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

Posted on December 13, 2023December 13, 2023 by mpn_admin

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.

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

Posted on December 13, 2023December 13, 2023 by mpn_admin

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.

No Significant Differences in Outcomes Seen Between Hydroxyurea and IFNα in Patients With MPNs

Posted on December 13, 2023December 13, 2023 by mpn_admin

December 12, 2023

John Schieszer

The final analysis of the DALIAH trial (ClinicalTrials.gov Identifier: NCT01387763), which was presented at the ASH Annual Meeting 2023, showed no significant differences with hydroxyurea (HU) and pegylated interferon-alpha2 (IFNα) in patients with myeloproliferative neoplasms (MPNs) receiving long-term treatment.

This modified intention-to-treat (ITT) analysis detected no significant difference in the molecular response (MR) or clinical hematologic response (CHR) rates between HU and IFNα with long-term treatment among patients with MPNs.

However, a higher treatment discontinuation rate in the IFNα group (65%) was noted, and when using the per-protocol principle the MR or CHR rates were superior in the IFNα group at 36 months and beyond. The study authors also noted that increasing evidence on the efficacy and safety of IFNα is emerging.

The DAHLIA study was a randomized phase III trial of HU versus IFNα in newly diagnosed or untreated patients with MPN. The cohort included a total of 203 patients with essential thrombocythemia (ET), polycythemia vera (PV), prefibrotic myelofibrosis (PreMF), and primary myelofibrosis (PMF).

All participants older than 60 years were randomly assigned (1:1:1) to HU, IFNα-2a, or IFNα-2b. Participants who were 60 years or younger were randomly assigned to receive IFNα-2a or IFNα-2b. The primary outcome was the JAK2V617F MR rate at 18 months, at 36 months, and at 60 months per 2009 European LeukemiaNetwork (ELN; ET, PV, PreMF) or 2005 European Myelofibrosis Network (EUMNET; PMF) criteria.

The 203 patients in the modified ITT cohort were made up of ET, 73 (36%); PV, 89 (44%); PreMF, 16 (8%); and PMF, 25 (12%). The baseline characteristics were well balanced in the different groups. However, the median age varied (HU, 68 years vs IFNα, 59 years; P <.0001).

The MR rate by ITT analysis was similar between HU and IFNα at 18 months (19% vs 21%), at 36 months (19% vs 26%) and at 60 months (23% vs 24%). However, the JAK2V617F allele burden was significantly lower in the IFNα group at month 36 and beyond.

The CHR rate by ITT analysis was higher with HU at 18 months (58% vs 38%, P =.03) but similar at all other time points. Comparable efficacy results were found in a post hoc subgroup analysis comparing HU with IFNα in patients older than 60 years. However, the MR and CHR rates were superior in the IFNα group compared to the HU group at 36 months and beyond among patients remaining on treatment.

The MR rates by per-protocol analysis were 23% HU versus 56% IFNα at 36 months, 27% HU versus 59% INFa at 48 months and 35% HU versus 67% INFα at 60 months. The CHR rates were significantly different at 36 months (33% HU versus 67% INFα) and at 60 months (38% HU versus 62% INFα).

Overall treatment discontinuation at 60 months was 60% (HU, 37%; IFNα, 65%; P =.0019). The most common cause of treatment discontinuation was adverse events (AEs; HU, 16%; IFNα, 43%). More AEs ≥ grade 3 occurred in HU (58%) vs IFNα (45%). In 16 patients, 19 major thrombotic events were reported (4 events in 4 patients with HU; 12 events in 10 patients with IFNα in patients older than 60 years; 3 events in 2 patients with IFNα in patients 60 years or younger).

No participants had their disease morph into secondary acute myeloid leukemia; however, 5 patients died during follow-up (HU, 2; IFNα, 3).

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

Reference

Knudsen TA, Lund Hansen D, Frans Ocias L, et al. Final analysis of the Daliah trial: a randomized phase III trial of interferon-α versus hydroxyurea in patients with MPN. Abstract 746.

The Potential of Tasquinimod in Treating Advanced Myeloproliferative Neoplasms: A Glimpse into the Future

Posted on December 13, 2023December 13, 2023 by mpn_admin

By:Anthony Emecheta

12 Dec 2023

Dr. Warren Fiskus, a renowned hematologist, recently presented the results of a promising study at #ASH23. His research focused on the use of tasquinimod, a novel drug, in preclinical models of advanced myeloproliferative neoplasms (MPNs). The findings suggest that tasquinimod warrants further investigation as a potential treatment for these rare but severe conditions.

Understanding Myeloproliferative Neoplasms (MPNs)

Before delving into the specifics of the study, it’s crucial to understand what MPNs are. These are rare forms of blood cancers that occur when the bone marrow, the body’s cell powerhouse, produces an excess of red blood cells, platelets, or certain white blood cells. This overproduction disrupts the balance of cells in the blood, leading to various symptoms and complications. The primary subtypes of MPNs include myelofibrosis, polycythemia vera, and essential thrombocythemia. Each condition is unique and presents its own set of challenges.

Myelofibrosis: A Closer Look

Myelofibrosis (MF), a primary subtype of MPNs, is a particularly severe condition. It causes scarring in the bone marrow, which hinders the normal production of blood cells. In some cases, MF is a secondary development following a diagnosis of polycythemia vera (PV) or essential thrombocythemia (ET). The risk factors for primary MF are not entirely clear, however, a history of PV or ET are known risk factors for the development of secondary MF. The disease is categorized as low, intermediate, or high risk, based on various International Prognostic Scoring System scales. The prognosis depends on individual risk factors, including age, comorbidities, and the response to treatment.

Tasquinimod: A Beacon of Hope

Enter tasquinimod. Dr. Fiskus’ study explored the efficacy of this drug in preclinical models of advanced MPNs. The findings were encouraging, suggesting that tasquinimod may present a viable treatment option for these conditions. While the research is in its early stages, this represents a significant step forward in the search for effective therapies for these severe diseases.

Implications and Next Steps

The positive results from Dr. Fiskus’ study indicate that tasquinimod should be further investigated as a potential treatment for advanced MPNs. More comprehensive studies are required to assess the drug’s safety, tolerability, and efficacy in a broader patient population. Additionally, further research is needed to identify the best ways to integrate tasquinimod into the current treatment landscape. This could involve using the drug as a standalone therapy or in combination with other treatments.

Overall, the findings from Dr. Fiskus’ study at #ASH23 bring a glimmer of hope for patients suffering from advanced MPNs. While there’s still a long road ahead, the potential of tasquinimod offers a new avenue for exploration in the quest to #EndCancer.

Megakaryocytes Derived PF4 a Key Driver of Myelofibrosis

Posted on December 13, 2023December 13, 2023 by mpn_admin

By Rob Dillard

December 12, 2023

Megakaryocytes (Mks) derived PF4 play an important role in the progression of myelofibrosis, according to a study that will be presented at the 65th ASH Annual Meeting & Exposition, which is taking place December 9-12 in San Diego, California.

“Previous research has shown that [Mks] play a role in myeloproliferative neoplasm (MPN) pathology by promoting inflammation and extracellular matrix deposition by activated stromal cells. However, the specific factors derived from Mks that contribute to the inflammatory milieu and myelofibrosis progression are not well defined,” the researchers wrote. In this study, they sought to determine which events drive bone marrow (BM) fibrosis via abnormal MK-stromal cross talk.

To conduct their analysis, Alessandro Malara and colleagues induced myelofibrosis in mice via injections of thrombopoietin-mimetic romiplostim (TPO^high). Then, they isolated and assessed Mks, BM cells, and platelets from TPO^high and control mice (injected with saline). They also analyzed protein extracts and cytokine levels in the plasma and BM cell-free fluids of treated mice.

To assess fibrosis-related markers, the investigators evaluated the expression of 2 myofibroblasts markers (a-SMA and vimentin), both in mouse embryonic fibroblasts (mEFs) and human BM mesenchymal stromal cells after stimulation with recombinant PF4 using Western blot.

The findings demonstrated that signaling pathways related to cytoskeletal reorganization, cell adhesion, and inflammation were commonly activated in the Mks, platelets, and BM cells of TPO^high mice versus the saline-injected control mice. Among the differentially expressed proteins, chemokinePF4/Cxcl4 was upregulated exclusively in the proteasomes of the TPO^high mice. Importantly, the investigators noted that the findings show these mechanisms were interconnected during Mk-mEF cross talk.

“Our findings identify a crucial role of Mk derived PF4 in the fibrosis progression of MPN, providing further support for the potential therapeutic strategy of neutralizing PF4,” the researchers concluded.

Reference

Malara A, Capitanio D, Calledda F, et al. Proteomic screening identifies megakaryocyte derived PF4/Cxcl4 as a critical driver of myelofibrosis. Abstract #1793. Presented at the 65th ASH Annual Meeting & Exposition; December 9-12, 2023; San Diego, California.

New Developments in MPN Management Provide Additional Options for Patients

Posted on December 13, 2023December 13, 2023 by mpn_admin

December 5, 2023

Kyle Doherty

Although myeloproliferative neoplasms (MPNs), which are comprised of essential thrombocythemia, polycythemia vera (PV), and myelofibrosis, remain relatively rare— with estimated annual incidence rates of 1.03, 0.84, and 0.47 per 100,000 individuals, respectively—there remains an unmet need for effective treatment options for patients with these diseases who progress on standard of care therapies.¹ However, significant progress has been made in terms of understanding this group of disorders and developing treatment strategies to combat them, with Naveen Pemmaraju, MD, saying the medical field has entered a “golden era” of MPN treatment.

During a recent OncLive Peer Exchange^® video series titled “Expert Insights Into the Management of MPNs,” Jamile M. Shammo, MD, explained, “MPNs represent a heterogeneous group of hematopoietic stem cell neoplasms that share common features. Myeloid proliferation is certainly something that we see [in MPNs], as well as a propensity for thrombotic events, symptoms that are related either to constitutional symptoms or splenomegaly related. All 3 entities tend to progress to higher myeloid neoplasms; essential thrombocythemia [to] PV that goes to myelofibrosis and then myelofibrosis can evolve into acute leukemia. Of course, the rate of progression varies from one entity to the other, with essential thrombocythemia having the lowest risk [of progression].”

The development of MPNs is almost always associated with mutations in JAK2, making this family of genes an attractive treatment target. JAK2 mutations are observed in approximately 95% of patients with PV and approximately 50% of both patients with essential thrombocythemia and myelofibrosis. Notably, the emergence of additional treatment targets also has sparked the development of novel agents in recent years.¹

During the discussion, expert oncologists reviewed updated findings from ongoing and completed clinical trials in the field. They primarily focused on studies evaluating emerging agents in PV and myelofibrosis.

MANAGING PV

Abdulraheem Yacoub, MD, began the discussion on PV by noting that the JAK1/2 inhibitor ruxolitinib (Jakafi) has been the standard-of-care agent in PV since 2015. Prior to this, PV was historically managed with phlebotomy, hydroxyurea, and/or interferons. Ruxolitinib became the first FDA-approved drug for the treatment of patients with PV in December 2014 when it received an indication from the agency for patients who had an inadequate response to or were intolerant of hydroxyurea.²

“The introduction of ruxolitinib to the treatment landscape of patients with myelofibrosis has truly been transformative,” Shammo commented. “We all remember the patients we had in the clinic [in the past] and how we had simply nothing but supportive care to offer. Ruxolitinib was approved based on the results of 2 phase 3 studies. COMFORT-I [NCT00952289] randomly assigned patients [with myelofibrosis] to receive ruxolitinib or placebo and examined [spleen] volume reduction and reduction in total symptom score from baseline at 24 weeks. COMFORT-II [NCT00934544], which ran mostly in Europe, randomly assigned patients to be treated with ruxolitinib or best available therapy [as selected by the investigator]. This study [also evaluated] spleen volume reduction, but at week 48. In either trial, ruxolitinib was statistically significantly more active in attaining the primary end point and for that reason it was approved. Some might say that the evidence is perhaps less compelling than what you would [typically] find in a phase 3 study, but when you have multiple studies showing the same thing, that treatment with ruxolitinib improves [outcomes] compared with placebo or best available therapy, I tend to feel like it’s reasonable enough to believe that actually is the case.”

Long-term data from 2 phase 3 trials, RESPONSE (NCT01243944) and RESPONSE-2 (NCT02038036), comparing the safety and efficacy of ruxolitinib with best available therapy in different patient populations with PV recently were published in The Lancet Haematology. RESPONSE enrolled adult patients with PV who were resistant to or intolerant of hydroxyurea and randomly assigned them 1:1 to receive either ruxolitinib (n = 110) or best available therapy (n = 112; hydroxyurea, interferon or pegylated interferon, pipobroman, anagrelide (Agrylin), approved immunomodulators, or observation without pharmacological treatment). RESPONSE-2 enrolled a higher-risk patient population; eligible patients had inadequately controlled PV without splenomegaly and were intolerant of or resistant to hydroxyurea with an ECOG performance status of 2 or less. They were randomly assigned to receive ruxolitinib (n = 74) or best available therapy (n = 75).^3,4

Follow-up data from RESPONSE demonstrated that the 5-year overall survival (OS) rate was 91.9% (95% CI, 84.4%-95.9%) in the ruxolitinib group vs 91.0% (95% CI, 82.8%-95.4%) in the best available therapy arm. Most patients (88%) in the best available therapy arm crossed over to receive ruxolitinib, and no patients remained in this arm after week 80. There were 25 primary responders in the ruxolitinib arm, 6 of whom had progressed by the time of the final analysis. The 5-year probability of maintaining a primary composite response was 74% (95% CI, 51%-88%), the probability of maintaining complete hematological remission was 55% (95% CI, 32%-73%), and the probability of maintaining overall clinicohematological responses was 67% (range, 54%-77%).³

At a median follow-up of 67 months (IQR, 65-70), findings from RESPONSE-2 showed that the 5-year OS rate was 96% (95% CI, 87%-99%) in the ruxolitinib arm compared with 91% (95% CI, 80%-96%) in the best available therapy arm. In the ruxolitinib arm, 22% of patients (95% CI, 13%-33%) achieved durable hematocrit control with an estimated median duration of control not reached (NR) at week 260 (95% CI, 144-NR). Most patients in the best available therapy arm (77%) crossed over to ruxolitinib, no patients continued with best available therapy after week 80 per protocol, and the median duration of hematocrit control was not reported due to the small number of responders at week 80.⁴

In light of findings from RESPONSE and RESPONSE-2, investigators in both studies concluded that ruxolitinib is a safe and effective long-term treatment option for patients with PV for whom hydroxyurea proved ineffective.^3,4

“Both studies have ong-term follow-up and have published 5-year data showing very durable responses,” Yacoub said. “There were very few late failures on ruxolitinib and no unexpected adverse effects were observed with longterm follow up. This has built a strong case for ruxolitinib as a standard treatment for patients [with PV] after hydroxyurea failure.”

Ropeginterferon Takes Center Stage

A more recent breakthrough for patients with PV was the emergence of the interferon ropeginterferon alfa-2b-njft (Besremi). In November 2021, ropeginterferon became the first agent to receive FDA approval for patients with PV regardless of their treatment history.⁵

Ropeginterferon was compared with hydroxyurea in the phase 3 PROUD-PV trial (NCT01949805) and its extension continuation study, CONTI-PV (NCT02218047). Eligible patients were 18 years or older and had earlystage PV with no history of cytoreductive treatment or less than 3 years of previous hydroxyurea treatment. Patients could opt to enter CONTI-PV after 1 year of initial treatment in PROUD-PV.⁶

Findings from the studies revealed that at a median follow-up of 182.1 weeks (IQR, 166.3- 201.7) patients in PROUD-PV who received ropeginterferon (n = 122) achieved complete hematological response with normal spleen size at a rate of 21% compared with 28% of patients who received hydroxyurea (n = 123). However, in CONTI-PV, 53% of patients in the ropeginterferon arm (n = 95) had a complete hematological response with improved disease burden at 36 months vs 38% of patients in the hydroxyurea arm (n = 74; P = .044). Moreover, at 36 months in CONTI-PV, the complete hematological response rate regardless of spleen criterion was 71% vs 51% in the investigative and comparator arms, respectively (P = .012); at 12 months in PROUD-PV these rates were 43% vs 46%, respectively (P = .63).⁶

Study authors concluded that ropeginterferon was effective in inducing hematological responses. Although noninferiority to hydroxyurea in terms of hematological response and normal spleen size was not observed at 12 months, improved responses vs hydroxyurea were present at 36 months. Thus, the authors wrote that ropeginterferon offers an effective and “safe long-term avenue for treatment with distinct features from hydroxyurea.”⁶

“It’s wonderful to have options because we get patients with PV [who] could not be any more different,” Yacoub said. “They have different goals of care, and at the end of the day, we are treating individual patients, not diseases. For each patient, we have to define what we are trying to achieve. There are patients who are going to live with the disease a lot longer. They have more high-risk presentations and would benefit from the maximum data that we have with the application of the effective agents. There are patients who have relatively low-risk disease, and they’re likely going to live their natural lives with some medical management from our end. We have to individualize our choices.”

Looking ahead, the phase 3 VERIFY trial (NCT05210790) is underway with the aim of adding rusfertide (PTG-300), a novel and potent hepcidin mimetic, to the PV treatment landscape. Rusfertide previously demonstrated clinical activity in early-phase studies, characterized by good tolerability and consistent and durable hematocrit control, as well as improvements in iron deficiency among patients who required higher than normal amounts of phlebotomies even after standard-of-care therapy.⁷

VERIFY is enrolling patients with PV who have received at least 3 phlebotomies in the previous 6 months or at least 5 in the previous 12 months as a result of inadequate hematocrit control, with or without concurrent cytoreductive therapy. Eligible patients will be randomly assigned 1:1 to receive either placebo plus ongoing therapy or rusfertide plus ongoing therapy.

Part 1a of the trial is the double-blind, placebo- controlled, add-on phase that will enroll parallel groups and last 32 weeks. During part 1b, patients who complete part 1a will receive rusfertide for 20 weeks. Patients who successfully complete part 1b will enter the long term extension phase, part 2, and will continue to be treated with rusfertide for 104 weeks. The primary end point is the proportion of patients achieving a response in from week 20 to week 32 in part 1A. The study was initiated in January 2022 and has a target enrollment of 250 patients.⁷

Managing Myelofibrosis

Patients with myelofibrosis have more FDA-approved treatment options than those with PV. To date, 3 Janus kinase (JAK) inhibitors have been approved for the treatment of patients with myelofibrosis: ruxolitinib, fedratinib (Inrebic), and pacritinib (Vonjo).

Similar to PV, ruxolitinib became the first FDA-approved therapy for the treatment of patients with myelofibrosis, gaining an indication for patients with intermediate- and high-risk disease in November 2011. In August 2019, patients with intermediate- 2 or high-risk primary or secondary myelofibrosis gained fedratinib as an FDA-approved option. Finally, the FDA approved pacritinib in March 2022 for the treatment of adult patients with intermediate- or high-risk primary or secondary myelofibrosis with platelet levels below 50,000/μL.^8-10

“The current NCCN [National Comprehensive Cancer Network] guidelines are really agnostic of the second-line therapy, which is interesting,” Raajit K. Rampal, MD, PhD, said. “You can start a patient who [at that time] has over 50,000 platelets on ruxolitinib or fedratinib. And if there is a need to change therapy, you could use any of these 3 agents. That’s an important message for our audience to remember, that the second line is not platelet restricted. We have an abundance of options.”

After summarizing updated data from pivotal trials of the already approved agents, the panelists shifted their focus to new findings from trials evaluating investigational therapies beyond JAK inhibitors in myelofibrosis. Updates from the studies were presented during the 2023 American Society of Clinical Oncology Annual Meeting in June.

Novel Agents Seek to Augment the Armamentarium

In the phase 2 ACE-536-MF-001 trial (NCT03194542), investigators examined the erythroid maturation agent luspatercept-aamt (Reblozyl) for the management of anemia in patients with myelofibrosis; it occurs in approximately 40% of patients. Investigators noted that luspatercept demonstrated anemia improvement across all cohorts of in the study, regardless of transfusion dependency and use of ruxolitinib. For example, 26.3% (95% CI, 13.4%- 43.1%) of patients who were red blood cell transfusion dependent and received prior ruxolitinib (n = 38) achieved transfusion independence following treatment with luspatercept.¹¹

The phase 1/2 LIMBER study (NCT04455841) evaluated the safety and efficacy of the oral ALK2 inhibitor zilurgisertib alone and in combination with ruxolitinib in adult patients with intermediate 1 or 2 primary or secondary myelofibrosis. Among patients in the monotherapy group who were not transfusion dependent (n = 6), anemia improvement (hemoglobin increase of ≥ 1.5 g/ dL relative to baseline) occurred in 1 patient; this level of improvement was observed in 3 of 9 patients in the combination group. Zilurgisertib monotherapy or combination therapy with ruxolitinib was determined to be generally well tolerated and displayed the potential for therapeutic activity, the study authors concluded.¹²

Another phase 1/3 trial, XPORT-MF-034 (NCT04562389) evaluated a ruxolitinibcontaining combination, this time with the selective inhibitor of nuclear export selinexor (Xpovio) in patients with JAK inhibitor–naive myelofibrosis. At week 24, efficacy-evaluable patients (n = 22) achieved spleen volume reduction of at least 35% (SVR35) from baseline at a rate of 64%. Investigators noted that the combination displayed encouraging activity, and updated data will be made available at a future date.¹³

Finally, in a single-arm phase 2b study (NCT04217993) the oral, novel JAK/ACVR1 inhibitor jaktinib showed promising activity in patients with myelofibrosis who were intolerant to ruxolitinib. Efficacy-evaluable patients who received jaktinib (n = 44) achieved an SVR35 rate of 43% at 24 weeks, and the best spleen response rate was 55%. Notably, response was maintained for a minimum of 12 weeks in 80% of patients.¹⁴

“It’s exciting to have all these non-JAK inhibitors [in the pipeline],” Rampal said in conclusion. “Ultimately, hopefully, we can figure out what the best fit is for an individual patient. We’re not there yet, but with an abundance of data, we’ll get there. It’s also important to note that there are a number of agents that are earlier on [in development] that are moving along. Even beyond this next generation of non-JAK inhibitors already in the pipeline, there is a generation beyond that that is in clinical trial development.”

References

McMullin MF, Anderson LA. Aetiology of myeloproliferative neoplasms. Cancers (Basel). 2020;12(7):1810. doi:10.3390/cancers12071810
FDA approves ruxolitinib. News release. FDA. Updated February 22, 2016. Accessed October 18, 2023. bit.ly/3PVXObQ
Kiladjian JJ, Zachee P, Hino M, et al. Long-term efficacy and safety of ruxolitinib versus best available therapy in polycythaemia vera
(RESPONSE): 5-year follow up of a phase 3 study. Lancet Haematol. 2020;7(3):e226-e237. doi:10.1016/S2352-3026(19)30207-8
Passamonti F, Palandri F, Saydam G, et al. Ruxolitinib versus best available therapy in inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): 5-year follow up of a randomised, phase 3b study. Lancet Haematol. 2022;9(7):e480-e492. doi:10.1016/ S2352-3026(22)00102-8
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Navitoclax with Ruxolitinib Improves Myelofibrosis with Manageable Safety

Posted on December 13, 2023December 13, 2023 by mpn_admin

By Patrick Daly

December 6, 2023

Ruxolitinib combined with navitoclax induced spleen volume reduction of ≥35% at week 24 (SVR35W24) at a rate twice as high as with ruxolitinib and placebo in Janus kinase (JAK) inhibitor–naïve patients with primary, post-polycythemia vera, and post-essential thrombocythemia myelofibrosis (MF), according to authors of the ongoing phase III TRANSFORM-1 study.

The study, evaluated the doublet therapy to address “a substantial unmet need for therapies that alter disease trajectory, improve outcomes, and enhance survival” in patients with MF, according to lead author, Naveen Pemmaraju, MD, of the University of Texas MD Anderson Cancer Center in Houston. Findings were presented at the 65th American Society of Hematology Annual Meeting & Exposition in San Diego, California.

The cohort included 252 patients with a median age of 69 (range, 37–87) and intermediate-2 or high-risk MF with splenomegaly, signs of MF-related symptoms, no prior JAK2 inhibitor therapy, and an Eastern Cooperative Oncology Group performance score of 2 or less.

The primary outcome was SVR35W24, and secondary outcomes included change in Myelofibrosis Symptom Assessment Form total symptom score (TSS) at week 24, SVR35 at any time, SVR35 response duration, anemia response, reduction in marrow fibrosis, overall survival, leukemia-free survival, reduction in fatigue, and improvement in physical functioning at the data cutoff of April 13, 2023.

Investigators noted 79 of 125 (63.2%) patients in the navitoclax group achieved SVR35W24 compared with 40 of 127 (31.5%) in the placebo group (P<0.0001). Furthermore, 96 (77%) patients on navitoclax achieved SVR35 at any time compared with 53 (42%) patients on placebo.

The median time to SVR response was 12.3 weeks (range, 10.1–48.3) in the navitoclax group versus 12.4 weeks (range, 11.3–72.3) in the placebo group. Patients in the navitoclax group had a mean change from baseline in TSS of –9.7 (95% CI, –11.8 to –7.6) at week 24, whereas patients in the placebo group had a mean change of –11.1 (95%CI, –13.2 to –9.1; P=0.2852).

Adverse events (AEs) of grade 3 or higher occurred in 85% and 70% of navitoclax and placebo patients, respectively. The most common AEs in greater than 30% of patients on navitoclax were thrombocytopenia, anemia, diarrhea, and neutropenia.

Serious AEs occurred in 26% of patients in the navitoclax and 32% of patients in the placebo group, including anemia in two and one patients, respectively, as well as thrombocytopenia and neutropenia in two and one navitoclax patients. Overall, 39% of navitoclax or placebo discontinuations were due to AEs, and 17% were due to a physician’s decision.

Overall, “the responses were durable; AEs of thrombocytopenia and anemia were common but manageable with dose modification without any clinically significant sequalae,” the authors summarized.

Reference

Pemmaraju N, Mead AJ, Somervaille TCP, et al. 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. Abstract #620. Presented at the 65th American Society of Hematology Annual Meeting & Exposition; December 9-12, 2023; San Diego, California.

Phase II Data on Pelabresib Combination for Myelofibrosis Leads to Launch of Phase III Double-Blind Trial

Posted on December 13, 2023December 13, 2023 by mpn_admin

By Patrick Daly

December 6, 2023

Pelabresib in combination with ruxolitinib exhibited significant clinical activity and disease-modifying potential without treatment-limiting toxicities among patients with myelofibrosis (MF) in the ongoing phase II MANIFEST study, according to lead author, Raajit Rampal, MD, PhD, of the Memorial Sloan Kettering Cancer Center in New York City.

Pelabresib is an investigational oral small-molecule agent that inhibits BET-driven gene transcription that contributes to MF pathogenesis.

Following the findings of MANIFEST, Dr. Rampal and colleagues initiated the phase III MANIFEST-2 trial to further evaluate pelabresib plus ruxolitinib. Primary findings from MANIFEST-2 were presented at the 65^th American Society of Hematology Annual Meeting & Exposition in San Diego, California.

The global, double-blind, active control study screened 591 patients at 138 sites, and ultimately randomized 431 Janus kinase inhibitor (JAKi)-naïve patients with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF to either pelabresib plus ruxolitinib or placebo plus ruxolitinib.

Patients were eligible if they had a Dynamic International Prognostic Scoring System score of intermediate-1 or higher, platelet count of ≥100 × 10⁹/L or greater, spleen volume of ≥450 cm³or greater, two or more symptoms with an average score of three or greater on the Myeloproliferative Neoplasm Symptom Assessment Form (or a Total Symptom Score [TSS] of ≥10), peripheral blast count less than 5%, and an Eastern Cooperative Oncology Group performance status of two or less.

The primary endpoint was spleen volume reduction of ≥35% (SVR35) at week 24, and secondary endpoints included TSS changes, safety, pharmacokinetics, bone marrow fibrosis changes, progression-free survival, overall survival, and transfusion requirement and rates.

“MANIFEST-2 has completed recruitment and will provide definitive efficacy results of combination therapy in JAKi treatment-naïve pts with MF,” the authors stated, adding that “MANIFEST-2 will also provide important insights in assessing the benefits of starting treatment at an earlier stage of the disease.”

Reference

Rampal RK, Grosicki S, Chraniuk D, et al. Pelabresib in combination with ruxolitinib for Janus kinase inhibitor treatment-naïve patients with myelofibrosis: results of the MANIFEST-2 randomized, double-blind, phase 3 study. Abstract #628. Presented at the 65th ASH Annual Meeting & Exposition; December 9-12, 2023; San Diego, California.

JAK Inhibitors and Resistance in Myelofibrosis

Posted on December 13, 2023December 13, 2023 by mpn_admin

December 8, 2023

Anthony Hunter, MD

Anthony Hunter, MD, assistant professor, Department of Hematology and Medical Oncology Emory University School of Medicine, medical director, Immediate Care Center, Winship Cancer Institute of Emory University, discusses JAK inhibitor resistance and optimal strategies for treatment of patients with myelofibrosis.

Transcription:

0:09 | JAK inhibitor resistance has been defined a little bit differently in different studies. Overall, failure includes sort of intolerance to treatment, and then that resistance/refractory sort of category can include patients who really never responded appropriately to agents, or who initially did have some response like spleen reductions, but then that spleen started to grow back instead of losing that response.

0:32 | What we know is that these patients historically do poorly. The full mechanisms this are not necessarily fully understood, and we do see that although this JAK/STAT pathway is sort of the key player in pathogenesis of myelofibrosis, there are many other signaling pathways. [There is] the PI3 kinase pathway, the RAS/MAPK pathway, and multiple of these other signaling pathways that are activated in myelofibrosis and likely lead, to the rationale that we can’t sort of cure the disease, obviously, with JAK inhibitors. [There is] still more to learn about you the exact sort of mechanisms for all this.

1:04 | We do now know that with multiple JAK inhibitors, historically after ruxolitinib [Rituxan] failure patients have done very poorly [with] survival [at] a little bit over a year. [There is a] lack of good treatment options, historically, but with sort of multiple emerging JAK inhibitors now either already approved or sort of likely to come out soon, many of which have data sort of in that second-line ruxolitinib failure setting, we’re gonna have more ability now to sort of salvage some of these patients with another JAK inhibitor, as well as a number of clinical trials, [including] with non JAK inhibitor therapy either alone or in combination with the JAK inhibitor that are emerging [and] that will be important for this population.

Ruxolitinib Treatment Outperforms Best Available Therapy in Pooled Analysis

Posted on December 13, 2023December 13, 2023 by mpn_admin

By Patrick Daly

December 6, 2023

Patients with polycythemia vera (PV) who received ruxolitinib treatment achieved sustained hematocrit control over 80 weeks and had improved symptom control at week 16 compared with patients who received best available therapy (BAT), based on a post hoc pooled analysis of data from the RESPONSE and RESPONSE 2 trials.

The efficacy data were presented at the 65^th American Society of Hematology Annual Meeting & Exposition in San Diego, California, by lead author, Claire Harrison, MD, of the Guy’s and St. Thomas’ NHS Foundation Trust in London, United Kingdom.

“Reductions in JAK2V617F allele burden were consistently observed through Week 208 in patients treated with ruxolitinib, including those who crossed over from BAT,” Dr. Harrison and colleagues reported.

The analysis assessed 371 pooled patients from RESPONSE and RESPONSE 2, of which 184 were treated with ruxolitinib and 187 with BAT. The cohort had a median age of 61.8 ± 11 years and most patients were White (88.1%) and male (62.5%). Hematocrit control was defined as hematocrit maintained below 45% starting week 16 plus one or less phlebotomy between baseline and week four.

At week 28, the proportion of patients with hematocrit control was 62.0% (95% CI, 54.5-69.0) in the ruxolitinib group versus 18.2% (95% CI, 12.9-24.5) in the BAT group. Further, 47.3% (95% CI, 39.9-54.8) of patients in the ruxolitinib group had sustained hematocrit control through week 80; authors noted nearly all patients in the BAT group had crossed over to the ruxolitinib group by that point.

The proportion of patients who achieved a 50% or greater reduction from baseline in Myeloproliferative Neoplasms Symptoms Assessment Form Total Symptom Score at week 16 was 48.7% (95% CI, 40.7-56.8) in the ruxolitinib group compared with 18.0% (95% CI, 12.5-24.6) in the BAT group (odds ratio, 4.3; 95% CI, 2.6-7.2), and the mean change in score was -4.4 ± 10.0 and 0.6 ± 6.9, respectively.

Additionally, patients randomized to ruxolitinib had consistently decreased JAK2V617F allele burden through week 208, and mean JAK2V617F allele burden decreased from 66.1% to 41.4% at four years.

“Taken together, these results provide further evidence of the patient benefit of ruxolitinib in patients with PV with or without splenomegaly,” Dr. Harrison and colleagues concluded.

Reference

Harrison C, Kiladjian JJ, Palandri F, et al. Ruxolitinib treatment in polycythemia vera results in reduction in JAK2 allele burden in addition to improvement in hematocrit control and symptom burden. Abstract #4553. Presented at the 65th ASH Annual Meeting & Exposition; December 9-12, 2023; San Diego, California.