Vonjo Improves Thrombocytopenia, Anemia in Patients With Myelofibrosis

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By Jax DiEugenio
Fact checked by Chris Ryan

Improvements in thrombocytopenia and anemia were observed in patients with myelofibrosis treated with Vonjo (pacritinib) in the real-world setting, as demonstrated in findings from a retrospective study presented at the 2024 SOHO Annual Meeting.

According to the National Cancer Institute, thrombocytopenia refers to a condition in which patients have a lower-than-normal number of platelets in the blood, and this can result in excessive bleeding from wounds and easy bruising. Anemia is a condition when patients have a low count of red blood cells.

Findings showed that patients with a platelet count below 100 x 109/L (which is considered low) at baseline (74 patients) experienced an early increase in platelet count following treatment initiation that was maintained throughout the observation period. Additionally, an early increase in median hemoglobin (a protein inside red blood cells that carries oxygen from lungs to tissues and organs) was reported in all patients, and this increase was sustained throughout the observation period. Patients with hemoglobin level of less than 8 g/dL (a level that indicates anemia) at the start of treatment (35 patients) experienced a hemoglobin increase of nearly 1 g/dL by day 30.

Notably, patients who received prior treatment with Jakafi (ruxolitinib; 69 patients) experienced an increase in platelet counts and hemoglobin levels following initiation of Vonjo. At baseline, the median platelet count and median hemoglobin level in this population was 91 x 109/L and 8.7 g/dL, respectively. At day 360, the median platelet count and median hemoglobin were 97 x 109/L and 10.4 g/dL, respectively.

“In addition to spleen and symptom benefits observed in previous clinical trials, real-world outcomes demonstrate stability or improvement in thrombocytopenia and/or anemia in patients with myelofibrosis treated with [Vonjo],” lead study author Michael Marrone and colleagues, wrote in a poster presentation of the data. Marrone is an assistant professor in the College of Medicine, Department of Public Health Sciences, at the Medical University of South Carolina in Charleston.

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Novel approach may eliminate survival disparity in HSCT, greatly expand access

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September 17, 2024

Key takeaways:

  • Post-transplant cyclophosphamide prophylaxis reduced the OS disparity in matched vs. mismatched unrelated donor hematopoietic stem cell transplant.
  • The approach could expand access to HSCT.

Use of post-transplant cyclophosphamide prophylaxis to prevent graft-versus-host disease could greatly expand access to hematopoietic stem cell transplantation, according to results of a retrospective study.

An analysis of patients who received post-transplant cyclophosphamide (PTCy) showed no statistically significant difference in OS or GVHD-free RFS (GRFS) between patients with matched (8/8) or mismatched (7/8) unrelated donors.

The ability to find a suitable unrelated donor with a 7/8 HLA match is “much greater” than finding one with 8/8 HLA match, according to researcher Steven M. Devine, MD, chief medical officer at NMDP and senior scientific director at Center for International Blood and Marrow Transplant Research (CIBMTR), told Healio.

“For an African American patient, [chances] go from 30% to over 80%,” Devine said. “It’s even higher for Hispanic or Asian individuals — into the 90% range.

“If you can go even lower [to a 6/8 match or 5/8 match], you can pretty much find a volunteer unrelated donor for almost 100% of patients,” Devine added. “We are enabling a transplant for everyone, regardless of their ancestry.”

Access disparities

Allogeneic HSCT — used to treat multiple blood cancers and blood disorders — produces the best results when stem cells of a related or unrelated donor matches at 8/8 HLA markers at the HLA-A, -B, -C and -DRB1 genes, according to study background.

Only 30% of patients have siblings, who are HLA-identical matches and therefore could donate.

Non-Hispanic white individuals have a 79% likelihood of finding an unrelated matched donor in the NMDP registry. The rate is between 29% and 58% for people of other races and ethnicities.

“Historically, there’s been roughly a 10% lower chance of survival with each level of mismatch,” Devine said. “That’s why for years the focus has been on trying to find full matches for all patients.”

Cyclophosphamide, a chemotherapy drug used to treat a variety of solid tumors and hematologic cancers, has been repurposed for about 20 years to prevent GVHD after HSCT.

“It’s really revolutionized [stem cell transplant] because its use is associated with a much lower risk for both the acute and more chronic forms of GVHD,” Devine said. “It’s improved outcomes overall, and it’s allowed us to perform mismatched transplants both from related and unrelated donors. So, [for this study], we [wondered whether] those historical differences in outcomes between matched and mismatched transplant [are] as great as they were years ago now that we’re using PTCy.”

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SOHO State of the Art Updates and Next Questions | Choosing and Properly Using a JAK Inhibitor in Myelofibrosis

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Michael J. Hochmanm, Colin A. Vale, Anthony M. Hunter

Abstract

Myelofibrosis (MF) is a chronic myeloid neoplasm characterized by myeloproliferation, bone marrow fibrosis, splenomegaly, and constitutional symptoms related to pro-inflammatory cytokine signaling. Biologically, MF is characterized by constitutive activation of JAK-STAT signaling; accordingly, JAK inhibitors have been rationally developed to treat MF. Following the initial approval of ruxolitinib in 2011, three additional agents have been approved: fedratinib, pacritinib, and momelotinib. As these therapies are non-curative, allogeneic stem cell transplantation remains a key treatment modality and patients with MF who are deemed candidates should be referred to a transplant center. This potentially curative but toxic approach is typically reserved for patients with higher-risk disease, and JAK inhibitors are recommended in the pre-transplant setting. JAK inhibitors have proven effective at managing splenomegaly and constitutional symptoms and should be started early in the disease course in patients presenting with these clinical manifestations; asymptomatic patients may initially be followed with close surveillance. Drug-related myelosuppression has been a challenge with initial JAK inhibitors, particularly in patients presenting with a cytopenic phenotype. However, newer agents, namely pacritinib and momelotinib, have proven more effective in this setting and are approved for patients with significant thrombocytopenia and anemia, respectively. Resistance or disease progression is clinically challenging and may be defined by several possible events, such as increasing splenomegaly or progression to accelerated or blast phase disease. However, with multiple JAK inhibitors now approved, sequencing of these agents appears poised to improve outcomes. Additionally, novel JAK inhibitors and JAK inhibitor-based combinations are in clinical development.

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Ruxolitinib Stands Out Among JAK2 Inhibitors for Myelofibrosis

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By Targeted Oncology Staff

In this virtual tumor board discussion, experts review the case of a 68-year-old woman diagnosed with primary myelofibrosis. The discussion focuses on recent data and emerging insights to guide clinical decision-making and explore the latest advances in treatment strategies for this challenging disease.

Prithvira J. Bose, MD: What are the first steps you would take for this patient, and how do you view multidisciplinary collaboration?

Julie Huynh-Lu, PA-C: Specific to [The University of Texas] MD Anderson [Cancer Center], the role of the physician assistant or nurse practitioner in the leukemia department is to evaluate the patient. Aside from doing a review of systems, I go over the myeloproliferative neoplasms [MPN] questionnaire with the patients to review any changes in their score. Whether they have started therapy or not, [we determine whether they] need to be on therapy based on their answers.

I do a physical assessment of the patient checking their spleen. We don’t order ultrasounds or CT scans on patients unless we’re unable to palpate due to pain in that area. I’ll measure the spleen size every time the patient comes in with a tape measure.

Having a second set of eyes evaluating the patient [is key] because some questions that I may ask, someone else may not—or the physician may ask questions that I may not know [to ask]. Collaboration among nurses, physician assistants or nurse practitioners, and physicians in compiling patient information ensures the best care for the patient.

We are lucky to have the MPN10 form in the Epic system on our flow sheet, and patients can fill out this form before they check in for their appointment. If they were unable to fill it out, I can go into that flow sheet, ask those questions, and fill it out with them. Then, the score [generates] for each patient.

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Phase 3 Trial of Bomedemstat in Essential Thrombocythemia Begins Enrollment

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By Sabrina Serani
Fact checked by Jordyn Sava

A pivotal phase 3 trial (NCT06456346) has initiated to evaluate bomedemstat (MK-3543; IMG-7289), an investigational agent for the treatment of patients with essential thrombocythemia (ET) who have previously not received cytoreductive therapy.1

“The standard of care in essential thrombocythemia has remained unchanged for decades, and patients are in need of new options that have the potential to not only improve disease control, but also improve their quality of life,” said Gregory Lubiniecki, MD, vice president, global clinical development, Merck Research Laboratories, in a press release. “We are rapidly advancing our clinical development programs with the goal of helping to address these unmet needs and bring more options to patients living with myeloproliferative neoplasms.”

The Shorespan-007 trial will compare the orally available LSD1 inhibitor bomedemstat with standard-of-care hydroxyurea in patients with treatment-naive ET, the most common myeloproliferative neoplasm. LSD1 is an enzyme that is potentially important for regulating the proliferation of hematopoietic stem cells, as well as the maturation of progenitor cells.

The study’s primary end point is durable clinicohematologic response rate, and secondary end points include duration of hematologic remission, event-free survival, incidence of adverse events, and disease progression rate. Additionally, investigators will be patient-reported outcomes, including fatigue and symptoms.

The FDA previously granted orphan drug and fast track designations to bomedemstat in ET and myelofibrosis, as well as orphan drug designation in acute myeloid leukemia.

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Donor Source Does Not Impact Survival for HCT in Myelofibrosis

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Vicki Moore, PhD

For patients with myelofibrosis (MF) who received hematopoietic cell transplantation (HCT), a study showed that overall survival (OS) outcomes at 3 months were similar whether haploidentical or matched unrelated donor (MUD) HCT was used. Study results were published in the journal Blood Advances.

The study was based on data obtained from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry. This analysis of donor trends included data for adults in the registry who received an initial HCT between January 2013 and December 2019 for primary or post-essential thrombocythemia or post-polycythemia vera MF. The study’s primary endpoint was OS.

There were 1597 HCTs identified over the study period. Among these, in 2013 there were 117 HCTs performed, while in 2019 this number had risen to 371. Additionally, the proportion of HCTs that involved haploidentical donors rose from 3% of total HCTs in 2013 to 19% in 2019.

Overall, 1032 patients met eligibility criteria for inclusion in further analyses for this study. Patients whose HCT involved mismatched unrelated donors (MMUDs; 64 patients) had a median age at HCT of 59.3 years, while patients with matched sibling donors (MSDs; 298 patients) had a median age at HCT of 61.4 years, patients with haploidentical donors had a median age of 62.5 years (119 patients), and patients with MUDs had a median age of 63 years (551 patients).

The median follow-up period was 46.5 months (range, 3.7-99.7) in this study. In univariate analyses, the 3-year OS rates were estimated to be 68.8% (95% CI, 63.3-74.1) for recipients of MSD-HCT, 59% (95% CI, 49.7-67.9) for recipients of haploidentical HCT, 61.3% (95% CI, 57.1-65.4) for recipients of MUD-HCT, and 55.2% (95% CI, 42.7-67.4) for recipients of MMUD-HCT (P =.03).

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Real-World Data for Pacritinib Show Improvement in Thrombocytopenia, Anemia in Myelofibrosis

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September 10, 2024

Author(s): Jax DiEugenio

Fact checked by: Chris Ryan

Pacritinib (Vonjo) generated improvements in thrombocytopenia and anemia in patients with myelofibrosis treated in the real-world setting, according to data from a retrospective study presented at the 2024 SOHO Annual Meeting.1

Findings showed that patients with a platelet count below 100 x 109/L at baseline (n = 74) experienced an early increase in platelet count following treatment initiation that was maintained throughout the observation period. Additionally, an early increase in median hemoglobin was reported in all patients, and this increase was sustained throughout the observation period. Patients with hemoglobin level of less than 8.0 g/dL at the start of treatment (n = 35) experienced a hemoglobin increase of nearly 1 g/dL by day 30.

Notably, patients who received prior treatment with ruxolitinib (Jakafi; n = 69) experienced an increase in platelet counts and hemoglobin levels following initiation of pacritinib. At baseline, the median platelet count and median hemoglobin level in this population was 91.0 x 109/L and 8.7 g/dL, respectively. At day 360, the median platelet count and median hemoglobin were 97.0 x 109/L and 10.4 g/dL, respectively.

“In addition to spleen and symptom benefits observed in previous clinical trials, real-world outcomes demonstrate stability or improvement in thrombocytopenia and/or anemia in patients with myelofibrosis treated with pacritinib,” lead study author Michael Marrone, PhD, MPH, and colleagues, wrote in a poster presentation of the data. Marrone is an assistant professor in the College of Medicine, Department of Public Health Sciences, at the Medical University of South Carolina in Charleston.

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MPN Word of the Month: Thrombocytosis

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Thrombocytosis is significant in MPNs because one of the hallmark features of some MPNs, like Essential Thrombocythemia (ET), is the excessive production of platelets. This overproduction can lead to complications, such as blood clotting disorders, which can result in strokes, heart attacks, or other serious vascular issues.

Thrombocytosis is typically detected through routine blood tests. A complete blood count (CBC) will reveal an elevated platelet count, often leading to further investigations to determine the underlying cause, such as an MPN.

Managing thrombocytosis is crucial in MPN patients. Treatments may include medications to reduce the platelet count and to lower the risk of clotting. In some cases, lifestyle changes, such as maintaining a healthy weight and avoiding smoking, can also help manage the risks associated with high platelet counts.

Understanding the word “thrombocytosis” is essential for anyone dealing with Myeloproliferative Neoplasms. It highlights one of the primary issues these patients may face: an overabundance of platelets that can lead to severe health complications. By familiarizing yourself with this term, you’ll have a better grasp of the challenges and treatments associated with MPNs, making the complex world of blood disorders a bit more understandable.

A Patient’s Story: Advocating for your Care

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By Sherri J.

My platelets were reported to be above 450 in 2015 at my first doctor’s appointment after returning to the United States from an 11-year assignment in Italy. My doctor told me it was nothing to worry about, to take a low-dose aspirin, and he would watch it. I inquired a time or two at follow-up appointments but was assured not to worry, without any explanation. Every time I got tested it was above normal, but I knew nothing about the seriousness of a potential MPN issue.

About a year ago I started having what I know now to be increasing symptoms of ET. I felt as if I was significantly aging with fatigue, lack of appetite, headaches, dizziness. Over the next 3 to 4 months, the symptoms became unbearable. I blamed all of my symptoms on other things: stress and anxiety, menopause, allergies, work life balance issues, my diabetes, my pursuit for my doctorate while working a fast pace full time job with 5 hours or less of sleep. You name it, I was able to tie almost every issue that I was experiencing to something else, so I never brought things up to the same doctor. Soon my platelet count jumped almost 100K and that was after a steady incline over the previous year. My PCP finally put some things together and decided it was time to see an oncologist.

The oncologist I saw was not an MPN specialist. My first sign that this oncologist was not a good match for me was at the initial appointment, I shared in writing and verbally my complete history, chief symptom complaints, and as he was leaving the room, he told me my platelet count wasn’t high enough to cause symptoms for what he has seen with other patients. He totally wrote it off. I didn’t say anything at the time because getting into specialists in my area is quite difficult. I told my husband on the way home, this was not the doctor for me.

The doctor did run extensive bloodwork, and one significant finding was that I am JAK2 positive. Knowing I was JAK2 positive, I decided to call UVA who has MPN experts and see if they were accepting new patients. She was surprised the first doctor did not order a BMB and said I would have that procedure the day of my first appointment if I agreed to it. An hour before my scheduled appointment, the doctor called and advised me I was JAK2 positive and to come back in 3 months. I asked him “what about my symptoms?” He said take a low dose aspirin and he would see me in 3 months, gave me a 1-minute explanation that I likely have an MPN. No talk about a BMB, any treatment, risks, explanation of what an MPN is, nothing.

From the moment I walked up to the desk at the UVA Cancer Center, I felt I made the right decision. I handed the intake nurse the same organized document and she passed it to the doctor before he came in. He was so happy to have that information and said he wishes more patients did that. He spent over an hour with my husband and me explaining what an MPN is, what the test results I had meant, what he would learn from the BMB, what each outcome could be (PV, ET, MF). He explained progression. He made sure every question was asked and fully answered. I advised him that my relationship with my medical team would be just as important as my treatment and that I wanted to feel as if I had a seat at the table for treatment planning. I knew I was in the right place.

Once my BMB confirmed my diagnosis, my doctor felt Besremi was the best course of treatment, but insurance approval could be an obstacle until it is FDA approved. We agreed I would start on 500 mg of Hydroxyurea twice a day and continue the low dose aspirin. At my next follow-up my platelets came down, the doctor said I wasn’t resistant to HU but I wasn’t tolerating it well, so he wanted to approach my insurance company about the Besremi and got approved a few days later.

After some tweaks of my dosing and some side effects, my numbers were perfect and what my doctor was hoping to see. Although my blood counts were all in line, I still have pretty significant symptoms, so he increased my dose of Besremi which really helped. I decreased HU to one 500 mg dose on Monday only. He said I’m super reactive and I may not have to go up to 500 mcg of the Besremi. The trial pushes folks as high as they can stand but he doesn’t think it is always necessary.

So as of early September, clinically, I am in good shape and any raises in the dosage will alleviate my symptoms, the worst are fatigue and headaches. He will continue biweekly dosage increases up to 300 mcg as long as I can tolerate it. He will then leave it up to me whether to titrate or not. There is a balancing act between toxicity and alleviating symptoms, so my feedback is important to him. My doctor is hopeful because HU brought my numbers down and Besremi made them perfect after only two doses. He has seen that that HU success coincides with success with Besremi.

Managing Ruxolitinib-Associated Liver Toxicity in Patients With Myelofibrosis Requires a Nuanced Approach

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September 4, 2024

William J. Hogan, MBBCh, MRCPI

Key Points:

  • Ruxolitinib plays an important role in the treatment of symptomatic myelofibrosis, but its associated toxicities and adverse withdrawal effects can pose a challenge.
  • Myelofibrosis is linked with hepatic dysfunction, and ruxolitinib—despite its associated risks of hepatic transaminitis—may limit inflammation and progressive fibrosis, with liver injury resolution reported after treatment.
  • Overall, management of liver injury related to ruxolitinib depends on the cause and severity.

 

Question: In patients with myelofibrosis, how do you manage liver toxicity from ruxolitinib use beside dose de-escalation?

Answer: Ruxolitinib is a small-molecule JAK1/2 inhibitor that has an established role in the treatment of patients with symptomatic myelofibrosis, hydroxyurea-resistant polycythemia vera, and acute and chronic graft-versus-host disease. It has a potent anti-inflammatory effect that can provide very useful palliation of constitutional symptoms and splenomegaly in patients with myelofibrosis via inhibition of the JAK 1 and 2 pathways, which are involved in the production of inflammatory cytokines and hematopoietic growth factors.1-3 Common toxicities include myelosuppression, hepatic transaminitis, diarrhea, fatigue, headache, and peripheral edema. In patients with advanced myelofibrosis or florid inflammatory states, sudden withdrawal can lead to a systemic inflammatory response syndrome that can precipitate cardiopulmonary decompensation in frail patients, especially those with tenuous cardiopulmonary function, and corticosteroid prophylaxis or treatment may be required.4

In a mouse model of liver injury using carbon tetrachloride, JAK1/2 expression was implicated in progression of liver fibrosis. Inhibition of JAK1/2 downregulates downstream signaling, reduces progression to fibrosis, and even accelerates fibrosis reversal by inhibiting proliferation, migration, and activation of hepatic stellate cells in vitro.5 Myelofibrosis is associated with hepatic dysfunction by several mechanisms, including infiltration by hematopoietic stem cells (ie, extramedullary hematopoiesis [EMH]), portal vein thrombosis, and obliterative portal venopathy. EMH may respond favorably to ruxolitinib, and liver injury resolution after ruxolitinib treatment has been reported in patients with severe liver compromise related to myelofibrosis.6 These findings suggest that the drug may be able to reduce the consequences of inflammation—limiting progressive fibrosis in some circumstances—and may be of durable benefit in selected patients. A retrospective review of patients with liver injury and underlying myeloproliferative disorders treated with ruxolitinib and evaluated by biopsy demonstrated a variety of etiologies7; however, it is not always easy to determine how much is related to the underlying disease versus drug effects based on the biopsy findings, and this distinction is predominantly a clinical decision.

Liver toxicity typically manifests as mild hepatic transaminitis and can be exacerbated by drug–drug interactions. The incidence of hepatic transaminitis has been reported to be between 25% and 50%. Typically, these elevations are mild and self-limited, with < 1.5% of patients having values > 5 times the upper limit of normal. The drug is metabolized in the liver predominantly via the CYP3A4 pathway, and liver injury may be the result of the production of a toxic intermediate. Drug–drug interactions, such as with azole antifungals, can increase the effective exposure and enhance the potential for toxicity. Because suppression of intracellular signaling impairs immune response, suppression of viral replication may be impaired, increasing the potential for reactivation of quiescent viruses. This has been reported with reactivation of hepatitis B, resulting in clinically meaningful liver injury in patients who are at risk. It appears that the risk of viral reactivation with transaminitis and hyperbilirubinemia is greater in patients with HBsAg positivity, but reactivation has also been reported in those with anti-HBc. Efficacy with entecavir has been reported in treating viral reactivation and prophylaxis, so a nucleoside analog such as entecavir or tenofovir should be considered in patients who are at high risk.8-10

Management of liver injury related to ruxolitinib depends on the cause and severity. Identifying contributing causes, such as drug–drug interactions and prior viral hepatitis exposure and excluding other hepatotoxins are the initial imperative. Prior viral exposure with reactivation should be treated or prophylaxed when applicable. For mild transaminase elevations without hyperbilirubinemia, monitoring or temporary dose reduction may be appropriate. In more significant liver injury, dose interruption may be necessary. Consideration of an alternative JAK inhibitor may occasionally be warranted, as there does not appear to be significant evidence to suggest cross-reactivity between ruxolitinib and other JAK inhibitors. Of note, a retrospective review of liver injury occurring in patients with myeloproliferative neoplasms receiving ruxolitinib suggested a variety of potential etiologies, including those unrelated to the drug itself (EMH), in addition to obstructive portal vein apathy and drug-induced liver injury.

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