Hello, my name is Karolina Faysman I’m an Advanced Oncology Certified Nurse Practitioner, specializing in the care of patients living with myelofibrosis
VONJO® (pacritinib) is indicated for the treatment of adults with intermediate or high-risk primary or secondary (post-polycythemia vera [PPV] or post-essential thrombocythemia [PET]) myelofibrosis (MF) with a platelet count below 50 x 109 per liter. This indication is approved under accelerated approval based on spleen volume reduction so continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
VONJO is contraindicated in patients concomitantly using strong CYP3A4 inhibitors or inducers.
Hey Nina. Thank you for reaching out and coming to see me today.
Having an MF expert partner with your physician back home is important, with a complex changing disease as MF. Especially, when complications such as thrombocytopenia are common. And since almost 70% of myelofibrosis patients will ultimately have thrombocytopenia, it wouldn't be a surprise to see it with Nina. Who is going to help us identify who is the right patient for VONJO, utilizing data from the PERSIST-2 phase 3 study. Today we're going to use your story to help physicians, help other patients like yourself.
Okay, the first thing you need to know is that MF is a complex disease and no two patients are alike. When you look at the patients in the PERSIST-2 phase 3 study for VONJO ages ranged from 32 years to 91 with a median age of 68 years.
Nina here is 62 years old. 86% of patients in the study were Caucasian and pretty evenly split between male and female.
It's important to know that PERSIST-2 was a phase 3 clinical trial that enrolled patients with intermediate or high risk, primary or secondary MF with thrombocytopenia, meaning a platelet count of less than or equal to 100,000 per microliter. Enrolled patients also had some measure of splenomegaly and prior JAK inhibitor treatment was also permitted.
46% of patients on VONJO and 51% of patients on BAT had received prior ruxolitinib therapy. In the VONJO arm 43% of patients had greater than or equal to two prior therapies versus 48% on the BAT arm.
In PERSIST-2, the VONJO and BAT treatment arms were balanced with respect to age, gender, race, ethnicity, body mass index and geographic region. 68% of patients had primary MF and the other 32% had secondary MF.
In PERSIST-2, the median baseline platelet count was 55,000 per microliter and 45% of patients had a platelet count less than 50,000 per microliter. 59% of patients on VONJO were anemic.
The median baseline hemoglobin level was 9.5 grams per deciliter and 23% of patients were red blood cell transfusion dependent at the study entry. With this in mind, VONJO was studied in an MF patient population with or without anemia.
Now I want to share some of the data from PERSIST-2, the phase three clinical trial, that lead to VONJO’s accelerated approval.
PERSIST-2 was designed to assess two co-primary endpoints: proportion of patients achieving greater than or equal to 35% SVR, or spleen volume reduction, at week 24, and a reduction of greater than or equal to 50% TSS, or total symptom score, at week 24.
VONJO had a strong treatment effect on spleen volume reduction in PERSIST-2, the percentage of patients with platelet counts below 50,000 per microliter achieving greater than or equal to 35% spleen volume reduction was 29% for VONJO versus 3% for BAT.
But before I get into the data, I want to share some important safety information with you.
Serious and fatal hemorrhages have occurred in VONJO-treated patients with platelet counts less than 100,000 per microliter and less than 50,000 per microliter. Grade greater than or equal to 3 bleeding events occurred in 15% of patients treated with VONJO compared to 7% of patients treated on the control arm and as a result VONJO dose reductions, dose interruptions, or permanent discontinuations occurred.
Avoid use of VONJO in patients with active bleeding and hold VONJO 7 days prior to any planned surgical or invasive procedures. Assess platelet counts periodically.
Now back to the PERSIST-2 data for VONJO.
The PERSIST-2 study also measured reduction of total symptom score in patients with severe thrombocytopenia for VONJO versus best available therapy. 26% of patients on VONJO versus 9% of patients on BAT achieved greater or equal to 50% reduction in TSS modified MFSAF version 2.0 from baseline to week 24.
It's important to note that the TSS endpoint was not met and no conclusions regarding the benefit or risk of VONJO can be established based on this data. These results are not included in the VONJO prescribing information.
That being said, I want to give you a heads-up on a potential side effect you may experience.
VONJO causes diarrhea in approximately 48% of patients compared to 15% of patients treated on the control arm. The median time to resolution in VONJO-treated patients was 2 weeks. The incidence of reported diarrhea decreased over time. Diarrhea resulted in treatment interruption in 3% of VONJO-treated patients and did not result in treatment discontinuation.
Serious diarrhea adverse reactions occurred in 2% of patients treated with VONJO compared to none in the control arm. Control preexisting diarrhea before starting VONJO treatment. Interrupt or reduce VONJO dose in patients with significant diarrhea.
Here’s something I think you’ll be interested to hear.
In post-hoc analyses of exploratory endpoints, the percentage of patients achieving transfusion independence over any 12-week interval through week 24 was 28% for VONJO versus 8% for BAT. 40% of patients on VONJO achieved greater than or equal to 50% transfusion reduction over any 12-week interval through week 24 versus 12% on BAT.
Please note that no conclusions regarding the benefit or risk of VONJO can be established based on the transfusion data as these are post-hoc analyses of exploratory endpoints from the PERSIST-2 trial and are not appropriately powered.
I want to pause here to give you some important safety information.
VONJO can cause worsening thrombocytopenia. VONJO dosing was reduced due to worsening thrombocytopenia in 2% of patients with preexisting moderate to severe thrombocytopenia (platelet count of less than 100,000 per microliter) and with preexisting severe thrombocytopenia (platelet count less than 50,000 per microliter).
Monitor platelet count prior to and during treatment. Interrupt VONJO in patients with clinically significant worsening of thrombocytopenia that lasts for more than 7 days. Restart VONJO at 50% of the last given dose once the toxicity has resolved. If toxicity recurs hold VONJO and restart at 50% of the last given dose once toxicity has resolved.
Like I said, MF is different for every patient, so decisions have to be made on that individual patient situation and how they respond to different treatments.
Unlike other disease states, it is difficult to create a nice neat treatment algorithm for MF.
The first thing is obviously going to be looking at the platelet count, and here we are not only looking at the static number, but we're also looking at the rate of the change.
If Nina has been stable on Ruxolitinib for 18 months and then suddenly falls to 100,000 platelets per microliter and progressively worsens to less than 50,000 platelets per microliter, we're going to consider a treatment change.
Other factors we're going to look at are constitutional symptoms that are not improving, the spleen is not getting smaller, and they continue to require blood transfusions. That could mean intolerance or side effects of their existing treatment. The treatment has stopped working or the disease is progressing beyond the ability of the drug to combat.
All of these different tests can then be applied to a scoring system to better assess risk and prognosis. The one we use is called DIPSS+ (or Dynamic International Prognostic Scoring System plus platelet count, transfusion dependency, and karyotype).
Typically, the more aggressive the disease, the more aggressive we would like to be with a treatment. All this could lead to a treatment like VONJO that may help achieve spleen volume reduction.
At that point, we are going to talk to Nina about changing to another treatment like VONJO, which may be able to address treatment goals like spleen volume reduction in advanced MF patients with thrombocytopenia.
Once platelets are impacted in patients with MF, it may be the time to reevaluate current dosing and current therapy. It is always important to refer to medications, prescribing information to confirm the right dose when counts decrease.
MF treatments may require a dose reduction because of the falling platelet levels, but this could result in less reduction in the spleen volume.
I found this to be important.
In the PERSIST-2 study, the majority of patients were able to start and stay on the full dose VONJO, or 200 milligrams, twice daily. VONJO was initiated within one week after discontinuation of previous MF therapy with no washout period. However, always refer to medications, prescribing information on how to taper or discontinue treatment.
Okay, some final safety information.
VONJO can cause prolongation of the QTc interval. QTc prolongation of >500 milliseconds was higher in VONJO-treated patients than in patients in the control arm. Adverse reactions of QTc prolongation were reported for 3.8% of VONJO-treated patients and 2% of control arm patients.
Avoid use of VONJO in patients with a baseline QTc of greater than 480 milliseconds, and with drugs with significant potential for QTc prolongation. Correct hypokalemia prior to and during VONJO treatment.
Other JAK-inhibitors, compared to TNF blockers or BAT, increased the risk of the following conditions, for which VONJO is not indicated: lymphoma and other malignancies excluding non-melanoma skin cancer, MACE (Major Adverse Cardiovascular Events) including cardiovascular death, myocardial infarction, and stroke. Patients who are current or past smokers and patients with other cardiovascular risk factors may be at increased risk.
Thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis.
Serious infections in patients with myeloproliferative neoplasms. Serious bacterial, mycobacterial, fungal and viral infections may occur in patients treated with VONJO. Delay starting therapy with VONJO until active serious infections have resolved.
Co-administration of VONJO with strong CYP3A4 inhibitors or inducers is contraindicated. Monitor for increased adverse reactions of VONJO when administered with moderate CYP3A4 inhibitors.
The safety of VONJO was evaluated in the randomized control PERSIST-2 trial.
The following table summarizes the adverse reactions reported during treatment. The most common adverse reactions reported in the greater than or equal to 20% of patients (N=106) were diarrhea, thrombocytopenia, nausea, anemia, and peripheral edema.
Here are the serious adverse reactions seen in the PERSIST-2 trial.
The most frequent serious adverse reactions occurring in greater than or equal to 3% patients receiving VONJO were anemia, thrombocytopenia, pneumonia, cardiac failure, disease progression, pyrexia, and squamous cell carcinoma of skin.
Fatal adverse reactions included events of disease progression, and multiorgan failure, cerebral hemorrhage, meningorrhagia, and acute myeloid leukemia.
The most common adverse reactions (reported in greater than or equal to 20% of patients) included diarrhea, thrombocytopenia, nausea, anemia, and peripheral edema.
Great job, Nina. Thank you for helping me paint a picture of who your VONJO patient may be.
