John O. Mascarenhas, MD, is a professor of medicine at the Icahn School of Medicine at Mount Sinai; as well as director of the Center of Excellence for Blood Cancers and Myeloid Disorders, director of the Adult Leukemia Program, and a member of The Tisch Cancer Institute

Dr Mascarenhas on the Efficacy of Imetelstat Plus Ruxolitinib in Higher-Risk Myelofibrosis

“We have some preliminary efficacy data demonstrating spleen responses, symptom responses, and even reductions in driver mutations, including 

, and subclonal, high-risk mutations like 

. We’ve seen this in the [imetelstat] monotherapy [and] relapsed/refractory settings, but [these are] really the first data demonstrating the tolerability, earlier on, with ruxolitinib and the ability to get these kinds of clinical outcome measures, [such as] spleen [response], symptom [improvement], and [measurement of] biomarkers of disease modification like reduction of 

John O. Mascarenhas, MD, a professor of medicine at the Icahn School of Medicine at Mount Sinai; as well as director of the Center of Excellence for Blood Cancers and Myeloid Disorders, director of the Adult Leukemia Program, and a member of The Tisch Cancer Institute, discussed efficacy findings and next steps for the phase 1/1b IMproveMF trial (NCT05371964) investigating imetelstat (Rytelo) plus ruxolitinib (Jakafi) in patients with intermediate-1, intermediate-2, and high-risk myelofibrosis.

Preliminary efficacy data demonstrated clinical responses like spleen volume response (SVR), symptom improvement, and decreases in driver mutations—including 

, and high-risk subclonal mutations like 

. Across all 4 imetelstat dose cohorts included in the study, investigators observed trends toward a reduction from baseline total symptom score over 12 weeks, as well as toward dose-dependent SVR. These findings, previously observed with imetelstat monotherapy and in the relapsed/refractory myelofibrosis setting, represent the first evidence of the tolerability and potential disease modification associated with this agent when combined with ruxolitinib in earlier treatment phases, he said.

As this cohort expands, further efficacy findings will include bone marrow fibrosis grading, marrow cellularity, mutational burden, and levels of circulating CD34-positive cells, Mascarenhas explained. The durability of treatment, patient retention on therapy, and sustained clinical benefit are key objectives of the phase 1b component, he stated. Additionally, part 2 of the study is now enrolling JAK inhibitor–naive patients to evaluate the upfront combination of imetelstat and ruxolitinib, aligning with broader efforts to assess early intervention strategies in myelofibrosis, he concluded.

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John O. Mascarenhas, MD, discussed findings from the IMproveMF trial investigating imetelstat plus ruxolitinib in patients with higher-risk myelofibrosis.

John Mascarenhas, MD, professor of medicine, the Icahn School of Medicine, Mount Sinai, director, the Center of Excellence for Blood Cancers and Myeloid Disorders, member, the Tisch Cancer Institute, Mount Sinai, discusses first-line treatment decisions for patients with myelofibrosis.

Although recent advancements have been made in the myelofibrosis treatment landscape, treatment in the frontline setting has remained largely unchanged over the past decade, Mascarenhas begins. Ruxolitinib (Jakafi) remains the treatment of choice for patients with platelet counts above 50 × 10

/L; however, when treating patients with platelet counts below 50 × 10

/L , pacritinib (Vonjo) should be used, Mascarenhas says. In February 2022, 

 to pacritinib for the treatment of adult patients with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 10

Although pacritinib is indicated for patients below the 50 × 10

/L platelet threshold, data from the phase 3 PERSIST-2 trial (NCT02055781) showed that the agent has efficacy in patients with platelets less than 100 × 10

/L, Mascarenhas continues. However, patients with platelet counts above 100 × 10

/L remain great candidates for treatment with ruxolitinib, he adds.

Additionally, fedratinib (Inrebic) could be considered as another option in the first-line setting for patients who have significant splenomegaly, Mascarenhas continues, noting that this agent could effectively reduce spleen size. He adds that fedratinib is typically used in the second-line setting.

Fedratinib does have a simpler dosing regimen in capsule form, and it is typically with a heavy meal to assist with the absorption to reduce some of the gastrointestinal toxicities. However, it is important to warn patients that they can have a degree of nausea and diarrhea; however, these adverse effects are generally manageable during the first few treatment cycles and rarely lead to discontinuation, Mascarenhas concludes.

John Mascarenhas, MD, discusses first-line treatment decisions for patients with myelofibrosis.


Dr Mascarenhas on First-line Treatment Decisions in Myelofibrosis

John O. Mascarenhas, MD, professor of medicine, hematology, and medical oncology, Icahn School of Medicine at Mount Sinai, director, the Center of Excellence for Blood Cancers and Myeloid Disorders, member, the Tisch Cancer Institute, discusses evolution of JAK inhibitors in the treatment landscape of myelofibrosis.

For nearly a decade, ruxolitinib (Jakafi) was the only JAK inhibitor approved for the treatment of patients with myelofibrosis after 

 as the first drug to specifically treat patients with myelofibrosis in November 2011. However, fedratinib (Inrebic) and pacritinib (Vono) joined the treatment paradigm in recent years. In 2019, 

 for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis and, most recently, in 2022, 

the FDA granted an accelerated approval to pacritinib

 for the treatment of adult patients with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 109/L. It is anticipated that momelotinib will be approved at some point in 2023, Mascarenhas notes.

Due to the expanding options for JAK inhibitors in the treatment of myelofibrosis, it is critical that practitioners be aware of the different niches that a JAK inhibitor may be applicable, Mascarenhas says.

Because ruxolitinib has been a part of the treatment landscape for nearly a decade and has an established role in the treatment of myelofibrosis, clinicians may be more comfortable with the drug due to a wealth of experience with that particular JAK inhibitor, and it will likely remain the mainstay of JAK inhibitor therapy for patients with myelofibrosis, Mascarenhas continues.

The other JAK inhibitor options can fill needs in specific subsets of patients. Pacritinib represents a treatment option for patients with platelet count of less than 50 x 109/L, and, notably, it can be utilized, irrespective of platelet count, as a second-line JAK inhibitor, Mascarenhas says. Moreover, fedratinib has broader label and can be utilized in the up-front or second-line settings, Mascarenhas says. As a second-line treatment, fedratinib represents a potential option specifically in patients who experience progression or a lack of spleen response with ruxolitinib, Mascarenhas adds. However, neither ruxolitinib nor fedratinib are good drugs for improving anemia and can be associated with myelosuppression, Mascarenhas concludes.

John O. Mascarenhas, MD, discusses evolution of JAK inhibitors in the treatment landscape of myelofibrosis.

Dr. Mascarenhas on the Evolution of JAK Inhibitors in Myelofibrosis

John O. Mascarenhas, MD, professor, Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, director, the Center of Excellence for Blood Cancers and Myeloid Disorders, member, the Tisch Cancer Institute, discusses updates from the phase 2 MANIFEST trial (NCT02158858) in patients with myelofibrosis.

The MANIFEST trial was a randomized, blinded study investigating pelabresib (CPI-0610) as a single agent and in combination with ruxolitinib (Jakafi).

In the third experimental arm, patients who had not been previously treated with a JAK inhibitor received the combination of pelabresib and ruxolitinib, which continued to demonstrate success with 68% of patients achieving a spleen volume reduction of at least 35%, Mascarenhas says. Additionally, 56% of patients saw at least a 50% improvement in total symptom score (TSS), Mascarenhas explains. Compared with historical data of single-agent ruxolitinib, the combination elicited higher efficacy for these patients, Mascarenhas notes.

In the second experimental arm featuring patients who had suboptimal responses to prior treatment with single-agent ruxolitinib, the combination achieved at least a 35% reduction in spleen volume in 30% of patients, and 37% of patients saw at least a 50% improvement in TSS, Mascarenhas concludes.

John O. Mascarenhas, MD, discusses updates from the phase 2 MANIFEST trial in patients with myelofibrosis.


Dr. Mascarenhas on Updates from the MANIFEST Trial in Myelofibrosis

John O. Mascarenhas, MD, associate professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai, director of the Adult Leukemia Program, and leader of Clinical Investigation within the Myeloproliferative Disorders Program at Mount Sinai, and a member of the Tisch Cancer Institute, discusses the role of genetic testing in myeloproliferative neoplasms (MPNs). 

At most cancer centers, genetic testing is typically performed at the time of diagnosis or if a patient’s diagnosis changes, explains Mascarenhas. At initial diagnosis, next-generation sequencing (NGS) may be performed if the patient’s bone marrow biopsy shows that their blood is not able to be aspirated. Physician preference often determines which NGS panel is utilized, Mascarenhas says.

Typically, NGS panels test for myeloid-associated genetic mutations commonly found in patients with myelodysplastic syndrome, MPNs, or acute myeloid leukemia, says Mascarenhas. Moreover, identification of driver mutations, such as 

 can confer prognostic significance. Additionally, the absence of these driver mutations indicates triple-negative disease, which is also prognostic. 

Currently, genetic testing results do not have therapeutic implications, Mascarenhas explains. However, immunotherapeutic agents directed toward calreticulin are in development as the gene codes for a potentially targetable cell surface mutation. Ultimately, MPNs are complex diseases so prognostically significant subclonal mutations are used in risk stratification, concludes Mascarenhas.

John O. Mascarenhas, MD, discusses the role of genetic testing in myeloproliferative neoplasms.  


Dr. Mascarenhas on the Role of Genetic Testing in MPNs 

John O. Mascarenhas, MD, an associate professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai, discusses thepotentialsignificance of pacritinib in patients with myelofibrosis.

Pacritinib is an important potential agent in this patient population, as it's the 1 JAK2 inhibitor that appears to cause the least amount of myelosuppression, Mascarenhas explains, especially in relation to thrombocytopenia. Patients who have a platelet count below 50,000, defined as severe thrombocytopenia, are an unmet need within the space; the current JAK inhibitors that are approved in myelofibrosis cannot be safely administered to this patient population, he adds.

This patient population is typified by a myelodepleted phenotype. While they don't always have enlarged spleens, they are typically characterized by low blood counts and poor outcomes, Mascarenhas concludes.

John O. Mascarenhas, MD, discusses the potential significance of pacritinib in patients with myelofibrosis.



Dr. Mascarenhas on the Significance of Pacritinib in Myelofibrosis

John O. Mascarenhas, MD, associate professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai; director of the Adult Leukemia Program; and leader of Clinical Investigation within the Myeloproliferative Disorders Program at Mount Sinai, and a member of the Tisch Cancer Institute, discusses emerging agents in myelofibrosis.

The BET inhibitor CPI-0610 and the BCL-2 inhibitor navitoclax have demonstrated efficacy in phase 2 clinical trials as monotherapy or in combination with ruxolitinib (Jakafi) in patients with refractory or intolerant advanced myelofibrosis, says Mascarenhas. The agents were shown to improve splenomegaly and symptom burden, as well as bone marrow fibrosis and anemia in a subset of patients, Mascarenhas explains.

As such, CPI-0610 and navitoclax are being evaluated in the frontline setting to determine if adding them to ruxolitinib could improve the efficacy demonstrated in the second-line setting, Mascarenhas says. For example, CPI-0610 in combination with ruxolitinib is being evaluated for patients with treatment-naïve myelofibrosis vs ruxolitinib plus placebo in the phase 3 MANIFEST-2 trial (NCT04603495). The hope is that the addition of CPI-0610 will deepen splenic and symptom responses, while reducing bone marrow fibrosis and anemia that is associated with JAK inhibition, concludes Mascarenhas.

John O. Mascarenhas, MD, discusses emerging agents in myelofibrosis.  


Dr. Mascarenhas on Emerging Agents in Myelofibrosis 

John O. Mascarenhas, MD, associate professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai; director of the Adult Leukemia Program; and leader of Clinical Investigation within the Myeloproliferative Disorders Program at Mount Sinai, and a member of the Tisch Cancer Institute, discusses the need to develop curative therapies in myelofibrosis.

Currently, the only curative-intent treatment for patients with myelofibrosis is hematopoietic stem cell transplant, says Mascarenhas.

However, many patients are not eligible for transplant due to advanced disease or comorbidities, Mascarenhas explains. Additionally, transplant is associated with significant toxicity, as well as an increased risk of morbidity and mortality.

Although JAK inhibitors have been a welcome addition to the myelofibrosis armamentarium, the agents do not elicit a survival benefit, says Mascarenhas. 

As such, novel combination regimens with JAK inhibitors should be evaluated for potential overall survival benefit among this population, Mascarenhas explains. 

Although it may not provide cure, the telomerase inhibitor imetelstat (GRN163L) could provide potential overall survival benefit in patients with myelofibrosis, concludes Mascarenhas.

John O. Mascarenhas, MD, discusses the need to develop curative therapies in myelofibrosis.  



Dr. Mascarenhas on the Need to Develop Curative Therapies in Myelofibrosis 

John O. Mascarenhas, MD, associate professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai; director of the Adult Leukemia Program; and leader of Clinical Investigation within the Myeloproliferative Disorders Program at Mount Sinai, and a member of the Tisch Cancer Institute, discusses the potential role of pacritinib in myeloproliferative neoplasms (MPNs).

Pacritinib is an investigational JAK2/FLT3 inhibitor, which demonstrated early efficacy and safety in patients with MPNs. According to Mascarenhas, the agent may have utility as frontline therapy for JAK-inhibitor naïve patients who have a platelet count less than 50,000/L. 

Additionally, pacritinib could be utilized in the second-line setting for patients who develop low platelet counts after stopping ruxolitinib (Jakafi) as these patients tend to have poorer outcomes, Mascarenhas says.

Also, pacritinib appears to be less myelosuppressive than other JAK2 inhibitors, which suggests it could be used in combination with other investigational non-JAK inhibitors, adds Mascarenhas. 

Notably, pacritinib also inhibits the interleukin-1 receptor-associated kinase 1, which triggers inflammasomes. As such, the agent is also being evaluated as a potential treatment for patients with the coronavirus disease 2019, concludes Mascarenhas.


John O. Mascarenhas, MD, discusses the potential role of pacritinib in myeloproliferative neoplasms.  



Dr. Mascarenhas on the Potential Role of Pacritinib in MPNs 

John O. Mascarenhas, associate professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai; director of the Adult Leukemia Program; and leader of Clinical Investigation within the Myeloproliferative Disorders Program at Mount Sinai; and a member of the Tisch Cancer Institute, discusses the impact of ruxolitinib (Jakafi) in the myelofibrosis treatment paradigm.

In 2011, ruxolitinib was approved by the FDA for myelofibrosis, and in 2014, it was approved for polycythemia vera. Prior to ruxolitinib, there weren’t any effective treatments available to address symptom burden and splenomegaly, which are 2 important aspects of the disease process, explains Mascarenhas.

With the commercial availability of ruxolitinib, quality of life and outcomes of patients with myelofibrosis changed significantly. Reports have shown that patients feel better, have less spleen-related complaints, and they are able to eat more. A reversal of cachexia has also been observed, and thus, patients are living longer than they would in the absence of the drug, says Mascarenhas.

Unfortunately, the great benefits of ruxolitinib come with a cost, adds Mascarenhas. For example, similar to some other cancer treatments, there is an element of myelosuppression. Investigators have also discovered that there is some degree of infectious risk, such as herpes zoster, urinary tract infections, or pneumonia. However, for most patients, the many benefits of the drug outweigh the risks, says Mascarenhas.

The median time of discontinuation with the agent is approximately 3 years, and 85% of patients discontinue treatment in 5 years. Ruxolitinib marks a huge advancement in the myelofibrosis treatment paradigm, according to Mescarenhas, but some unmet needs remain.

John O. Mascarenhas, MD, discusses the impact of ruxolitinib in the myelofibrosis treatment paradigm.

John O. Mascarenhas, MD

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