David S. Snyder, MD, associate chair of the Department of Hematology and Hematopoietic Cell Transplantation, professor of Hematology and Hematopoietic Cell Transplantation, and hematologist/oncologist at City of Hope, discusses how ruxolitinib (Jakafi) and fedratinib (Inrebic) may be used to pave the way toward transplant for patients with myelofibrosis.

The drugs that are available for the treatment of MPNs, ruxolitinib and fedratinib, are effective at helping to control systemic symptoms and to help reduce splenomegaly, says Snyder. However, they do not cure the disease nor do they change the natural history of the diseases. As such, ruxolitinib and fedratinib are not substitutes for transplant but they may help pave the way toward transplant. Patients who are treated with those drugs may experience a reduction in the size of their spleen and improvement in performance status, which are characteristics that could help their outcomes after transplant, concludes Snyder.

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David S. Snyder, MD, discusses how ruxolitinib and fedratinib may be used to pave the way toward transplant for patients with myelofibrosis.

Dr. Snyder on How Ruxolitinib and Fedratinib May Pave the Way to Transplant in Myelofibrosis

David S. Snyder, MD, associate chair of the Department of Hematology and Hematopoietic Cell Transplantation, professor of Hematology and Hematopoietic Cell Transplantation, and hematologist/oncologist at City of Hope, discusses tools to improve the use of allogeneic stem cell transplant in myelofibrosis.

Allogeneic stem cell transplant is currently the only curative option available to patients with myelofibrosis, says Snyder. Investigators are working on developing better tools to select the appropriate candidates for transplant, improve outcomes after the procedure, and predict who is likely to do well post-transplant, says Snyder.

To this end, new prognostic scoring systems are under development. The original systems used in this space was the Dynamic International Prognostic Scoring System (DIPSS) and DIPSS Plus. Other systems have since emerged, such as the latest the Mutation-Enhanced International Prognostic Score System (MIPSS) and MIPSS70-plus version 2.0.

These systems incorporate molecular and karyotypic information and help stratify patients in terms of prognosis and survival, not necessarily after transplant but overall with general treatment, according to Snyder. While these tools may help decide which patients should be considered for transplant, they do not help predict what outcomes will look like after transplant, concludes Snyder.

David S. Snyder, MD, discusses tools to improve the use of allogeneic stem cell transplant in myelofibrosis.

Dr. Snyder on Tools to Improve Use of Allogeneic Stem Cell Transplant in Myelofibrosis

David S. Snyder, MD, associate chair, Department of Hematology and Hematopoietic Cell Transplantation, professor, Hematology and Hematopoietic Cell Transplantation, and hematologist/oncologist, City of Hope, discusses updates in treating patients with myelofibrosis who undergo transplant.

Due to reduced-intensity conditioning regimens, it is safer to offer transplant to patients who are older and/or have other comorbidities, explains Snyder. Now, there is a physiologic age rather than a chronologic age that determines a patient’s eligibility for transplant. The majority of Snyder’s patients with myelofibrosis are in their 60s or 70s, according to Snyder.

The scoring systems for myelofibrosis are improving, including Dynamic International Prognostic Scoring System (DIPSS) and DIPSS-plus now available. Now, there is also Mutation-Enhanced International Prognostic Scoring System (MIPSS) and MIPSS-plus. Researchers are trying to fine-tune the precision of prognostication using molecular markers, genetics, and clinical parameters to better stratify patients, says Snyder. There is a learning curve to these prognostic scoring systems, but they are going to aid in selecting patients who are at higher risk and determine if they should move towards transplant sooner, concludes Snyder.

David S. Snyder, MD, discusses updates in treating patients with myelofibrosis who undergo transplant.

Dr. Snyder on Transplant Updates in Myelofibrosis

David S. Snyder, MD, associate chair, Department of Hematology and Hematopoietic Cell Transplantation, professor, Hematology and Hematopoietic Cell Transplantation, and hematologist/oncologist, City of Hope, discusses the utility of transplant in myeloproliferative neoplasms (MPNs).

Historically, patients up to the age of 50 to 55 were considered for transplant. However, the use of reduced-intensity conditioning regimens has enabled patients up to 75 years of age, as well as those with comorbidities to undergo transplant, says Snyder.

The availability of donors has also expanded, says Snyder. Patients eligible for transplant who do not have a fully matched sibling may be paired with a fully matched unrelated donor, or a partially mismatched unrelated donor. Alternative options include cord blood and haploidentical donors.

Patients who are candidates for transplant should be started on a JAK2 inhibitor, says Snyder. During treatment, it is important to determine the optimal time to move forward with transplant.

New prognostic scoring systems have the potential to simplify the decision of when to undergo transplant, concludes Snyder.

David S. Snyder, MD, discusses the utility of transplant in myeloproliferative neoplasms.

Dr. Snyder on the Utility of Transplant in MPNs

David S. Snyder, MD, associate chair, Department of Hematology and Hematopoietic Cell Transplantation, professor, Hematology and Hematopoietic Cell Transplantation, and hematologist/oncologist, City of Hope, discusses ongoing research in myelofibrosis.

Momelotinib is one of the JAK inhibitors under investigation in myelofibrosis. Unlike ruxolitinib (Jakafi), momelotinib can preserve hemoglobin, says Snyder. Although trials showed conflicting results, it’s under continued evaluation.

Pacritinib is another JAK inhibitor that seems to be platelet-sparing, which is one of the main limiting factors of using ruxolitinib. As such, this agent may be useful in patients with platelet counts below 50,000. If pacritinib moves forward in development, it could extend the utility of JAK inhibition in myelofibrosis. A phase II trial with the agent has just completed and a phase III trial is planned, which is geared toward patients who have very low platelet counts.

The telomerase inhibitor, imetelstat is also being evaluated. There was initial excitement with the agent in early studies, but it can be difficult to manage because of myelosuppression, says Snyder. Nonetheless, it is still being evaluated in clinical trials, he concludes.

Dr. Snyder Discusses Ongoing Research in Myelofibrosis

David S. Snyder, MD, associate chair, Department of Hematology and Hematopoietic Cell Transplantation, professor, Hematology and Hematopoietic Cell Transplantation, and hematologist/oncologist, City of Hope, discusses ongoing research dedicated to providing more curative options to patients with myelofibrosis.

Prior to the approval of the JAK2 inhibitor fedratinib (Inrebic), ruxolitinib (Jakafi) was the only available drug with the ability to target key clinical features of myelofibrosis, such as splenomegaly and constitutional symptoms. Despite its benefits, not all patients are able to tolerate the agent due to its associated toxicities, like thrombocytopenia.

Fedratinib, a drug that attacks the JAK2 protein in two places rather than one, not only offers an additional option to patients, but may prove to be more effective than ruxolitinib. JAK inhibitors alone have not been successful in changing the biology of myelofibrosis; however, combination approaches are under investigation.

Investigators have been channeling all of their efforts into developing a drug or combination of agents that will take the place of transplantation in the space, says Snyder, a shift comparable to that seen in chronic myeloid leukemia, where the emergence of imatinib (Gleevec) and other TKIs have revolutionized the management of the disease. With these novel agents, stem cell transplants are rarely in these patients. However, because myelofibrosis is more complex than CML, this will be a difficult task to accomplish, says Snyder, and as such, transplantation will likely remain the only curative option in the coming years.

Dr. Synder on the Quest to Revolutionize Management of Myelofibrosis

David S. Snyder, MD, associate chair and professor, Department of Hematology and Hematopoietic Cell Transplantation, and hematologist/oncologist, City of Hope, discusses mainstays of treatment in polycythemia vera (PV).

There have not been many updates to the treatment paradigm of PV in recent years, says Snyder. Low-dose aspirin and phlebotomy have been the mainstays of treatment for a while. There are robust data that illustrate the importance of using low-dose aspirin and recommending phlebotomy to maintain hematocrit below 45% for men and 42% for women.

For high-risk patients who are in need of additional cytoreductive therapy, hydroxyurea has been the gold standard, adds Snyder. Interferon can also be considered for select patients—especially pegylated interferon, which is better tolerated. Another formulation called ropeginterferon alfa-2b (PEG-Intron) has also been shown to be of benefit. The therapy is longer-acting than prior formulations, but it is not yet approved for use in the United States. However, a randomized clinical trial comparing ropeginterferon with hydroxyurea has shown an advantage in the agent’s ability to reduce of JAK burden, enabling symptom control.

Dr. Snyder on Mainstays of Treatment in Polycythemia Vera

David S. Snyder, MD, associate chair and professor, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, discusses emerging agents in myelofibrosis.

The field of myeloproliferative neoplasms (MPNs) is hitting its stride, says Snyder. There are multiple molecular markers and driver mutations being found, and investigators are beginning to better understand that secondary mutations are prognostically important. The hope is that some of these findings will lead to targeted therapies for the treatment of patients with MPNs.

One of these targeted agents is the JAK2 inhibitor ruxolitinib (Jakafi). Ruxolitinib is being used in the treatment of patients with myelofibrosis, and it is the only FDA-approved drug in this indication. There are other JAK2 inhibitors in clinical trials, such as pacritinib. Synder says that there are also non-JAK2 inhibitors being studied in myelofibrosis, including the telomerase inhibitor imetelstat.

Dr. Snyder Discusses Emerging Agents in Myelofibrosis

David S. Snyder, MD, associate chair and professor, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, discusses the use of ruxolitinib (Jakafi) in myelofibrosis.

Ruxolitinib is very good at shrinking spleen size and controlling constitutional symptoms, which are very important sources of clinical problems for patients. It is part of the reason why patients lose weight, have decreased muscle mass, and poor performance status, says Snyder. If physicians can significantly reduce the spleen size and improve their patient's ability to eat, that can help performance status. Reducing some of the constitutional symptoms also improves a patients' quality of life.

The use of ruxolitinib does however lower platelet count. Physicians must be careful about that and adjust the dose appropriately, Snyder says. It may worsen anemia, at least initially, which is a problem that most patients are dealing with already. For most patients, if their hemoglobin drops, it will recover to baseline after a few months. That effect does not seem to impair or impact the ultimate benefits to the drug, says Snyder.

David S. Snyder, MD

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