Allogeneic HSCT Improves Overall Survival in MDS/MPN With Neutrophilia

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Lauren Dembeck, PhD
A large, nationwide, population-based study of patients with myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) with neutrophilia found that, to date, only allogeneic hematopoietic stem cell transplantation (alloHSCT) significantly improves overall survival (OS), according to research published in Blood Advances.

“MDS/MPN with neutrophilia is a very rare disease. It carries a poor median overall survival of 15 months (with a reported range of 12.4 to 37 months),” the study authors explained in their report. “Without treatment, 30-40% of patients progress to acute myeloid leukemia.”

Researchers retrospectively analyzed a cohort of 347 adult patients diagnosed with MDS/MPN with neutrophilia, previously known as atypical chronic myeloid leukemia, who were registered in the Netherlands Cancer Registry between 2001 and 2019. The aim of the study was to validate known prognostic markers, identify novel prognostic markers, and provide evidence-based treatment recommendations.

The demographic baseline data of the cohort was consistent with those of cohorts from other studies. Most patients were male (65%) and >65 years old (71%). The median age at diagnosis was 72 years (range, 22-95 years). Only 5 patients (1.4%) were known to have a prior hematological malignancy (MDS, n=2; lymphoma, n=3). The median OS for the overall cohort was 15.8 months (95% CI, 13.8-17.2 months), and no significant difference in OS was observed between the sexes.

Among 110 patients diagnosed between 2014-2019, cytogenetic testing data was available for 89% of patients. Of those, 15% had cytogenetic abnormalities, which were all in patients aged >65 years. The most common cytogenetic abnormality was trisomy 8 (6/15 patients).

Within the same subgroup, molecular analysis was available for 92% of patients. Of those, 49 patient harbored a total of 16 distinct molecular mutations, with some patients (16/101) having up to 3 different mutations. The most frequent mutations were in ASXL1 (22%), SETBP1 (18%), SRSF2 (12%), and CSFR3 (12%).

In the overall cohort, a multivariable Cox regression analysis adjusted for primary therapy revealed that age (>65 years of age hazard ratio [HR], 1.85; 95% CI, 1.34-2.55; P =.001) and alloHSCT (HR, 0.51; 95% CI, 0.26-0.97; P =.039) were associated with OS.

“As no other treatment modality, seemed to impact survival and might cause toxicity, we propose that all patients eligible for alloHSCT should whenever possible receive an allogeneic transplant. It is imperative that we strive to improve outcomes for patients not eligible for alloHSCT,” the study authors concluded in their report.

Reference

Klein SK, Huls GA, Visser O, Kluin-Nelemans HC, Dinmohamed AG. Characteristics, primary treatment, and survival of MDS/MPN with neutrophilia: a population-based study. Blood Adv. Published online November 7, 2023. doi:10.1182/bloodadvances.2023011181

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SRSF2 Mutations Lead to Lessened Frequency of Polycythemia in Preclinical MPN Models

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Kyle Doherty

The presence of mutated SRSF2 in knock-in mouse models of JAK2 V617F–driven myeloproliferative neoplasms (MPNs) reduced the rate of polycythemia and hampered hematopoietic progenitor functions, according to findings from a preclinical study published in Blood Cancer Journal.

Findings from the study demonstrated that coexpression of mutant SRSF2 P95H decreased red blood cell (RBC), neutrophil, and platelet counts, as well as attenuated splenomegaly in JAK2 V617F-positive mice. Notably, bone marrow fibrosis was not induced in JAK2 V617F-positive mice. Coexpression of SRSF2 P95H was also found to reduce the competitiveness of JAK2 V617F–mutated hematopoietic stem/progenitor cells.

Additionally, RBC, hemoglobin, and hematocrit levels were significantly reduced in the bone marrow of JAK2 V617F–positive mice that displayed enforced expression of S100A9. Mutated SRSF2 P95H decreased TGF-β levels and increased S100A8 and S100A9 expression in JAK2 V617F–positive mice.

“We demonstrated that SRSF2 P95H mutant reduces polycythemia and impairs competitiveness of JAK2 V617F–mutant hematopoietic stem/progenitor cells but does not promote the development of bone marrow fibrosis inJAK2 V617F-induced MPN,” lead study author Yue Yang, MD, of the Department of Biochemistry and Molecular Genetics at the University of Virginia School of Medicine in Charlottesville, and coinvestigators wrote.

To conduct their study, investigators created JAK2 V617F knock-in, SRSF2 P95H knock-in, and Mx1Cre transgenic mouse models, all on a C57BL/6 background. Intraperitoneal injection of 3 doses of polyinosine-polycytosine 300 μg were given at 4 weeks after birth in order to induce Mx1Cre expression. Wild-type C57BL/6 and UBC-GFP mice were acquired from an outside laboratory.

To create non-competitive bone marrow transplantation assays, 1 x 106 bone marrow cells were taken from the mice in each of the 4 groups (control of wild-type or Mx1Cre; SRSF2 P95H-positive; JAK2 V617F-positive; and SRSF2 P95H/JAK2 V617F-positive) and transplanted into lethally irradiated C57BL/6 mice. Polyinosine-polycytosine was administered to the recipient mice at a dose of 300 μg 3 times at 4 weeks following transplantation.

Competitive transplantation assays were created by mixing bone marrow cells from uninduced JAK2 V617F-positive/GFP-positive or SRSF2 P95H/JAK2 V617F-positive/GFP-positive were mixed with wild-type competitor bone marrow cells at a 1:1 ratio and transplanted into wild-type C57BL/6. Recipient mice received 3 doses of polyinosine-polycytosine 300 μg at 4 weeks post transplantation.

To create colony-forming assays, investigators plated 2 X 104 mouse bone marrow cells in cytokine-containing complete methylcellulose medium. After 1 week, burst forming units-erythroid and granulocyte-macrophage colony-forming units were tallied. Spleen cells at a quantity of 1 x 105 were plated in MethoCult M3234 medium without cytokine to detect epo-independent colony-forming units-erythroid.

Epo-independent colony-forming units-erythroid were stained with benzidine solution and counted 2 days afterwards. Colony-forming units-megakaryocytes were determined by plating 1 x 105 bone marrow cells in collagen-based MegaCult medium with Tpo, IL-3, IL-6, and IL-11. Colony-forming units-megakaryocytes were scored at day 8.

S100A8 or S100A9 overexpression’s effect on granulocyte-macrophage colony-forming units and burst forming units-erythroid formation of JAK2 V617F-positive bone marrow, cells lineage-negative cells were isolated from the bone marrow. Puromycin 2.5 μg/mL administered for 48 hours was used to select infected cells and 2.5 × 103 lineage-negative cells were plated in duplicates in cytokine-supplemented complete methylcellulose medium.

Study authors analyzed the mice models using flow cytometry and real-time quantitative PCR. Additionally, the TGF-β1 ELISA kit was used to determine TGF-β1 serum levels.

Further findings revealed that mice with heterozygous JAK2 V617F displayed polycythemia vera with increased white blood cell, neutrophil, platelet, RBC, hemoglobin, and hematocrit counts in peripheral blood compared with control mice. Those with heterozygous SRSF2 P95H experienced decreased hemoglobin with increased mean corpuscular volume vs the control group. SRSF2 P95H/JAK2 V617F-positive mice had significantly decreased white blood cell, neutrophil, platelet, RBC, hemoglobin, and hematocrit levels vs JAK2 V617F–positive mice. Concurrent expression of JAK2 V617F and SRSF2 P95H mutations resulted in higher mean corpuscular volume values and reduced spleen size and weight vs JAK2 V617F–positive mice, which displayed splenomegaly.

JAK2 V617F–positve mice bone marrow sections had hypercellularity with significant increase in erythroid precursors and megakaryocyte clusters compared with JAK2 V617F/SRSF2 P95H–positive mice, which had normal bone marrow cellularity and a reduction of erythroid precursors and megakaryocyte clusters. At 24 weeks, reticulin staining of bone marrow of SRSF2 P95H/JAK2 V617F–positive mice did not reveal fibrosis; bone marrow fibrosis was also not observed at 1 year following induction.

Together, JAK2 V617F and SRSF2 P95H mutations significantly reduced LSK, short- and long-term hematopoietic stem cell, and multipotent progenitor counts in the bone marrow of mice with both alterations. In comparison, mice with only JAK2 V617F mutations had increased frequencies and totals in terms of LSK, short- and long-term hematopoietic stem cells, and multipotent progenitors. The presence of both mutations also resulted in decreased frequency and total numbers of myeloid progenitors, common myeloid progenitors, granulocyte-macrophage progenitors, and megakaryocyte-erythroid progenitors in the bone marrow compared with mice with JAK2 V617F mutations alone.

Expression of an SRSF2 P95H mutation was also found to reduce the competitiveness of JAK2 V617F hematopoietic stem/progenitor cells. Mice that received of JAK2 V617F–positive bone marrow displayed significantly higher percentages of GFP-positive granulocyte, erythroid, megakaryocyte, B-lymphocyte, and T-lymphocyte cells in the peripheral blood compared with those that received SRSF2 P95H/ JAK2 V617F–positive bone marrow. Reduced percentages of the same hematopoietic stem/progenitor cells were observed in the bone marrow of mice that received SRSF2 P95H/ JAK2 V617F–positive bone marrow vs JAK2 V617F–positive bone marrow.

“Similar observations [to ours] have been made in a recent study by Willekens et al. Additional mutations or genetic abnormalities are required in association with SRSF2 P95H and JAK2 V617F mutations in the development of full-blown myelofibrosis,” the study investigators concluded.

Reference

Yang Y, Abbas S, Sayem MA, et al. SRSF2 mutation reduces polycythemia and impairs hematopoietic progenitor functions in JAK2V617F-driven myeloproliferative neoplasm. Blood Cancer J. 2023;13(1):171. doi:10.1038/s41408-023-00947-y

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AI Model May Help Distinguish Between Two Rare Hematologic Malignancies

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By The ASCO Post Staff

Posted: 12/13/2023

A novel artificial intelligence (AI) model may help physicians distinguish and identify prefibrotic primary myelofibrosis from essential thrombocythemia, according to new findings presented by Srisuwananukorn et al at the 2023 American Society of Hematology (ASH) Annual Meeting and Exposition (Abstract 901).

Background

Myeloproliferative neoplasms are a type of cancer in which the bone marrow overproduces certain types of blood cells. Prefibrotic primary myelofibrosis is rarer and has a much worse prognosis than essential thrombocythemia—with a median survival of 12 years vs 22 years, respectively. As a result, prefibrotic primary myelofibrosis may require more aggressive treatment; however, experts may not always agree on a definitive diagnosis when interpreting laboratory and biopsy results.

Despite being integral to informing treatment approaches and enrolling patients in clinical trials, distinguishing the two hematologic malignancies is often challenging with current diagnostic methods.

Study Methods and Results

In the new study, researchers used a novel AI model—which had previously been trained with 32,000 pan-cancer biopsy images and was familiar with general pathologic features—to analyze images from U.S. and Italian patients in order to differentiate between prefibrotic primary myelofibrosis and essential thrombocythemia.

To aid diagnosis, the researchers trained an AI model to distinguish features indicating the two conditions in bone marrow biopsy images from 200 patients. They then tested the model’s ability to differentiate the two types of myeloproliferative neoplasms in biopsies from 26 additional patients.

The researchers found that the AI model was able to return results in an average of just over 6 seconds for a new patient and performed well, demonstrating a 92.3% rate of agreement with human experts. The sensitivity and specificity for prefibrotic primary myelofibrosis diagnosis was 66.6% and 100%, respectively.

Conclusions

“With the combined accuracy, sensitivity, and specificity we saw, it would allow the physician to be confident in one diagnosis vs another and help rule in or rule out the rarer [prefibrotic primary myelofibrosis] diagnosis, particularly for clinical trials,” emphasized lead study author Andrew Srisuwananukorn, MD, Assistant Professor at The Ohio State University Comprehensive Cancer Center. “[Our] hope is that it would maintain this accuracy when tested in larger cohorts,” he added.

The researchers hope that with further testing, the novel AI model could potentially be used as a companion tool for clinical diagnoses and may help physicians match patients with the most appropriate clinical trials—which could result in more effective treatments. However, the researchers cautioned that the model was intended to complement, not replace, human experts.

“What we’re trying to develop is a clinical decision support tool, with an emphasis on support. Physicians with no computer science backgrounds are increasingly recognizing the value of AI [models] and closer to being able to use them for their clinical practice. [M]ore investigations would be needed for this [model] to be used in clinical practice, including testing in cohorts with different racial backgrounds,” underscored Dr. Srisuwananukorn.

The researchers plan to continue refining the AI model and hope to test it with larger data sets. The researchers concluded that AI models could potentially be utilized in the advancement of basic research on myeloproliferative neoplasms to link biologic processes with particular morphological features visible on biopsy slides and develop strategies to predict prognoses or response to treatment.

Disclosure: For full disclosures of the study authors, visit ash.confex.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

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Managing blood cancer: Claire Harrison on ruxolitinib for polycythemia vera

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Rod Tucker
13 December 2023
The recent UK approval of ruxolitinib for the blood cancer polycythaemia vera marks a significant milestone in tackling unmet need for an under-represented patient population. Here, consultant haematologist Professor Claire Harrison speaks to Rod Tucker about ongoing challenges for the condition’s management, how this latest approval will benefit patients and clinicians, and other key research in the pipeline.

Ruxolitinib is a Janus kinase 2 (JAK2) inhibitor with diverse indications covering conditions such as eczema, psoriasis, vitiligo and myelofibrosis.

Most recently, in the UK at least, it has been added to the treatment arsenal for the rare blood cancer polycythaemia vera (PV) after its recommendation in October 2023 by the National Institute for Health and Care Excellence (NICE).

Professor Claire Harrison, consultant haematologist, professor of myeloproliferative neoplasms at Guy’s and St. Thomas’ NHS Foundation Trust in London, UK, has dedicated much of the last decade to researching ruxolitinib for use in PV and was instrumental in securing NICE’s endorsement.

‘It’s [a good] example of following a scientific story from discovery of the mutation, development of the drug, testing it in a more severe but related condition (myelofibrosis) then putting it into second line for PV,’ she says.

Despite the approval, there’s still work to be done to achieve the next ambition of ruxolitinib being approved for first-line use in PV. And Professor Harrison is on hand to get the ball rolling.

Diagnosing and managing polycythaemia vera

Today, diagnosing PV is much easier than when Professor Harrison first started as a consultant in 2001.

Previously, the diagnosis was arrived at following a series of tests to exclude all other possible causes of a patient’s symptoms and abnormal blood count. But after the description of a JAK2 mutation which is present in 97–98% of patients with PV, the diagnosis can be arrived at much more quickly.

‘This particular mutation for which it’s very easy to test for. It’s a cheap test and, for the most part, if it’s present, the patient has either got PV or one of the family of conditions, or it has very low levels of mutations but is likely to change into that,’ Professor Harrison says.

In general, the lay perception of a cancer diagnosis is that it represents a death sentence, and it becomes difficult to assuage patients of this fear.

While PV is incurable and lowers life-expectancy, it is not usually life-threatening, although Professor Harrison says some patients do present with life-threatening blood clots.

‘It’s a cancer but some low-risk patients we just treat with aspirin and phlebotomy, so removing blood,’ she says. ‘So that’s quite tricky saying “you’ve got cancer, but all we’re going to give you is an aspirin and take a pint of blood off you”, and other patients we do give treatments to, but we have limited options.’

Moreover, while these treatments do provide a clinical benefit in some patients, they frequently fail to alleviate symptoms.

This has become abundantly clear from the findings of the ongoing prospective REVEAL study. This showed that patients with PV experience symptoms that affect their quality of life and lead to work productivity impairments with an overall negative impact on their lives.

‘So, 80% of patients will complain of fatigue,’ Professor Harrison says. ‘It’s PV, it’s not a nothing condition: 20% of patients have to give up work or reduce their working time, others do die of the condition and the average life-expectancy is probably 15 to 20 years.’

Professor Harrison also highlights poor awareness of PV. ‘What patients would say, probably, is that people don’t understand the condition, GPs don’t understand the condition and their employers don’t understand the condition. It takes up a lot of their time and it has a big burden on their quality of life.’

She hopes that greater awareness of the condition will make it easier for people to support and make adaptations for this patient group.

Addressing unmet needs in PV

There haven’t been any new treatments for PV in around 20 years, with hydroxyurea and interferon alpha having long been the two options.

But that all changed with the description of the mutation. Professor Harrison says that after first helping with diagnosis, these learnings aided the development of drugs that could target the downstream effects of that mutation, principally JAK inhibitors.

‘These were first tested and used in more aggressive conditions in the family such as myelofibrosis. But with the advent of these drugs and their use in PV, we have been able to show that we can address some of the other unmet needs for patients,’ she says.

‘I could comment on how disappointing it is that the UK is five years behind the rest of Europe in the approval of ruxolitinib for PV, but I would prefer to celebrate that it’s a really important milestone for patients that they have an alternative therapy.’

This is particularly important as resistance or intolerance to treatments can develop in some patients, and there are other side effects and contraindications that mean traditional treatments may not be suitable.

‘An important side effect of hydroxyurea, which is also a side effect of ruxolitinib, is skin cancer,’ says Professor Harrison. ‘That’s something that we need to manage very carefully. If a patient has a skin cancer on hydroxyurea, we will sometimes change the therapy.

‘Interferon does cause quite serious mood disturbance – sometimes suicidal ideation – so it can’t really be used in patients who’ve got a significant history of anxiety or depression.

‘Similarly, [hydroxyurea] can’t be used for the 20% of patients below the age of 40 who might want to conceive a child. But we have the option to alternate between the first-line therapies.’

Emerging benefits of ruxolitinib

One of the key studies that led to the approval of ruxolitinib for PV in the UK was MAJIC-PV. This phase II trial, for which Professor Harrison was the lead author, randomised patients to either ruxolitinib or best available care in those intolerant or resistant to hydroxyurea, which is the current standard care therapy.

What was clear from MAJIC-PV was the superiority of ruxolitinib, with 43% of patients achieving a complete response based on several haematological criteria compared with only 26% of those receiving current best practice care.

While ruxolitinib does not cure PV, the MAJIC-PV trial provided reassurance that over five years no new longer-term safety issues emerged, Professor Harrison notes.

The trial also uncovered several additional biological actions of the drug. During the study, researchers measured the amount of abnormal JAK2 present in patients. This enabled clinicians to determine whether treatments had any effect on the aberrant mutations that were present.

Surprisingly, in those assigned ruxolitinib, there was a reduction in the level of this mutation.

As such, the MAJIC-PV study hinted at a mutation-specific effect of the drug which hadn’t previously been observed. Furthermore, this reduction in the level of abnormal JAK was associated with an increased life expectancy and a reduction in PV-related complications for patients.

‘Interestingly, when we were using the drug to treat patients with myelofibrosis, colleagues in Italy were reporting that their patients who had myelofibrosis but had the autoimmune condition alopecia, the hair was coming back,’ Professor Harrison adds. This hints at the wider benefits of ruxolitinib as an anti-inflammatory drug which is being harnessed in for example the treatment of eczema.

Delving deeper, Professor Harrison also describes how in research by colleague Adam Mead ruxolitinib appeared to modify PV at the stem cell level using research tools enaling the analysis of mutations at a single cell level.

Ruxolitinib as a first-line option?

Despite MAJIC-PV showing that ruxolitinib reduced levels of the abnormal JAK mutations, the current NICE approval recommends that the drug is used second-line for patients who either become resistant to or intolerant of hydroxyurea.

Notwithstanding this restriction, Professor Harrison still feels that it is important for patients to have access to ruxolitinib as another treatment option, either because of contra-indications or adverse effects from the currently available drugs.

Another consideration is the issue of drug resistance. ‘All of the available drugs are generally effective for the majority of patients, but over time, around 20–25% of patients will become resistant to that drug,’ she explains.

As a result, relying on a single drug isn’t the most effective way of controlling a patient’s blood count over time.

Encouraged by the findings from MAJIC-PV, a further phase III open-label trial, MITHRIDATE, for which Professor Harrison is the chief investigator, is starting to enrol patients.

It is designed to compare ruxolitinib with either hydroxyurea or interferon alpha as first-line therapy for high-risk PV patients.

Ruxolitinib also has a powerful effect on disease related symptoms for example patients with PV experience pruritus (itching) which can be extremely disabling, and the drug has a big impact on this troublesome symptom.

Although it is too early to draw any conclusions, Professor Harrison is hopeful that the MITHRIDATE trial will demonstrate the advantages of using ruxolitinib as a first-line treatment option and perhaps offer further insight into the drug’s disease-modifying properties.

Future treatment developments

While the introduction of JAK inhibitors such as ruxolitinib are a welcome addition to a clinician’s arsenal in the treatment of PV, Professor Harrison believes that future treatments need to focus on the off-target effects of these drugs such as immune suppression.

Although the development of JAK mutation-specific therapies in PV would be an advantage, Professor Harrison is of the opinion that it is just as important to improve understanding of how and when to use ruxolitinib in patients with PV.

Alongside the potential development of mutation-specific drugs, there is increasing interest in immune-mediated therapy.

‘I think we’ve had this massive step forward with description of molecular markers and therapies targeting JAK. We’ll probably go to treating PV earlier, and treating with a disease-modifying therapy,’ she concludes.

But focusing on the latest developments, Professor Harrison believes the introduction of innovations such as ruxolitinib would not have been possible without the support of various charities such as MPN Voice and Blood Cancer UK, as well as various academic centres and companies such as Novartis.

Working collaboratively, it has been possible to clearly demonstrate that ruxolitinib can go a long way towards helping to relieve the symptom burden of patients living with polycythaemia vera and improve quality of life for this under-represented patient population.

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New therapies against myelofibrosis, a blood cancer that risks evolving into acute leukemia – breaking latest news

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Myelofibrosis is a chronic myeloproliferative neoplasm which every year is diagnosed in approximately one thousand Italians, mostly in their sixties, but many cases occur in young people. There are therapies capable of keeping the disease under control even for years, but two important problems remain open: preventing the disease from evolving into acute myeloid leukemia (this happens in approximately 10% of patients) and preventing excessive enlargement of the spleen, very frequent, which entails serious consequences for patients. A step forward comes from one study presented at the annual meeting of the American Society of Hematology, underway in San Diego (California), whose main author is Francesco Passamonti, director of Hematology at the IRCCS Polyclinic Foundation of Milan: Obtaining a response on the spleen in a high percentage of patients and managing to maintain it for a long time implies well-being for the patient and a greater share of control over the disease – comments the expert -. This is why this result is important.

What is myelofibrosis

Myelofibrosis is a bone marrow disease characterized by the presence of alterations in the blood count (anaemia, thrombocytopenia, leukopenia or leukocytosis), accompanied by an increase in the spleen (splenomegaly) and the presence of symptoms such as fever, night sweats and a drop in weight. a rare pathology that determines the gradual appearance in the bone marrow of a fibrous tissue that no longer allows it to function correctly, with a consequent alteration in the production of blood cells – explains Passamonti – The disease is due to the presence of acquired genetic mutations in the JAK2 genes , MPL and CALR. These mutations determine the clinical manifestations of the disease, also releasing pro-inflammatory substances and a survival advantage for the diseased cells which then populate the marrow and spleen. In the early stages, myelofibrosis remains asymptomatic and the diagnosis may be made incidentally after a blood test performed for other reasons. Most patients are diagnosed in more advanced stages and manifest themselves with even serious symptoms such as anemia, enlargement of the spleen (splenomegaly) and thrombosis. It is therefore important to have new drugs available that can combat more advanced disease.

Enlarged spleen and other symptoms

The enlargement of the spleen affects approximately 8 out of 10 patients and causes symptoms such as digestive difficulties, sensations of heaviness, discomfort in the abdomen, early satiety and alterations in normal intestinal functions. In some cases the spleen is so enlarged that it occupies a large part of the abdomen and compresses the lungs (causing a dry cough). In some cases, its surgical removal is necessary. Other extremely debilitating symptoms, which can prevent you from carrying out normal daily and work activities and having a normal social and relational life, are fatigue or asthenia, a chronic sense of tiredness, to which fever, night sweats, itching can be added. widespread throughout the body (which worsens with contact with water, also known as aquagenic itching) and weight loss due to lack of appetite and digestive difficulties adds Passamonti.

The therapies

The therapies available today make it possible to extend the survival of patients and reduce debilitating symptoms, allowing, in most cases, a return to daily and work activities and a normal social life, but the only treatment that allows for definitive recovery is bone marrow transplant from a healthy donor, reserved for certain phases of the disease, for those in good general condition and under 70-75 years of age. The disease is progressive with an increase in the size of the spleen, a progressive decline in hemoglobin and platelets and increasingly disabling symptoms – says Passamonti -. It can also progress to acute leukemia. Based on the clinical characteristics of the pathology and the age of the patient, the risk of worsening of myelofibrosis is calculated: depending on the level of risk, a decision can be made for simple observation without therapy up to an allogeneic bone marrow transplant. Today, effective drugs such as JAK inhibitors (ruxolitinib and fedratinib) are available in Italy, aimed at those genetic alterations that we know are responsible for the neoplasm, allowing patients to extend their survival and reduce debilitating symptoms, allowing, in most cases, the return to daily and work activities and a normal social life. However, they have limitations: The response of the drugs on the spleen is limited and, even when they work, the validity of the treatment decreases over time – continues the expert -. And the transplant is a complex procedure, which cannot be offered to the majority of patients.

The new TRANSFORM-1 study

In short, we need new treatments that have a greater effect on the spleen and control symptoms in the long term. And they fit into this context data from the TRANSFORM-1 study, presented at the American Hematology Conference. This is a phase three trial (the last before the final approval and entry onto the market of a medicine) which enrolled over 250 patients with myelofibrosis who had not yet received any therapy, but who needed to start one . One half received the current standard treatment (ruxolitinib) and the other half ruxolitinib plus the new drug navitoclax. Navitoclax is an oral therapy which, by hitting a precise target (the BCL-2/BCL-XL proteins which promote tumor activity), causes the death of diseased cells which would otherwise live too long – clarifies Passamonti -. was administered as first line treatment with the goal of shrinking the spleen by more than 35% (measured by nuclear magnetic resonance imaging). The milestone, after six months of treatment, was reached in 63% of patients with the combination navitoclax and ruxolitinib and in 31% of those receiving standard care alone. The response was obtained in 76% and 41% in the two populations respectively. Furthermore, loss of response was recorded in 18% of patients with the combination and in 26% with ruxolitinib alone.

Chronic myeloproliferative neoplasms

In hematology, great progress in the last 20 years has been achieved thanks to the discovery of genetic mutations underlying numerous diseases and often responsible for tumor proliferation, as well as its resistance to treatment – comments Paolo Corradini, president of the Italian Society of Hematology (Sie) -. Scientific research then began to create drugs that only affected DNA alterations, sparing healthy cells. This has also led to important results in chronic myeloproliferative neoplasms, such as myelofibrosis, polycythemia vera (characterized by the progressive increase in red blood cells) and essential thrombocythemia involving the excessive increase in the number of platelets. They are rare diseases, which together cause around a thousand new cases to be recorded in Italy every year. They can accompany the patient for years without worsening, requiring only periodic checks or therapies, more or less aggressive depending on the case. The important role of our country in the TRANSFORM-1 trial demonstrates, once again, the high quality of Italian hematology.

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MorphoSys’ Pelabresib Improves All Four Hallmarks of Myelofibrosis in Phase 3 MANIFEST-2 Study

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Pelabresib and ruxolitinib combination significantly reduced spleen size, with an SVR35 response rate nearly double that of placebo plus ruxolitinib

Showed a strong positive trend in reducing symptom burden and a twofold increase in patients achieving both SVR35 and TSS50 versus placebo plus ruxolitinib

Improved measures of anemia, including higher hemoglobin response rates, fewer patients requiring transfusions and fewer anemia adverse events versus placebo plus ruxolitinib

Improved bone marrow fibrosis by at least one grade in more patients versus placebo plus ruxolitinib

Demonstrated safety results consistent with prior clinical trials, with fewer grade ≥3 adverse events compared with placebo plus ruxolitinib

MorphoSys will host an investor event to review findings on Monday, December 11

MorphoSys AG (FSE: MOR; NASDAQ: MOR) today announced comprehensive results from the Phase 3 MANIFEST-2 study investigating pelabresib, an investigational BET inhibitor, in combination with the JAK inhibitor ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis. These findings were presented in an oral presentation at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California.

Myelofibrosis is characterized by four hallmarks: an enlarged spleen, anemia, bone marrow fibrosis and disease-associated symptoms. In MANIFEST-2, all hallmarks were improved with the pelabresib and ruxolitinib combination versus placebo plus ruxolitinib, which is the standard of care in myelofibrosis. Ruxolitinib dosing was similar in both arms of the study and was determined based on its approved myelofibrosis indication.

“The MANIFEST-2 results demonstrated clear benefits across the four hallmarks of myelofibrosis, including a significant reduction in spleen size – a key finding given the known association between spleen volume reduction and patient survival,” said Raajit K. Rampal, M.D., Ph.D., Director, Center for Hematologic Malignancies, and Director, Myeloproliferative Neoplasms Program, Memorial Sloan Kettering Cancer Center. “The comprehensive results presented at ASH also show that the pelabresib combination improves anemia, disease-associated symptoms and bone marrow fibrosis, and that it is well-tolerated. These findings point to pelabresib and ruxolitinib as a potential paradigm-shifting first-line treatment of this debilitating disease.”

MANIFEST-2 Comprehensive Findings

MANIFEST-2 is a global, multicenter, double-blind, Phase 3 study of 430 JAK inhibitor-naïve adults with myelofibrosis, randomized 1:1 to receive the pelabresib and ruxolitinib combination or placebo plus ruxolitinib. MANIFEST-2 is one of the largest studies in this disease to date.

Strong Reductions in Spleen Size and Symptoms

In the MANIFEST-2 study, pelabresib and ruxolitinib demonstrated a near doubling in the proportion of patients achieving a ≥35% reduction in spleen volume (SVR35) at 24 weeks, the primary endpoint, versus placebo plus ruxolitinib (p<0.001).

For the first key secondary endpoint assessing symptom reduction, absolute change in total symptom score (TSS) at 24 weeks, there was a strong numerical improvement for patients receiving pelabresib and ruxolitinib versus placebo plus ruxolitinib. The response rate for the second key secondary endpoint, proportion of patients achieving ≥50% reduction in symptom score (TSS50) at 24 weeks, was also numerically greater for patients receiving pelabresib and ruxolitinib. Significant improvements in both key secondary endpoints were observed with the pelabresib combination for patients classified as intermediate-risk (Dynamic International Prognostic Scoring System [DIPSS] Int-1 and Int-2), who account for over 90% of the MANIFEST-2 population.

The proportion of patients achieving both SVR35 and TSS50 at 24 weeks was doubled with pelabresib and ruxolitinib versus placebo plus ruxolitinib (40.2% vs. 18.5%, respectively).

Details are included in the table below.

Endpoint Pelabresib + Ruxolitinib
(N=214)		 Placebo +
Ruxolitinib
(N=216)		 Difference
SVR35 65.9% 35.2% 30.4%*
P-value: p<0.001
Absolute Change in TSS -15.99
(Mean Baseline: 28.26)		 -14.05
(Mean Baseline: 27.36)		 -1.94**
P-value: 0.0545
TSS50 52.3% 46.3% 6.0%*
P-value: 0.216

*Difference calculated using Cochran–Mantel–Haenszel (CMH) common risk difference

**Least square mean estimate

Improvement in Anemia

Patients receiving pelabresib in combination with ruxolitinib reported fewer anemia adverse events (43.9%, grade ≥3: 23.1%) compared with placebo plus ruxolitinib (55.6%, grade ≥3: 36.4%). Additionally, by week 24, fewer patients in the pelabresib and ruxolitinib arm required red blood cell transfusions compared with the placebo arm (30.8% vs. 41.2%, respectively).

A greater proportion of patients achieved a hemoglobin response — defined as a ≥1.5 g/dL mean increase in hemoglobin levels over baseline in the absence of transfusions during the previous 12 weeks — with pelabresib and ruxolitinib versus placebo plus ruxolitinib (9.3% vs. 5.6%, respectively). Average hemoglobin levels were greater in patients receiving pelabresib and ruxolitinib than in those receiving placebo plus ruxolitinib, starting at week 9 and continuing to week 24. Anemia benefits were observed across all studied patient risk groups.

“Anemia can reduce patients’ quality of life by causing severe fatigue and necessitating blood transfusions,” said Professor Claire Harrison, Guy’s and St. Thomas’ NHS Foundation Trust, London, United Kingdom. “In MANIFEST-2, patients receiving the combination therapy showed clear benefits on anemia, including greater hemoglobin levels, fewer red blood cell transfusions and fewer anemia and fatigue adverse events. Given its strong efficacy, safety profile and signs of disease modification, the pelabresib and ruxolitinib combination has the potential to become the new standard of care in the first-line treatment of myelofibrosis.”

Improvement in Bone Marrow Fibrosis

Bone marrow fibrosis, or the replacement of bone marrow with fibrous scar tissue, is a central pathological feature of myelofibrosis. In MANIFEST-2, fibrosis was improved by at least one grade in a greater proportion of patients receiving pelabresib and ruxolitinib (38.5% vs. 24.2% with placebo plus ruxolitinib) and worsened by at least one grade in a smaller proportion of patients receiving pelabresib and ruxolitinib (16.3% vs. 28.3% with placebo plus ruxolitinib) at 24 weeks. Bone marrow fibrosis is graded on a scale from 0 (normal) to 3 (most severe) based on fiber density; studies suggest a correlation between the grade of bone marrow fibrosis and patient prognosis.

Biomarker Analysis Suggests Disease Modification

In a biomarker analysis, average plasma levels of inflammatory cytokines (IL-8, IL-6, TNF-α and NF-κB-regulated cytokines) were reduced in patients receiving pelabresib and ruxolitinib compared with placebo plus ruxolitinib at 24 weeks. Increased cytokine levels are associated with all four disease hallmarks; increased IL-8 levels are also associated with worse survival outcomes. These biomolecular improvements suggest early evidence of a disease-modifying effect.

Well-Tolerated Safety Profile

Overall, grade ≥3 treatment-emergent adverse events (TEAEs) were reported less frequently with pelabresib and ruxolitinib than with placebo plus ruxolitinib (49.1% vs. 57.5%, respectively).

In the pelabresib and ruxolitinib arm, the most common (≥10%) hematologic TEAEs were anemia (43.9%; grade ≥3: 23.1%), thrombocytopenia (32.1%; grade ≥3: 9.0%) and platelet count decrease (20.8%; grade ≥3: 4.2%). In the placebo plus ruxolitinib arm, the most common hematologic TEAEs were anemia (55.6%; grade ≥3: 36.4%), thrombocytopenia (23.4%; grade ≥3: 5.6%) and platelet count decrease (15.9%; grade ≥3: 0.9%).

The most common (≥10%) nonhematologic TEAEs in the pelabresib and ruxolitinib arm were diarrhea (23.1%; grade ≥3: 0.5%), dysgeusia (18.4%; grade ≥3: 0.5%), constipation (18.4%; grade ≥3: 0%), nausea (14.2%; grade ≥3: 0.5%), cough (12.7% grade ≥3: 0), asthenia (11.8% grade ≥3: 0.5%), fatigue (11.8%; grade ≥3: 0.5%), dizziness (11.3%; grade ≥3: 0%), headache (11.3% grade ≥3: 0.5%) and COVID-19 (11.3%; grade ≥3: 0%). The most common nonhematologic TEAEs in the placebo plus ruxolitinib arm were constipation (24.3%; grade ≥3: 0%), diarrhea (18.7%; grade ≥3: 1.4%), fatigue (16.8%; grade ≥3: 0.9%), COVID-19 (15.9%; grade ≥3: 1.9%), nausea (15.0%; grade ≥3: 0%), asthenia (13.6%; grade ≥3: 0%), dyspnea (13.1%; grade ≥3: 0.9%), cough (11.2%; grade ≥3: 0%) and headache (10.7%; grade ≥3: 0%). Discontinuation rates due to adverse events were 10.7% with pelabresib and ruxolitinib and 6.5% with placebo plus ruxolitinib.

The safety profile of the pelabresib and ruxolitinib combination therapy was consistent with previous clinical studies. No new safety signals were observed.

“The four hallmarks of myelofibrosis – enlarged spleen, anemia, bone marrow fibrosis and disease-associated symptoms – have a strong impact on a patient’s life. In MANIFEST-2, the combination of JAK and BET inhibition addressed all four of these hallmarks with the potential to modify the course of the disease,” said Tim Demuth, M.D., Ph.D., MorphoSys Chief Research and Development Officer. “We are confident that the comprehensive data package will provide impactful insights into the promising and well-tolerated combination of pelabresib and ruxolitinib. Our goal now is to bring this first-line therapy to patients with intermediate- and high-risk myelofibrosis as quickly as possible. We look forward to meeting with regulatory agencies regarding these data and are diligently preparing regulatory filings with the intention of submitting applications to the U.S. Food and Drug Administration and the European Medicines Agency in the middle of 2024.”

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Karyopharm Shares Data at ASH 2023 Showing Strong SVR and TSS Durability Observed from Phase 1 Study of Selinexor 60mg and Ruxolitinib in JAK Inhibitor (JAKi)-Naïve Myelofibrosis Patients, with no SVR or TSS Progressions Observed As of the Data Cutoff(1)

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Biomarker Data from Phase 1 Study of Selinexor in Combination with Ruxolitinib in Treatment-Naïve Myelofibrosis (MF) Suggestive of Disease Modification

Data Reinforce the Potential for Selinexor in Combination with Ruxolitinib to Become a Novel, First-Line Treatment for JAKi-Naïve Patients with MF

NEWTON, Mass., Dec. 10, 2023 /PRNewswire/ — Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a commercial-stage pharmaceutical company pioneering novel cancer therapies, today announced long-term follow up of treatment-naïve patients with myelofibrosis (MF) who participated in the Phase 1 portion of its study evaluating once-weekly selinexor in combination with ruxolitinib (NCT04562389). The data, featured in an oral presentation at the 65th American Society of Hematology Annual Meeting and Exposition (ASH 2023), show patients treated with 60mg selinexor, and who achieved ≥35% reduction in spleen volume (SVR35) at week 24, continued to remain in radiographic response. In addition, all patients who achieved TSS50 at Week 24 remained in response as of the data cut-off.

The data included in the oral presentation for ASH 2023 were based on the Phase 1 portion of the Phase 1/3 study evaluating the safety and efficacy of once-weekly selinexor in combination with ruxolitinib in patients with treatment-naïve MF (NCT04562389). As of August 1, 2023, 24 patients had been assigned to either selinexor 40mg (N= 10) or 60mg (N=14), in combination with ruxolitinib. The maximum duration of follow-up was 78 weeks with a median duration of 32 weeks for SVR35 durability, and a maximum duration of follow-up was 64 weeks with a median duration of 51 weeks for TSS50 durability.

An exploratory biomarker analysis showed a reduction of variant allele frequency (VAF) at week 24 for all three MF driver genes (CALR, MPL, and JAK2) and rapid and sustained reduction of pro-inflammatory cytokine production. Early cytokine reduction at Week 4 was associated with spleen volume reduction (SVR) at Week 24 and was sustained until the end of treatment. The clinical efficacy associated with biomarkers impacting MF biological hallmarks may suggest disease modification.

“The growing body of data from this study suggests that selinexor in combination with ruxolitinib may provide spleen reduction, symptom improvement, long-term durability and disease modification, expanding the benefit this combination may provide to patients with treatment-naïve myelofibrosis, ” said Reshma Rangwala, MD, PhD, Chief Medical Officer of Karyopharm. “We’re excited about the potential to change treatment paradigms for these patients – and expand the number of patients who benefit from first-line therapy.”

The safety profile was consistent with previous data cuts with no new safety signals observed as of Aug 1st.

“The current standard of care is not associated with consistent molecular or pathologic responses,” said Dr. Sri Tantravahi, University of Utah. “The long-term findings are very exciting as they underscore the potential for durable, clinically relevant responses and modification of disease course. The wait for new options has been long and difficult for the myelofibrosis community, and we welcome this important research to help advance the understanding of XPO1 and JAK inhibitor combinations as a meaningful treatment option for patients.”

“We are encouraged by the attention MPNs (Myeloproliferative Neoplasms) are getting in recent years from companies like Karyopharm,” said Kapila Viges, Chief Executive Officer of MPN Research Foundation. “With patients waiting for more answers to these chronic yet serious blood cancers, we look forward to the data readouts at ASH this year. Efforts to develop better therapies and now combinations of therapies bring hope to the myelofibrosis community and open the potential for more options in the treatment paradigm. For patients, options matter.”

About XPOVIO® (selinexor)

XPOVIO is a first-in-class, oral exportin 1 (XPO1) inhibitor and the first of Karyopharm’s Selective Inhibitor of Nuclear Export (SINE) compounds to be approved for the treatment of cancer. XPOVIO functions by selectively binding to and inhibiting the nuclear export protein XPO1. XPOVIO is approved in the U.S. and marketed by Karyopharm in multiple oncology indications, including: (i) in combination with Velcade® (bortezomib) and dexamethasone (XVd) in patients with multiple myeloma after at least one prior therapy; (ii) in combination with dexamethasone in patients with heavily pre-treated multiple myeloma; and (iii) in patients with diffuse large B-cell lymphoma (DLBCL), including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy. XPOVIO (also known as NEXPOVIO® in certain countries) has received regulatory approvals in various indications in a growing number of ex-U.S. territories and countries, including but not limited to the European Union, the United Kingdom, China, South Korea, Canada, Israel and Taiwan. XPOVIO and NEXPOVIO is marketed by Karyopharm’s partners, Antengene, Menarini, Neopharm and FORUS in China, South Korea, Singapore, Australia, Hong Kong, Germany, Austria, Israel and Canada.

Please refer to the local Prescribing Information for full details.

Selinexor is also being investigated in several other mid- and late-stage clinical trials across multiple high unmet need cancer indications, including in endometrial cancer and myelofibrosis.

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Navitoclax Combo Significantly Reduces Spleen Volume in Myelofibrosis

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Silas Inman

Combining navitoclax with ruxolitinib produced significant reductions in spleen volume by at least 35% at week 24 (SVR35W24) compared with ruxolitinib plus placebo but did not lead to significant changes in total symptom score (TSS) in those with myelofibrosis, according to data from the phase 3 TRANSFORM-1 study (NCT04472598) presented during the 2023 American Society of Hematology (ASH) Annual Meeting and Exposition.1

After a median follow-up of 14.9 months (range, 0.0-29.5), navitoclax and ruxolitinib elicited a SVR35W24 for 63.2% of patients compared with 31.5% for placebo plus ruxolitinib, marking a significant overall difference of 31.0% (95% CI, 19.5%-42.5%; P <.0001). At week 24, there was a mean -9.7 change in TSS with navitoclax/ruxolitinib from baseline (95% CI, -11.8 to -7.6) compared with a change of -11.1 for placebo plus ruxolitinib (95% CI, -13.2 to -9.1), which was not statistically significant (P = .2852).

“The spleen volume reduction was doubled and highly statistically significant. There’s no question there, but for the secondary end point, the total symptom score, both groups have the reduction, but it was not statistically significant,” said lead investigator Naveen Pemmaraju, MD, Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. “There may be multiple reasons for that. Ruxolitinib alone is a nice drug for symptom improvement, but when you add in a second drug, you’re improving the outcomes for the patient but maybe introducing a bit more toxicity. The statistical significance may not have come out because of that.”

Oral navitoclax is a BCL-XL, BCL-2, and BCL-W inhibitor, which may impart unique efficacy for myeloproliferative neoplasms (MPN). “It turns out in MPN and myelofibrosis that the BCL-XL pathway appears to be a bit more important than the BCL-2,” said Pemmaraju. “In myelofibrosis, BCL-XL appears to be upregulated and so in vitro studies showed that either the navitoclax by itself or even better in combination with the ruxolitinib can overcome JAK resistance and add benefit.”

In the combination arm, navitoclax was administered at a starting dose of 200 mg if platelet counts were above 150 x 109 per liter or, if not, at 100 mg, which was later escalated to 200 mg if tolerated and after platelet counts reached greater than 75 x 109 per liter. This methodology was implemented to avoid thrombocytopenia, which was observed in earlier trials with the agent. Ruxolitinib was administered at the standard dose in each arm, although Pemmaraju noted with necessary dose reductions the relative dose intensity was lower. There were 125 patients in the combination arm and 127 in the control group.

In the combination arm, the median age of patients was 70 years (range, 42-87) compared with 69 years (range, 37-85) in the control group. The time from diagnosis to study entry was 8 months (range, 0.3-181.6) in the combination arm and 6 (range, 0.3-198.8) in the control group. Most patients had primary myelofibrosis, at 50% in the investigational arm and 57% in the control group. Other types included transformed version of myelofibrosis, namely those post polycythemia vera and post-essential thrombocythemia. The median spleen volume at entry was 1441 cm3 (range, 419-8020) in the combination group and 1639 cm3 (range, 219-5664) in the control arm.

The median TSS in the combination arm was 21 (range, 0.1-60.6) compared with 24 (range, 6.7-61.6) in the control group. A minority of patients were transfusion dependent at baseline, at 4% in the combination group and 3% in the control arm. The most common risk score was intermediate-2, at 83% in the combination group and 87% in the control. JAK2 V617F was the most common driver mutation, with approximately two-thirds having this mutation in each group. Nearly half of patients had mutations associated with high molecular risk. “These high molecular risk mutations are very important,” said Pemmaraju. “Earlier studies may not have captured this, and we were fortunate to capture this in the majority of patients.”

There was a significantly higher rate of SVR35 with the combination at all time points throughout the study. Across the full-time scale of the study, 76.8% of those in the combination arm experienced a SVR35 compared with 41.7% with ruxolitinib plus placebo, which was a meaningful 34.6% reduction (95% CI, 23.6%-45.6%; P <.0001). The median time to first SVR35 response was similar between groups, at 12.3 (range, 10.1-48.3) vs 12.4 (range, 11.3-72.3) weeks, for the combination and control arms, respectively. Fewer patients lost SVR35 in the combination group (18.8%) compared with the control arm (26.4%). Nearly three-fourths of patients had a 12-month duration of SVR35 in each arm (76.7% vs 76.9%, combination and control, respectively).

The rate of any grade adverse effect (AE) was common between arms, with more patients in the combination arm having a grade 3 or higher AE (85% vs 70%). The most common grade 3 or higher AEs in the combination vs control arms, respectively, were thrombocytopenia (51% vs 15%), anemia (46% vs 39%), and neutropenia (38% vs 4%). For all grade events, diarrhea was more commonly seen with the combination vs control (34% vs 14%). Serious AEs were less common with the combination at 26% compared with 32% for the control arm. AEs that led to dose reduction or dose interruption were twice as common in the combination arm.

“Importantly, dose reductions and interruptions were mostly due to the thrombocytopenia, but importantly none of those were due to clinical bleeding,” said Pemmaraju.

In 2022, AbbVie, the company developing navitoclax noted plans for a submission to the FDA in 2023, pending pivotal study results.2 At this time, the agent is not approved.

References

  1. Pemmaraju N, Mead AJ, Somervaille T, et al. Transform-1: a randomized, double-blind, placebo-controlled, multicenter, international phase 3 study of navitoclax in combination with ruxolitinib versus ruxolitinib plus placebo in patients with untreated myelofibrosis. Blood. 2023;142(suppl 1):620.doi:10.1182/blood-2023-173509
  2. AbbVie presents positive investigational navitoclax combination data in phase 2 REFINE study suggesting anti-fibrosis activity for patients with myelofibrosis. News release. AbbVie. April 12, 2022. Accessed December 10, 2023. https://news.abbvie.com/2022-04-12-AbbVie-Presents-Positive-Investigational-Navitoclax-Combination-Data-in-Phase-2-REFINE-Study-Suggesting-Anti-Fibrosis-Activity-for-Patients-with-Myelofibrosis

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Fedratinib Demonstrates Promising Efficacy in MDS/MPN and Chronic Neutrophilic Leukemia

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Janelle Bradley

12/09/2023

Fedratinib demonstrates promising clinical activity in patients with myelodysplastic syndrome (MDS)/myeloproliferative neoplasms (MPN) and chronic neutrophilic leukemia (CNL), according to data presented at the 2023 ASH Annual Meeting.

Fedratinib is a JAK2 inhibitor that is currently approved by the FDA for the treatment of higher-risk myelofibrosis. Given fedratinib potential inhibition of FLT3 and BRD4 and suppression of c-Myc expression, researchers hypothesize that the drug could have biologic relevance in MDS/MPN.

Andrew Kuykendall, MD, Moffitt Cancer Center, Tampa, Florida, presented results from the ongoing phase 2, multinational investigator-initiated clinical trial that evaluated the efficacy of fedratinib in atypical chronic myeloid leukemia (CML), CNL, MDS/MPN-unclassifiable, and MDS/MPN-ring sideroblasts and thrombocytosis. The primary end point of this trial is overall response rate, which is defined as complete or partial response or clinical benefit at 24 weeks.

Bone marrow was collected at baseline and week 24 and stained for c-Myc. C-myc expression was scored by multiplying the percentage of positive cells by intensity.

Eligible patients had splenomegaly ≥5 cm below left costal margin or ≥450 cc and/or an MPN total symptom score ≥10. Patients were excluded if they had a platelet count higher than 35 x109/L or peripheral peripheral/marrow blasts >10%. The planned trial enrollment is 25 patients with an interim analysis completed after 9 patients are eligible for efficacy.

At data cutoff, 10 patients have been enrolled in the trial (1 with atypical CML, 4 with CNL, 4 with MDS/MPN-ring sideroblasts and thrombocytosis, and 1 with MDS/MPN-unclassifiable) with a median follow-up of 5 months. Of whom, 8 patients remain on treatment.

Overall, 5 patients were evaluable for response. Of whom, 3 had a response at week 24, including 3 symptom responses and 1 spleen response. A total of 6 patients completed 12 weeks of treatment with 1 spleen response and 2 symptom responses. Among these 6 patients, spleen volume decreased in 5 by an average of -23%. Among 5 patients with significant baseline symptom burden, 4 experienced an improvement in symptom burden by an average of -43%.

IHC staining was done in a median of 10% of cells to demonstrate c-Myc expression at baseline. The average baseline c-Myc expression was 26.5. Among 4 patients with paired samples, c-Myc expression decreased in all cases by an average of 51% (P = .02).

For safety analysis, 10 patients were evaluable. The most common adverse events (AEs) were anemia, platelet count decrease, diarrhea, nausea, muscle cramp, and constipation. Grade ≥3 AEs included anemia and neutropenia. One patient discontinued treatment due to disease progression after initial response and another due to patient decision unrelated to disease or treatment.

“Fedratinib demonstrates promising clinical efficacy in MDS/MPN and CNL patients with proliferative features. The safety profile is consistent with prior experience,” concluded Dr Kuykendall and colleagues, adding “fedratinib’s unique kinase inhibition profile may provide a mechanism for enhanced effectiveness in this patient population.”

Source:

Kukendall AT, Pettit KM, Singh A, et al. A Phase 2 Study of Fedratinib in Patients with MDS/MPN and Chronic Neutrophilic Leukemia; December 9-12, 2023; San Diego, CA. Abstract 73.

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Study yields ‘encouraging’ preliminary data for navitoclax combination in myelofibrosis

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December 11, 2023

Key takeaways:

  • Navitoclax plus ruxolitinib led to improvement in spleen volume reduction in patients with untreated myelofibrosis.
  • Adverse events of thrombocytopenia and anemia appeared common but manageable.

SAN DIEGO — Navitoclax added to ruxolitinib led to a significant improvement in spleen volume reduction compared with placebo among patients with untreated myelofibrosis, study results presented at ASH Annual Meeting and Exposition showed.

Findings from the phase 3 TRANSFORM-1 study suggest the combination therapy has a manageable safety profile that appeared consistent with the use of both agents in previous studies, according to researchers.

“The is the first randomized trial in JAKi-naive [myelofibrosis] with a navitoclax and ruxolitinib combination, which led to a in spleen volume reduction 35% at week 24 twice as high as placebo plus ruxolitinib, with similar symptom response despite a lower average dose of ruxolitinib,” Naveen Pemmaraju, MD, associate professor in the department of leukemia at The University of Texas MD Anderson Cancer Center, said during a presentation.

Background and methodology

The double-blind TRANSFORM-1 study assessed the efficacy and safety of navitoclax (AbbVie) — and investigational Bcl-2 inhibitor — plus the JAK2 inhibitor ruxolitinib (Jakafi, Incyte) compared with placebo plus ruxolitinib among adults with JAK2 inhibitor-naive myelofibrosis.

Inclusion criteria included adults with intermediate- or high-risk myelofibrosis with measurable splenomegaly, evidence of myelofibrosis-related symptoms, no prior JAK2 inhibitor treatment, and an ECOG performance score less than or equal to 2.

Researchers randomly assigned patients in a 1:1 ratio to ruxolitinib plus either navitoclax or placebo.

Spleen volume reduction 35% at week 24 served as the study’s primary efficacy endpoint. Secondary endpoints included change in total symptom score at week 24, spleen volume reduction 35% at any time, duration spleen volume reduction 35%, anemia response, reduction in marrow fibrosis, OS, leukemia-free survival, reduction in PROMIS Fatigue scale and improvement in EORTC QLQ-C30 physical functioning scale.

The study included 252 patients (125 received navitoclax and ruxolitinib, 127 received placebo plus ruxolitinib; median age, 69 years; 57% male) with a median follow-up of 14.9 months (0 – 29.5 months).

Results and next steps

Researchers reported that 79 patients (63.2%) in the investigative arm achieved spleen volume reduction 35% at week 24, compared with 40 patients (31.5%) in the control arm, thus meeting the study’s primary efficacy endpoint. Additionally, researchers noted that 96 patients (77%) in the investigative arm achieved spleen volume reduction 35% at any time, whereas 53 patients (42%) did so in the control arm.

Median duration of spleen volume reduction 35% had not been reached in the investigative arm compared with 19.4 months (95% CI, 16.8 months to not yet reached) in the control arm.

Researchers observed grade 3 or higher adverse events among 85% of patients in the navitoclax arm and for 70% of patients in the placebo arm. The most common adverse events among patients receiving navitoclax included thrombocytopenia, anemia, diarrhea, and neutropenia.

Additionally, 26% of patients in the navitoclax arm and 32% of patients in the placebo arm experienced serious adverse events, including anemia, thrombocytopenia and neutropenia.

With navitoclax treatment, adverse events led to a dose reduction of the agent in 101 patients (81%) and treatment interruption in 87 patients (70%).

Among enrolled patients, 83 (33%) discontinued study treatment. The most common reason for discontinuation included adverse events (n=32; 39% of discontinuations) and physician decision (n=14; 17% of discontinuations). Thirteen patient deaths occurred in each study arm.

“Adverse events of thrombocytopenia, anemia and neutropenia were common but manageable with dose modification without any clinically significant sequelae,” Pemmaraju said. “Preliminary data are encouraging and additional evaluations are ongoing to assess additional outcomes of overall survival and responses in subgroups.”

Source: 

Pemmaraju N, et al. Abstract 620. Presented at: ASH Annual Meeting and Exhibition; Dec. 5-9, 2023; San Diego.

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