Study Advances Knowledge Base About Children and Adolescents With Myeloproliferative Neoplasms

August 10, 2022
Jennifer Larson

Myeloproliferative neoplasms (MPNs) are uncommon in children and young people. As a result, the guidelines currently used to reduce the risk of thrombosis and hemorrhage in patients with MPNs are based on literature involving patients over the age of 60.

A team of researchers set out to learn more about children and young adults with MPNs, due to the lack of sparse existing data. They published their findings in Blood Advances.

The researchers conducted a retrospective study that included members of the European Hematology Association MPN scientific working group who were diagnosed with an MPN before the age of 25. They examined data from 444 patients from 15 countries, 53.8% of who were diagnosed between the ages of 20 and 25.

They confirmed that the most common MPN subtype was essential thrombocythemia (ET), representing 71.6% of this cohort. Another 18.2% had the polycythemia vera (PV) subtype, and the remaining had primary myelofibrosis (PMF), prefibrotic myelofibrosis (PreMF), or unclassified MPN (MPN-u).

They also found what they called “interesting perspectives on how these MPN are perceived by physicians” and how they are managed. “Importantly, we demonstrate that standard prognostic scores do not perform well in this cohort,” they wrote. “As an example, 67.8% received at least one cytoreductive drug when only 21.4% of them should have received such therapy according to currently [European LeukemiaNet (ELN)] recommendations.”

They added that the proportion of certain prescriptions for the participants also suggested that their physicians didn’t apply ELN recommendations “where interferon is the recommended first-line therapy in patients aged below 60 years old because of its lack of leukemogenicity  and its low teratogenicity.” But as they noted, no MPN guidelines exist for children or adolescents, so the differences likely reflect “historical shifts in guidelines and availability of therapy.”

The researchers also uncovered higher-than-anticipated rates of thrombosis, hemorrhage, and transformation in their real-world cohort compared with the rates in their literature review. And 11% of patients had a history of thrombotic events, especially in patients with PV (21.5%).

“Due to the predominance of venous events, classical management with low-dose aspirin to prevent thrombosis should perhaps be questioned in this specific population, as it mainly reduces the risk of arterial events,” the researchers wrote. “The use of anticoagulants could be a way to reduce the incidence of venous thrombotic events.”

The study did have limitations, such as its retrospective nature, which may have resulted in some biases. Also, without specific treatment guidelines for young patients, the management could have been heterogeneous among the various centers, which could have influenced the rate of complications. However, they did point out that they had a “very high number of such extremely rare patients….suggesting that we revealed a reliable picture of MPN in very young patients.”

Ultimately, the research revealed a high disease burden with incidences of thrombotic events and transformations that were higher than previously reported in this particular population. The information could be used for future biomarkers studies, clinical trials, and the creation specific treatment guidelines for younger MPN patients.

Disclosures: Some authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

Reference

Sobas M, Kiladjian J, Beauverd Y, et al. Real world study of children and young adults with myeloproliferative neoplasms identifying risks and unmet needsBlood Adv. Published online July 8, 2022. doi:10.1182/bloodadvances.2022007201

 

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New JAK Inhibitors in Myelofibrosis Treatment

August 3, 2022

Experts discuss data on the recently approved agents fedratinib and pacritinib for myelofibrosis treatment.

Rami Komrokji, MD: There’s no doubt that ruxolitinib was transformative for our patients. It’s still a mainstay in treatment for many patients, especially upfront, but there are areas of unmet need in patients who are cytopenic. Ruxolitinib failure is still an issue for a lot of our patients. Recently it was exciting for our patients that there were 2 new drugs approved: fedratinib, with an interesting comeback, and pacritinib, for which Ruben and I did the phase 1 probably 10 years ago. It took the drug a while to get approved, but it finally is. Ruben, can you walk us through fedratinib and pacritinib and where you see their role now that they’re available for our patients?

Ruben Mesa, MD: Sure. It’s good that we have more options, and exciting that we now have 3 approved drugs in myelofibrosis [MF]. In the…community, we haven’t had an opportunity to use either of these. Let me share a little about what we think about each of them. First, fedratinib is a very good JAK inhibitor—JAK2, FLT-3—approved from the JAKARTA (NCT01437787) and JAKARTA-2 (NCT01523171) studies. JAKARTA studied it front line, and JAKARTA-2 in second line vs placebo in the front line. It was a study almost parallel with the COMFORT study. It’s clearly superior to placebo for improving the spleen and symptoms, and as far as adverse effects, it didn’t cause cytopenias.

The approval of the drug was delayed because there was a very low rate of Wernicke encephalopathy, probably interfering with thiamine metabolism to a small degree. There’s a black box warning that sounds pretty scary but in practice is fairly simple. You check thiamine levels and you replace thiamine, and thiamine is dirt cheap. I give patients a bottle. Then you monitor for Wernicke. That’s pretty small. The more likely adverse effects can be GI [gastrointestinal]. I give some folks some antinausea, some antidiarrhea medications. They can take it. It’s very helpful in the second line.

If they used ruxolitinib and still have [an enlarged] spleen and symptoms, and you don’t have a trial available, fedratinib is a good option. It can be used at full dose in patients with platelets between 50,000 and 100,000 per mm3. I helped present some of those data. It’s a very solid option, with a couple of those small caveats. It was approved in fall of 2019 just before the pandemic, so folks still have less familiarity with it.

Much more recently, pacritinib has a long history. We noticed early on when we did that phase 1—back when it called SB1518—that you could use it irrespective of platelet count. You could use it in marked thrombocytopenia. Over time, a mechanism was found explaining why that could be the case. It inhibits IRAK1. It might be better for patients with cytopenic MF. In critical studies, it could be used safely and effectively in individuals with platelet counts of less than 50,000 per mm3. It’s approved for individuals with marked thrombocytopenia in the front line and second line. It might also help to improve anemia.

It has been approved since February 2022. It’s a good option. It will be used either up front or more frequently in the second line to be that thrombocytopenic. It’s already being woven into the NCCN [National Comprehensive Cancer Network] Guidelines in a group that didn’t have an option before. It will be well positioned for combination strategies. Many of the drugs that have different mechanisms of action also tend to cause thrombocytopenia, so it might be a very nice adjunct for that.

People sometimes say: “Myelofibrosis isn’t that common. Can we have all these drugs?” Yes. The more options we have, the better. These drugs will end up having ranges of use in a range of diseases, including anti-inflammatory diseases, cutaneous diseases, and rheumatologic diseases. You don’t have to worry about the drug not having enough patients. But even though myelofibrosis isn’t common, it can be pretty heterogenous. We have MPN [myeloproliferative neoplasm] and MDS [myelodysplastic syndromes] overlap. We’ve got patients with ET [essential thrombocythemia] and PV [polycythemia vera]. The more options we have, the better.

Rami Komrokji, MD: I absolutely agree. Cytopenic MF is a challenging disease. As you alluded to, most of the time we deal with it later in the course of the disease as a natural history of progression. But there’s a subset of up to 20% of those patients, even upfront, that has limited the use of ruxolitinib in that setting. To your point also, we’ve been exploring those drugs in other diseases. We have ongoing trials in CMML [chronic myelomonocytic leukemia] with JAK2 inhibitors and other types of MDS and MPN. It’s always exciting to have more options that fill different gaps of unmet need for our patients.

Jeanne Palmer, MD: We also know that the role of JAK inhibitors prior to transplant can be very beneficial. It has been studied being used 2 months before transplant up until the time of transplant, and even through transplant up until engraftment or day 30. There’s even 1 study looking at it for 1 year. Additionally, after transplant, these drugs can treat graft-vs-host disease. In some of the studies, there are prophylactic studies using JAK inhibitors for all patients. But it’s a gray area for patients who have myelofibrosis who have been on them, because the worst thing you can do is taper them off their JAK inhibitor right before transplant. That causes them to flare up and have lots of transplant complications.

Rami Komrokji, MD: Before the JAK inhibitor era, we couldn’t take many patients to transplant because of how much they were deconditioned. We used to even talk sometimes about doing splenectomy before transplant. Now, when those drugs work, the patient’s performance improves and their spleen shrinks, so it’s good preparation for the transplant. But to your point, even at our institution, we have a protocol where we don’t stop those drugs. You keep [patients on them] until the transplant because patients will have a quick rebound of their symptoms.

 

Transcript edited for clarity.

Myeloproliferative Neoplasms: Myelofibrosis

Rami Komrokji, MD: Let’s talk about myelofibrosis [MF]. Of those diseases, this is probably the most symptomatic disease, with a high burden on patients and worse outcome in general. Jamile, can you walk us through myelofibrosis? How do we diagnose, differentiate, and approach it? How do you risk stratify those patients?

Jamile Shammo, MD, FACP, FASCP: Myelofibrosis is the MPN [myeloproliferative neoplasm] associated with the worst outcome. It’s so critical to identify it right away. The most challenging piece about myelofibrosis is getting the doctors to do a bone marrow biopsy, because the only way to make a diagnosis of myelofibrosis is by demonstrating that you have 2- or 3-plus reticulin fibrosis. That becomes more critical in patients who have prior PV [polycythemia vera] or ET [essential thrombocythemia].

Because the progression can be insidious unless you’re totally on top of it, it’s important to look at the whole leukoerythroblastic picture if you’re familiar with the diagnosis of post-ET or post-PV MF, the development of anemia, leukoerythroblastosis, new splenomegaly, etc. You look at the constitutional symptoms and whether your patient with PV isn’t requiring phlebotomy and developing anemia when they shouldn’t, then perhaps you do a bone marrow biopsy. In someone who may have thrombocytosis without an explanation, you’d need to do bone marrow biopsy to make that diagnosis.

Essentially, that’s what should be done to make this diagnosis. Then it’s important to obtain all additional genetic testing that’s included in the cytogenetics when the diagnosis is made. But there’s a problem with that, because sometimes those patients can be a dry tap and you might not be able to obtain genetic tests or genetics. I typically get them from the peripheral blood, but I’m curious to see what you do. Next-generation sequencing has become so important for risk stratification and to determine what to do in terms of stem cell transplant, which continues to be the only curative treatment for this subset of patients. Granted, assessment of symptoms is so important in this patient population. It should be done at baseline and as we move forward with various treatments we employ.

Rami Komrokji, MD: I agree. We now know more about the phenotypes of myelofibrosis: cytopenic vs proliferative. The patient presentation with myelofibrosis is either those who have cytopenia predominantly up front or proliferative with splenomegaly constitutional symptoms. I always like to point out that not every fibrosis you see in the bone marrow is myelofibrosis. That can be seen with diseases that mimic myelofibrosis, like myelodysplastic syndrome. I’ve had several cases where it was marginal zone lymphoma or hairy cell leukemia. Not every fibrosis in the bone marrow is myelofibrosis.

On the other hand, you don’t always need to see fibrosis to establish the diagnosis of myelofibrosis, because now we talk about this prefibrotic myelofibrosis entity, where the classical megakaryocytic clustering that we see in MPN is enough to make the diagnosis. They don’t have to have the +2, +3, but it’s key. A lot of those patients will have evidence of a clonal marker. Almost 90% will have either JAK2MPL, or calreticulin. I always go extensively more than if they were triple negative to make sure we’re labeling this the right way. To your point, we do most of the next-generation sequencing on peripheral blood in those patients. The concordance is pretty good and high. As you mentioned, many times with the bone marrow, it’s a dry tap.

Transcript edited for clarity.

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SARS-CoV-2 Vaccination Reduces Risk of Mortality and Hospitalization in MPNs

By Andrea S. Blevins Primeau, PhD, MBA
Hematology Advisor

Vaccination for SARS-CoV-2 infection reduced the risk of COVID-19 mortality and hospitalization in patients with myeloproliferative neoplasms (MPNs), according to the results of a study that was presented at the EHA 2022 Hybrid Congress.

Prior to this study, there were “no robust data on characterizing the clinical outcomes of patients with MPN and COVID-19 in the United States,” the authors reported.

The single-center, retrospective, observational cohort study evaluated data from 388 patients with MPN and COVID-19 between April 2020 and December 2021. Of these patients, 53 had positive SARS-CoV-2 test results by RT-PCR.

“To date, this is the largest cohort of MPN patients with COVID-19 infection in the US, which accounts for 14% of the MPN patients in our center,” the authors reported.

The median age at baseline was 59 years, 51% of patients were men, and 46% had a body mass index (BMI) of 30 kg/m2 or higher. The cohort comprised 55% of patients with myelofibrosis (MF), 28% with polycythemia vera (PV), and 17% with essential thrombocythemia (ET). The most common comorbidities were hypertension, present in 60% of patients, and diabetes, which was present in 19%.

Hospitalization was required for 47% of patients; of these patients, 68% required supplemental oxygen. Patients with MF had the highest rates of hospitalization, at 68%, compared with patients with PV or ET. The median length of stay was 8 days.

There were 49% of patients who had been vaccinated. Infection after the first dose of the vaccine occurred in 23% of patients.

Vaccination against SARS-CoV-2 was associated with better outcomes. Hospitalization rates were lower among patients who were immunized, at 28%, compared with 72% for patients who were not immunized.

Of the 9 patients who died, all but 1 were unvaccinated. The median overall survival of vaccinated patients was not reached, compared with 19.9 months among patients who were unvaccinated.

Overall, the case fatality rate of SARS-CoV-2 infection was 17%. The median overall survival was not reached during a median follow-up of 14.8 months.

The authors concluded that SARS-CoV-2 vaccination significantly decreases the risk of mortality and hospitalization in patients with MPN. In addition, they added that BMI 30 kg/m2 or higher appears to be an important risk factor.

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Mutations in the miR-142 gene are not common in myeloproliferative neoplasms

Authors: Paulina Galka-Marciniak, Zuzanna Kanduła, Adrian Tire, Wladyslaw Wegorek, Kinga Gwozdz-Bak, Luiza Handschuh, Maciej Giefing, Krzysztof Lewandowski & Piotr Kozlowski

Abstract

Recent data indicate that MIR142 is the most frequently mutated miRNA gene and one of the most frequently mutated noncoding elements in all cancers, with mutations occurring predominantly in blood cancers, especially diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. Functional analyses show that the MIR142 alterations have profound consequences for lympho- and myelopoiesis. Furthermore, one of the targets downregulated by miR-142-5p is CD274, which encodes PD-L1 that is elevated in many cancer types, including myeloproliferative neoplasms (MPNs). To extend knowledge about the occurrence of MIR142 mutations, we sequenced the gene in a large panel of MPNs [~ 700 samples, including polycythemia vera, essential thrombocythemia, primary myelofibrosis (PMF), and chronic myeloid leukemia], neoplasm types in which such mutations have never been tested, and in panels of acute myeloid leukemia (AML), and chronic lymphocytic leukemia (CLL). We identified 3 mutations (one in a PMF sample and two others in one CLL sample), indicating that MIR142 mutations are rare in MPNs. In summary, mutations in MIR142 are rare in MPNs; however, in specific subtypes, such as PMF, their frequency may be comparable to that observed in CLL or AML.

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Hematocrit levels, white blood cell counts influence thrombosis risk in polycythemia vera

Aaron T. Gerds, MD, MS, spoke with Healio about the REVEAL study, results of which were presented at this year’s European Hematology Association Congress.

REVEAL is the largest prospective, observational study of patients with polycythemia vera ever completed.

Researchers aimed to collect data on disease burden, clinical management and patient-reported outcomes of more than 2,500 adults with polycythemia vera.

The analysis presented at EHA showed elevated hematocrit levels, white blood cell counts and platelet counts influenced thromboembolism risk in this patient population.

In this video, Gerds — associate professor of medicine at Cleveland Clinic Taussig Cancer institute — provides an overview of the study findings and their potential implications.

“This represents a very ripe database that will most certainly pay off for years in the future as we go through several iterations of analysis,” Gerds told Healio.

Read more and watch the video

Reference:

Gerds AT, et al. Abstract P1062. Presented at: European Hematology Association Congress; June 9-12, 2022; Vienna.

The Outcome of Fatherhood in Patients With Philadelphia-Negative Myeloproliferative Neoplasms: A Single-Institution Experience

Abstract

Background

Fertility is a highly complex subject; it involves more than one individual and has profound psychological and economic implications. Moreover, it is affected by several factors, including age, significant systemic illness in either partner, exposure to environmental toxins, medications, or radiation. In patients with malignancy, fertility is more complicated. Patients with a malignancy might have reduced fertility due to the disease, medication, and radiation. Besides the reduced fertility, there are more concerns regarding the subsequent effect of cancer treatment on their offspring and the possibility of having healthy children. There were many studies regarding fertility in patients with cancer; however, in male patients with Philadelphia-negative myeloproliferative neoplasms (MPNs), there are very limited data.

Objectives

In this study, we aim to see the outcome of fatherhood in male patients with Philadelphia-negative myeloproliferative neoplasms (MPNs), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) whether on treatment or not.

Methods

A retrospective mixed-design study of male patients with Philadelphia-negative MPN was followed up in our institute (National Center for Cancer Care and Research (NCCCR)), Doha, Qatar, between January 1, 2008, and January 1, 2020. Patients were interviewed regarding fertility-related information. All included patients had a confirmed diagnosis of Philadelphia-negative MPN according to World Health Organization (WHO) 2008 or WHO 2016 criteria for MPN, aged more than 18 years old.

Results

A total of 124 male patients were interviewed, and only 20 patients met the inclusion criteria. The majority of the patients were lost to follow-up or could not be contacted, and 28.8% of the excluded patients had their families completed by the time of diagnosis. The treatment received included hydroxycarbamide (n=8), pegylated interferon 2 alpha (n=10), ruxolitinib (n=1), and phlebotomy (n=1). The mean duration of exposure to treatment before pregnancy was 4.7 years. The mode of delivery was normal vaginal delivery in 71.4% of the pregnancies. The total number of offspring was 30, and the total number of conceptions was 30.

Conclusion

Our data showed that most Philadelphia-negative MPN male patients on treatment had their offspring born normally with no serious complications, congenital anomalies, or reports of MPN-related cancers. Patients’ concerns regarding fertility should be addressed well to ensure a better quality of life.

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Introducing PAN’s Newly Expanded Transportation Fund

The PAN Foundation today announced an expansion of its transportation fund, providing up to $500 per year to help eligible patients access affordable and reliable transportation to services and activities that improve their overall health outcomes.

PAN’s transportation program, which first launched in 2020, addresses socioeconomic barriers to medical care and medication adherence. A survey of PAN patients in 2021 showed that after receiving a transportation grant, medication adherence increased by 52 percent and adherence to physician visits increased by 29 percent.

Under the expanded program, patients will be able to use their grants to pay for transportation to access healthcare services, get social support, and even travel to the grocery store.

Expanding the program and covered services will better serve the holistic needs of each patient. Improving access to transportation removes barriers to medical care, reduces social isolation, and decreases risks for food insecurity, particularly for older adults and people living with serious illnesses.

“Since its inception, PAN’s transportation fund has led to better health outcomes for thousands of patients who needed help getting to their medical care,” said PAN President Kevin L. Hagan. “We know this expansion will help even more patients, who will now be able to use funding to better access social support and healthy food. We are grateful for the continued support of our generous donors, who enabled the expansion of this program that will reduce health barriers and improve lives.”

Patients who qualify are eligible to receive $500 per year in financial assistance in the form of a prepaid debit card, which is authorized for eligible expenses.

Eligibility requirements

To get financial assistance for transportation, patients must:

  • Be currently enrolled in a co-pay or premium disease fund at the PAN Foundation and receiving treatment for that disease.
  • Reside and receive treatment in the United States or U.S. territories. (U.S. citizenship is not a requirement.)
  • Have health insurance that covers the qualifying medication or product.
  • Have an income that falls at or below 500 percent of the federal poverty level.

How to apply

Patients or caregivers applying on their behalf can apply for assistance using the PAN Foundation’s online patient portal. A series of how-to guides are also available for the patient portal, including common tasks like creating an account and applying for assistance online.

 

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GSK Reaches Agreement to Acquire Late-Stage Biopharmaceutical Company Sierra Oncology For $1.9bn

04/13/2022
  • Sierra Oncology’s differentiated momelotinib has the potential to address the critical unmet medical needs of myelofibrosis patients with anemia
  • Momelotinib complements GSK’s existing expertise in haematology, with Sierra Oncology anticipating US regulatory submission in Q2 this year and EU submission in the second half of 2022
  • Sales contribution expected to start in 2023 with significant growth potential thereafter
  • Supports development of strong portfolio of new specialty medicines and vaccines

GlaxoSmithKline plc (LSE/NYSE: GSK) and Sierra Oncology, Inc (Nasdaq: SRRA) today announced that the companies have entered into an agreement under which GSK will acquire Sierra Oncology, a California-based, late-stage biopharmaceutical company focused on targeted therapies for the treatment of rare forms of cancer, for $55 per share of common stock in cash representing an approximate total equity value of $1.9 billion (£1.5 billion).

Myelofibrosis is a fatal cancer of the bone marrow impacting the normal production of blood cells. Anaemia represents a high unmet medical need in patients with myelofibrosis. At diagnosis, approximately 40% of patients are already anaemic, and it is estimated that nearly all patients will eventually develop anaemia.1,2 Patients treated with the most commonly used JAK inhibitor will often require transfusions, and more than 30% will discontinue treatment due to anaemia.3 Anaemia and transfusion dependence are strongly correlated with poor prognosis and decreased overall survival.4

Momelotinib has a differentiated mode of action with inhibitory activity along key signalling pathways. This activity may lead to beneficial treatment effects on anaemia and reduce the need for transfusions while also treating symptoms. In January 2022, Sierra Oncology announced positive topline results from the MOMENTUM phase III trial. The study met all its primary and key secondary endpoints, demonstrating that momelotinib achieved a statistically significant and clinically meaningful benefit on symptoms, splenic response, and anaemia.

Luke Miels, Chief Commercial Officer, GSK said: “Sierra Oncology complements our commercial and medical expertise in haematology. Momelotinib offers a differentiated treatment option that could address the significant unmet medical needs of myelofibrosis patients with anaemia, the major reason patients discontinue treatment. With this proposed acquisition, we have the opportunity to potentially bring meaningful new benefits to patients and further strengthen our portfolio of specialty medicines.”

Stephen Dilly, MBBS, PhD, President and Chief Executive Officer, Sierra Oncology said: “Uniting with GSK creates the best opportunity for Sierra Oncology to realise its mission of delivering targeted therapies that treat rare forms of cancer while also delivering compelling and certain value for our stockholders. Now we have a partner with a global infrastructure and oncology expertise that enables us to deliver momelotinib to patients as quickly as possible and on a global scale.”

Momelotinib complements GSK’s Blenrep (belantamab mafodotin), building on GSK’s commercial and medical expertise in haematology. The proposed acquisition aligns with GSK’s strategy of building a strong portfolio of new specialty medicines and vaccines. If the transaction is completed and momelotinib is approved by regulatory authorities, GSK expects momelotinib will contribute to GSK’s growing specialty medicines business, with sales expected to begin in 2023, with significant growth potential and a positive benefit to the Group’s adjusted operating margin in the medium term.

Financial considerations

Under the terms of the agreement, the acquisition will be effected through a one-step merger in which the shares of Sierra Oncology outstanding will be cancelled and converted into the right to receive $55 per share in cash. Subject to customary conditions, including the approval of the merger by at least a majority of the issued and outstanding shares of Sierra Oncology, and the expiration or earlier termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976, the transaction is expected to close in the third quarter of 2022 or before.

The per share price represents a premium of approximately 39 per cent to Sierra Oncology’s closing stock price on 12 April 2022 and a premium of approximately 63 per cent to Sierra’s volume-weighted average price (VWAP) over the last 30 trading days. Sierra Oncology’s Board of Directors has unanimously recommended that Sierra’s stockholders vote in favour of the approval of the merger. Additionally, stockholders of Sierra Oncology holding approximately 28 per cent of Sierra’s outstanding shares, have agreed to vote their shares in favour of approval of the merger.

GSK will account for the transaction as a business combination and expects it to be accretive to adjusted EPS in 2024, the expected first full year of momelotinib’s sales. New GSK reaffirms its full-year 2022 guidance, the medium-term outlook for 2021-2026 of more than 5% sales and 10% adjusted operating profit CAGR* at CER**, and long-term sales ambition.

The value of the gross assets of Sierra Oncology to be acquired (as of 31 December 2021) is $109 million (£83 million at the rate of £1 = $1.312, being the 31 March 2022 spot rate). The net losses of the business were $95 million for the 12 months ended 31 December 2021 (£70 million, at the rate of £1 = $1.38, being the average rate for the period).

* CAGR: Compound Annual Growth Rate; **CER: Constant Exchange Rate

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AbbVie Presents Positive Investigational Navitoclax Combination Data in Phase 2 REFINE Study Suggesting Anti-Fibrosis Activity for Patients with Myelofibrosis

–          Navitoclax is being studied in myelofibrosis, a rare, difficult-to-treat blood cancer
–          Results are from an exploratory analysis of 34 myelofibrosis patients who received at least one dose of navitoclax in combination with ruxolitinib after suboptimal response or disease progression with ruxolitinib monotherapy
–          Median overall survival was not reached for patients who had a ≥ 1 grade improvement in bone marrow fibrosis or ≥ 20% variant  allele frequency reduction
–          At the time of analysis with > 2 year follow up the survival estimate was 100% in patients who had improvements in bone marrow fibrosis or variant allele frequency
–          Results were presented at the American Association for Cancer Research annual meeting

NORTH CHICAGO, Ill.April 12, 2022 /PRNewswire/ — AbbVie (NYSE: ABBV) today announced new data from a Phase 2 trial of navitoclax in combination with ruxolitinib in patients with myelofibrosis. The results were presented at the American Association for Cancer Research annual meeting (AACR 2022, abstract #LB108). Navitoclax is an investigational, first-in-class, oral BCL-XL/BCL-2 inhibitor that is designed to activate programmed cell death (apoptosis) in cancer cells. Navitoclax and its safety and efficacy are under evaluation as part of ongoing Phase 2 and registrational Phase 3 studies.

“Myelofibrosis is a cancer that originates in the bone marrow, leading to fibrosis. Currently, available therapies do not address the underlying disease biology and have not shown a consistent effect on both biomarkers of disease modification and overall survival. Disease control with reversal of bone marrow fibrosis is a key objective for improving patient outcomes,” said Mohamed Zaki, M.D., Ph.D., vice president and global head of oncology clinical development at AbbVie. “That’s why we are especially pleased about these early results of navitoclax in combination with ruxolitinib that indicate its novel mechanism of action of inducing cell death may cause reversal of bone marrow fibrosis and extend survival for patients who respond to treatment.”

Myelofibrosis is a rare, difficult-to-treat blood cancer that results in excessive scar tissue formation (fibrosis) in the bone marrow. Anti-fibrosis activity, measured by reversal of bone marrow fibrosis (BMF) and reduction in driver gene variant allele frequency (VAF) have been suggested as potential biomarkers to measure disease modification in myelofibrosis, but their association with a survival benefit have not been widely described.These data build on AbbVie’s history of transforming standards of care in blood cancers with significant unmet needs.

The results presented at AACR 2022 were from REFINE (NCT03222609) – a Phase 2 trial evaluating navitoclax in combination with ruxolitinib (a JAK1/2 inhibitor), which included patients with myelofibrosis who had progressed on or had a suboptimal response to at least 12 weeks of ruxolitinib monotherapy. Median exposure to prior ruxolitinib was 91 weeks (range: 19 weeks – 391 weeks) in the first 34 patients enrolled earlier in the trial.

In the exploratory analysis of 32 patients who were evaluable for improvements in BMF, 12 (38%) had a ≥1 grade improvement during any time point in the study. For driver gene VAF reduction, 26 patients were evaluable and 6 (23%) achieved a ≥20% reduction at week 24. Five patients achieved both BMF and VAF responses.

Median overall survival (OS) for all patients was not reached as presented previously by Harrison2 et al. For patients who had a ≥1 grade improvement BMF median OS was not reached compared with 28.5 months for patients who did not experience an improvement. Similarly, median OS was also not reached for patients who achieved a ≥20% driver gene VAF reduction versus 28.5 months for patients who did not.

All 34 patients (100%) experienced at least one adverse event (AE), and 15 (44%) experienced a serious adverse event (SAE).2 The most common AEs of any grade were thrombocytopenia  (n= 30, 88%), diarrhea (n= 24, 71%), fatigue (n= 21, 62%), and nausea (n= 13, 38%). The most common SAEs were pneumonia (n= 4, 12%) and splenic infarction (n= 2, 6%).2 There were no SAEs of bleeding and thrombocytopenia was manageable and reversible with dose reduction/interruption of navitoclax and/or ruxolitinib.2 REFINE was a dose-finding study and the target dose of navitoclax was reduced subsequent to these findings.

“Data obtained from this exploratory analysis holds promise for potential future clinical research,” said Jacqueline S. Garcia, M.D., Dana-Farber Cancer Institute, assistant professor of medicine at Harvard Medical School. “What is most notable in this analysis is the overall survival among patients who demonstrate VAF and BMF responses and all patients were alive at time of analysis. Patients in this Phase 2 trial had suboptimal response to ruxolitinib at time of study entry and then had navitoclax added to ruxolitinib on the trial. VAF and BMF responses occurred despite the presence of high molecular risk mutations, which suggests the potential efficacy of combination navitoclax and ruxolitinib could be independent of underlying risk factors.”

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