Jacqueline S. Garcia, MD, physician, Dana-Farber Cancer Institute, assistant professor of Medicine, Harvard Medical School, discusses the future expectations of trials and therapies to improve outcomes in myelofibrosis.

Within the treatment landscape of myelofibrosis, many clinical trials and therapies primarily focused on improving and managing the symptoms of the disease, Garcia says. Because myelofibrosis is a chronic condition, patients suffer quite a bit from their symptoms, which can include splenomegaly, disease burden, fever, fatigue, body aches, pain, depression, and more. However, there remains an unmet need to develop therapies that can modify the disease, rather than only improve symptoms.

For example, treatment with ruxolitinib (Jakafi) can reduce the symptoms; however, the underlying disease remains, and damage is still being done to the bone marrow, Garcia explains. As a result, bone marrow fibrosis reduction is not observed on a common basis, and current treatments for symptom management have not translated into a survival benefit.

As new drugs and therapies are developed and tested, particularly in combination therapy, the hope is to see increased evidence of disease modification. Garcia and colleagues published a review of clinical trials in myelofibrosis in 

 that detailed asks and expectations that could help investigators research regimens that can improve outcomes for patients with myelofibrosis now that there are more active drugs that could benefit this patient population.

If achieving transfusion independence, bone marrow fibrosis reduction, and mutant allele reduction can correlate with a survival benefit, these would serve as meaningful end points for clinical trials, Garcia notes. The review also concluded that clinical trials tend to take place in the heavily pretreated setting, and the greatest impact of disease-modifying treatment could be observed when treatment is initiated early.

It is hoped that newer drugs will expand the treatment portfolio and positively impact patients over time, Garcia concludes.

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Jacqueline S. Garcia, MD, discusses the future expectations of trials and therapies to improve outcomes in myelofibrosis.

Dr. Garcia on Future Expectations of Trials and Therapies in Myelofibrosis 

Jacqueline S. Garcia, MD, physician, Dana-Farber Cancer Institute, assistant professor of Medicine, Harvard Medical School, discusses the role of ruxolitinib (Jakafi) in myelofibrosis.

After ruxolitinib was approved by the FDA in 2011 for the treatment of myelofibrosis based on splenic volume reduction compared with placebo and best available therapy in the phase 3 COMFORT-I (NCT00952289) and COMFORT-II (NCT00934544) trials, respectively, the agent became the standard of care for patients with symptomatic advanced myelofibrosis, Garcia says. Long-term follow-up also demonstrated that ruxolitinib produced an overall survival benefit compared with placebo and best available therapy, Garcia adds.

However, many patients treated with ruxolitinib may develop resistance, have suboptimal responses, or experience relapse or progression, creating a need for additional therapies, Garcia explains. In August 2019

, the FDA approved the JAK inhibitor fedratinib (Inrebic)

 for the treatment of adult patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis. In February 2022, 

the FDA has granted an accelerated approval to pacritinib (Vonjo)

 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.

At the dose of ruxolitinib typically given to patients with a platelet count below 50 × 109/L, the agent is not as active, Garcia continues. Findings from the phase 3 PERSIST-1 (NCT01773187) and PERSIST-2 (NCT02055781) trials showed that pacritinib was effective in this subset of patients, and additional findings from PERSIST-2 are still anticipated, Garcia concludes.

Jacqueline S. Garcia, MD, discusses the role of ruxolitinib (Jakafi) in myelofibrosis.

Dr. Garcia on the Role of Ruxolitinib in Myelofibrosis

Jacqueline S. Garcia, MD, assistant professor of medicine, Harvard Medical School, physician, Dana-Farber Cancer Institute, discusses the results of the phase 2 REFINE trial (NCT03222609) in patients with myelofibrosis.

Patients eligible to participate in the REFINE trial had progression or suboptimal response to prior ruxolitinib (Jakafi) treatment, Garcia explains. In results published in the 

, 41% of patients who received the combination of the BCL-XL/BCL-2 inhibitor navitoclax and ruxolitinib experienced spleen volume reduction of at least 35% at any time on study. Moreover, bone marrow fibrosis improved by 1 or 2 grades in 33% of patients, and the median overall survival was not reached with a median follow-up of 21.6 months. 

In terms of safety, although 88% of patients experienced thrombocytopenia in the trial, this adverse effect was temporary and mild. The drop in platelet levels was manageable with dose modification, Garcia concludes.

Jacqueline S. Garcia, MD, discusses the results of the phase 2 REFINE trial in patients with myelofibrosis. 

Dr. Garcia on the Results of the REFINE Trial in Myelofibrosis 

Jacqueline S. Garcia, MD, instructor in medicine, Department of Medical Oncology, Harvard Medical School, and physician, Dana-Farber Cancer Institute, discusses results from a phase II trial examining the addition of the BCL-2/BCL-XL inhibitor navitoclax to ruxolitinib (Jakafi) in patients with primary or secondary myelofibrosis with acquired resistance to ruxolitinib.

Results from the study were impressive, according to Garcia. Investigators were able to demonstrate the regimen’s tolerability in 34 patients treated on the study. Evidence of thrombocytopenia, fatigue, and diarrhea were reported, says Garcia. Cytopenias occurred with the regimen, but leukocytosis improved. Generally, hemoglobin remained stable across the board for several weeks, even up to week 72, adds Garcia.

Platelet levels dropped between weeks 6 and 8 of treatment; however, the mean platelet level was 90,000, which is acceptable, according to Garcia. Most of the toxicities were low grade with only 1 incidence of grade 4 thrombocytopenia reported; that event was found to be reversible with a temporary dose hold.

Investigators are looking forward to see more data from the trial to confirm the safety of the regimen and further evaluate its efficacy, says Garcia. Ongoing efforts are dedicated to further categorizing these patients as well as to study navitoclax in combination as a monotherapy for patients with advanced myelofibrosis, concludes Garcia.

Jacqueline S. Garcia, MD, discusses results from a phase II trial examining the addition of the BCL-2/BCL-XL inhibitor navitoclax to ruxolitinib in patients with primary or secondary myelofibrosis with acquired resistance to ruxolitinib.

Dr. Garcia on Efficacy of Navitoclax in Ruxolitinib-Resistant Myelofibrosis

Jacqueline S. Garcia, MD, instructor in medicine, Department of Medical Oncology, Harvard Medical School, and physician, Dana-Farber Cancer Institute, discusses unmet needs for patients with myelofibrosis who progress on JAK inhibitors.

Currently, there are no approved treatments for patients who progress on ruxolitinib (Jakafi) or fedratinib (Inrebic), says Garcia. Often patients who develop resistance to JAK inhibitors will experience disease progression.

Findings from a phase II study demonstrated a clinically meaningful reduction in spleen volume and improvement in symptoms with the addition of the BCL-2/BCL-XL inhibitor navitoclax to ruxolitinib in patients with primary or secondary myelofibrosis with acquired resistance to ruxolitinib.

Eligible patients had to have received a minimum of 12 weeks of continuous ruxolitinib. Additionally, patients had to have been on a stable dose of ruxolitinib of at least 10 mg twice daily for 8 weeks. By doing this, investigators could establish the toxicity profile of ruxolitinib alone and ensure patients derived the best response on ruxolitinib before coming onto study, says Garcia.

Patients received a starting dose of 50 mg of navitoclax and ≥10 mg of ruxolitinib twice daily. After weekly assessments, the dose of navitoclax was escalated to 300 mg daily based on tolerability and platelet counts.

The primary endpoint of the study was splenic volume reduction from baseline. Secondary endpoints included total symptom score benefit, overall response rate, rate of anemia response, improvement in bone marrow fibrosis, and safety, concludes Garcia.

Jacqueline S. Garcia, MD, discusses unmet needs for patients with myelofibrosis who progress on JAK inhibitors.

Dr. Garcia on Unmet Need in Myelofibrosis

Jacqueline S. Garcia, MD, instructor in medicine, Department of Medical Oncology, Harvard Medical School, and physician, Dana-Farber Cancer Institute, discusses the management of thrombocytopenia with navitoclax in patients with myelofibrosis.

Navitoclax can induce thrombocytopenia, which can be a problem for patients with advanced myelofibrosis who don't have normal platelet levels. However, in a phase II trial, investigators were able to manage thrombocytopenia with a slow ramp-up of navitoclax and an individualized dose based on the patient’s platelet level, says Garcia. Alternatively, the dose of navitoclax could have been reduced.

With this approach, no evidence of clinically significant bleeding was observed. Patients who remained on the combination by weeks 6 to 8 experienced thrombocytopenia, but this was expected and consistent with the use of ruxolitinib (Jakafi), concludes Garcia.

Dr. Garcia on the Managing Thrombocytopenia With Navitoclax in Myelofibrosis

Jacqueline S. Garcia, MD, instructor in medicine, Department of Medical Oncology, Harvard Medical School, and physician, Dana-Farber Cancer Institute, discusses the tolerability of the combination of navitoclax plus ruxolitinib (Jakafi) in patients with myelofibrosis.

Half of the patients with high-risk molecular mutations had ≥2 mutations, explains Garcia. Data suggest that the more mutations a patient has, the more resistant they will be to therapy. A spleen volume response (SVR) was seen in 43% of patients and responses could have occurred beyond 6 months, suggesting that with longer follow-up, there might be an improvement in SVR, says Garcia. Assessments and paired questionnaires showed that total symptom score was reduced in 65% of patients from week 24 compared with baseline.

Furthermore, patients found the regimen tolerable. The combination showed evidence of thrombocytopenia, fatigue, and diarrhea but most were low grade. There was 1 patient with isolated grade 4 thrombocytopenia, but it was reversible with a temporary dose hold and the patient was able to resume therapy, concludes Garcia.

Jacqueline S. Garcia, MD, discusses the tolerability of the combination of navitoclax plus ruxolitinib in patients with myelofibrosis.

Dr. Garcia on the Tolerability of Navitoclax/Ruxolitinib in Myelofibrosis

Jacqueline S. Garcia, MD, instructor in Medicine, Department of Medical Oncology, Harvard Medical School, and physician, Dana-Farber Cancer Institute, discusses how navitoclax differs from other agents in primary or secondary myelofibrosis.

Navitoclax is an oral BH3 memetic that targets cells that are dependent on BCL-XL and not as dependent on BCL-2 and BCL-W, explains Garcia. This therapy shows that myelofibrosis cells undergo apoptotical priming, and there’s evidence for the activity of BCL-XL inhibition in reversing fibrosis and causing apoptosis, says Garcia.

In preclinical models, there has also been activity with BCL-XL inhibition and 

-mutant and -resistant models, according to Garcia. There is evidence of synergy when BCL-XL inhibitors and JAK2 inhibitors, such as ruxolitinib, are combined. Additionally, navitoclax as an oral therapy makes the combination interesting, concludes Garcia.

Jacqueline S. Garcia, MD,discusses how navitoclax differs from other agents in primary or secondary myelofibrosis.

Dr. Garcia on the Role of Navitoclax in Myelofibrosis

Jacqueline S. Garcia, MD, instructor in Medicine, Department of Medical Oncology, Harvard Medical School, and physician, Dana-Farber Cancer Institute, discusses research with the combination of navitoclax and ruxolitinib (Jakafi) in patients with myelofibrosis.

Investigators evaluated the efficacy and safety of navitoclax in combination with ruxolitinib in patients with primary myelofibrosis (n = 16), post-essential thrombocythemia myelofibrosis (n = 5), and post-polycythemia vera myelofibrosis (n = 13).

Patients had to have received ≥12 weeks of ruxolitinib prior to enrolling on the phase II trial. Among 34 treated patients, the median treatment duration was 330 days, suggesting that the combination is well tolerated, says Garcia. Responses were reported across all investigational dose levels, including 100 mg, 200 mg, and 300 mg. Moreover, 68% of patients reached the maximum tolerated dose of navitoclax at 300 mg daily.

In terms of clinical benefit, 30% of patients (n = 10) achieved a spleen volume reduction of ≥35%, says Garcia; this included the majority of patients with high-risk molecular mutations. Among the entire population, 17 of 33 patients harbored ≥1 high-risk mutation, concludes Garcia.

Jacqueline S. Garcia, MD

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