Lactate is a Key Regulator of Immune Escape, Bone Marrow Fibrosis in Myelofibrosis

Posted on February 12, 2025February 12, 2025 by MPN Advocacy & Education

February 11, 2025

Author(s):

Luke Halpern, Assistant Editor

New study results published in the Journal of Translational Medicine reveal that circulating lactate is a key regulator of immune escape and bone marrow (BM) fibrotic transformation in patients with myelofibrosis (MF), with a marked increase in lactate concentration and lactate import channel monocarboxylate transporter 1 (MCT1) expression in the site of blood cell production. The investigators suggest that MCT1 blocking could be used as a novel antifibrotic strategy in patients with MF.¹

Myelofibrosis can cause fibrosis in bone marrow. | Image Credit: © Jasmine – stock.adobe.com

According to the study authors, the pathophysiology of MF is significantly influenced by alterations in the BM microenvironment, and these changes are often associated with the metabolic reprogramming of cancer cells in patients. Glycolysis is a hallmark aspect of the changes that occur in cancer cells; prior evidence from investigational models strongly suggests that lactate production is associated with tumor microenvironment (TME) progression in patients with certain types of cancer.^1-3

Prior observations also indicate that increases in lactate dehydrogenase A (LDHA) have a central role in glycolysis, with high LDHA levels typically found in the sera of patients with MF, predicting shorter overall and leukemia-free survival. Within this context, excess lactate that is secreted by cancer cells can promote immune suppression and angiogenesis while also possibly playing a role in increasing the number of cancer-affiliated phenotypes (CAF), which promote fibrotic tumor formation, the investigators wrote.^1,4

These authors sought to fill a gap in knowledge within the characterization of TME metabolic composition in patients with MF. Through their analysis, they demonstrated that the amount of circulating lactate increases in patients with MF, which eventually leads to the expansion of immunosuppressive subsets and the development of fibrosis. Furthermore, they observed that the expression of lactate export channel monocarboxylate transporter 4 (MCT4) in the TME becomes deeply remodeled during fibrotic transformation, “suggesting a link between lactate trafficking and pro-fibrotic establishment.”¹

Reevaluating Available Options for Anemia in Myelofibrosis

Posted on February 7, 2025February 7, 2025 by MPN Advocacy & Education

February 6, 2025

By Targeted Oncology Staff

Fact checked by Jonah Feldman

DISCUSSION QUESTIONS

How do you monitor and manage anemia in patients with primary myelofibrosis prior to starting Janus kinase (JAK) inhibitor therapy?
While receiving a JAK inhibitor therapy?

Andrew Kuykendall, MD: How do you monitor and manage anemia in patients with myelofibrosis even prior to starting a JAK inhibitor? If you’re initially evaluating someone, they come in with hemoglobin of 7 or 8 g/dL or something like that, how does that impact your thinking, and how do you work that up?

Lazaros Lekakis, MD: The first thing is to make sure that they don’t have something easily fixable [such as] iron, B12, or folate deficiency. Theoretically, if you don’t have any nutritional cause or any immune causes, you could use erythropoietin analogs, but they are very tricky because they don’t help with the spleen, at least in my experience, and they may increase the risk of clots. I try to avoid them if possible. If I have to start a JAK inhibitor, if they have symptoms, either I go away from ruxolitinib [Jakafi] or I start a low dose of ruxolitinib. Sometimes I use anabolic steroids and prednisone. We have the thalidomide/prednisone [regimen] that now is kind of forgotten about.

Kuykendall: Erythropoietin-stimulating agents [ESAs] are limited in what they do, and certainly not helping other aspects of the disease. You did mention one of my favorite regimens, thalidomide/prednisone, which is looked over a bit nowadays, but has quite a potential for efficacy in terms of improving hemoglobin. But it’s probably something that’s gone by the wayside in many practices.

Luis Sumoza, MD: As Dr Lekakis says, there are some other options that you can use. Danazol is sometimes something you can use perfectly in this patient population. From the JAK inhibitors, there is momelotinib [Ojjaara]. But a priority for me is to refer a patient for a stem cell transplant; when I was a fellow, we did the first allogeneic bone marrow transplant at the University of Illinois, Chicago, and it was a very nice experience.

Kuykendall: [Dr Lekakis] also mentioned steroids, [and we are] thinking about things like danazol, androgen derivatives. We saw from the MOMENTUM study [NCT04173494] looking at momelotinib that danazol is an active agent.¹ It was a large, randomized trial, one of the first randomized trials with danazol. The focus there was on momelotinib, but there’s also a lot to learn about what danazol could do as well from that study.

Sumoza: You’re mainly talking about anemia here, and [if], the patient is not a candidate for a transplant or a clinical trial [there are] the data about navitoclax/ruxolitinib, which basically double the response and reduction of the spleen.²

Kuykendall: Yes, these emerging therapies to some degree may change how we approach this disease. But I think that with some of these older therapies, especially when you’re when you’re first talking about someone who’s coming in with anemia, you need to think about ESA, danazol, and thalidomide/prednisone.

I think that ESA is probably the most prominently used. How many of you are checking serum erythropoietin levels in these patients to assess their candidacy for ESAs, is that a common practice?

Mukesh Kumar, MD: Yes, I’m checking on all of my patients.

Second-Line Fedratinib Produces Early Platelet Count Improvements in Myelofibrosis

Posted on February 7, 2025February 7, 2025 by MPN Advocacy & Education

February 5, 2025

Author(s): Jax DiEugenio

Fact checked by: Chris Ryan

Patients with myelofibrosis who received second-line fedratinib (Inrebic) experienced early increases in platelet count compared with those given best available therapy (BAT), and a higher magnitude of benefit was observed in patients with a low platelet count at baseline, according to findings from the phase 3 FREEDOM2 trial (NCT03952039) presented at the 2024 ASH Annual Meeting.

Findings showed that in the overall safety population, fedratinib generated improvements in mean platelet count and mean change from baseline platelet count, most noticeably in early treatment cycles.

In patients with a low platelet count at baseline, defined as at least 50 to less than 100 x 10⁹/L, patients treated with fedratinib (n = 34) experienced a mean increase in platelet count of 45% on day 15 of cycle 1 compared with 11% for those given BAT (n = 21). Among patients with a high platelet count at baseline of at least 100 x 109/L, these rates were 27% for fedratinib (n = 85) and –6% for BAT (n = 39).

During a presentation of the data, lead study author Haifa Kathrin Al-Ali, MD, explained that increased platelet count was not correlated with changes in spleen size, pointing to a potential benefit for fedratinib on thrombopoiesis.

“These data suggest a platelet-sparing effect of second-line fedratinib vs BAT, and support fedratinib as a promising second-line treatment option for patient with myelofibrosis with low or high baseline platelet count,” said Al-Ali, who is a professor of translational oncology and head of the Krukenberg Cancer Center at the University Hospital of Halle (Saale) in Germany.

Calreticulin Mutations Can Worsen Survival Outcomes in Ruxolitinib-Treated Patients With Myelofibrosis

Posted on February 3, 2025February 3, 2025 by mpn_admin

January 31, 2025

Author(s): Luke Halpern, Assistant Editor

Patients with myelofibrosis (MF) who harbor calreticulin (CALR) mutations begin treatment with ruxolitinib presenting severe disease with a longer median time from diagnosis, with inferior spleen responses and lower rates of symptom responses observed at 6-months, according to study results published in Annals of Hematology.¹

CALR mutations in patients with myelofibrosis being treated with ruxolitinib can lead to worsened outcomes. | Image Credit: © rost9 | stock.adobe.com

CALR mutations can be found in around 20% of patients with primary and post-essential thrombocythemia (ET) MF. Patients who harbor CALR mutations often present with distinct clinical features compared with Janus kinase (JAK)2-mutated patients. Typically, they feature lower levels of hemoglobin and white blood cells, present at younger age, and are associated with better survival rates.^1,2

Ruxolitinib (Jakfafi; Incyte) is a targeted therapeutic option for patients with MF that has shown efficacy regardless of the driver mutation in patients. However, new therapies continue to be developed that specifically target CALR, necessitating further research on therapies that are currently standard in CALR-positive patients, according to the investigators.^1,3

The study authors reported the outcomes of a sub-analysis of the RUX-MF clinical trial, documenting 135 patients with CALR mutation who received ruxolitinib in a real-world setting. The analysis was performed with major considerations, including that the younger age of CALR-mutated patients compared with JAK2-mutated patients may influence survival outcomes, and that younger patients are eligible for allogeneic stem cell transplantation, which the investigators noted could meaningfully impact the treatment algorithm.¹

In total, 786 patients from the RUX-MF trial were JAK2-mutated, while 135 had a CALR mutation. Only 78 CALR-mutated patients were evaluable, in which their mutation was type 1-like in 66.7% of the population, while 30.8% had type 2-like mutation. At the beginning of ruxolitinib initiation, CALR-mutated patients were younger, had higher percentages of peripheral blasts, and lower median hemoglobin levels compared with JAK2-mutated patients.¹

Responses to ruxolitinib and patient outcomes according to mutation type were reported at 6 months. There were no major differences in spleen responses (CALR: 21.4%; JAK2: 25.7%), and there were comparable rates of treatment-emergent anemia (CALR: 35.7%; JAK2: 30.4%) and both overall and treatment-emergent thrombocytopenia. However, symptoms response was significantly lower in CALR-mutated patients (56.1% vs 66.7%), and overall anemia rates (60.3% vs 50.3%) were higher in this population compared with JAK2-mutated participants.¹

Across the 135 patients with CALR mutation, there were no factors associated with spleen or symptom response. Notably, factors correlated with worse survival included hemoglobin below 10 g/dL and a high burden of symptoms. In the subgroup of 72 CALR-mutated patients who began ruxolitinib over 2 years following diagnosis, anemia (HR: 1.92; 95% CI, 1.02-3.79) and the use of a reduced ruxolitinib initiation dose (HR: 2.29; 95% CI, 1.15-4.56) were associated with poor overall survival.¹

Real-world treatment patterns and health outcomes for patients with myelofibrosis treated with fedratinib

Posted on January 30, 2025January 30, 2025 by mpn_admin

January 14, 2025

Francesco Passamonti Shalon Jones e , a,b , Siddhi Korgaonkar c Dorothy Zissler e , , Keith L Davis Rohan C Parikh c c , Manoj Chevli d , and Samantha Slaff

ABSTRACT

Aim: Assess real-world fedratinib (FEDR) treatment patterns and clinical outcomes in patients with primary or secondary myelofibrosis following discontinuation of ruxolitinib (RUX). Patients & Methods: This study was a retrospective, noninterventional medical record review of patients in Canada, Germany, and the United Kingdom (UK). A total of 70 physicians (primarily hematologist-oncologists [78.6%]) provided data for 196 eligible patients.

Results: Patients were mostly male (62.8%) with primary myelofibrosis (76.5%) and initiated FEDR at a mean age of 67.7 years. Median treatment duration was 11.5 months (median follow-up, 13.8 months), and nearly half (49.5%) of patients initiated FEDR at the label-indicated dose of 400 mg daily. Six months post-initiation, 77.7% and 66.8% of patients experienced symptom and spleen response, respectively. Kaplan-Meier estimates of median progression-free and overall survival from initiation were 23.8 months (95% CI, 21.1–27.6) and 29.8 months (95% CI, 23.9-NE), respectively.

Conclusion: These findings demonstrate real-world FEDR effectiveness among patients with myelofibrosis who discontinued RUX.

PLAIN LANGUAGE SUMMARY

What is this summary about?

Myelofibrosis (MF) is a rare blood cancer that can cause unhealthy spleen growth and symptoms, such as feeling tired, loss of appetite, bone pain, and fever. This is a summary of an article that reviewed medical records of patients with MF from treatment centers in Canada, Germany, and the United Kingdom (UK). The study looked at people who had been taking a medication called fedratinib (FEDR) for their MF after they had stopped taking a different medication called ruxolitinib (RUX). Many of the people stopped taking RUX because their MF got worse within a few years. The study wanted to see if taking FEDR reduced symptoms and spleen size for people with MF after they stopped taking RUX.

What were the results?

After at least 6 months of taking FEDR, 77.7% of the people in the study had fewer symptoms, and 66.8% of people in the study had a decrease in spleen size or no spleen growth. Additionally, most people taking FEDR after discontinuing RUX went nearly 2 years without their MF symptoms or illness getting worse.

What do the results mean?

These results suggest that FEDR is an effective treatment for people with MF who have stopped taking RUX.

Cardiovascular Risk Factors Increase Thrombosis, Mortality in Patients With Myelofibrosis, Other MPNs

Posted on January 28, 2025January 28, 2025 by mpn_admin

January 27, 2025

Author(s): Luke Halpern, Assistant Editor

Cardiovascular risk factors (CVRFs) that increase thrombosis and overall mortality are more prevalent in patients with myeloproliferative neoplasms (MPNs), and especially those with myelofibrosis (MF), who have increased rates of hyperlipidemia and hypertension compared with patients with essential thrombocythemia (ET) or polycythemia vera (PV), according to study results published in Blood: Vessels, Thrombosis, and Hemostasis.¹

Thrombosis is a potentially serious complication of myelofibrosis. | Image Credit: © Artur | stock.adobe.com

Managing thrombosis risk in patients with MF are pillars of optimal treatment, along with controlling bleeding. Studies have indicated that thrombosis is common across a variety of MPNs, including MF, ET, and PV, and more common in those patients when compared with the general population. CVRFs such as hypertension, hyperlipidemia, type 2 diabetes, and obesity have known effects on thrombosis in the general population, but data is unclear on the impact of CVRFs on patients with MF or other MPNs.^2,3

For patients with MF, it is critical for pharmacists and treatment providers to recognize the prevalence of thrombosis and its potential risk factors, including CVRFs. In this current study, the investigators conducted a retrospective cohort analysis of 1005 patients with MPNs to evaluate the impact of CVRFs on real-world patient outcomes. Additionally, study authors investigated the likelihood of MPN transition to conditions such as MF or acute leukemia.^1,2,3

Across the study sample, 215 patients had MF, 28 had pre-MF, 415 had ET, and 313 had PV. Patients with MF were found to be more likely to harbor at least 1 CVRF compared with those with ET, PV, and the general patient population (46% vs 34% in the general MPN population), according to the investigators. The most common CVRFs observed in the overall patient population were hypertension (21%), hyperlipidemia (16%), and having a body mass index (BMI) greater than or equal to 30 (12%). For patients with MF, these incidences were 31%, 22%, and 11% respectively.¹

Fedratinib for the treatment of myelofibrosis: a critical appraisal of clinical trial and “real-world” data

Posted on January 20, 2025January 20, 2025 by mpn_admin

January 14, 2025

Adrian Duek, Ilona Leviatan, Osnat Jarchowsky Dolberg & Martin H. Ellis

Abstract

Fedratinib is a predominantly JAK2 inhibitor that has shown efficacy in untreated and ruxolitinib-exposed patients with myelofibrosis (MF). Based on randomized clinical trial data, it is approved for use in patients with International Prognostic Scoring System (IPSS) or Dynamic International Prognostic Scoring System (DIPSS) intermediate-2 or high-risk disease and is distinguished from ruxolitinib in that it can be administered without dose reduction in patients with thrombocytopenia, to a platelet count above 50,000/µL. In these trials, fedratinib achieved significant spleen volume reduction in ~30–45% of patients and improvement in total symptom scores in 35–40% with good tolerability. In contrast, recently published real-world data suggest that these responses may not be as robust outside clinical trials. In the context of routine clinical practice spleen responses are documented in only 13–68%, with varying degrees of symptom improvement. This may be due to the lack of a uniform definition of ruxolitinib failure, which may influence the timing of initiating fedratinib as a second-line treatment and result in a more prolonged exposure to ruxolitinib prior to intitaing fedratinib treatment. We suggest that given the growing number of drugs available for use in MF, recognizing the failure of first-line (and potentially subsequent) treatments is critical to allow timely transition to potentially more active agents, as highlighted by the data pertaining to fedratinib.

Arterial and Venous Thrombosis May Be Linked to More Aggressive MF

Posted on January 20, 2025January 20, 2025 by mpn_admin

Özge Özkaya, MSc, PhD

January 14, 2025

The impact of thrombosis on myelofibrosis (MF), mortality, and formation of solid tumors in myeloproliferative neoplasms (MPN) has been discussed in a new review article published in the Blood Cancer Journal.

For the review, the authors, led by Alessandro M. Vannucchi, MD, from Università di Firenze in Florence, Italy, analyzed large personal patient databases of MPN.

Arterial and venous thrombosis seem to be associated with a more aggressive disease course, they said.

Moreover, biomarkers of inflammation like the neutrophil-to-lymphocyte ratio seem to be associated with the aggressiveness of polycythemia vera and essential thrombocythemia, linking thrombosis to the risk of secondary cancer, the researchers added.

They suggested that this means there may be a common inflammatory pathway shared between cardiovascular diseases and cancer.

“These data underscore the need for new studies to validate these associations, delineate the sequence of events, and identify therapeutic targets to mitigate thrombotic events and potentially improve overall patient outcomes in [myeloproliferative neoplasms],” they concluded.

They highlighted the limitations of the viewpoint, including the fact that most of the studies that they reviewed were retrospective and the lack of investigations on the effect of cytoreductive therapy and associated comorbidities.

Bromodomain and BET Inhibitor INCB057643 Shows Benefit for Patients With Myelofibrosis

Posted on January 6, 2025January 6, 2025 by mpn_admin

12/19/24

Emily Estrada

According to research presented by Justin Watts, MD, Sylvester Cancer Center Institute, University of Miami, Miami, Florida at the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition in San Diego, California, INCB057643 may improve patient outcomes in the treatment of hematologic malignancies, including myelofibrosis (MF).

A small-molecular bromodomain and extra-terminal BET protein inhibitor, INCB057643, has shown safety and tolerability as monotherapy and combination with Janus kinase (JAK) 1 and 2 inhibitors among patients with MF in previous phases of the ongoing phase 1/2 clinical trial. In this dose-escalation and expansion portion of the trial, the dose of INCB057643 in patients with MF receiving monotherapy was increased from 4mg to 12mg and for patients with MF who had an inadequate response to ruxolitinib, combination therapy dosage was increased from 4mg to total maximum dosage.

The primary end points were safety and tolerability, as well as dose-limiting toxicities of INCB057643 at 24 weeks. The secondary end points included spleen volume reduction greater than 35% from baseline (SVR35), symptom reduction by greater than 50% from baseline via MPN-Symptom Assessment Form (TSS50), and anemia response of a hemoglobin increase at least 1.5 g/dL from baseline in patients that were not receiving transfusions or transfusion-free for at least 12 weeks for patients dependent on transfusions at baseline.

Patients with relapsed/refractory MF (84.1%%), essential thrombocythemia ([ET]; 4.5%), myelodysplastic syndromes (MDS), or myeloproliferative neoplasm (MPN) syndromes (11.4%). were included in the study. In total, 18 patients were treated with a monotherapy dose escalation and 10 patients received dose expansion. Combination therapy dose escalation was received by 16 patients whose median age was 71 years and whose median ruxolitinib dose was 22.4mg per day. The median duration of INCB057643 exposure was 195.5 days for patients in the monotherapy dose-escalation cohort and 139.0 days for patients in the dose-expansion cohort. As for patients who were in the combination therapy dose-escalation cohort, median INCB057643 exposure was 194.0 days.

At 24 weeks, 3 out of 16 patients who received monotherapy achieved SVR35 and 5 out of 14 achieved TSS50 with any dose of INCB057643, of which 3 received a dose of at least 10 mg. During any time of treatment, improvements in spleen volume and TSS50 best response were demonstrated by 13/19 and 12/15 patients, respectively. Among patients who received combination therapy of INCB057643 and ruxolitinib, 3 out of 12 patients achieved SVR35 and 6 out of 11 achieved TSS50 at any combo dose. Improvements were seen at any time during treatment for both SVR35 and TSS50 in 13 out of 16 and 10 out of 15 patients, respectively. Of patients not dependent on blood transfusions, an anemia response was demonstrated by 3 patients in both the monotherapy and the combination group. Additionally, of 6 patients who were blood transfusion dependent at BL, 2 achieved transfusion independence.

Combination of PXS-5505 With Standard Ruxolitinib Therapy Shows Potential Benefit for Patients With Myelofibrosis

Posted on January 6, 2025January 6, 2025 by mpn_admin

12/16/2024

According to data from an ongoing multicenter, open-label phase 1/2a trial, the addition of the pan-lysyl oxidase inhibitor PXS-5505 to standard Janus kinase (JAK) inhibitor therapy demonstrated safety and potential efficacy for patients with intermediate or high-risk myelofibrosis (MF).

Peter T Tan, MBSS, One Clinical Research Pty Ltd, Nedlands, Australia presented these findings at the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition in San Diego, California.

Previous dose escalation and cohort expansion of PXS-5505 trial phases have established safety and tolerability of a monotherapy dose of 200 mg BID over 24 weeks in patients with MF. Researchers evaluated the safety and efficacy of a 200 mg BID dose of PXS-5505 as an add-on to standard JAK2 inhibitor, ruxolitinib (RUX), therapy among patients with MF.

Enrolled in the study were patients with MF with a Dynamic International Prognostic Scoring System (DIPPS) score of intermediate-2/high risk disease. Before initial PXS-5505 administration, patients had been under current RUX treatment for 12 or more weeks, with a stable dose for at least 8 weeks. A bone marrow biopsy was completed within 3 months of start date for all patients. Patients received PXS-5505 for 52 weeks or until progressive disease, dose limiting toxicity, or unacceptable toxicity. Dosage of PXS-5505 remained consistent at 200 mg BID, however patients were entitled to change RUX dose or discontinue RUX therapy while continuing to receive PXS-5505.

In this add-on phase of the trial, 15 patients were included, of which 6 had primary MF, 2 had post-ET MF, 7 patients had post-PV MF, 3 patients were considered high risk, and all other patients were Int-2. Among patients, the median duration of RUX treatment was 26 months (range, 3.5-74) and a median of 58 months (range 6.5-120) since time of MF diagnosis. The median myeloproliferative neoplasms symptom asssessment form total symptom score (PMN-SAF TSS) was 22.5. The median baseline spleen volume was 1353 cm³(n=14) and medial baseline hemoglobin was 94 g/dL.

Additionally, 11 patients had hemoglobin levels over 100 g/dL at baseline and almost half had platelet levels below 100×10⁹/L, 2 of which were transfusion-dependent at the start of the study. Baseline mutation profiles for 11 patients revealed a JAK2 V617F mutation among 7 patients and 6 patients with more than 1 high risk mutation.

“The results from this trial using a novel combination of PXS-5505 and RUX will add to the existing safety profile of PXS-5505 and provide preliminary indicators of efficacy to help inform future investigations of PXS-5505 in patients with MF,” the researchers concluded.