Hydrea: Facts and Myths

by John Hoogland, november 2024

In the history of MPN, Hydrea is undoubtedly the most commonly prescribed medication. Even with the development of new drugs, it still plays an important role in managing blood counts in all types of MPN. Until the introduction of newer medications, Hydrea generated little controversy. However, in recent years, we’ve seen a growing number of reports about supposed side effects and the risk of developing other types of cancer. Time to dig a little deeper into the facts surrounding this old, yet still effective, drug.Hydrea has been around for a long time—much longer than you might think. A lot longer.

The medical name for Hydrea is hydroxycarbamide, previously known as hydroxyurea. The first synthesis of hydroxyurea was in 1869 by a German chemist, although he had no idea of its potential medical uses. Only in the 1950s did researchers begin exploring its therapeutic value. Lab studies revealed anti-tumor properties, and it wasn’t until 1967 that the drug was approved for treating certain types of leukemia and skin cancer.Much later, it was discovered that Hydrea could also help in treating sickle cell disease, a severe condition caused by abnormally shaped red blood cells. It is still used for this purpose today, particularly in countries where more expensive treatments are not affordable.

In the 1970s, hydroxyurea began being used to treat leukemia and MPN, under the brand name Hydrea.Hydrea turned out to be an effective treatment for MPNs because it suppresses the production of abnormal blood cells. It is widely used as a first-line treatment for people with PV and ET, especially in high-risk patients—those more likely to develop complications such as bleeding or thrombosis.Patient education has become increasingly regulated over the years, especially regarding risks and side effects. This has led to complex regulations that require pharmaceutical companies to list anything that could potentially be a side effect or risk—without distinguishing between doses. For example, in sickle cell disease and leukemia, dosages can go up to 40 mg per kilogram of body weight—easily exceeding 3000 mg per day. In contrast, the typical maintenance dose for MPN is 500–1000 mg per day. As you can imagine, the risk of side effects generally increases with the dosage. In the 2010s, due to its chemical properties, there were concerns that Hydrea might not only combat cancer but possibly also cause it. Since skin problems are a commonly reported side effect of Hydrea, it was hypothesized that the drug might increase the risk of skin cancer. This concern was added to the official drug information.

However, strong medical evidence is lacking to support this. In fact, a large study conducted last year investigated Hydrea’s potential link to other cancers: Study by Wang et al., Blood Advances, March 14, 2023.
Hydroxyurea is widely used in MPNs to reduce blood cell counts, but because it affects DNA synthesis, there have been concerns that it might cause cancer. However, the study showed that this is not the case.The study analyzed data from 4,023 older patients (average age 77) with MPN. About 67 percent of them used hydroxyurea. The study found no significant association between hydroxyurea use and the development of secondary cancers, including acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS).

Conclusion: Hydroxyurea does not appear to increase cancer risk in older MPN patients—a reassuring finding for both patients and doctors. (summarized by ChatGPT)

Skin cancer does occur in Hydrea users, but probably not or only slightly more than in people who don’t use Hydrea. A comprehensive literature review from 2021 (Gavini et al., PubMed 34527458) that included only robust studies concluded:True incidence and causation cannot be ascertained due to the scarcity of research on this topic. Multi-center prospective studies in large groups of Philadelphia Chromosome negative MPN patients are recommended to determine the temporal relationship between Non Melanoma Skin Cancer and Hydryurea treatment.Hydrea is also often suspected of causing various side effects. In my view, this is partly due to its classification as chemotherapy, and the warnings some pharmacists still include—for example, not to touch it with bare hands or to dispose of it as chemical waste. On forums like MPN World, it is not uncommon to see people refer to Hydrea as chemical junk or toxic stuff. And although Hydrea does have side effects (see box below), these are often milder compared to those of other MPN medications. In fact, Hydrea is one of the safest MPN medications we know, precisely because we have such a long history of experience with it. By contrast, the long-term effects of newer medications are, by definition, less well understood.

Why, then, is Hydrea in a lot of countries no longer the first choice? That has to do with two key developments:

Some newer medications (like Jakafi – ruxolitinib) show clear benefits for symptoms such as fatigue, itching, and spleen size—areas where Hydrea is less effective.
Newer first-line treatments like Pegasys, Besremi, and Jakafi appear to have a positive long-term effect on disease progression, potentially even slowing the transition to MF (myelofibrosis). This is based on consistent findings of a decrease in the percentage of mutated stem cells in the bone marrow. While more research is needed, this trend is already influencing treatment decisions.

So what’s the conclusion? There is nothing wrong with Hydrea. It is a safe and effective medication for people with PV and ET. In the long term, you might benefit more from one of the alternatives—but these come with different and often more serious side effects, and their long-term outcomes are less certain. Should you stop taking Hydrea?
That’s a question to discuss with your hematologist. Together, you can make the best decision for your situation.Side Effects BoxLike all medications, Hydrea can cause side effects. If these occur, your hematologist will usually prescribe an alternative or something to counter the side effects.Note that many side effects listed in the official leaflet are rare or milder at the relatively low doses typically used in MPN. Also, some reported symptoms may be related to the disease itself, not the medication. Think of fatigue, itching, bruising, bleeding, etc.Common side effects include skin issues such as redness, rashes, dry or flaky skin, sores, or ulcers. This often leads hematologists to avoid Hydrea in patients with existing skin problems—just to be safe.Diarrhea and constipation are also frequently reported.There are more serious side effects as well, but these are very rare.

References:

Rong Wang, Rory M. Shallis, Jessica M. Stempel, Scott F. Huntington, Amer M. Zeidan, Steven D. Gore, Xiaomei Ma, Nikolai A. Podoltsev; Second malignancies among older patients with classical myeloproliferative neoplasms treated with hydroxyurea. Blood Adv 2023; 7 (5): 734–743.
Gavini DR, Salvi DJ, Shah PH, Uma D, Lee JH, Hamid P. Non-melanoma Skin Cancers in Patients on Hydroxyurea for Philadelphia Chromosome-Negative Myeloproliferative Neoplasms: A Systematic Review. Cureus. 2021 Aug 7;13(8):e16978. doi: 10.7759/cureus.16978. PMID: 345274