Jason Gotlib, MD, MS
	Associate Professor of Medicine (Hematology) Stanford University School of Medicine/Stanford Cancer Institute Stanford, California

This is a controversial issue. Myeloproliferative neoplasm investigators are in specific camps, with some believing that hydroxyurea is definitely leukemogenic and some taking a middle-ground stance. A study from the Polycythemia Vera Study Group didn’t show a statistically significant association between hydroxyurea monotherapy and leukemia, but with further follow-up the association started to become statistically significant. That is only 1 study, however. Retrospective data out of Sweden suggest that hydroxyurea monotherapy did not increase the risk of leukemia. They reported that there was an inherent risk of leukemia in 25% of patients with myeloproliferative neoplasms who had not received hydroxyurea or another type of cytoreductive therapy. In my opinion no adequate data exist to say for certain that hydroxyurea is leukemogenic.

If someone is relatively young and has no urgent need or substantial therapeutic need for a drug like hydroxyurea, then I don’t administer it. If the patient is defined as being at high risk due to their age or history of thrombosis, then I generally use hydroxyurea as a first-line therapy. I am comfortable using it. I do discuss the issue of leukomogenicity with patients because it always comes up.

I am intrigued, though, by the idea of using ruxolitinib in place of hydroxyurea for a young patient with uncontrolled phlebotomy requirements and/or a patient who had thrombosis and who needed a cytoreductive drug. We know that ruxolitinib is effective in reducing phlebotomy requirements and provides a symptom benefit, so it would be interesting to consider the idea of using ruxolitinib in place of hydroxyurea for those younger patients in particular.

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

Hydroxyurea is not leukemogenic in MF. In trials with patients with polycythemia vera it was not shown to be leukemogenic, and I believe the same holds true in MF. When considering that patients with MF have a shorter expected survival rate, I have no concern about the possible leukemogenicity associated with hydroxyurea.

	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

My estimation of this complex issue after all of these years of data is that I do not think that hydroxyurea is very leukemogenic. When I speak with patients, I cannot guarantee them that hydroxyurea adds zero additional risk toward leukemia, but I do think that if it adds risk, the risk is fairly small.

	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

There isn’t general agreement that hydroxyurea is leukemogenic, but it’s “the emperor’s new clothes” because the data that exist are from Level 1, Grade A randomized, controlled clinical trials but people don't want to believe it. No chemotherapeutic agent in MF has prolonged survival. I can show that none of these drugs prolong life in this disorder. They shorten life expectancy and they increase the instance of cancer. They do nothing. I realize that not everyone agrees with me, but I will argue my stance in any open forum.

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

Some controversy exists regarding this issue. I think if hydroxyurea has any leukemogenicity, it’s nowhere near what chlorambucil, busulfan, radio-phosphorus or some of those older agents that were used for myeloproliferative neoplasms carry. I would say that for the patient older than 60 years, the leukemogenicity of hydroxyurea, if there is any, is so low that it’s not worth talking about. However, for a 35-year-old diagnosed with MF there is a concern. Are they going to be on hydroxyurea for decades, and is that going to cause them problems? The original hydroxyurea studies now have almost a 20-year follow-up, and I think if it has any leukemogenic potential, it’s very low.

	Srdan Verstovsek, MD, PhD
	Professor of Medicine Chief, Section for Myeloproliferative Neoplasms (MPNs) Department of Leukemia Director, Clinical Research Center for MPNs The University of Texas MD Anderson Cancer Center Houston, Texas

Many consider hydroxyurea not to be too leukemogenic to use in older patients but are cautious about using it in patients who are younger, such as 30, 40 or 50 years old. Indeed, the guidelines from the European Leukemia Net recommend that for younger patients with polycythemia vera, interferon rather than hydroxyurea should be used in the front line.