What Did We Learn About MPNs at ASH 2022?

For MF and ET patients who have a CALreticulin (CALR) mutation, there is a first potential immunological approach to treating MPNs.

Some are calling it a CALR potential “vaccine.” It is actually an antibody that specifically targets the mutated CALR mutation. It does not appear to damage normal healthy cells.

While promising, it has not yet been tested in humans. Clinical trials will need to prove safety and success in treating an MPN.

Treatment of ET is for the control of an overproduction of platelets. Some ET patients also have increased white blood counts and/or an enlarged spleen.

A “watch and wait” approach is common. Aspirin – an anti-coagulant (blood thinner) – is often a first-line “maintenance” treatment to control the risk of clots. Prescription anti-coagulants may also be prescribed.

Hydroxyurea and anagrelide (Agrylin) are the traditional standard therapies, and sometimes interferon.

Drugs approved for other MPNs are being looked at for ET patients.

For instance, the JAK inhibitor ruxolitinib (Jakafi), currently approved for PV and MF, may help symptomatic ET patients by reducing enlarged spleen and/or fatigue.

Bomedemstat (IMG 7289), which works differently than a JAK inhibitor, has shown disease control in some patients.

A global study is comparing ropeginterferon (Besremi), a long-acting interferon approved for PV, as a second-line therapy for ET.

The goal of any new drug development is to develop safe, simple, and effective therapy, and all three need to be measurable.

Since ET patients most often have few or no symptoms, it is very difficult and time consuming to evaluate them for a drug aimed at symptom reduction.

Offering a symptom-free patient a drug that might have side effects is more challenging, for a physician and patient.

Rusfertide, now in Phase 3 clinical trials, has shown patients with PV receiving twice weekly injections have a significantly lower need for phlebotomies without significant side effects.

Studies of ruxolitinib in PV patients show not only the expected symptom improvement, but also over time, a decrease in JAK 2 mutation (allele burden), identified as the primary driver of the disease. This molecular response has been connected with a decrease in transformation to MF.

A JAK gene mutation is present in the great majority of people living with myelofibrosis. JAK inhibitors target the gene’s mutation to stop it from signaling the bone marrow to behave abnormally.

Currently, approved JAK inhibitors include:

• Ruxolitinib
• Pacritinib
• Fedratinib

Interferon is also approved for MF, which works differently than a JAK inhibitor.

Now in Phase 3 trials, momelotinib is a JAK inhibitor expected to be approved by the FDA in 2023. Momelotinib was found to reduce spleen size, improve fatigue, bone pain, and other MF symptoms. It was not found to reduce hemoglobin (red blood cell counts), a common JAK inhibitor side effect. It potentially increases hemoglobin, so some transfusion-dependent patients no longer require blood transfusions.

Pacritinib is approved for MF patients with cytopenia, very low platelets, which can also co-exist with low red cell counts and anemia.

A new finding shows pacritinib can not only increase platelets but also increase hemoglobin in some patients. With increased hemoglobin comes reduction or elimination of anemia-related blood transfusions.

Global phase 3 trials are still in process, but each of these combined with ruxolitinib offers promising early data:

• Navitoclax (ABT-263), involved in how cells decide to live or die.
• Pelabresib (BET inhibitor CPI-0610), changes how genes are packaged and expressed in cells.
• Parsaclisib (P13 kinase inhibitor), uses a new and different signaling pathway to MF.

Several other drugs are in earlier stages of development, with some just entering clinical trial phases.

Studies of COVID-19 and blood cancer patients, including MPN patients, suggest that MPN patients and those close to them should remain vigilant.

Continue to follow experts’ guidelines to avoid becoming seriously ill and/or hospitalized with the virus. Keep vaccinations up to date, wear masks, avoid crowds, and practice social distancing. If you are exposed to COVID-19 or become symptomatic, contact your physician immediately.