By Abdulraheem Yacoub, MD
What were the results of the MPN (myeloproliferative neoplasm) Study of the add-on of Parsaclisib to Ruxolitinib therapy? At the American Society of Hematology (ASH) 2022 in New Orleans, I had the opportunity to present the final safety and efficacy results of the add-on Parsaclisib study in patients with myelofibrosis and suboptimal response.
This is the final results of a phase 2 study. Ruxolitinib has been approved for myelofibrosis, for clinical benefits. That includes splenic reduction, symptom improvement, and survival advantage. However, some patients manifest a suboptimal response to Ruxolitinib. This is believed to be partially related to PI3K signaling.
The co-inhibition of PI3K and JAK inhibition can result in additional clinical benefit in patients with suboptimal response. Thus, we designed a study adding Parsaclisib, which is a potent and highly selective PI3K delta inhibitor. In patients with Ruxolitinib and a suboptimal response, the design of the study is enabled to measure the advantages of a single agent addition on a backbone of Ruxolitinib. Patients included on the study where patients on a stable and optimized dose of Ruxolitinib who continue to manifest a suboptimal response by evidence of enlarged spleen and or enlarged spleen and persistent symptoms. The primary endpoint was clinic volume reduction at week 12 by imaging. Multiple other secondary endpoints were included.
Patients were not excluded for anemia, even with transfusion independence, and patients were included with a platelet count as low as 50,000. The study design included randomization to different dosing levels and schedules with predominantly, ideally weekly dosing schedule and an all daily dosing schedule.
In regard to patient disposition 16 patients continue on active therapy on an open-label protocol, and only 13 subjects or 17 percents were discontinued for adverse advanced purposes. Five patients were removed of the study to proceed with allogeneic stem cell transplant; 74 patients enrolled on the study.
These are the baseline characteristics of patients enrolled on the study. In general, patients had a diagnosis of myelofibrosis of over 3 years and have been on therapy with Ruxolitinib for an average of one and a half years with a median dose of around 30 milligrams a day. Despite this, patients continue to manifest significant splenomegaly and symptoms burden, thus qualifying for this protocol.
In terms of results, the median follow up was 48 weeks and the median dose of Ruxolitinib and Parsaclisib made the same at 5 milligrams and 30 milligrams per day, respectively. 66 patients or 89% continued therapy into the primary endpoint assessment, and as a testimony for to safety of this combination, 31 subjects continue on a study for over 1 year, 10 subjects continue on therapy for over 2 years and 16 subjects continue on therapy as we speak on active open label protocol. In regards to efficacy, the additional Parsaclisib to patients on Ruxolitinib resulted in further standard volume reduction at week 12. That was more evident at week 24 and numerically this, the responses are listed below and some responses were deep. The addition of Parsaclisib to Ruxolitinib resulted in further symptom improvement at week 12 and at week 24. The results are numerically listed below as you notice responses were observed on both adjusting schedules that all daily and the daily weekly.
However, the responses in the all daily were more favorable, including a 48%, patients achieved 50% reduction in their total symptom score.
So improvement in symptoms was also confirmed by MPN (myeloproliferative neoplasms) -SAF-TSS symptom daily score by self reporting by subjects which were very concordant with the with the previous slide. This graph shows the dynamic changes in splenic length and symptom scores as reported by patient, which show early response and continued response, for both symptoms and splenic length throughout the study.
This was more notable and more favorable in patients who received the all daily dosing. In terms of adverse events, there were very few treatment emerge adverse events that of high grade. And if we focus on the all daily dosing schedule, which is the dose that is going forward with phase 3 studies, there were very few grade 3 or higher adverse events reported on the study.
They were serious TEAEs that are listed on the slide and 6 cases of fatal TEAEs. None of them were related to study procedures.
In regard to treatment, emergent adverse events of special interest in patients with MAL neoplasms or on patients on therapy with PI3K inhibitors. We did not observe any high grade toxicities including no high grade diarrhea, no dermatitis, no colitis or perforation, and no CMV infection.
Platelet counts remained stable on this study and some patients manifested thrombocytopenia. However, given the low baseline platelet count for patients enrolled in the study we reported some grade 3 or in grade 4 thrombocytopenia. In general, most patients remained at the same platelet level, or had a decrease by one grade level of platelet count during the study. To further elicit this is the prospective full of the platelet count and the hemoglobin in patients enrolled in the study. And it shows stability of the platelet count and the hemoglobin in both dose levels and including accounting for patients who were enrolled in the study with severe thrombocytopenia, severe anemia and transfusion dependance.
These are the treatment emergent adverse events resulting in discontinuation. There were very few such events without any specific pattern. In conclusion, in patients with myelofibrosis and suboptimal response to therapy with Ruxolitinib, the addition of Parsaclisib resulted in further splenic volume reduction, and further symptom improvement without additional toxicities.
Neither hematological or non-hematological. The addition they, the once daily Ruxolitinib dosing was the more favorable dosing schedule. And this is going to move forward with two randomized prospective phase 3 clinical trials. The LIMBER-304, which is an add-on approach that mimics the phase 2 study and the LIMBER-313, which is an upfront combination of Parsaclisib and Ruxolitinib in treatment naive patients with low platelet cuffs will be enrolled in these studies. Thank you very much for your interest and your attention.
In regard to the design of the study we wanted to elicit that this there was a part one that is a safety around end and the randomization was to two different dosing schedules. One was daily followed by weekly schedule with different dosing of Parsaclisib, and the other dosing schedule was all daily with different dosing schedules for other study. And one of the endpoints of the study was to identify the optimum dosing schedule, which at the conclusion of the study was the all daily dosing schedule and the 5 milligrams once a day. Was the Optimum dosing for Parsaclisib, which was associated with the highest efficacy as well as the highest tolerability and safety in this study.
Incyte Corporation developed Parsaclisib (INCB050465), a PI3K inhibitor, as an antineoplastic and immunomodulatory drug, as claimed in their patent WO2014134426A1. The chemical structure is one of those claimed in patent WO2013033569A1, however it was unclear which example it was from a mixture of diastereoisomers 345-348 (347 and 348 exhibited the strongest inhibitory potency against PI3K, whereas 347 was tested in vivo). Yue et al2019 .'s revelation validated the structure as patent example 346. Comparing parsaclisib to first-generation PI3K inhibitors, preclinical and phase 1/2 clinical evidence suggests that its hepatotoxicity is minimized.
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What are myeloproliferative neoplasms (MPNs)?
Myeloproliferative neoplasms are a group of disorders in which the bone marrow produces an abnormally high number of red blood cells, white blood cells, and platelets.
Typically, the bone marrow produces blood stem cells (immature cells) that mature over time into grow blood cells.
A blood stem cell can differentiate into either a myeloid or lymphoid stem cell. A lymphoid stem cell differentiates into a white blood cell. A myeloid stem cell differentiates into one of three adult blood cell types:
Red blood cells that transport oxygen and other chemicals to all bodily tissues.
- Granulocytes, which are white blood cells that aid in the battle against sickness and infection.
- Platelets that halt bleeding by forming blood clots.
In myeloproliferative neoplasms, an excessive number of blood stem cells differentiate into one or more blood cell types. Typically, neoplasms progress gradually as the quantity of red blood cells grows.
The type of myeloproliferative neoplasm is determined by whether an excessive amount of red blood cells, white blood cells, or platelets are produced. Occasionally, the body produces too many of more than one type of blood cell, but typically only one type of blood cell is damaged. The six forms of chronic myeloproliferative neoplasms are as follows:
- Chronic myelogenous leukemia.
- Polycythemia vera.
- Primary myelofibrosis (sometimes called chronic idiopathic myelofibrosis) (also called chronic idiopathic myelofibrosis).
- Essential thrombocythemia.
- Chronic neutrophilic leukemia.
- Chronic eosinophilic leukemia.
The combination of Parsaclisib in patients already on Ruxolitinib has been associated with very little adverse events. In testimony to the safety, most patients continued on the therapy at the same dose intensity through other study. So the median dose of Parsaclisib was actually 5 milligrams at the end of the study and the median dose of facilitatory by the end of the of the study was 30 milligrams a day, which is very similar to the median dose Ruxolitinib at in the study. So the combination did not result in dose reduction of either of the active agents. In addition, patients continued on the study and the majority of patients remained on the study until the primary endpoint assessment.
So there has not been any drop-off early due to adverse events and many patients continue with therapy for over a year and over 2 years. And some patients continue to be on therapy on an open label protocol due to clinical benefit. Tolerability. We did not observe high grade toxicities, particularly in the once daily dosing, and we have not observed any high grade treatment emergent adverse events of special interest of concerns to PI3K inhibitors and, the most distinguished safety was the hematologic safety as the patient continued to have relatively stable platelet count and hemoglobin throughout the study without worsening, which is definitely a, an important issue for patients on myelofibrosis therapy, given the overlapping toxicities of active agents and hematologic toxicity, which we were fortunate to not observe on this protocol.
So the next question would be regarding the efficacy. So if I'm going to describe the efficacy of this combination. So the answer will be on the study evaluated patients who have been on a on therapy with Ruxolitinib. The median duration of therapy has been nearly one and a half years in patients enrolled in the study with the minimum being 6 months and the median dose of Ruxolitinib for patients enrolled in the study was 30 milligrams daily, which is a relatively high dose of Ruxolitinib. So those patients have definitely been optimized with Ruxolitinib therapy prior to enrollment on the study, and they continue to have significant minimal enlargement and symptom burden. The addition of Parsaclisib in these patients with high dose Ruxolitinib has resulted in further splenic volume reduction.
I would like to quote the splenic volume reduction in patients with the all daily dosing schedule that was nearly 28% of patients achieved deep splenic volume reduction with the additional Ruxolitinib, more impressively, the improvement in symptom burden was very noted in our study with patients on the all daily dosing schedule.
Who achieved 50% reduction in symptoms score were observed in 48% of subjects. This is definitely an indication of high activity for myelofibrosis related endpoints, this improvement was also concurrent on the patient reported outcomes and the patient reported diary symptoms. This is definitely a truly active combination with impact on screen volume and on symptom burden for patient.
How are the blood cells affected in Myeloproliferative Neoplasms (MPNs)?
The following techniques and tests may be used:
Physical exam and health history: An examination of the body to look for general signs of health, such as lumps or anything else that seems out of the ordinary. In addition, the patient's medical history, including past diseases and treatments, will be recorded.
Complete blood count and differential: A technique wherein a blood sample is collected and examined for the following:
The number of red blood cells and platelets in the bloodstream.
The quantity and composition of white blood cells.
The quantity of hemoglobin (the oxygen-carrying protein) in red blood cells.
The proportion of a blood sample consisting of red blood cells.
A technique in which a blood sample is examined for the presence of the following:
Whether red blood cells have the shape of teardrops.
The quantity and composition of white blood cells.
Quantity of platelets.
Whether blast cells are present.
Blood chemistry studies: A method in which a blood sample is analyzed to determine the levels of specific compounds produced into the blood by organs and tissues. An abnormally high or low level of a chemical may indicate the presence of a disease.
Bone marrow aspiration and biopsy: The removal of bone marrow, blood, and a small piece of bone from the hipbone or breastbone using a hollow needle. Under a microscope, a pathologist examines bone marrow, blood, and bone for abnormal cells.
Cytogenetic analysis: A laboratory examination in which the chromosomes of cells in a sample of bone marrow or blood are counted and examined for any abnormalities, such as missing, damaged, altered, or additional chromosomes. Changes in specific chromosomes may indicate the presence of cancer. Cytogenetic analysis is utilized to aid in cancer diagnosis, therapy planning, and evaluation of treatment efficacy.
A laboratory test performed on a sample of bone marrow or blood to detect mutations in the JAK2, MPL, or CALR genes. A JAK2 gene mutation is typically detected in patients with polycythemia vera, essential thrombocythemia, or primary myelofibrosis. Patients with essential thrombocythemia or myelofibrosis have mutations in the MPL or CALR gene.
So the field of myelofibrosis has evolved and has been very dynamic. Ruxolitinib therapy has been the standard of care for nearly 10 years or longer, and there's been a significant movement towards combination with Ruxolitinib to enhance Ruxolitinib activity, achieve a deeper or more durable response.
There has been extensive research in this regard, including on multiple Ruxolitinib combinations. Parsaclisib along with Ruxolitinib has resulted in some of the highest activity in these clinical trials with remarkable symptom improvement with splenic reduction activity and an outstanding safety profile that seems to distinguish this combination in the setting of Ruxolitinib combinations in both suboptimal response and now this is being investigated in upfront setting. So once these studies are completed, Parsaclisib seems to be a good partner with Ruxolitinib to enhance the activity of Ruxolitinib, both in the spleen (eg. enlarged spleen) and in symptoms, without collateral hematologic or non hematologic side effects. Something we all have been striving to achieve for awhile.
So we're all very excited about the advances in myelofibrosis and the many novel agents that are being investigated for myelofibrosis with multiple mechanisms of action. We're also excited about novel JAK inhibitors in development. So the field is getting very promising, and we are excited to have more tools for our patients.
Hopefully once per subclinical trials are complete, and hopefully the clinical activity is confirmed on phase 3 clinical trials. This will add a new treatment tool for patients in which patients can receive the standard approved drug select in therapy, along with a combination of Parsaclisib to achieve a deeper and more durable response with more meaningful clinical benefit without additional toxicity.
So we look forward to the conclusion of the phase 3 clinical trials, and we encourage physicians and patients to refer to the clinical trials that are ongoing. And hopefully, once these clinical trials are completed, we will have a new standard of care for patients with myelofibrosis.
Abdulraheem Yacoub, MD - About The Author, Credentials, and Affiliations
Dr. Abdulraheem Yacoub is board certified by the American Board of Internal Medicine, which demonstrates his extensive knowledge and experience in the fields of internal medicine as well as hematology and oncology. He received his fellowship at the University of Arkansas for Medical Science, where he also received his education. After receiving his medical degree from the University of Jordan, he completed his residency at Saint Louis University School of Medicine. Prior to that, he had attended the University of Jordan. He is currently at the University of Kansas Medical Center.