clinicians, we will make significant progress.

MPNforum: What can MPN patients do to help the field make progress?

Dr. Silver: Certainly, in the last 10 years, through efforts by Zhenya Senyak and others like yourself, patients have played a great role in stimulating the National Institutes of Health for funding and for raising awareness. The Leukemia and Lymphoma Society, MPN Consortium, MPN Research Foundation, the Cancer Research and Treatment Fund, all are working together on MPN science and treatment. Patients supporting these organizations is critically important. We are making progress. No longer does an elevated platelet count get ignored by an internist.

MPNforum: Do you have any advice for local hematologists who cover so many diseases?

Dr. Silver: Understandably, the diseases they focus on are the common ones: breast, prostate, lung, colon cancers… Some will treat chronic lymphocytic leukemia, lymphoma myeloma – again, the more common blood cancers. They tend to not be as informed about MPNs because these diseases are much less common. They don’t always know about the prognostic scoring system we have for MPNs.

MPNforum: Why are some patients told they have ET and find out they have PV, or vice versa?

Dr. Silver: We have a poster here at ASH this year describing the difficulty in determining Essential Thrombocythemia from Polycythemia Vera in certain stages of the disease. If you have an ET patient with a high Hct and a PV patient with a low Hct, it can be hard to distinguish. A single blood count cannot determine if red cell volume is truly increased.

We insist on doing a chromium -51 red cell mass. By labeling the red cells, you have an absolute count. Most don’t do this in the US other than Weill Cornell and Johns Hopkins. It is a common practice in Europe.

We believe that in 85-90% of cases, a bone marrow biopsy can help distinguish between PV and ET. This is important when chromium -51 red cell mass isn’t used.

MPNforum: How important is the experience of the pathologist for reading bone marrow biopsies?

Dr. Silver: Most pathologists are not as attuned to MPNs because they don’t see many of them. The patient must make sure their slides are read by a pathologist in an institution where many MPN patients are seen. The more they see, the better they get in distinguishing ET from PV.

I always encourage people to get a second opinion by someone recognized as an authority.

MPNforum: What are your thoughts on stem cell transplantation for MPN patients?

Dr. Silver: It’s a very arduous procedure. Sometimes we patients are referred without really understanding what they are getting into. We only refer patients with myelofibrosis. If you transplant too late, the results are poor. If you transplant too early, they might have benefitted from other treatments.

In general, if a patient is young and has a sibling match and in otherwise good health, we go to transplant if the severity of the disease warrants it. If a patient is old with other health problems, we won’t recommend it. However, we just transplanted a 72 year old man who was otherwise in good health. He is doing great.

It’s important for every one to eat healthy, keep in shape, don’t smoke, and exercise.

I try to work out every day. Of course, I don’t smoke.

MPNforum: Does your musical gift play into the way you go about research? I understand you are a master clarinetist.

Dr. Silver: You’ve done your research! (laughs) I play the clarinet and I play tennis. I was a professional clarinetist. But I wasn’t good enough to be first chair in the New York Philharmonic so I went into medicine. My competitive instinct! The person I played with was a class above me. He was first chair. Stanley Drucker was his name and he had a 60 year career there. There are a number of doctors, physicists and mathematicians who also are excellent musicians. I played in a doctors orchestra for a number of years. They started letting lawyers in, too, to my chagrin. But if you need a violinist or a cellist or a tuba player, what are you going to do? (laughs)