Laura C. Michaelis, MD, associate professor, Medical College of Wisconsin, discusses safety considerations with the combination of venetoclax (Venclexta) and azacitidine in acute myeloid leukemia (AML).

Findings from the phase 3 VIALE-A trial (NCT02993523) demonstrated a 34% reduction in the risk of death with venetoclax/azacitidine vs azacitidine alone in patients with treatment-naïve AML who were ineligible for intensive therapy. Although the regimen appears to be better tolerated compared with more cytotoxic therapies for this patient population, safety considerations are needed, says Michaelis. 

Notably, the majority of patients with newly diagnosed AML present with baseline disease-related toxicities, such as night sweats, fatigue, neutropenia, thrombocytopenia, and liver function test abnormalities, Michaelis explains. Over time, treatment with venetoclax/azacitidine can lead to myelosuppression, Michaelis adds.

Traditionally, bone marrow biopsies are not routinely conducted after the first cycle of treatment with single-agent azacitidine or single-agent hypomethylating agents, Michaelis says. It could take up to 6 cycles of therapy for patients to achieve the maximal response and treatment-related cytopenias are generally manageable, so biopsies are not needed initially, Michaelis says. With the combination of venetoclax/azacitidine, obtaining a bone marrow biopsy following cycle 1 of treatment can be useful in determining whether a patient can delay treatment for treatment-related cytopenia, Michaelis says. If the bone marrow biopsy shows that the patient is in remission, delaying treatment could be beneficial, whereas if the patient has active disease, treatment should be continued, concludes Michaelis.

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Laura C. Michaelis, MD, discusses safety considerations with the combination of venetoclax and azacitidine in acute myeloid leukemia. 



Dr. Michaelis on Safety Considerations With Venetoclax/Azacitidine in AML 

Laura C. Michaelis, MD, associate professor, Medical College of Wisconsin, discusses the role of interferon in myeloproliferative neoplasms (MPNs).

Hydroxyurea is a common treatment arm in randomized trials in polycythemia vera and essential thrombocythemia, says Michaelis. However, interferon has seen an uptick in utility for patients with JAK2-positive MPNs. Notably, data suggests that interferon can lessen a patient’s molecular mutation burden.

The National Comprehensive Cancer Network guidelines have indicated interferon as an appropriate frontline treatment for some patients with MPNs, says Michaelis.

Interferon may be better tolerated in younger patients with MPNs, explains Michaelis. Moreover, interferon is less likely to cause fertility-related adverse events in patients.

In terms of long-term treatment considerations, it is important to remember that hydroxyurea is associated with skin toxicities, explains Michaelis.

Pegylated interferon is well tolerated and should be considered in the up-front treatment of patients with MPNs, concludes Michaelis.

Laura C. Michaelis, MD, discusses the role of interferon in myeloproliferative neoplasms.

Dr. Michaelis on the Role of Interferon in MPNs

Laura C. Michaelis, MD, associate professor, Medical College of Wisconsin, discusses potential combination strategies with ruxolitinib (Jakafi) in myelofibrosis.

The JAK inhibitors ruxolitinib and fedratinib (Inrebic) are approved for the treatment of patients with myelofibrosis. Both agents have shown improved symptom burden and splenomegaly in patients with intermediate- or high-risk disease, says Michaelis.

However, some patients do not respond well to ruxolitinib, develop significant toxicities, or progress on the agent, explains Michaelis. As such, multiple combination strategies are being investigated to improve outcomes for these patients.

Ruxolitinib in combination with hypomethylating agents such as decitabine (Dacogen) or azacitidine (Vidaza) have been evaluated in patients who have newly diagnosed or accelerated phase disease, says Michaelis.

Agents such as interferon, danazol, or immunomodulatory agents like thalidomide (Thalomid), lenalidomide (Revlimid), pomalidomide (Pomalyst) could also lead to improved outcomes in combination with ruxolitinib, says Michaelis.

Finally, combining ruxolitinib with PI3K inhibitors, BET inhibitors, BCL-2 inhibitors, and NEDD8 inhibitors could lead to the development of important targeted approaches beyond the JAK/STAT pathway, concludes Michaelis.

Laura C. Michaelis, MD, discusses potential combination strategies with ruxolitinib in myelofibrosis.

Dr. Michaelis on Potential Combination Strategies With Ruxolitinib in Myelofibrosis

Laura C. Michaelis, MD, associate professor, Medical College of Wisconsin, discusses the direction of future myelofibrosis research.

The myelofibrosis treatment paradigm has progressed significantly since the approval of ruxolitinib (Jakafi), yet the clone still has not been successfully eradicated, leaving some remaining questions in the field, says Michaelis. One such question has to do with whether it’s even necessary to eradicate the clone. Better stratification systems exist now and some patients with myelofibrosis can live with the disease for a long time, making treatment potentially unnecessary, according to Michaelis. Many patients can be observed with no treatment, she adds.

For someone with higher-risk disease, how is the disease being modified? Ruxolitinib alone or JAK inhibitors as a whole are not going to answer that question, according to Michaelis, although they are good for splenic response and reduction symptom response. Another unanswered question is whether more drugs should be used earlier, even in patients who have lower risk of disease, to prevent the clone from expanding. Additionally, “Are new drugs needed to tackle the clone at different areas of vulnerability, not just the JAK-STAT pathway?”

Another area of research should focus on making transplant safer and performing transplants earlier before patients develop resistant, damaged marrow and other organs, such as liver or lungs, as that can make the procedure more dangerous, concludes Michaelis.

Laura C. Michaelis, MD, discusses the direction of future myelofibrosis research.

Dr. Michaelis on Unanswered Questions in Myelofibrosis Treatment

Laura C. Michaelis, MD, associate professor of medicine, Division of Hematology and Oncology, Medical College of Wisconsin, discusses the treatment of patients with myelofibrosis and anemia.

It is common for patients with myelofibrosis to present with anemia, says Michaelis. Notably, treatment with ruxolitinib (Jakafi) may exacerbate anemia in this patient population.

Combining ruxolitinib with an erythropoiesis-stimulating agent like darbepoetin alfa (Aranesp), or an androgen agent like danazol (Danocrine) may mitigate anemia in some patients.

Additionally, some patients with myelofibrosis and anemia have extramedullary hematopoiesis resulting from an enlarged spleen. Patients receiving ruxolitinib may see a rise in their hemoglobin as their spleen shrinks despite the drug’s myelosuppressive effect, concludes Michaelis.

Laura C. Michaelis, MD, discusses the treatment of patients with myelofibrosis and anemia.

Dr. Michaelis on Treating Patients With Myelofibrosis and Anemia

Laura C. Michaelis, MD, associate professor, Medical College of Wisconsin, discusses the integration of fedratinib (Inrebic) into the treatment paradigm of myelofibrosis.

While Michaelis has not yet used fedratinib in frontline therapy, she believes that many doctors will experience this transition period as they become more familiar with the drug and what patients will respond well to it.

Michaelis has 2 patients who have inadequate response who have progressed on ruxolitinib (Jakafi). Therefore, Michaelis is exploring treatment options, including fedratinib as a second-line therapy or enrolling them in clinical trials. The myelofibrosis field still needs to explore ruxolitinib versus fedratinib in patients with myelofibrosis, Michaelis concludes.

Laura C. Michaelis, MD, discusses the integration of fedratinib into the treatment sequence of myelofibrosis.

Laura C. Michaelis, MD

Articles

Dr. Michaelis on Safety Considerations With Venetoclax/Azacitidine in AML

Dr. Michaelis on the Role of Interferon in MPNs

Dr. Michaelis on Potential Combination Strategies With Ruxolitinib in Myelofibrosis

Dr. Michaelis on Unanswered Questions in Myelofibrosis Treatment

Dr. Michaelis on Treating Patients With Myelofibrosis and Anemia

Dr. Michaelis on Fedratinib in Myelofibrosis Treatment